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MITOCHONDRIAL DISORDERS

Biochemical Pathways   Fatty acid oxidation   Oxidative phosphorylation Mitochondria   General features   Mitochondrial DNA (mtDNA)     General Features     Mutations   Nuclear encoded proteins     General Features     Mutations   Proteins Mitochondrial disorders   Biochemical classification   Clinical syndromes   Evaluation     Clinical Signs     Laboratory   General mechanisms     Mutation types       Mitochondrial       Nuclear encoded proteins     Functional defects   Pathology     Histology     Ultrastructure

Mitochondria: General³³

• Primordial eukaryotic cells lacked ability to use oxygen metabolically
  • Colonized by aerobic bacteria
  • Intracellular aerobic bacteria
    • Added oxidative metabolism to cells
    • Evolved into mitochondria
• Time: > 10⁹ years ago

• Outer membrane
• Intermembrane space: Between outer & inner membranes
• Inner membrane: Composed predominantly of cardiolipin
• Matrix: Region inside inner membrane

• Only organelle other than nucleus with own DNA
• Different structure than nuclear DNA

• General
  • 1500 mitochondrial proteins
  • Mitochondrial genes: 37
    • Code for 13 peptides
      • Complex I
        • MTND1
        • MTND2
        • MTND3
        • MTND4
        • MTND4L : LHON
        • MTND5
        • MTND6
      • Complex III
        • MTCYB
      • Complex IV
        • MTCO1
        • MTCO2
        • MTCO3
      • Complex V
        • MT-ATP6
        • MT-ATP8
    • Pathways
      • Synthesized in mitochondrial matrix
      • Sorted to matrix or inner membrane
      • Oxidase assembly (OXA) pathway
        • Specialized for MTCO2 & few nuclear proteins to inner membrane
        • Protein components: Oxa1; COX18; Mba1
  • Most (> 99%) mitochondrial proteins are nuclear encoded
    • Precursors synthesized in cytoplasm with mitochondrial targeting sequence
    • Protein types: Based on mitochondrial targeting sequence
      • N-terminal targeting presequence
        • Protein locations: Most matrix; Some inner membrane
        • Presequences can form positively charged amphiphilic helical structure
        • Presequence cleaved in matrix
      • Internal targeting signal in mature protein
        • No cleavable presequence
        • Protein locations: Inner membrane (Polytopic); IMS (soluble); Outer membrane
    • Transported into mitochondria⁹⁶
      • Translocation through outer membrane: Translocase of outer mitochondrial membrane (TOM40 complex)
        • Receptor subunits: TOMM20 (MAS20P) , TOMM22 , TOMM70
        • Channel forming subunit: TOMM40 ; 2 or 3 pores per TOM40 complex
        • TOMM70 chaperones: HSP90 & HSP70
        • TOM5 : Integral membrane protein; Transfers proteins from receptor to pore
        • TOM6 : Stabilizes TOM40 complex
        • trans receptor site of TOM40 complex: Binds proteins on intermembrane-space side of outer membrane
      • Transfer from TOM40 to TIM23 complex
        • Proteins with presequence destined for mitochondrial matrix: Recognized by TIMM50 of the TIM23 complex
        • Proteins with no presequence
          • Recognized in IMS by
            • Small Tim proteins
            • Tim9-Tim10 complex and/or
            • Tom8-Tim13 complex in the IMS
          • Substrate proteins forwarded to
            • Inner membrane: TIM23 complex
            • Outer membrane: TOB/SAM complex
                (topogenesis of mitochondrial outer membrane β-barrel proteins/sorting & assembly machinery)
              • SAMM50
              • SAMM35
              • SAMM37
      • Translocation through inner membrane: Translocase of inner mitochondrial membrane (TIM23 complex)
        • Protein signal: N-terminal; Directs proteins to TIM23 complex
          • Positively charged
          • Mitochondrial matrix-targeting
        • TIM23 complex: Transport from IMS to matrix
          • At least 10 subunits
          • Partly membrane-embedded
          • TIMM17 , TIMM23 & TIMM50 : Make up translocation channel & receptors
          • Maintenance factors: Tam41; Ups1; Ups2/Gep4
          • Complete translocation of precursors into matrix
            • Requires repeated cycles of binding & release from mitochondrial heat shock protein 70 (mtHsp70)
          • mtHsp70
            • Recruited to translocase by Tim44
            • Binds to incoming precursors in ATP-dependent manner
            • Regulated by nucleotide exchange factor Mge1 & J-complex Tim14-Tim16
            • Maintenance factor: Tim15
          • Other subunits: Modulate activity of translocase in antagonistic manner
            • Tim21
            • Pam17
      • Disorders
        • Deafness-Dystonia-Dementia: TIMM8A
        • Dilated Cardiomyopathy with Ataxia (DCMA): DNAJC19
• Intermembrane space (IMS) proteins⁹⁴
  • Transport of soluble IMS proteins: Different mechanisms
    • Proteins with bipartite presequences
      • Features of presequence
        • N-terminal matrix-targeting signals, followed by
        • Hydrophobic sorting domains
      • Transport mechanisms
        • TOM & TIM23 complexes
        • Reaction depends on: Membrane potential &, often, ATP
      • Insertion into inner membrane
      • Mature part of released into IMS by proteolytic cleavage event
      • Protein examples
        • Apoptosis-inducing factor (Programmed cell death 8; PDCD8; AIF)
        • Cytochrome c peroxidase
        • Cytochrome b2
        • Endonuclease G (ENDOG)
        • Smac/Diablo
    • Small proteins
      • Properties: Single folding unit
      • Unfolded state: Pass through TOM pore
      • Folded conformation
        • Trapped in IMS space
        • Folding related to
          • Cofactor binding
          • Disulfide bonds between cysteinyl thiols: Common in IMS proteins
            • IMS proteins with disulfide bonds
              • Copper chaperone for superoxide dismutase (CCS)
              • Cox11
              • Cox12 (COX6B1 )
              • Cox17
              • Erv1 : See homologous protein GFER
              • Coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4; Mia40)
              • Qcr8 (UQCRQ)
              • Rieske iron sulfur protein (UQCRFS1)
                • Possible disorder: Mitochondrial myopathy with a defect in mitochondrial-protein transport
              • SCO1
              • SOD1 : Binds to CCS in IMS; Import independent of Mia40
              • Small Tim proteins
            • Disulfide Relay System: "Oxidative" protein folding
              • Mia40: Intramitochondrial IMS import receptor; Interacts via disulfide bond
              • Erv1: Sulfhydryl oxidase: Reoxidizes Mia40
              • Posible function: Oxygen sensing
    • Functions: IMS proteins
      • Transport of metabolites, proteins, or metal ions between mitochondrial membranes
      • Detoxification of reactive oxygen species
      • Pro-apoptotic components: Stored until programmed cell death is induced
• Matrix proteins
  • Synthesized in cytosol
  • Targeting signals
    • Amino terminal extensions
    • Recognized by receptors on mitochondrial surface
    • Proteolytically removed in matrix
  • Pathway of import: 2 membrane embedded protein complexes
    • Translocase of outer membrane (TOM40)
    • Translocase of the inner membrane (TIM23)
  • Transportation driven by: 2 sources of energy
    • Membrane potential across inner membrane
    • Hydrolysis of adenosine 5'-triphosphate (ATP) in matrix
• Outer membrane proteins
  • Structure
    • Non-cleavable internal mitochondrial signal
    • No cleavable N-terminal presequence
  • Imported into membrane via TOM40 & TOB complexes
  • Examples
    • β-barrel proteins (Tob55; Porin)
    • VDAC1
    • VDAC2
• External link: MitoCarta

• Stimulated by
  • Differentiation of myoblasts into mature myotubes
  • Increasing concentrations of extracellular pyruvate
  • Energy demand exceeding oxidative capacity: Endurance training
• Reduced by
  • Cessation of exercise
  • Aging
• Fusion & Fission molecules
  • Regulate morphology of mitochondrial network
  • Pro-fusion
    • MFN2: Disorders - CMT2A2, HMSN VI
    • OPA1: Disorders - Optic atrophy type 1
  • Fission
    • DNM1L: Disorder - Encephalopathy with defect of mitochondrial and peroxisomal fission
• Regulation
  • Peroxisomal proliferator activator receptor gamma co-activator 1α (PGC-1α)
    • High levels in skeletal muscle
    • Acts through coactivation of transcription factors
      • PPAR
      • NRF: Nuclear respiratory factors
      • ERR: Estrogen related receptor
    • Coactivates peroxisome proliferator activated receptors (PPARs): Upregulation of fatty acid oxidation
    • Induces
      • Transcription of oxidative phosphorylation genes: Coactivates nuclear respiratory factor (NRF) 1 & 2
      • Mitochondrial biogenesis
      • Fatty acid oxidation
      • Brown fat thermogenesis
      • Expression of clock genes: BMAL1 (ARNTL) & Rev-erb-alpha (NR1D1)
  • Pyruvate
    • Increases mitochondrial mass & functionality
    • Not dependent on PGC-1α
  • Transcription factor A, mitochondrial (TFAM; TCF6)
    • Activator of mitochondrial transcription
    • Regulation of mtDNA copy number

• Pyruvate oxidation: Disorders
• Krebs cycle: Liver
• Metabolism: Amino acids; Fatty acids; Steroids
• Generation of energy as adenosine triphosphate (ATP): Via
  • Electron-transport chain
  • Oxidative-phosphorylation system (Respiratory chain)
  • Location: Inner mitochondrial membrane
• Gluconeogenesis: Liver & Kidney
• Calcium homeostasis
• Cell death mediation: Apoptosis

Mitochondrial DNA (mtDNA): General features

• Structure
  • Double-stranded, circular molecule
    • Exception: D-loop is triple stranded (Contains extra 7S DNA)
  • Nucleotide pair number: 16,569
  • Copies
    • 2 to 10 in each mitochondrion
    • Polyplasmy: > 1,000 in each cell
  • Strands
    • Heavy (H) strand
      • Rich in guanines
      • 28 genes
    • Light (L) strand
      • Rich in cytosines
      • 9 genes: ND6; 8 tRNAs
• Genes & Functions: mtDNA encodes for 37 genes
  • Peptides
    • Encodes 13 of mitochondrial peptide subunits
    • All 13 peptides are in mitochondrial respiratory-chain complex (OXPHOS)
    • Remaining > 67 OXPHOS subunits are nuclear encoded
  • rRNAs: 2
  • tRNAs: 22; Located between every 2 rRNA or Protein coding genes
  • Non coding region: Triple stranded (D) displacement-loop
    • Produced from additional synthesis of a piece of mitochondrial DNA, 7s DNA
    • Contains promoter region
      • Origins of replication for H and L strand replication
      • Contains elements for initiation of leading strand replication
  • Other mitochondrial proteins encoded by nuclear DNA
  • Mitochondrial genes: External links
    • Mitomap
    • Gene locations
    • mtDNA map
• Inheritance of mtDNA
  • Maternal
    • Usual pattern
    • Sperm mtDNA is actively degraded
  • Paternal
    • Transmission of mtDNA in skeletal muscle (but not in other tissues) reported³⁴:
    MTND2 mutation
• Transcription & translation of mtDNA
  • Promoters: Controlled by nucleus
    • 3 Promoters
    • H1: H-strand; Produces complete symmetric transcription of heavy strand of mtDNA
    • L: L-strand; Produces complete symmetric transcription of light strand of mtDNA
    • H2: Synthesis of 2 rRNAs; Acts with factor, mTERF
    • Promoters started by: Mitochondrial RNA polymerase + Specificity factor (mtTFA)
    • Promoter location: D-loop; Only non-coding region of mtDNA
      • 7% of mtDNA length
      • Contains cis elements involved in mtDNA replication & transcription
  • Transcripts: Large
    • Produced by H1- & L-strand
    • Subsequently cleaved into individual genes
• Mitochondrial DNA variation
  • Normal: Homoplasmy; All copies of mtDNA are identical within coding region
  • Heteroplasmy: Single cells contain different mtDNA populations
    • Occurs with some mtDNA mutations
    • Due to presence of multiple mitochondria in one cell, each containing several mtDNA copies
    • Produces tissue variation
    • Post-mitotic tissues
      • Usually contain highest levels of mutated mtDNA
      • Neurons; Skeletal & Cardiac muscle; Endocrine tissue
      • Mutations in mtDNA
        • % vs normal in mtDNA can vary widely among tissues in an individual
        • Mutational loads may change over time
        • Tissues are differentially sensitive to levels of mtDNA mutations: ? Related to oxidative energy requirements
    • Pathogenic heteroplasmic mutations: Severity of related symptoms
      • Increase with higher proportion of mutated mtDNA
      • Relation to severity not necessarily linear
  • Frequency of mtDNA-related disorders: 6 to 17 per 100,000 population
• Differences from nuclear DNA
  • No introns
  • Small intergenic spacing: Coding sequences of most genes are contiguous or separated by 1 or 2 bases
  • Codon sequences
    • Different start, stop & arginine, tryptophan, isoleucine
    • Some mitochondrial genes lack termination codon: Insertion of UAA at the transcriptional level instead
  • Replication of mtDNA
    • Rapid rate
    • Lacks proofreading
    • Mutation rate 10 to 100x > than nuclear DNA
  • Mitochondria lack an adequate DNA-repair mechanism
  • Mode of inheritance: mtDNA inherited maternally
• mtDNA Replication: Asynchronic & asymmetric mechanism
  • DNA synthesis
    • Starts in origin of replication of heavy strand (O_H)
    • Procedes unidirectionally: To origin of replication of light strand (O_L)
      • 2/3 of way around genome
      • Between cluster of 5 tRNA genes
    • When O_L is single stranded mtDNA synthesis starts in opposite direction
  • Other factors in mtDNA replication
    • Primer for H-strand replication: Small RNA synthesized from L-strand promoter
    • Transition between mtDNA replication & transcription: Produced by ribonucleoprotein, RNase MRP
    • Polymerase for mtDNA replication: DNA polymerase γ (pol γ)
    • Mitochondrial single-stranded binding protein (mtSSB)
  • All factors involved in maintenance, replication & expression of mtDNA: Nuclear encoded
• External links
  • Mitochondrial genome picture

Mitochondrial disorders: General pathogenic mechanisms⁷

• Mitochondrial disorders: Mutation types
  • Mitochondrial DNA (mtDNA) mutations: General features
    • Mutation effects
      • Often cause deficient function in respiratory-chain
      • Abnormal Oxidative-phosphorylation enzymes
    • Threshold effect
      • % of mutant mtDNAs must be above a threshold to produce clinical manifestations
      • % of mutant mtDNAs needed to cause cell dysfunction varies according to tissue oxidative requirements
      • Disease signs especially manifest in
        • Tissues with a high energy expenditure: Dependent on oxidative metabolism
        • Specific tissues: Brain, Heart & Muscle
      • Mitotic segregation
        • % of mutant mtDNAs in daughter cells can shift at cell division
        • Produces rapid changes of genotype that may lead to crossing of threshold
      • Skewed heteroplasmy
        • mtDNA mutation surpasses pathogenic threshold in 1 tissue
        • Examples: A3243G may produce only cardiomyopathy; Myopathy with early respiratory involvement
    • Inheritance
      • During fertilization mtDNA is derived only from the oocyte
      • Maternal inheritance: mtDNA mutations transmitted only from mother
      • Mutations transmitted to all offspring, Male & Female
      • Increased Mutant mtDNA in the mothers' blood ® Increased Frequency of affected offspring
      • Risks of having affected offspring differ between different mtDNA mutations
        • Same level of maternal mutation load ® Increased frequency of affected offspring for
          A3243G MELAS mutation compared to A8344G MERRF mutation
  • Mutations in nuclear DNA coding for mitochondrial components
    • Some identified mutations cause defects in oxidative-phosphorylation
  • Defects of intergenomic communication
    • Probably nuclear DNA mutations
    • Alter control of replication & expression of mitochondrial genome leading to
      • Multiple mtDNA deletions
      • Reduced amounts of mtDNA
  • Mutation distribution
    • Homoplasmic: Similar distribution of mtDNA mutation in all tissues
    • Heteroplasmic: Variable distribution of mtDNA mutation in different cells or tissues
  
  
• Mitochondrial gene disorders: Effects on protein synthesis
  • Disorders of general protein synthesis
    • Mutations: Single deletions & point mutations in rRNA or tRNA genes
    • Clinical features
      • Typical: Multisystem disorders
      • Other: Myopathy
    • Laboratory: Lactic acidosis
    • Muscle: Mitochondrial proliferation; COX negative ragged red fibers
  • Mutations in Protein-coding genes
    • Clinical syndromes: LHON; NARP/MILS; Exercise intolerance
    • Inheritance: Maternal or Sporadic
    • Mitochondrial proliferation: Absent in LHON & NARP; Present with Complex III deficiency
  
  
• Mitochondrial disorders: Biochemical & Genetic abnormalities of mitochondrial function
  
  

  Mitochondrial substrate transport   ATP/ADP translocator     ATPase deficiency   Carnitine-acylcarnitine translocase   Carnitine deficiency       Primary       Secondary   Carnitine palmitoyl transferase   Protein import defects   Solute carriers Substrate utilization   Pyruvate disorders   β-oxidation defects (Fatty acid)   Ketone synthesis     HMG-CoA lyase     HMG-CoA synthase Citric acid (TCA) cycle   Aconitase deficiency   Lipoamide dehydrogenase   Fumarase deficiency Lipid membrane defect: Barth Fusion & Fission Lactate Oxidation-Phosphorylation coupling   ATP Synthase   Luft's disease Respiratory chain   Composition     I. NADH-CoQ Reductase     II. Succinate-CoQ Reductase       Succinate dehydrogenase     III. CoQ-Cytochrome C Reductase     IV. Cytochrome oxidase     V. ATP Synthase   Coenzyme Q10   Combined defects mtDNA mutations   Disorders   Intergenomic communication     Multiple mtDNA deletions     mtDNA depletion   mtRNA   Mutations, Mitomap genes     rRNA& tRNA     Other     Deletions   Mutations, Mitomap syndromes     rRNA& tRNA     Other Nuclear gene defects   Tissue-specific   Generalized   mtDNA depletion

  TCA cycle External link: Mitochondrial energetics   Normal   Diabetes

Mitochondrial Disorders: mtDNA-related mutations

• mtDNA: General disease features
  • Laboratory: Lactic acidosis
  • Pathology: Mitochondrial proliferation in muscle
    • Massive
    • Produces ragged-red fibers
      • Mutant mtDNAs accumulate preferentially in ragged-red fibers
      • Ragged-red fibers are typically negative for cytochrome c oxidase activity
  • Genetics
    • Relatively few mutations in rRNA genes: All confined to 12s RNA
    • Heteroplasmy: Pathogenic threshold of mtDNA mutations
      • Phenotype changes when threshold in a previously unaffected tissue is surpassed
      • Threshold for disease is lower in tissues highly dependent on oxidative metabolism
        • Brain, Heart, Skeletal muscle, Retina, Renal tubules, Endocrine glands
  • Mutation effects on protein synthesis
    • Impairment of all mitochondrial protein synthesis
      • mtDNA rearrangements (deletions or duplications)
      • Mutations in mtRNA genes
      • Mutations in rRNA genes
    • Altered activity of specific respiratory chain complex
      • Mutation of individual gene encoding protein subunits of complex
• Point mutations in mtDNA & related genes
  • Many different point mutations identified in mtDNA related genes
    • May occur in genes for mtRNA, rRNA or proteins
    • Most common in mtRNA genes
      • Hot spots
            mtRNA^{Leu [UUR]} (MTTL1) ; mtRNA^Ile (MTTI) ; mtRNA^Lys (MTTK)
      • Other mtRNA mutations
            mtRNA^Leu (MTTL2) ; mtRNA^Ser (MTTS1) ; mtRNA^Ser (MTTS2) ;
            mtRNA^Trp (MTTW) ; mtRNA^Gln (MTTQ) ; mtRNA^Ala (MTTA) ;
            mtRNA^Tyr (MTTY) ; mtRNA^Glu (MTTE) ; mtRNA^Asp (MTTD) ;
            mtRNA^Thr (MTTT) ; mtRNA^Phe (MTTF) ; mtRNA^Pro (MTTP) ; mtRNA^Met (MTTM)
    • Skeletal muscle restricted mtDNA point mutations
      • Associated with 652 base pair duplication in D-loop (control region) of mtDNA⁴³
    • External links: Mutations
      • Coding & Control: Location; Phenotype
      • rRNA or mtRNA mutations: Location; Phenotype
  • Clinical: Point mutations associated with wide variety of syndromes
    • NARP
    • MELAS
    • MERRF
    • Cardiopathy
    • Myopathy
    • PEO
    • Leber's Hereditary Optic Neuropathy
    • Diabetes
    • Deafness
    • Leigh's Syndrome
    • Hepatic disorders
  • Gene types with point mutations
    • Genes needed for mitochondrial protein synthesis
      • Usually tRNA genes
      • Mutations generally impair mitochondrial protein synthesis
      • Mutations produce defects in all respiratory chain complexes except Complex II (Nuclear encoded)
    • Genes encoding proteins
      • Respiratory chain subunits
      • Mutations produce defects in single respiratory chain complex
  • Example of tRNA mtDNA gene mutation: A-to-G mutation at nucleotide 3243 (A3243G)
    • Most frequent mtDNA mutation
      • > 16/100,000 in the adult population (Finland)
    • Varied clinical presentations
      • Leigh syndrome
      • MELAS
      • Oligosymptomatic
        • Systemic: Diabetes, Short stature, Pigmentary retinopathy
        • Neural: Migraine, Hearing loss, Cognitive decline,
            Occipital infarction (Young patients)
    • Higher levels of mutated mtDNA: More severe disease
      • Leigh > MELAS > Oligosymptomatic
  • Example of mutation in protein encoding mtDNA gene: Nucleotide 8993 in gene for ATPase6, T-to-G & T-to-C
    • General correlations
      • 8993C clinically milder than 8993G
      • Mutant loads: Similar in Different fetal and adult tissues; No age-related variation
      • Greater Median % mutant load with Increased Severity of symptoms.
      • Threshold effect: Severe symptoms Increased when mutant load reaches
        • 60% to 70% for 8993G mutation
        • 80% to 90% for 8993C mutation
      • Disturbs H⁺-translocating, membrane spanning F₀ region of ATPase complex
    • Syndrome correlations
      • NARP with intermediate levels of mutated mtDNA
      • Maternally inherited Leigh's Syndrome with high (> 95%) levels of mutated mtDNA
  
  
• Deletions and Duplications of mtDNA occur.
  • Features
    • Single deletions are usually
      • Large
      • Involve: Both tRNA and Protein encoding mitochondrial genes
    • 50% of patients with single deletion share common mutation (4977-bp deletion)
    • Epidemiology
      • Frequency of single large deletions in Finland: 1.6 per 100,000
  • Clinical associations
    • Single large deletions are associated with
      • Kearns-Sayre
      • Ocular Myopathy (sporadic)
      • Pearson's syndrome
      • Some syndromes: MNGIE & Leigh syndrome
    • Multiple different mtDNA deletions occur in single individuals with
      • Autosomal dominant PEO
      • Inclusion body myositis
      • Normal aging
    • Tissue dysfunction
      • Correlates better with number of deleted mtDNA molecules
      • Less correlation with location or size of deletion in mtDNA
    • Inheritance
      • Deletions: Usually sporadic
      • Duplications: May be maternally inherited
  • mtDNA changes
    • DNA break points differ in disorders with single or multiple DNA deletions.
    • Patients with mtDNA deletion also often have mtDNA duplication
      • Duplication corresponds mtDNA in deleted region
  
  
• Quantitative loss of entire mtDNA molecules occurs in some syndromes.
  • mtDNA regulation
    • Nuclear transcription factor (NRF-1) : Interacts with several nuclear genes encoding mitochondrially-destined proteins
    • Levels of mitochondrial DNA can be regulated by one of these proteins, mitochondrial transcription factor (mtTFA) .
  • Disorders
    • Inherited mitochondrial deletion disorders: Usually autosomal recessive
    • Toxins may also cause mtDNA depletion: AZT
  
  
• Specific disorders with mtDNA mutations
  
  

  mtDNA Point mutations Cardiomyopathy Leber's optic neuropathy Leigh's syndrome MELAS MERRF NARP/MILS Single deletion or duplication Ataxia, Leukodystrophy Diabetes: Maternal inheritance   Kearns-Sayre Pearson's PEO: Sporadic Multiple deletions Aging Myositis   Inclusion body   COX- muscle fibers MNGIE PEO Wolfram Depletion of mtDNA   Infantile myopathy   Fatal   "Later-onset" AZT treatment Several types of mtDNA defect Deafness Diabetes External ophthalmoplegia (PEO)   Sporadic   Maternal   Dominant   Recessive Leigh's Myopathy Rhabdomyolysis Sensory neuropathy Systemic disorders

  Intense SDH staining of a muscle fiber with mitochondrial proliferation

• rRNA/tRNA
• Control regions
• Mitomap: General

Nuclear encoded mitochondrial proteins

• General features
  • Synthesized in cytoplasm
  • Imported into mitochondria
  • Respiratory chain molecules targeted to inner mitochondrial membrane
  • 67 nuclear encoded proteins in respiratory chain
  • ~ 1,000 mitochondrial peptides not involved in the respiratory chain
• Nuclear mutations causing Mitochondrial disorders
  • Inheritance: Dominant or Recessive
  • General clinical feature
    • Onset age: Infant onset more common than in mtDNA disorders
  • Respiratory chain elements: Structural
    • Mutations found only in complexes I & II: ? Complex III-V mutations lethal
    • Clinical associations of mutations
      • Severe neurologic disorders of childhood: Leigh’s syndrome; Leukodystrophy
      • Neoplasms: Paraganglioma; Pheochromocytoma
  • Ancillary proteins of respiratory chain
    • Function: Needed for assembly or insertion of cofactors
    • Mutations: Cause defects in Complexes I, III, IV & V
    • Disease: General clinical features
      • Multisystem syndromes: Usually involve muscle
      • No isolated myopathies described
    • Disorders may be tissue specific
      • SURF1: Brain (Leigh’s syndrome)
      • SCO2 & COX15: Infantile cardiomyopathy & brain disease
      • COX10: Kidney disease
      • SCO1: Liver disorders
  • Defects in intergenomic signaling: Nuclear mutations affect mtDNA quantitatively or qualitatively
    • Quantitative: mtDNA depletion syndromes
    • Qualitative
      • Multiple mtDNA deletion syndromes
      • Syndromes: Ophthalmoplegia +...; MNGIE
    • Types of genes
      • Products functioning at mtDNA replication fork
        • POLG
        • POLG2
        • TWINKLE
      • Products supplying mitochondria with deoxynucleotide triphosphate pools needed for DNA replication
        • TK2
        • DGUOK
        • TP
        • SUCLA2
        • ANT1
        • MPV17
  • Other types of mitochondrial dysfunction caused by nuclear defects
    • Membrane structure: Barth syndrome
    • Protein importation into mitochondria: Deafness-Dystonia syndrome
    • Mitochondrial motility: Optic neuropathy (OPA1); CMT 2A (MFN2; Kinesin); SPG 10
    • Neurodegenerative disorders: Friedreich ataxia; Spastic paraparesis (7; 13); Wilson's
  • Non-human changes: Mutations often found in highly conserved subunits also found in simpler complex I in yeast
  • Mitochondrial disorders with nuclear mutations
    • Myopathies
      • PEO
      • Myopathy
      • MNGIE
      • Congenital muscular dystrophy
      • Carnitine disorders
        
    • Encephalopathies
      • Leigh: SURF-1; NDUFS7; NDUFS8; NDUFV1; SDHA; Pyruvate carboxylase; PDHC
      • Infantile
      • Wilson's disease : ATP7B
      • COX10
      • Deafness-Dystonia syndrome: DDP protein
    • Other systemic disorders
      • Cardiomyopathies: SCO2
      • DIDMOAD
      • Friedreich ataxia
      • HHH syndrome
      • Optic neuropathy
      • Paraganglioma
      • Sideroblastic anemia & Ataxia
      • Spastic paraparesis: 7; 13
      • Stuve-Wiedemann syndrome
      • Triosephosphate isomerase
    • Mitochondrial disorders due to mutations in non-mitochondrial proteins
      • MNGIE: Thymidine phosphorylase
      • Huntington's disease: Huntingtin
  • Nuclear genes affecting multiple mitochondrial enzymes
    • Lon proteases
    • Import proteins
      • Deafness-Dystonia syndrome: DDP protein
      • Infantile encephalopathy: Chromosome 2p14-p13
    • mtDNA Depletion syndromes
      • Fatal infantile myopathy
      • Benign infantile myopathy
      • Hepato-Cerebral syndrome
      • MNGIE
      • Myopathy

General clinical features of mitochondrial disorders

• Onset
  • Infancy: Infantile with COX- Fibers; Encephalopathy; Leigh's
  • Childhood
    MELAS; MERRF; Leigh's; Myopathy & cardiomyopathy; Kearns-Sayre
  • Adult: CNS; PEO
• CNS
  • Ataxia
    • MELAS, MERRF; NARP; Deafness; Leukodystrophy; Leigh's; HAM; Friedreich ataxia
    • Other
  • Seizures: MELAS; MERRF; MILS; Myoclonic epilepsy
  • Movement disorders
    • Myoclonus: MERRF; HAM
    • Dystonia: MELAS; Leber's; Deafness-Dystonia
  • Spinal
    • SPG7
    • SPG13
    • SPG31
    • HHH syndrome
    • Spastic dystonia
    • Mitochondrial tRNA Ile
    • Leber's
    • Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL)
  • Migraine: MELAS; Myopathy
  • Cognitive disorders
    • Striatal necrosis: ATPase 6 (Leigh's) mutation
    • Retardation: Leigh's, Maternal (MILS)
    • Psychomotor regression: MELAS; Kearns-Sayre; Infantile encephalopathies
    • Dementia: MELAS; MERRF; Kearns-Sayre; PEO 3; Cytochrome b; ND3
    • Episodic encephalopathy: MELAS; MERRF; Myopathy; Infantile; Leigh's
  • Septo-optic dysplasia
  • Encephalopathies
• Myopathy
  • Weakness
  • Rhabdomyolysis: Recessive syndromes
  • Fatigue: Associated with high serum lactate at rest in PEO
• Polyneuropathy
  • Mitochondrial DNA: NARP; MNGIE; MERRF; Myopathy + Diabetes
  • Autosomal: HADHA; CMT 2A (MFN2); CMT 4A; Friedreich ataxia; SCO2 (Motor); POLG1; Sensory ataxic; Alpers-Huttenlocher; SLC25A19; ATP5E
• Autonomic: MNGIE; Wolfram; Cartilage-Hair hypoplasia
• Ophthalmologic
  • Ophthalmoplegia & Ptosis: Kearns-Sayre; External ophthalmoplegia (PEO); MELAS (Rare); MNGIE
  • Visual loss
    • Cortical: MELAS
    • Pigmentary retinopathy: Kearns-Sayre; NARP; MNGIE; Leigh's; MELAS
    • Optic neuropathy: Leber's; OA1, Dominant; NARP; Leigh's
• Hearing loss: Kearns-Sayre; Other
  
• Systemic
  • Short stature: MELAS; MERRF; Kearns-Sayre
  • Diabetes
  • Heart
    • Conduction block: Kearns-Sayre
    • Cardiomyopathy
  • Gastrointestinal & Hepatic
    • Pseudoobstruction: MELAS; Cartilage-Hair hypoplasia
    • Hepatic failure, infantile: SCO1
    • Hepato-Cerebral syndrome
    • Hepatoencephalopathy
    • Alpers-Huttenlocher disease
    • Cartilage-Hair hypoplasia
• Neoplasms
  • Paraganglionoma: SDH subunits B, C, D
  • Leiomyomatosis: Fumarate hydratase
  • Renal cell cancer: Fumarate hydratase
  • B-cell lymphoma: BCL2 overexpression
  • Lymphoma: Cartilage-Hair hypoplasia

Laboratory evaluation of mitochondrial disorders

• Lactate & Pyruvate
  • Source
    • Arterial better than venous
    • CSF may be abnormal when blood normal
  • Usually elevated in children
  • Lactate/Pyruvate ratio
    • High (> 50:1): Suggests metabolic block in respiratory chain
    • Normal: Metabolic block is upstream, e.g. Pyruvate dehydrogenase complex
  • High lactate at rest
    • Rare with pure CPEO
    • Common (80%) with A3243G and A8344G mutations
    • Suggests fatigue is likely
  • Normal values do not exclude mitochondrial disorders
    • Examples: NARP; MILS
    • May become elevated with short exercise
• Serum CK
  • Usually: Normal or Mildly elevated
  • High: Chronic progressive external ophthalmoplegia (CPEO) & Ptosis; Limb weakness
  • Very high: Mitochondrial DNA depletion
• Muscle biopsy: Distinctive features
  • Succinate dehydrogenase (SDH) stain
    • Usual abnormality in mitochondrial disorders: Increased staining of muscle fibers
    • Most sensitive & specific stain for mitochondrial proliferation in muscle fibers
    • Specific confirmation of mitochondrial dysfunction & proliferation
    • Muscle fibers with increased staining
      • Mitochondrial disease: Mitochondrial proliferation
      • Other: Regenerating muscle fibers
    • Strongly SDH reactive blood vessels: MELAS
    • SDH positive (Ragged red) muscle fibers with prominent lipid accumulation: Coenzyme Q₁₀ deficiency
  • Gomori trichrome stain
    • Stains "Ragged red" muscle fibers
    • Much less specific & sensitive for mitochondrial proliferation than SDH
  • Cytochrome oxidase (COX) stain changes
    • General
      • Usual pathologies
        • Absent or reduced staining of muscle fibers: Reduced COX activity; May be diffuse or in scattered fibers
        • Increased staining of fibers: Mitochondrial proliferation; Variably present depending on syndrome
      • May identify patients with mitochondrial disorders not detected by SDH stains
    • Scattered COX- fibers ± Ragged red fibers: Suggests
      • mtDNA mutation affecting mitochondrial protein synthesis
      • Mutations in COX I, COX II, or COX III genes
      • Heteroplasmic mutation
    • Muscle fibers with both COX-positive & Increased SDH staining : Suggests specific mutations
      • MELAS: Many SDH+ fibers are COX+
      • Mutations in mtDNA protein encoding genes, except COX genes
        • Cytochrome b: All SDH+ fibers are COX+
        • ND genes
      • See: Pathology
    • COX reduction: Diffuse
      • Severe: Sparing Spindles & Smooth muscles of vessels
        • Fatal or benign infantile myopathy
        • Homoplasmic mutation
      • Moderate: Including Spindles & Smooth muscles of vessels
        • Leigh syndrome with COX deficiency
    • Ragged red COX- fibers with reduced immunocytochemical detection of cytochrome oxidase II
      • Suggests mutations affecting mitochondrial protein synthesis generally
    • Reduced mtDNA-encoded COX subunits I and II in COX-deficient muscle fibres: mtDNA mutations
    • Reduction of all COX subunits in all muscle fibers: ? Nuclear mutations
  • Sudan black: Increased lipid in muscle fibers
    • Lipid pattern: Droplets enlarged
    • Lipid increase: Muscle fiber patterns
      • Scattered fibers with mitochondrial proliferation (SDH+)
      • Selectively increased: Type I muscle fibers
      • Increased in all muscle fibers
  • Inflammation
    • Uncommon in most mitochondrial disorders
    • Present with: Inclusion body myositis; PM/COX-
  • Muscle fiber necrosis & regeneration: Uncommon
  • Electron microscopy⁵³
    • Usually not specific or sensitive in adults with non-diagnostic histochemistry results
    • Children
      • Ultrastructure may be only evidence of mitochondrial pathology in 6%
      • No data regarding specificity of these morphologic changes for mitochondrial disease
    • May be helpful in confirming mild pathologic changes on histochemistry
    • Not helpful in mitochondrial differential diagnosis
  • Also see: Mitochondrial pathology
• Neuroradiology (MRI)¹⁰⁶
  • General patterns
    • Specificity for mitochondrial disorders: Symmetric involvement of deep gray structures in absence of hypoxia
      • Hyperintensity: T2 & FLAIR images
      • Hypointensity: T1
    • Other: Delayed myelination
  • Bilateral signal intensities in putamen, globus pallidus, & caudate: Leigh's
  • Posterior cerebral hemisphere
    • Stroke-like lesions: MELAS
    • Other: Alpers
  • Basal ganglia calcifications: Kearns-Sayre; MELAS
  • White matter
    • Diffuse signal change in central subcortical white matter (U-fibers): Kearns-Sayre
    • Leukoencephalopathy with spared corpus callosum: MNGIE
    • Diffuse white matter changes: Some electron transport chain disorders (I-IV)
    • Macrocystic lesions: Complex I disorders
• Biochemistry analysis
  • Muscle preferable to cultured fibroblasts
  • Fresh or Frozen muscle may be used
  • Combined partial defects of respiratory enzymes containing mtDNA-encoded subunits: Suggests mtDNA mutations
  • Can be normal in mitochondrial disorders: Especially with multiple mtDNA deletion syndromes
• Molecular genetics: Mutation screening
  • Positive result: Confirms diagnosis
  • Screen for most common mutations associated with syndrome
    • e.g. MELAS A3243G then T3271C
  • Blood DNA: Adequate for
    • Point mutations in tRNA genes: MELAS; MERRF
    • Some mutations in structural genes: NARP; Lebers
    • Single large mtDNA deletions with systemic disorders: Kearns-Sayre; Pearson
  • Muscle DNA: Required for
    • Multiple deletions
    • Single mtDNA deletions in PEO & other localized disorders
    • MELAS point mutation in oligo- or asymptomatic relatives
    • Some point mutations in structural genes
• Treatment
  • Aerobic training
    • Exercise tolerance: Increased
    • Serum lactate: Reduced

NARP

• Genetics
  • Inheritance: Maternal
  • Load of mutations may differ in different tissues
  • Same mutations in maternally inherited Leigh's syndrome (MILS)
  • Others in same family may have MILS syndromes
• ATPase 6 (Complex V)
  • mtDNA point mutations: T8993G & some Kearns-Sayre
  • % of abnormal mtDNA: Correlates with clinical severity
    • Heteroplasmy of 70% to 90%: Associated with NARP syndromes
    • Heteroplasmy > 90%; Leigh's syndromes (MILS) & more clinical severity
  • Other mutations in same gene (nt-8851 & nt-9176)
    • Striatonigral degeneration, infantile, mitochondrial
      • Also see: Familial bilateral striatal necrosis, autosomal recessive (19q13)
• Disease mechanism
  • ? Inefficient coupling between proton transport & ATP synthesis
  • Reduced ATP synthesis rate
• Clinical features
  • Sensory neuropathy: Reduced vibration
  • Weakness: Proximal & Distal
  • Tendon reflexes: Reduced at ankles
  • Retinitis pigmentosa
    • May be presenting feature
    • Reduced night vision
    • May primarily affect cones or rods
    • Retina
      • Bull's eye maculopathy
      • Pigment in posterior pole & mid-periphery
      • Small retinal scars
      • Vascular narrowing
    • Perimetry: Central & paracentral scotomas
    • ERG: Reduced amplitude of photopic b wave
  • Cerebellar ataxia
  • Other CNS
    • Dementia
    • Seizures
      • More common with early onset NARP
      • Later: EEG abnormalities; Tonic-Clonic seizures
    • Developmental delay
    • Pyramidal signs
    • Dystonia
  • Cardiac: Mostly with MILS syndromes
• Laboratory
  • Serum lactate: Normal or Mildly elevated
  • Muscle pathology: No ragged red or COX- fibers
  • NCV: Axonal loss, Sensory > Motor
  • Brain MRI
    • Cerebral atrophy
    • Cerebellar cortical atrophy with dilation of 4th ventricle
    • Lenticular nuclei: High T2 signal
  • CNS pathology: Similar to Leigh syndrome⁶⁴
    • Focal cystic necrosis
    • Pathways: Visual, Auditory & Olfactory pathways,
    • Cerebellar system: Inferior olive; Dentate nucleus
    • Striatum: Especially putamen

MELAS

• Inheritance
  • Maternal
  • Occasional sporadic & non-inherited mutation (tRNA Leu)
  • Clinical heterogeneity
    • Rare to find more than 1 fully expressed MELAS in same family
    • Maternal relatives often oligo- or asymptomatic
  • Nuclear mutation (Rare): POLG1
• Genetics: mtDNA point mutations are common causes
  • Heteroplasmic: Mutant mtDNA proportion ~ 56% to 95%
  • Genes
    • mtRNA Leu (MTTL1)
      • Common mutation
        • A3243G mutation: 80% of MELAS syndromes
      • Other MELAS mutation loci
        • T3271C
          • More common in Japan
          • Later age of onset
          • Associated with Distal arthrogryposis
        • 3291
      • Other syndromes with tRNA Leu (MTTL1) mutations
        • Riboflavin sensitive myopathy (T3250C)
        • Isolated cardiomyopathy (A3243G; A3260G)
        • Diabetes (A3243G; C3256T)
        • Sudden infant death (SIDS)
        • MERRF-like with diabetes, optic neuropathy & retinopathy (C3256T)
        • Fatigue
        • Rhabdomyolysis (A3243G)
        • PEO
    • mtRNA Leu 2 (MTTL2; CUN) : Also cardiomyopathy, PEO, sideroblastic anemia
    • Cytochrome c Oxidase (Subunit 3 of Complex IV) : COX reduced; Few SDH + fibers
    • mtRNA Val (G1642A) : Also Leigh syndrome
    • mtRNA Ser (MTTS1) : MERRF/MELAS overlap
    • mtRNA Phe (MTTF)
      • Mutation: G583A
      • Other tRNA Phe syndromes
        • Myoglobinuria
        • Mitochondrial myopathy, late onset (G622A)
        • MERRF (G611A)
    • mtRNA Lys (T8316C) : MERRF with other mutations
    • mtRNA His (T12417G)
    • mtRNA Gln (A4332G) : Atypical MELAS syndrome with deafness
    • NADH-Dehydrogenase Subunit 1 (MTND1) : MELAS, LHON or overlap phenotype
    • MTND3 : MELAS + Epilepsia partialis continua
    • MTND5 (Complex I): MELAS + Leigh syndromes
    • MTND6 (Complex I): LHON is most common phenotype; Occasional early onset MELAS or Leigh with Complex I deficiency
    • Cytochrome b (Complex III): Myopathy is most common phenotype; Occasional MELAS
  • Genetic counseling: A3423G mutation
    • % of affected offspring: Increased with higher mutant load in maternal blood
    • Mutant load 1% to 19%: 20% chance of affected offspring
    • Mutant load > 20%: 50% chance of affected offspring
    • Full expression of phenotype in multiple family members: Rare
    • Partial expression in multiple family members: Common
• Clinical Syndrome⁸⁰
  • Onset
    • Mean = 10 years; Range = 2 to 40
    • Migraine-like attacks: Headache & Vomiting
    • Hearing loss
    • Occasional seizures
  • Encephalopathy: Often episodic
    • Generalized
      • Headache & vomiting (90%)
      • Loss of consciousness (85%)
      • Seizures (85%): May be precipitated by Valproate
      • Dementia or mental retardation (50%-60%)
    • Focal events ("Strokes")
      • Onset
        • Typical: < 15 years
        • Usual: < 40 years
        • Range: Infancy to Late adulthood
      • Distribution: Do not conform to single vascular territories
      • Cortical visual defect
        • Often 1st focal manifestation
        • Occipital blindness or hemianopia
      • Hemiplegia
      • Associated with
        • Neuronal hyperexcitability: Focal epileptiform discharges in acute period
        • Basal ganglia calcifications
      • MRI
        • T1-weighted hyperintense cortical signal
        • Compatible with cortical laminar necrosis & cytotoxic edema
        • Distribution: Do not conform to single vascular territories
        • Reduced diffusion
  • Myopathy
    • Clinical features in 50% with A3243G mutation
      • High incidence by 5th decade
      • Cumulative by 70 years: 77%
    • Weakness
      • Proximal
      • Symmetric
      • Mild to Moderate
      • Face: Some patients
    • Exercise intolerance
      • Some patients with no weakness
    • Ocular
      • Ptosis
      • External ophthalmoplegia
    • No association with inactivity
  • Polyneuropathy⁶¹
    • Clinical
      • Gait: Imbalance
      • Sensory: Paresthesias & Numbness; Distal
      • Tendon reflexes: Reduced
      • Legs > Arms
      • More common with: Myopathy, Increased age, Male
      • Asymptomatic in 50%
      • Exacerbated by dichloroacetate
    • Laboratory
      • NCV: Axonal, sensory neuropathy
      • Fasting glucose: May be abnormal
  • Other CNS
    • Hearing loss (25%): Sensorineural
    • Headache, cluster
    • Extrapyramidal
      • Chorea
      • Parkinsonism
      • Basal ganglia calcification
    • Ataxia
  • Systemic features
    • Eye
      • Pigmentary retinopathy (10% to 40%): More common in symptomatic relatives
      • Macular dystrophy
      • Optic atrophy
      • Visual field defects
      • Hypertelorism
    • Cardiomyopathy (15%)
      • Hypertrophic: More progression in diabetics
      • Left ventricular noncompaction
    • Short stature
    • Diabetes
      • May occur as isolated syndrome: More frequent in Asians than Caucasians
      • Maternally inherited (MIDD)
    • GI
      • Pancreatitis
      • Gastric dysmotility: Constipation; Diarrhea; Intestinal pseudoobstruction (ileus)
      • Nausea, cyclic or episodic vomiting
      • Dysphagia
      • Abdominal pain, epigastralgia
      • Sialoadenitis
    • Renal failure
      • Focal, segmental glomerulosclerosis
      • Renal cysts
      • Tubular dysfunction
      • Nephrotic syndrome
    • Endocrine
      • Multihormonal hypopituitarism, short stature
      • Hashimoto thyroiditis, goiter
      • Hypoparathyroidism
      • Addison's disease
      • Ovarian failure, abortion, miscarriage
    • Skin
      • Lipoma
      • Atopic dermatitis, local melanoderma
      • Asymmetric vascular dilatation
  • Course
    • Mean life span with full clinical syndrome ~ 2 to 4 decades
    • Causes of death: Cardiopulmonary failure; Status epilepticus; Pulmonary disease
    • May deteriorate after general anesthesia
• Laboratory
  • Lactic acidosis: Blood & CSF (85%)
  • EMG: Normal or Myopathic
  • Serum CK: Normal to 2x high (32%)
    • More commonly high with associated: Lactic acidosis; Diabetes; CNS disorders
  • EEG: Slowing, diffuse or focal
  • MRI
    • Strokes
      • Multifocal, mainly cortical, grey matter, lesions
      • Lesion locations: Not confined to vascular territories
      • Focal lesions may be transient
      • Features: T2 & FLAIR hyperintensities; Acute lesions have reduced diffusion coefficient
    • White matter lesions: Some patients
      • Diffuse
      • Often involve periventricular white matter & centrum semiovale
  • Respiratory chain dysfunction
    • Variable: More abnormal with greater mutation load (> 80%)
    • Most common: Reduced activity of Complex I (42% of patients)
    • Other reduced activity: Complex IV (29%); Complex III (23%)
  • Pathology⁶ (A3243G mutation)
    • Muscle: Abnormal in 72%
      • Ragged red fibers (RRF)
        • COX + & SDH + fibers: More common than most other mitochondrial myopathies
        • COX - fibers: More common in patients with clinical myopathy
        • Few RRF in cytochrome c mutation
        • More with: Diabetes mellitus; Epilepsy; Lactic acidosis
        • Mutation heteroplasmy
          • Normal muscle fibers: Mean = 50%
          • Ragged red muscle fibers: Mean = 88%; Similar in COX- & COX+ RRFs
      • Mitochondrial heterplasmy in muscle fibers
      • Mitochondrial proliferation in blood vessels
    • CNS
      • Abnormal cellular metabolism
      • Mitochondrial capillary angiopathy: CNS ± Heart
      • ± Changes in larger vessels: ? Endothelial pathology
      • Regional changes
        • Basal ganglia calcification: 26%
        • Cerebral: Focal necrosis; Cortical atrophy; White matter gliosis
        • Cerebellum: Cortical atrophy; White matter gliosis;
            Purkinje dendrite cactus formations with increased mitochondria (60%)
      • Possible mechanisms of damage
        • Ischemia 2° mitichondrial angiopathy
        • Cytopathy 2° mitochondrial dysfunction
• Possible treatments⁴⁴
  • Dichloroacetate
    • No efficacy
    • Side effects common: Causes polyneuropathy
  • L-arginine (0.5 g/kg): For acute stroke-like episodes

MERRF ⁶⁶

• Inheritance: Maternal
• mtDNA point mutations: Heteroplasmic
  • mtRNA Lys (MTTK) : A8344G (Frequent); T8356C; G8363A; G8361A
    • Syndromes: MERRF or MERRF/MELAS overlap
    • More likely inheritance: High mutation frequency in mother
    • Other mitochondrial mtRNA Lys syndromes
      • Cardiomyopathy (G8363A)
      • PEO with myoclonus (G8342A)
      • Deafness & Diabetes (A8296G)
      • Multiple Symmetric Lipomatosis (A8344G)
      • Leigh syndrome (A8344G)
      • Parkinson syndrome, Neuropathy & Myopathy (A8344G)
      • MELAS
      • MNGIE (G8313A)
  • mtRNA Ser (MTTS1)
    • Syndromes: MERRF/MELAS overlap; Epilepsia Partialis Continua; HAM
    • 7472-insertion mutation in tRNA^{Ser (UCN)}: May have MERRF or Pure myopathy
  • mtRNA Ser (MTTS2) : MELAS/MERRF overlap syndrome
  • mtRNA Leu (MTTL1)
  • mtRNA Phe (MTTF)
  • mtRNA His (MTTH) : MERRF/MELAS overlap
  • mtRNA Pro (MTTP)
    • Mutation: G15967A; Heteroplasmic
    • Clinical
      • Myoclonic epilepsy
      • Myopathy: Proximal
      • Deafness: Sensorineural
      • Cerebellar ataxia
      • Pigmentary retinopathy
• Onset: Late adolescence - Adult
• Clinical syndrome: Also see HAM syndrome
  • CNS
    • Myoclonus (60%)
      • Treatment: Levetiracetam 1500 mg
    • Epilepsy (45%)
    • Cerebellar dysfunction
      • Ataxia
      • Gait disorder
    • Dementia
    • Optic atrophy (20%)
  • Polyneuropathy (20%)
    • Distal sensory loss (large fiber modalities)
  • Hearing loss (40%)
  • Myopathy
    • Weakness: Proximal
    • Muscle pain: Resting or Exercise-related
    • Cramps
    • Fatigue
  • Short stature (10%)
  • Lipomata (10%)
• Genetic counseling: G8344A mutation
  • Mutant load < 35% in maternal blood: Transmission risk < 5%
  • Prognosis: Related to mutant load in blood
• Laboratory
  • Serum CK: Normal
  • Lactic acidosis: Variable
  • Pathology of muscle
    • Ragged red fibers: SDH +, COX -
    • Muscle may be morphologically normal
    • Oxidative enzymes: Complexes I, III & IV may have reduced activity

MNGIE¹⁰

• Epidemiology: Diverse ethnic populations
• Nosology: POLIP, OGMID, MEPOP
• Thymidine phosphorylase genetics: MNGIE mutations
  • Most common: Missense mutations
  • Occasional: Insertions, Deletions, Stop or Splice acceptor change in intron
  • Location
    • > 30 Different mutations identified
    • More than 1 family with A3371C, G1419A, c.1160-1G>A
    • More in Exons 4 & 7
    • Mild, late onset disease without neuropathy: E379K + c.1160-1G>A
• Thymidine phosphorylase protein (Endothelial cell growth factor, platelet derived (ECGF1))
  • Not present in muscle
  • Functions
    • Catalyzes phosphorolysis of thymidine to thymine & deoxyribose 1-phosphate
    • Plays role in homeostasis of cellular nucleotide pools
    • ? Has angiogenic effects
  • Mutations: Loss of function of thymidine phosphorylase
    • MNGIE patients
      • Most patients: Absent, or nearly complete loss of, TP function
      • Milder patients may have residual activity
      • Measured in leukocytes
    • Carriers: ~ 35% of normal activity; Range 15% to 60%
• Clinical features: Homogeneous
  • Onset
    • Age: Often < 20 years (75%); Mean 19 years; Range 5 mo to 53 years
    • Signs: Gastric dysmotility (45%); Extraocular (26%)
  • Visceral neuropathy (100%)
    • Diarrhea
    • Obstipation
    • Episodic intestinal pseudo-obstruction & Gastroparesis
      • Nausea
      • Vomiting
      • Weight loss
      • Malabsorption
    • Borborygmi 96%
    • Early satiety
    • Diverticulae: In duodenum & jejunum
  • Ocular
    • External ophthalmoplegia (100%)
    • Ptosis (100%)
    • Retinal degeneration (6% to 25%)
    • Optic atrophy
  • Musculoskeletal
    • Thin body habitus & Cachexia: Weight loss (100%)
    • Short stature (70%)
  • Neuropathy (87%)
    • Sensory predominant: Distal loss; Pain
    • Weakness
      • Distal: Early
      • Proximal with disease progression
      • Symmetric
    • Tendon reflexes: Absent (45%)
    • Course: Progressive
    • Nerve conduction testing
      • Axonal loss
      • Demyelinating features: Some patients³⁸
        • Conduction velocity: Reduced (<80% of lower limit of normal)
        • Conduction block & temporal dispersion in some patients
  • CNS
    • Hearing loss (60%)
    • Cognition: Normal intelligence in most; No dementia
  • Cardiac: Occasional; Incomplete right bundle branch block
  • Disease course
    • Progressive: Months to Years
    • Spontaneous fluctuations may occur
    • Early death: Mean 38 years, Range 18 to 53 years
• Lab
  • Serum
    • Lactic acidosis (64%)
    • Plasma thymidine levels: Increased 20-fold
    • Plasma deoxyuridine & deoxythymidine levels: Increased
  • EKG: Abnormal in 18% to 35%
  • CSF: High protein (89%)
  • MRI
    • Leukoencephalopathy: Very common
      • Symmetric
      • Spares corpus callosum
      • Widespread
      • T2: Hyperintense
      • T1w: Hypointense
    • Brain atrophy: Not prominent early in course; May be severe late
  • MRS
    • Reduced N-acetylaspartate (NAA) & choline in severely affected areas
    • No lactate peak
  • EMG
    • Neurogenic only: 61%
    • Neurogenic + Myogenic: 39%
  • Muscle pathology
    • Mitochondrial changes in muscle fibers
      • Mitochondrial proliferation
      • COX - fibers (90%)
      • SDH + fibers (60%)
      • Oxidative enzyme levels: May be normal
      • Eye muscles: Myopathic changes
    • Neurogenic changes
  • mtDNA³⁵
    • Multiple deletions without duplications (62%)
      • Microdeletions occur at
        • Imperfectly homologous breakpoints (Similar but not identical mtDNA sequences)
        • Perfect direct sequence repeats
      • Five major species of mtDNA deletions
      • Hot-spot for mtDNA rearrangements
        • Nicotinamide adenine dinucleotide dehydrogenase 5 (ND5) gene
        • Occurs in 4 of 5 species of deletions
      • Deletions in tissue: Most prominent in skeletal muscle; Not present in intestine
    • Somatic point mutations: High frequency of 5’-ATT to 5’-GTT
    • mtDNA abnormalities may be produced by
      • Increased intracellular Thymidine & Deoxyuridine that may cause
      • Imbalances of mitochondrial nucleotide pools
      • Homologous recombination
    • mtDNA depletion: Variable
      • 6% to 20 % of normal total mtDNA, especially in liver
      • ? Secondary to mtDNA point mutations & multiple deletions
  • Biochemistry: Thymidine phosphorylase activity < 5% of normal in leukocytes
  
  
• MNGIE variant: Late onset with TP mutations
  • Partial loss of thymidine phosphorylase activity: 10% to 15% residual
  • Clinical
    • Late onset: 5th decade
    • Eye: Ophthalmoplegia; Ptosis
    • Gastrointestinal features
    • Neuropathy: Axon loss ± Demyelination
  • Pathology
    • Muscle: COX- muscle fibers, scattered
    • Nerve: Axon loss
  
  
• MNGIE variant: MNGIM syndrome without encephalopathy³⁶
  • Genetics: No thymidine phosphorylase or dNT-2 mutations
  • Onset: 2nd decade
  • Clinical
    • Gastrointestinal malabsorption
      • Diarrhea
      • Borborygmia,
      • Abdominal pain
      • GI pseudo-obstruction
      • Weight loss
      • Parenteral nutrition eventually needed
    • Eye
      • Ophthalmoplegia
      • Ptosis: Mild
    • Weakness
      • Diffuse
      • Associated with cachexia
    • Polyneuropathy
      • Pain
      • Gait disorder: Sensory ataxia
      • Axonal loss: Sensory > Motor
    • CNS: Normal
    • Disease course: Death in 4th decade
  • Laboratory
    • Serum CK: Normal
    • Serum Lactate: Normal
    • Plasma thymidine: Normal
    • CSF protein: High
    • MRI: Normal brain
  • Muscle
    • COX negative muscle fibers: 5%
    • Raged red fibers: Occasional
    • Complex I–IV activities: 24% of normal
  
  
• MNGIE variant: POLG mutation
  
  
• MNGIE variant: Neurogastrointestinal syndrome
    l mtRNA Trp ; Sporadic
  • Mutation
    • G5532A
    • Heteroplasmic
    • Present in all tissues: Highest in muscle (92%)
    • Low levels of mutation (7% to 9%) found in patient's unaffected mother & brother
  • Clinical
    • Onset
      • Age: 1 year
      • Early: Recurrent vomiting; Failure to thrive
    • Later features
      • Leg discomfort
      • Eye: Ptosis, Ophthalmoplegia, Pigmentary retinopathy, Constricted visual fields, Blindness
      • Ear: Sensorineural deafness
      • Muscle: Wasting
      • CNS: Cognitive regression, Seizures
      • GU: Incontinence
      • GI: Feeding difficulties; Constipation; Diarrhea; Colitis
      • Skeletal: Short stature
  • Muscle
    • SDH positive fibers: COX-negative & -positive
    • Complexes I & IV: Reduced activity (< 20% of normal)
    • COX- fibers have highest levels of mutation
  • Laboratory
    • Lactate: High in Blood & CSF
    • MRI of brain: General atrophy; Periventricular white matter changes
  
  
• MNGIE variant: Neurogastrointestinal syndrome⁸⁸
    l mtRNA Val (MTTV) ; Sporadic
  • Mutation: Heteroplasmic; A1630G
  • Clinical
    • Onset age: Early childhood
    • Cachexia
    • Headache
    • Gastrointestinal motility problems: Ileus, Abdominal pain; Megacolon
    • Hearing loss: High frequency
    • Developmental delay
    • Eye movements: Normal
  • Laboratory
    • Serum lactate: High
    • Brain MRI: Normal
    • Muscle biopsy: COX-, SDH+ muscle fibers; Complex I & IV deficiency
  • Other mtRNA Val mutations
    • Ataxia, Seizures & Hearing loss (G1606A)
    • Leigh syndrome (Homoplasmic C1624T & Heteroplasmic G1644T)
    • MELAS (G1642A)
    • Learning difficulties, Hemiplegia & Movement disorder (Heteroplasmic T1659C)

LHON ³⁰

• Genetic-Clinical correlations: Maternal Inheritance
  • Recurrence risks: Brother 30%; Sister 8%; Nephew 46%; Niece 10%; Male cousin 31%; Female cousin 6%
  • 40% of patients with commonest mutation (G11778A) have negative family history
  • Large families with maternal inheritance: G11778 & T14484C mutations
• Genetics: Many different mtDNA point mutations
  • Each mutation has a characteristic clinical manifestation in terms of degree of severity
  • Manifestations of severity include
    • Genetic factors
      • Penetrance
      • Dependence on secondary mtDNA mutations for clinical expression
      • PARL polymorphism
    • Tendency to recover from episodes of visual loss (4% to 40%)
    • Extraocular neural involvement
  • Mutations
    • General
      • 3 Mutations account for 96% of cases
        • All in Complex I genes
        • Mutations: ND4 (G11778A) (69%), ND1 (G3460A) (13%), ND6 (T14484C) (14%)
      • Mutation pattern
        • Most patient's mutations are homoplasmic
        • Some patients in each family may be heteroplasmic
    • NADH-Dehydrogenase Subunit 4 (MTND4) : Complex I
      • Mutation: G11778A
        • Missense: R340H
        • Most common LHON mutation
        • Mutation load in an individual's blood: Correlations
          • Higher mutation load: Frequency of blindness in males greater
          • Frequency of clinically affected sons: Related to mutant mtDNA in mother's blood
            • Mothers with < 80% less likely than Mothers with 100%
          • Changes in mutation load from one generation to the next
            • Largely determined by random genetic drift
        • Clinical features: LHON
          • Most severe syndrome
          • No light perception
          • Visual recovery in 4% after 36 months
          • Other occasional CNS
            • Ataxia syndrome: Adult-onset
            • Paraparesis: Spastic
        • Other MTND4 mutations
          • LHON + Dystonia
          • MELAS: Typical & Later onset
    • NADH-Dehydrogenase Subunit 1 (MTND1) : Complex I
      • ND1 encoding
        • Guanine-rich heavy (H) strand of mtDNA
        • Located between nucleotide pairs 3307 & 4262
      • Mutation: G3460A
        • Missense: A52T
        • Moderate severity
        • Recovery in 22%
      • Mutation: G3376A
        • Clinical syndromes: LHON; MELAS; LHON/MELAS overlap
      • Other MTND1 mutations
        • LHON: G3733A; C4171A⁵⁰
        • Familial Non-Arteritic Anterior Ischemic Optic Neuropathy (NA-AION): G4132A, Ala276Thr
        • MELAS
        • Exercise intolerance
        • SIDS
        • Dystonia
        • LHON
        • Diabetes, maternally inherited
        • Cardiomyopathy
    • NADH-Dehydrogenase Subunit 6 (MTND6) : Complex I
      • Mutation: T14484C
        • Mutation type: Missense (M64V); May be homoplasmic
        • Best prognosis
        • Recovery in 37% at 16 months
        • French-Canadians: Common; Introduced in 17th century introduction by female founder⁴⁸
        • Han Chinese: Low penetrance (10%)
      • Mutation: A14495G¹¹
        • Heteroplasmic
        • Onset: 17 to 30 years
        • Improvement in visual acuity after event in some patients
      • Other mutations causing LHON ± Dystonia
        • G14459A/A72V; C14482G/M64I; C14498T/Y59C; C14568T/G36S; T14596A/I26M
        • Hotspot in hydrophobic cleft
      • Other MTND6 mutations
        • Leigh
        • MELAS
        • Parkinson's 6 modifier (PINK1 )
    • Other mutations
      • MTND 4L
        • ND4L encoding
          • Guanine-rich heavy (H) strand of the mtDNA
          • Location between nucleotide pairs 10470 & 10766
        • LHON
          • Mutation: T10663C; Homoplasmic
          • Biochemistry: Complex I deficit, partial
        • Other disorders: Colorectal cancer
      • NADH dehydrogenase (MTND) (Subunits 2 or 5 ): Complex I
      • Cytochrome c Oxidase (MTCO) (Subunits 1 or 3 ): Complex IV
      • Cytochrome b (MTCYB) : Complex III
      • ATP Synthase 6 (MTATP6) : Complex V
• Clinical features: General
  • Male predominance
    • No relation to any X-linked genes
  • Onset
    • Midlife: Mean 30 years; Range 1 to 70
    • Visual loss
  • Visual loss
    • Clinical features
      • Painless
      • Visual loss pattern
        • Central or Ceco-central
        • May extend to periphery
      • Severity: May deteriorate to 20/200 or less
      • Progression: Mean 4 months; Range 1 to 24 months
      • Interval between eyes affected: ~ 2 months
      • Tendency to recover depends on mutation
      • Pupillary reactions: May be relatively spared for degree of visual loss
      • May be precipitated by: Ethambutol
    • Ocular pathology
      • Early
        • Disc microangiopathy
        • Pseudo disc edema
        • Vascular tortuosity
      • Late: Optic atrophy
  • Other features: Some families
    • Cardiac conduction defects: Pre-excitation syndromes
    • Spastic paraparesis⁵⁵
      • Mutation: Complex I, Subunit ND4 (MTND4 ), G11778A; Homoplasmic
      • Onset: 3rd decade, before visual loss in 1 patient
      • Family: Not present in other family members
      • Leg stiffness: Painful
      • Sexual & Urinary disturbances
      • Visual evoked potentials: Abnormal
    • Spastic dystonia: Complex I, Subunit ND4 (MTND4)
    • Dystonia ⁹²
      • NADH-Dehydrogenase Subunit 1 (MTND1, Complex I)
      • NADH-Dehydrogenase Subunit 3 (MTND3, Complex I)
      • NADH-Dehydrogenase Subunit 4 (MTND4, Complex I)
      • NADH-Dehydrogenase Subunit 6 (MTND6, Complex I)
    • Other CNS: "Multiple sclerosis-like" disorder; Encephalopathy
• Laboratory
  • Muscle pathology⁴⁹
    • No ragged red fibers
    • EOM mitochondria: Diffuse increase in number and size; Disorganized cristae
    • Preservation of myofibrils
  • MRI: Optic nerve may enhance on T2 weighted images
• Also see: Optic neuropathy

Kearns-Sayre Syndrome

• Family history
  • Sporadic: Most patients
  • Familial cases: Rare; Mother to offspring³⁷
• Genetics
  • mtDNA mutation types
    • Single large mtDNA deletion (2 to 8 kb)
      • Most common mutation type (80%)
      • Identical deletions in Pearson syndrome & PEO
      • Common deletions
        • Most common: 4977 base pairs from 8488 to 13460; 13 base pair repeat at mutation break point
        • Thai patients: 3558 bp deletion; 10204 to 13761, or 10208 to 13765
      • Most deletions preserve
        • Promoters of transcription of heavy & light strands
        • 12S & 16S ribosomal RNA genes
        • Origin of heavy strand replication
      • Change in number of deletions over time
        • Increased in muscle
        • Reduced in rapidly turning over cells (hematopoetic)
    • Large scale tandem duplication
    • Also patients with NARP/T8993G mutation
  • Heteroplasmic distribution of mutations
• Clinical features
  • General
    • Characteristic signs: PEO; Pigmentary degeneration of retina; Heart block; Mitochondrial myopathy
    • Partial expression of signs common
  • Onset: < 20 years; Later onset patients may have only PEO
  • Ocular
    • External Ophthalmoplegia
      • Progressive
      • Limitation, or absence, of movement in all fields of gaze
    • Ptosis
    • Retinal Pigmentary Degeneration (Retinitis pigmentosa): Peripheral retina > Central
  • Dysphagia: 50% of adults symptomatic
    • Regurgitation of liquids
    • Problems with solids also
    • Weight loss
    • Most commonly associated with cricopharyngeal achalasia¹⁷
    • Treatment: ? Cricopharyngeal myotomy
  • Myopathy
    • Weakness (90%): Proximal > Distal; Symmetric
    • Occasional fatigue or pain on exertion
    • Course: Slowly progressive
  • Polyneuropathy (10%): Sensory-Motor
  • CNS
    • Respiratory drive: Reduced
    • Hearing loss (95%)
    • Ataxia (90%)
    • Dementia, or impaired intellect (85%)
    • Upper motor neuron: Spasticity; Increased Tendon reflexes
    • Stroke (8%)
  • Systemic features
    • Cardiac: Conduction Block
      • Onset age: May develop in childhood
      • Rapid progression
      • Sudden death
    • Endocrinopathies
      • Glucose Intolerance (15%)
      • Hypothyroidism
      • Hypoparathyroidism (6%)
    • Skeletal: Short stature
  • Prognosis: Death common in 3rd or 4th decade
• Laboratory
  • Muscle pathology
    • Ragged red fibers (98%): COX + and COX -
    • Variation in muscle fiber size
  • Lactic acidosis (80%)
  • CSF
    • Protein: High
    • 5-Methyltetrahydrofolate (5-MTHF)
      • Very Low
      • Lower with higher CSF protein
      • Higher with increasing age
    • Homovanillic acid (HVA): High
    • ? Abnormal choroid plexus function
  • Head CT: Basal ganglia calcifications (5%)
  • MRI
    • Atrophy: Cerebrum & Cerebellum
    • T2 hyperintensity in
      • White matter: Subcortical U-fibers; Not periventricular
      • Variable: Basal ganglia; Thalamus
  • Brain pathology
    • Status spongiosis: Gray & White matter
    • Regions involved: Brainstem; Basal ganglia; White matter of cerebrum & cerebellum
• Treatment: ? Folinic acid
• Variant syndromes: Related to KS, or other, disorders with single large mtDNA deletion
  • Pearson's Syndrome
    • Sideroblastic anemia
      • Pancytopenic crises
      • Macrocytic
      • Bone marrow: Normal cellularity; Vacuolization
    • Pancreatic insufficiency: Insulin-dependent diabetes; Malabsorption
    • Infancy: Low birth weight; Death; Metabolic & lactic acidosis
    • May precede development of Kearns-Sayre syndrome if survival past infancy
  • 2-Oxoadipic aciduria & 2-Aminoadipic aciduria
    • Onset: 2 years
    • Organic acidemia
      • Episodes of ketosis & acidosis
      • Progressive to coma
      • Resolution of clinical & metabolic features
      • Kearns-Sayre syndrome may develop later in childhood
  • Leukodystrophy
    • Genetics: Large mtDNA deletion
    • Clinical
      • Ataxia, progressive
      • Bulbar palsy
    • Laboratory
      • CNS imaging: Diffuse white-matter lesions in occipital to parietal lobes
      • Lactate: Slightly high in CSF
      • Muscle biopsy: SDH+ & COX- muscle fibers
  • PEO
  • Syndromic deafness
  • Diabetes

PEO + (Progressive External Ophthalmoplegia)

Sporadic   Mitochondrial DNA changes       Single mtDNA deletion, or       Multiple mtDNA deletions   Kearns-Sayre: Single large mtDNA deletion   PEO + Proximal myopathy   Sensory ataxic neuropathy   ? Immune (HyperThyroid) Dominant   Mitochondrial DNA changes       Multiple mtDNA deletions   Twinkle: 10q23   ANT1: 4q35   POLG: 15q25   POLG2: 17q   RRM2B: 8q23   OPA1: 3q28   Hypogonadism Recessive   Mitochondrial DNA changes       mtDNA depletion, or       Multiple mtDNA deletions   Leigh, PEO & Optic atrophy: c12orf65; 12q24   MNGIE: Thymidine phosphorylase; 22q13   POLG: 15q25   PEO + Cardiomyopathy   PEO + Myopathy & Parkinsonism   Sensory neuropathy Also see: Congenital ophthalmoplegia

Maternal   Mitochondrial DNA changes       mtDNA point mutations       May be sporadic   mtRNALeu(UUR)     MELAS     PEO   mtRNALeu(CUN)   mtRNAAsn   mtRNAGln: PEO-plus   mtRNAAla: PEO-plus   mtRNATyr: PEO-plus   mtRNALys: PEO-plus   mtRNAIle   mtRNAPro

• Gaze limited in all directions
• Eye movement speed: slow
• Bilateral
• Associated with ptosis
• Course: Slowly progressive
• Extraocular muscle pathology⁴⁹
  • Mosaic pattern of muscle fiber damage
  • Myofibril disorganization

• Syndromes with severe ophthalmoplegia
  • Kearns-Sayre: Single large mtDNA deletion
  • PEO + Proximal myopathy
  • PEO
• Chronic PEO with few systemic features
  • Mutation
    • Single large mtDNA deletion
    • Heteroplasmic
    • Location: Less commonly in blood than with multisystem syndromes
  • Clinical
    • Onset age: > 20 years
    • Ophthalmoplegia
    • Systemic: Heart block in some patients
• PEO + Sensory ataxic neuropathy⁸
  • Also see: Sensory neuropathy, Recessive with POLG mutations
  • Onset
    • Age: 10 to 31 years
    • Gait unsteadiness
  • Clinical features
    • Polyneuropathy
      • Sensory loss: Joint position; Vibration; Mildly reduced pain & temperature
      • Gait disorder: Sensory ataxia; Romberg +
      • Motor: Normal in most; Late distal weakness
      • Tendon reflexes: Absent
    • Cranial nerve disorders
      • External ophthalmoplegia: Onset after neuropathy
      • Ptosis
      • Dysarthria
      • Facial weakness: Mild
    • Myopathy: Mild proximal weakness
    • Cerebellar: Normal
    • Progression: Slow over decades
  • Laboratory
    • Electrophysiology
      • Sensory NCV: Axonal loss (Reduced or absent SNAP amplitude, Legs > Arms
      • Motor NCV: Normal, or Low CMAP amplitude in legs
      • EMG: Distal denervation; Proximal normal or myopathy
    • Serum CK: Mildly elevated
    • Serum lactate: Normal or Mildly elevated
    • Muscle biopsy
      • Myopathic changes: Mild
      • Ragged red muscle fibers 50%
    • Nerve biopsy: Loss of large & Small axons
    • Mitochondrial DNA: Multiple deletions
  
  
• tRNA^Gln : PEO
  • Genetic
    • Case reported is sporadic
    • Mutation
      • 1 base-pair insertion, 4366A
      • Heteroplasmic
      • Most in skeletal muscle; Some in fibroblasts
  • Clinical
    • Onset: 5 years; Weakness; Ptosis
    • Cranial nerves
      • Facial weakness
      • Dysphonia; Dysphagia
      • Ptosis: Bilateral; Symmetric; Severe
      • Ophthalomoplegia
    • Weakness: Mild; Extremity
    • Tendon reflexes: Reduced
    • No signs of cardiac, cerebellar, or retinal disorders
  • Laboratory
    • NCV: Normal
    • EMG: Myopathic
    • Muscle pathology
      • Ragged red fibers
      • Many COX- muscle fibers (89%)
      • Impairment in mitochondrial protein synthesis
      • Mutated DNA: Skeletal muscle (87%); EOM (61%)
  
  
• tRNA^{Ala 16}: PEO
  • Genetics: T5628C mutation
  • Onset
    • 6th decade
    • Ptosis
  • Clinical
    • Family history: Negative
    • Eye movements: Decreased in horizontal direction
    • Weakness: Proximal; Symmetric; Mild
    • Dysphagia
  • Laboratory
    • Muscle
      • Many COX negative muscle fibers ± Mitochondrial proliferation
      • Biochemistry: Partial defect of Complex I
    • EMG: Myopathic
    • Serum CK: Normal
  
  
• tRNA^Leu(UUR) : PEO
  • Genetics: T3273C mutation
    • Other tRNA^Leu(UUR) mutations causing PEO+: A3243G; A3244G; A3251G; C3256T
    • Other tRNA^Leu(UUR) mutations in anticodon stem
      • A3260G: Myopathy & Cardiomyopathy; MELAS
      • T3271C: MELAS
    • DHU loop mutations: Associated with MELAS & MERRF, not PEO
  • Onset
    • 5th decade
    • Ptosis
  • Clinical
    • Family history: Migraines
    • Eye movements: Decreased L > R
    • Exercise intolerance
    • Short stature
  • Laboratory
    • Muscle
      • Many COX negative, ragged red muscle fibers
      • Biochemistry: Partial defects of Complex I & IV
      • Mutant mtDNA: RRF with 99%; Normal fibers 88%
    • Lactate: Normal
    • Serum CK: Mildly elevated
  
  
• mtRNA^{Tyr 20}: PEO
  • Genetics: T5885del mutation
  • Onset
    • 4th decade
    • Ptosis
    • Exercise intolerance: Muscle pain
  • Clinical
    • Family history: Negative
    • Eye movements: Ophthalmoplegia
    • Exercise intolerance: Muscle pain
  • Laboratory
    • Muscle
      • Myopathy: Varied fiber size; Increased connective tissue
      • Many COX negative muscle fibers with increased SDh staining
      • Biochemistry: Partial defect of Complex I & IV
      • Mutation load: COX+ fibers 20%; COX- fibers 79%
    • EMG: Myopathic
    • Serum lactate: Abnormal increase after exercise
    • Serum CK: Normal
  • Other mtRNA^Tyr syndromes
    • Exercise intolerance with Complex III deficiency: A5874G
    • Focal segmental glomerulosclerosis & Dilated cardiomyopathy: A5843G
    • Sensory ataxic neuropathy in Golden Retriever dogs: 5304delA ⁹⁷

• mtDNA Point mutations
  • t-RNA Leu : See MELAS
    • Myopathy
    • Psychiatric disorder
    • Sudden death
  • mt-RNA Asn
    • Ophthalmoplegia only
  • Other mtRNA
    • tRNA^Gln
    • tRNA^Ala
    • tRNA^Lys: PEO + Myoclonus

Autosomal Dominant PEO: Clinical features
Ophthalmoplegia	Triple furrowed tongue
Twinkle: 10q23   ANT1: 4q35   OPA1: 3q28   POLG: 15q25   POLG2: 17q   RRM2B: 8q23   Hypogonadism

• Mitochondrial DNA breakage syndromes: Autosomal dominant PEO
  • PEOA3 (PEO 1)
    l Twinkle (C10ORF2) ; Chromosome 10q23.3-q24.3; Dominant
    • Epidemiology: Multiple families & sporadic cases with different ethnic origins
    • Genetics
      • Gene mutations
        • Missense most common: Homozygotes (Ala359Thr) more severe than heterozygotes
        • Severe CNS phenotype with polyneuropathy: 39 bp duplication
        • Locations
          • Cluster in region of protein involved in subunit interactions
          • Amino acids 303 to 508
          • No mutations in N-terminal half of gene
        • Frequency: 15% of Italian PEO with multiple mtDNA deletions
      • Muscle: Multiple mtDNA deletions
        • May occur in similar patterns in diferent patients
        • No strong correlation between deletion load & clinical severity
        • mtDNA copy number: Not reduced
      • Allelic with: IOSCA
      • Twinkle mutations common with PEO onset after 4th decade
    • Twinkle protein
      • Structural similarity to phage T7 gene 4 primase/helicase
      • Colocalizes with mtDNA in mitochondrial nucleoids (units of mtDNA segregation)
        • Not dependent on DNA binding
      • Binds to: β-subunit of polymerase-γ (POLG)
      • Mutations have no effect on Twinkle localization or multimerization
      • Functions
        • DNA helicase, adenine nucleotide dependent: Essential replication helicase of mtDNA
        • mtDNA maintenance: Regulates mtDNA copy number
      • Functional domains
        • 3' Helicase region
        • Linker region: Involved in oligomerization into a hexamer required for helicase activity
        • 5' primase domain
      • Mutation actions
        • ? Alter subunit interactions: ? Dominant negative action
        • ? Gain of function: Alter nucleotide metabolism
        • No effect on Twinkle localization or multimerization
      • Splice variant: Twinky
        • Present diffusely in mitochondria
        • ? Function
    • Clinical features⁹⁰
      • Onset age
        • Average = Early 20's to early 30's;
        • Variable within families
        • Range: 17 top 73 years
      • Eye (96% to 100%)
        • Ptosis: Bilateral
        • External opththalmoplegia
      • Myopathy (50% to 70%)
        • Weakness: Proximal (45%)
        • Cramps
        • Respiratory failure: Occasional
      • Occasional
        • Bulbar weakness (18%): Dysarthria; Dysphagia; Dysphonia
        • Muscle pain
        • Polyneuropathy (15%): Sensory; Axon loss
        • CNS
          • Parkinsonism (13%)
          • Ataxia (9%)
          • Depression (13%)
          • Avoidant personality traits
          • Memory loss
        • Cataracts (5%)
        • Hearing loss (4%)
    • Laboratory
      • Muscle Pathology
        • SDH+ muscle fibers
        • COX- muscle fibers
        • Ragged red fibers
      • Mutant mtDNA: Brain > Muscle & Heart
      • Ketoacidosis: Occasional
      • Serum CK: High (36%) or Normal
      • Serum lactate: Normal or High (17%)
      • Brain MRI: Normal, Ccortical atrophy or White matter lesions
    • Twinkle Variant syndrome: SANDO with Ataxic sensory neuropathy⁵²
      • Mutations
        • Twinkle (C10ORF2)
        • Missense: Lys319Glu
      • Dominant
      • Also see: SANDO with POLG mutations
    • Variant syndrome: PEO + Parkinsonism⁷³
      • Mutation: R374Q
      • Some families with same mutation do not have Parkinsonism
    • Variant syndrome: PEO + Late-onset Dementia
      • Mutation: R374W
      • Clinical
        • PEO: Ptosis & Ophthalmoparesis; Bilateral
        • Dementia: Late-onset; Alzheimer-like
        • Hearing loss
        • Myopathy
          • Weakness: Proximal; Mild to Severe
        • Bulbar: Dysphagia, Dysphonia
        • Neuropathy: Sensory
      • Laboratory
        • Serum CK: Normal
        • Serum Lactate: Normal
        • Muscle: COX+ & COX- muscle fibers
    • Variant syndrome: Encephalopathy with mtDNA depletion⁷⁴
      • Epidemiology: 2 siblings
      • Genetics
        • Recessive
        • Compound heterozygous mutations: A318T & Y508C
      • Onset age: 5 to 6 months
      • Clinical
        • Hypotonia
        • Athetosis
        • Neuropathy: Sensory
        • Ataxia
        • Hearing deficit
        • Ophthalmoplegia,
        • Epilepsy: Intractable
      • Laboratory
        • Serum transaminases: High
        • mtDNA depletion: Liver & Brain > Muscle
        • Sural nerve: Reduced numbers of large myelinated axons
        • Spinal cord: Loss of axons in posterior columns
    
    
  • PEOA2 (PEO 2/PEO 3)
    l Adenine nucleotide translocator 1; (ANT1; SLC25A4) ; Chromosome 4q35; Dominant
    • Genetics mutations
      • Mutation type: Missense
      • Familial patients: Ala114Pro; Leu98Pro
      • Sporadic patient: Val289Met
      • Mutation effects
        • Structural: Alter α-helix of protein
        • Alters oxidative metabolism
        • mtDNA mutations
      • Other disease associations
        • Allelic with: Cardiomyopathy + Myopathy, Recessive
        • FSH dystrophy
          • Gene location: Near FSH locus on 4q35
          • Over-expression of ANT1 in FSH dystrophy muscle
    • SLC25A4 protein
      • Class: Mitochondrial solute carrier
      • Adenine nucleotide translocator (ANT1)
      • Most abundant protein in inner mitochondrial membrane
    • Epidemiology: Italian & Greek families
    • Onset: 20 to 35 years
    • Clinical
      • Ocular: Ophthalmoplegia & Ptosis
      • Severity: Milder than 10q linked PEO
      • Weakness: Variable
        • Some patients: No fatigue or generalized muscle weakness
        • Occasional: Dysphagia, Dysphonia, Face, Proximal & Respiratory
      • Cataracts: After 40 years
      • Other changes in some patients
        • Sensorineural hypoacusia
        • Goiter
        • Dementia
        • Bipolar affective disorder²⁸
    • Laboratory
      • Serum: High lactic acid
      • Muscle mtDNA: Multiple deletions
      • Respiratory-chain enzymes with mtDNA-encoded subunits: Mild deficiency of some
    
    
  • PEOA1 (PEO²⁵)
    l Polymerase, DNA, Gamma (POLG; POLG1) ; Chromosome 15q25; Dominant or Recessive
    • Genetics
      • Dominant mutations
        • Tyr955Cys: Most common mutation
        • Other: G923D; R943H; Arg953Cys; A957S; Asn468Asp; Ala1105Thr; S1176L; G268A; R1146C
        • Some dominant mutations (G923D; A957S) may have
          • Low penetrance
          • Severe phenotype & more mtDNA mutations if homozygous
      • Recessive mutations (PEOB1 ): Usually missense
        • Homozygous: Ala467Thr; Leu304Arg; Arg3Pro; G848S
        • Compound heterozygotes: T251I & R309L; P587L & R853W; T251I+P587L & M603L; D1184N & N468D
      • Other mutations
        • Absence of ten-repeat polyglutamine tract encoded by CAG repeat: Associated with male infertility
      • External link: Mutation database
    • POLG protein
      • Catalytic subunit of mitochondrial DNA polymerase
      • Function
        • Required for mitochondrial DNA replication and repair
        • C-terminal domain: DNA polymerase responsible for mtDNA replication
        • N-terminal exonuclease (exo) domain: Increases the fidelity of mtDNA replication
      • Location: Diffusely in mitochondria
      • Binds to: Twinkle
      • Accessory subunit of DNA polymerase: POLG2
    • Epidemiology
      • Common (45%) cause of familial PEO with multiple mitochondrial DNA deletions
    • Clinical features: PEO syndrome
      • Onset: 16 to 39 years
      • Ophthalmoplegia, Progressive external
      • Muscle
        • Weakness: Proximal
        • Exercise intolerance
      • Neuropathy
        • Sensory loss: Vibration
        • Tendon reflexes: Often absent
      • Endocrine
        • Poorly formed 2° sex characteristics: Breasts; Pubic hair
        • Early menopause: < 35 years
        • Testicular atrophy
      • Parkinsonism⁴⁵
        • Increased association with POLG pol-domain mutations
        • Onset: After PEO
        • Oset: 4th to 8th decade
        • PET scan: Dopaminergic neuron loss
        • Levodopa responsive
      • Severe disease
        • Proximal weakness & wasting: May be severe
        • Cranial nerves: Dysphagia; Dysphonia; Facial diplegia
        • Abnormal gait: Due to spinal ataxia or distal weakness
        • Depression,
        • Extrapyramidal syndrome: Also seen in recessive syndrome
    • Pathology
      • Muscle
        • Ragged red fibers
        • COX- & SDH + fibers: Numerous
        • Multiple mtDNA deletions
      • Normal mtDNA copy number in affected tissues
    • Laboratory
      • Serum CK: Mildly high
      • Serum Lactate: Mildly elevated
      • EMG
        • Denervation: Distal
        • Myopathy: Proximal
    • Variant syndrome: Sporadic mitochondrial myopathy syndromes with multiple mtDNA deletions
      • Onset: 20 to 62 years
      • PEO: All patients
      • Myopathy: Most patients
      • Dysphagia: 2 patients
      • Neuropathy: Sensory-Motor; 1 patient
      • MNGIE-like syndrome
    • Variant syndrome: SANDO (Hereditary sensory neuropathy)
      • Sensory Ataxic Neuropathy, Dysarthria & Ophthalmoparesis
      • Recessive inheritance
      • POLG1 mutations in exo-domain: Lys319Glu⁴⁷; W748S; A467T
      • Ataxic sensory neuropathy
      • No Parkinsonism
    • Variant syndrome: Sensory neuropathy, PEO & Tremor
      • Dominant inheritance
    • Variant syndrome: PEO + Severe axonal and demyelinating sensory–motor neuropathy⁵⁸
      • Genetics
        • Mutation: Homozygous G763R
        • Inheritance: Recessive
      • Clinical
        • Onset: 2nd decade
        • Weakness: Distal > Proximal; Face
        • Sensory loss: Distal legs; Panmodal
        • Tendon reflexes: Absent
        • PEO + Ptosis
        • Bulbar: Dysphonia; Dysphagia
      • Laboratory
        • NCV: Axonal loss
        • Nerve pathology: Axonal loss; Thin myelin sheaths
        • Muscle: Ragged red fibers; COX- fibers
        • Mitochondrial (Muscle): Complexes I, III & IV partially reduced
    • Variant syndrome: MIRAS⁵¹
      • Mitochondrial Recessive Ataxia Syndrome
      • Epidemiology: Common in Finland (Carrier frequency 1:125) & Europeans
      • POLG1 mutations
        • W748S + E1143G in cis
        • Homozygous W748S or A467T
        • Similar seen in MSCAE
      • Recessive inheritance: Many sporadic cases
      • Onset
        • Age: Range 5 to 38 years
        • Balance disorder
        • Epilepsy
      • Clinical: Hetergeneous
        • Ataxia: Gait & Limb; Dysarthria; Nystagmus (60%)
        • Polyneuropathy
          • Tendon reflexes in legs: Reduced or Absent
          • Vibration sense: Reduced
          • Pain: Some patients
          • Electrodiagnostic changes (100%): Sensory neuropathy; Axonal loss
        • Muscle: Strength reduced (30%); Cramps (25%)
        • Epilepsy (50%)
        • Cognitive impairmnent (80%): Mental retardation; Psychiatric
        • Involuntary movements: Athetosis; Tremor
        • Obesity (70%)
        • Eye movement disorders: Mainly CNS; No PEO
      • Laboratory
        • MRI: Cerebellar atrophy & white matter changes
        • Muscle: Denervation; Mitochondrial changes rare
        • EEG: Abnormal background
      • Carriers
        • No prominent clinical phenotype
        • Subclinical: Sensory polyneuropathy in majority
    • Variant syndrome: SCA + Epilepsy (MSCAE)⁷⁷
      • POLG1 genetics
        • Recessive
        • Homozygous: A467T; Gln497His; W748S
        • Similar seen in MIRAS
      • Onset: 2nd & 3rd decade
      • Clinical
        • Migraine
        • Myoclonus or Myoclonic seizures
        • Seizures
          • Often presenting symptom
          • Occipital lobe: Scotomas; Flickering; Visual loss; Visual hallucinations; Nystagmus
          • Simple partial: Motor; Involves arm or head
          • Complex partial
          • Secondary generalized epilepsy & Status epilepticus
          • Treatment
            • Sodium channel blocker + Benzodizepine
            • NOT Valproate
            • Lamotrigine & Gabapentin: May increase myoclonus
        • Ataxia
          • Cerebellar
          • Posterior column lesions
      • Laboratory
        • EEG: Seizure activity, Occipital
        • MRI
          • T2 high signal: Thalamus; Occipital cortex; Cerebellum
          • Cerebellar: Atrophy; Dentate
          • Olives: Enlarged
          • Stroke-like lesions
    • Variant syndrome: Alpers
      • Genetics
        • Recessive
        • Mutations
          • Glu873Ter & A467T
          • Similar seen in MIRAS & MSCAE
      • POLG protein: Very low residual POLG activity
      • Clinical
        • Progressive neurological disorder
        • Liver failure
      • Laboratory
        • mtDNA depletion in some patients
    • Variant syndrome: Parkinsonism without External ophthalmoplegia⁵⁷
      • Epidemiology: 2 Sisters
      • Genetics
        • Recessive
        • Mutations: Heterozygous; G737R & R853W
      • Onset
        • Age: 3rd decade
        • Extrapyramidal: Parkinsonism or Dystonia
      • Clinical
        • Parkinsonism
        • Weakness (50%): Distal, Mild
        • EOM: Full
      • Laboratory
        • Serum Lactate: High in one patient
        • Serum CK: Normal
        • Muscle
          • COX- muscle fibers
          • Oxidative metabolism: Reduced (50%) enzymes with mitochondrial subunits
        • Nerve conduction studies: Polyneuropathy
          • Axonal
          • Sensory > Motor
        • MRI: Moderate generalized cerebral & cerebellar atrophy
    • Variant syndrome: MELAS
      • Mutations: Heterozygous missense; R627Q, G848S
    • Differential diagnosis
      • Friedreich ataxia
      • IOSCA
    
    
  • PEOA4
    l POLG2 ; Chromosome 17q; Dominant
    • Epidemiology: 2 generation family + Sporadic patient
    • Genetics: Mutations
      • Heterozygous
      • Gly451Glu (c.1352GrA/p.G451E); c.1207_1208ins24
    • POLG2 protein
      • Accessory subunit of DNA polymerase
        • Catalytic subunit of DNA polymerase: POLG
      • Component of mitochondrial replication machinery
      • Dimer contains distinct sites for POLGA binding, dimerization, & DNA binding
      • Mutated protein: Promotes mtDNA deletions by stalling DNA replication fork
    • Clinical: PEO+
      • Onset
        • Age: 30 to 40 years
        • Ptosis
      • Ocular
        • Ptosis
        • External ophthalmoplegia
      • Muscle
        • Exercise intolerance
        • Pain
        • Weakness: Mild
          • Face
          • Limbs
    • Laboratory
      • Glucose tolerance: Impaired
      • Cardiac conduction defect: Left bundle branch block; Intermittent bigeminy
      • Lactate: High
      • Serum CK: 664
    • Muscle
      • Histology: COX- muscle fibers or Normal
      • Oxidative enzyme activity: Normal
    
    
  • PEO 2
    
    • Disorder mistakenly localized to Chromosome 3p
    • See PEO 3
  
  
• Dominant PEO: Other
  
  • PEO + Hypogonadism
    l Autosomal Dominant
    • Epidemiology: Swedish family
    • Clinical
      • Hypogonadism: Delayed sexual maturation, 1° Amenorrhea, Early menopause; Testicular atrophy
      • Cataracts
      • CNS: Cerebellar ataxia; Tremor; Parkinsonism; Depression Mental retardation
      • Polyneuropathy
        • Vibratory loss: Distal; Symmetric
        • Tendon reflexes: Reduced
      • Muscle
        • PEO
        • Bulbar: Dysarthria; Dysphonia
        • Proximal weakness
        • Rhabdomyolysis precipitated by alcohol: 1 patient
      • Hypoacusis
      • Pes cavus
    • Laboratory
      • EMG: Myopathic
      • Muscle biopsy
        • Ragged-red fibers
        • Cytochrome c oxidase negative muscle fibers
        • Multiple mtDNA deletions
  
  

• PEO + Cardiomyopathy
  l Autosomal Recessive
  • Onset: 1st decade
  • PEO
  • Cardiomyopathy: Dilated
  • Proximal weakness
  • Fatal in 2nd decade
  • Pathology: Multiple mtDNA deletions; Ragged red fibers
    
  
  
• PEO + Myopathy & Parkinsonism²²
  l Autosomal Recessive
  • Epidemiology: Libyan Sephardic Jewish family
  • Onset
    • 30 to 74 years
    • Ptosis or Extrapyramidal signs
  • Clinical
    • Extrapyramidal: Akinesia; Rigidity; Rest tremor
    • Eyes: Ptosis; Ophthalmoplegia
    • Myopathy: Proximal & Facial weakness: Occasional distal leg weakenss
    • Hearing loss (50%)
  • Laboratory
    • Muscle
      • Mitochondrial proliferaion: SDH +, COX - muscle fibers
      • Biochemistry: Reduced complex III + Varied other complexes
      • Multiple mtDNA deletions
  
  
• PEOB1: POLG mutations
  
  
• Hereditary sensory neuropathy + Ophthalmoplegia¹ (SANDO)
  l Polymerase, DNA, Gamma (POLG; POLG1) ; Chromosome 15q25; Recessive or Dominant
  • Nosology: SANDO (Sensory Ataxic Neuropathy Dysarthria Ophthalmoparesis)
  • Genetics: Recessive syndromes
    • Common mutation: A467T; Compound heterozygotes or homozygotes
    • Other: Missense; N468D, G517V, G737R, R1138C, E1143G
    • Recessive POLG disorder mutations
      • Heterozygous
      • One in linker region
      • One in polymerase region
      • More common than dominant mutations
      • Full SANDO syndrome: POLG Mutation frequency 78%
    • SANDO syndrome also produced by Dominant Twinkle mutations
  • Onset
    • Age: 16 to 38 years
    • Exercise intolerance
    • Ptosis
    • Paresthesias
  • Clinical
    • Neuropathy: 1st manifestation
      • Sensory loss
        • Large & Small fiber: Vibration; JP; Temperature
        • Sensory ataxia: Ataxic gait; Pseudoathetosis
        • Small fiber modality loss may be earliest feature
      • Strength: Variable
        • Normal, Distal weakness or Diffuse weakness
      • Gait: Unsteady
      • Tendon reflexes: Absent or Reduced
    • Later signs
      • PEO: Ptosis; Ophthalmoplegia
      • Ataxia
      • Other cranial nerves: Dysarthria; Facial weakness
      • CNS: Myoclonic epilepsy; Depression
    • Course
      • Progressive
      • Death
        • Age: As early as 4th decade
        • Due to epileptic status in some patients
  • Laboratory
    • Electrophysiology: Axonal neuropathy
      • SNAPs: Absent or Reduced amplitude
    • Lactate: High in CSF & Serum in some patients
    • Serum CK: Normal or Mildly elevated
    • CNS: Some patients
      • Degeneration of spinocerebellar & dorsal column tracts
      • Thalamic lesions in some patients
      • Cerebellum: Atrophy or White matter changes
    • Mitochondrial DNA
      • Multiple deletions
      • No depletion
    • Muscle Pathology: Variable
      • Ragged red fibers: COX + and COX -
      • SDH+ muscle fibers
      • May be Normal
      • Mitochondrial oxidative enzyme activities: Often normal
      • Citrate synthase: May be increased
    • Nerve pathology
      • Loss of myelinated & unmyelinated axons
      • Axonal regeneration
  • Variant syndrome: Sensory neuropathy with Dominant POLG mutation
    • Mutations: Ala889Thr missense in cis with Glu1143Gly polymorphism
    • Sensory neuropathy
    • Tremor
    • PEO
  • Variant syndrome: Ataxia + Sensory neuropathy, Recessive¹⁰⁵
    • POLG mutations
      • Frequency: 23% of patients with clinical syndrome
      • Type: Homozygous intronic; Homozygous W748S; Heterozygous missense
    • Onset age: 18 to 39 years
    • Sensory neuropathy: Axonal
    • No ophthalmoplegia
  • Also see
    • Ataxic sensory neuropathy, Sporadic
    • PEO, Recessive
    • SANDO, dominant: Twinkle mutations
    • MELAS
    • Alpers syndrome

Myopathy, Myoglobinuria & Fatigue: Mitochondrial Disorders

Mitochondrial disorders: Sporadic Myopathy & Fatigue syndromes

• Myopathy with large mtDNA mutations
  • Kearns-Sayre: Single large mtDNA deletion
  • Large scale tandem mtDNA duplication
• Myopathy with point mutations in tRNA genes: No eye signs
  • tRNA^Leu (UUR) (A3243G): Myoglobinuria; Multiple other presentations (MELAS)
  • tRNA^Leu (UUR) (T3250C): Riboflavin responsive myopathy/ SIDS
  • tRNA^{Leu (UUR)} (A3302G): Myopathy
  • tRNA^Pro (G15990A): Myopathy, childhood
  • tRNA^Phe (T618C): Myopathy
  • tRNA^Met (T4409C) : Myopathy; Exercise intolerance; Growth retardation
  • tRNA^{Ser (UCN)} (A7480G): Myopathy; Deafness; Dementia; Ataxia
  • tRNA^Asp (A7526G): Exercise intolerance & Fatigue
  • Also see: Maternal myopathies
• Myopathy with point mutations in tRNA genes: Eye signs present
  • tRNA^Leu (CUN) (A12320G): Myopathy; Ptosis
  • tRNA^Gln: PEO
  • tRNA^Ala: PEO
  • tRNA^Tyr
    
• Exercise intolerance
  • Myopathy, Exercise intolerance, Encephalopathy, Lactic acidemia
    l Cytochrome c Oxidase, Subunit III (Complex IV)
  • Exercise intolerance, Proximal weakness ± Myoglobinuria
    l Cytochrome b (MTCYB; Complex III)
  • Exercise intolerance ± Mild weakness: Several mitochondrial genes identified
    l mtRNA Trp : T5543C
    l Cytochrome b (Complex III) : A14846G
    l MTND1 (Complex I) : Inversion of 7 nucleotides; Preserves reading frame
    l MTND2 (Complex I) : 2 bp deletion
    l MTND4 (Complex I) : G11832
    
  • Coenzyme Q₁₀ deficiency
  • Also see: Myopathies with Pain & Myalgias
• Multiple mtDNA deletions
  • Inflammatory myopathies
    • Inclusion Body Myositis
    • Polymyositis with COX- muscle fibers
  • Myopathy with aging
• Other
  • Selenium deficiency
  • PEO
  
  

• Myopathy, Exercise intolerance, Encephalopathy, Lactic acidemia
  l Cytochrome c Oxidase, Subunit III (MTCO3) (Complex IV)
  • MTCO3 encoding
    • Guanine-rich heavy (H) strand of mtDNA
    • Located between nucleotide pairs 9207 & 9990
  • MTCO3 Mutations
    • G9952A point mutation at 3' end of gene
      • Stop codon
      • Heteroplasmic
      • Sporadic: Not maternally inherited
    • Deletion
    • Missense: T9789C (S195P), Probably maternally inherited
  • COX III protein
    • Forms catalytic core of Cytochrome c oxidase with COX I & COX II subunits
    • Associated 10 nuclear subunits: Modify or stabilize complex; No mutations found
  • Onset: Adult ~ 20 years
  • Clinical
    • Muscle
      • Weakness: Proximal; Some patients
      • Myalgia & Fatigue
      • Myoglobinuria
        • With deletion & missense mutations
        • Associated with prolonged exercise
    • CNS syndromes
      • Encephalopathy: Recurrent
      • Migraine
      • Spastic paraparesis, Mental retardation & Ophthalmoplegia
  • Lab
    • Serum CK: High or Normal
    • Serum lactate: High
  • Biochemistry: Isolated COX deficiency
  • Pathology
    • Cytochrome c oxidase (COX) activity: Reduced in 90% of muscle fibers
    • Few SDH positive fibers
    • Lipid accumulation in type I fibers
    • Severe reduction in COX activity (10% to 20% residual)
    • Immunohistochemistry: Reduced COX II & COX III subunits in COX- fibers
  • Variant: Isolated myopathy
    • Somatic nonsense mutation: G9379A
    • Clinical
      • Childhood: Severe weakness
      • Course: Improvement in teens to near normal
    • Pathology
      • Childhood: Severe diffuse COX deficiency; Mutation load 93%
      • 20 years: Persistent RRF (47%) & COX+ fibers (14%); Reduced mutation load (50%)
  • Other COX III syndromes
    • Myoglobinuria
    • Maternally inherited myopathies
    • MELAS-like disorder
  
  
• Myoglobinuria & Exercise intolerance
  l Cytochrome c Oxidase, Subunit I (MTCO1)(Complex IV)
  • Genetics
    • Encoding
      • Guanine-rich heavy (H) strand of mtDNA
      • Located between nucleotide pairs 5904 & 7444
    • Mutation: G5920A
      • Nonsense
      • Heteroplasmic: Especially abundant in COX negative muscle fibers
      • Sporadic: Not maternally inherited
    • Also see: Maternally inherited myopathies
  • Onset
    • Childhood
    • Exercise intolerance
  • Clinical
    • Myoglobinuria: Recurrent
    • Exercise intolerance: Fatigue
    • Strength between episodes: Normal
  • Lab at rest
    • Serum CK: Normal
    • Serum lactate: Normal
    • EMG: Normal
    • Exercise testing: Low oxygen use by muscle
    • Biochemistry: COX deficiency; Mild defects in complex I & III
    • Muscle Pathology
      • Cytochrome c oxidase (COX) immunostaining
        • Reduced for mitochondrial encoded COX I & COX II
        • Normal for nuclear encoded COX IV & VIc
      • SDH positive fibers: COX reduced
      • Many muscle fibers with reduced COX staining
  • Other Cytochrome c Oxidase, Subunit I clinical syndromes
    • Acquired sideroblastic anemia
    • Deafness, Ataxia, Blindness
    • Motor neuron disease
    • LHON
  
  
• Exercise intolerance, Proximal weakness ± Myoglobinuria
  l Cytochrome b (MTCYB; Complex III)
  • Genetics: Sporadic syndromes; Also see Familial myalgias
    • MTCYB encoding
      • Guanine-rich heavy (H) strand of mtDNA
      • Located between nucleotide pairs 14747 & 15887
    • Heteroplasmic: Muscle specific mutations in mtDNA
    • Mutation types: Most point; G to A
      • Nonsense: G15059A; G15084A; G15168A; G15723A; G15762A
      • Missense: G14846A
      • Deletion: 24-bp; Nucleotides 15498 to 15521
      • ? Frequency of mutations in this gene related to oxidative damage
  • Clinical
    • Onset: Childhood
    • Exercise intolerance
      • Progressive with age
      • Sensation of cramps, myalgias or fatigue
      • Precipitants: Normal daily activities; Chewing
    • Weakness
      • Proximal limb: Mild
      • Face: Occasional
      • EOM: Normal
    • Myoglobinuria: Some patients (28%)
    • CNS: Septo-optic dysplasia; Retardation; Encephalopathy & Seizures
  • Laboratory
    • Serum lactate: High
    • Serum CK: Normal at rest
    • EMG: Mildly myopathic
    • Muscle biochemistry: Deficient Complex III activity
    • Muscle morphology
      • Ragged red fibers (5% to 22%); All SDH + & COX +
      • Some mutations: Reduced Complex III staining in some muscle fibers
  • Cytochrome b (MTCYB) mutations: Variant syndromes
    • Encephalopathy & Seizures
      • Mutation: G15242A
      • Clinical
        • Onset
          • 9 years
          • Exercise intolerance
          • Lactic acidosis
        • Encephalopathy
          • Episodic
          • Poor balance
          • Seizures: Complex partial
          • Visual hallucinations
          • Psychiatric problems: Depression, Emotional lability
      • Laboratory
        • EEG: Abnormal
        • Muscle: Ragged red fibers
      • Treatment: Menadione + Ascorbate
    • Septo-optic dysplasia²¹
      • Mutation: T14849C; Heteroplasmic
      • Clinical
        • Mental retardation
        • Motor: Delayed walking; Exercise intolerance
        • Eye: Retinitis pigmentosa; Optic atrophy
        • Cardiomyopathy: Hypertrophic; Wolff-Parkinson-White
      • Laboratory
        • Lactic acidosis
        • MRI: Septo-optic dysplasia; Cerebellar hypoplasia
    • Familial myalgia syndrome⁵
      
      • Mutation: Missense T15747C; Homoplasmic
      • Myalgias
      • Muscle pathology: Lipid storage
      • Also see: Sporadic exercise intolerance
    • Exercise intolerance: A14846G
    • LHON
    • Colon cancer
    • Cardiomyopathy: Noncompaction of left ventricular myocardium (LVNC)
    • Parkinsonism/MELAS Overlap: 4-BP Del, 14787TTAA
    • Obesity, susceptibility to: Gly251Ser
  
  
• Exercise intolerance ± Mild weakness⁹
  • Mutations in several mitochondrial genes identified
    l mtRNA Trp : T5543C
    l Cytochrome b (Complex III) : A14846G
    l MTND1 (Complex I) : Inversion of 7 nucleotides; Preserves reading frame
    l MTND2 (Complex I) : 2 bp deletion
    l MTND4 (Complex I) : G11832
    
  • Genetics
    • Distribution of mutations
      • Usual: Heteroplasmic
      • MTND2 mutation: Homoplasmic
    • Paternal inheritance identified with ND2 mutation
  • Clinical features
    • Onset: Childhood
    • Examination
      • Weakness: Mild; Proximal
      • May be Normal
    • Exercise: Dyspnea; Tachycardia
  • Laboratory
    • Serum lactate: High, especially with exercise
    • Biochemistry: Working muscle not able to extract available O₂
    • Muscle: Some ragged red fibers are COX +
  
  
• Myopathy, Exercise intolerance & Growth retardation
  l mtRNA Met (MTTM) : T5543C
  
  • Clinical
    • Myopathy: Dystrophic
    • Exercise intolerance
    • Growth retardation
  • Laboratory
    • Lactic acidosis
  • Other MTTM mutations
    • Exercise intolerance & Autoimmune polyendocrinopathy + Lactic acidosis: A4415G + COX III mutation; Heteroplasmic
    • LHON modulator/Hypertension risk factor: A4435G
    • Myopathy: G4450A

Mitochondrial myopathy: Maternal; mtDNA Point Mutations

• tRNAs
  • Leu (MTTL1) : Cramps & Weakness (A3288G)
  • Leu (MTTL2) : Isolated myopathy (A12320G)
  • Pro
    • G15990A anticodon mutation: Pure myopathy; 1st decade onset
    • A16002G: Muscle weakness & exercise intolerance
    • G15995A: Fatigue; Dysphagia; Unsteady gait
  • Met : Myopathy; Exercise intolerance (T5543C)
  • Ser : Myopathy; Exercise intolerance (G7497A + other)
  • Gln : 1st decade; Weakness; Ptosis; dysphonia; Dysphagia (4366insA)
  • Glu : With diabetes (T14709C)
  • Trp : Encephalomyopathy (G5521A)
  • Asp : 1st decade; Exercise intolerance & Fatigue (A7526G)
  • Phe : Late onset (G622A)
• Myopathy
  • Clinical
    • Weakness
      • Distribution: Proximal > Distal; Symmetric; ± PEO
      • May be normal strength with subclinical myopathy on EMG or biopsy
    • Exercise intolerance
    • Rhabdomyolysis
    • Riboflavin sensitive: tRNA Leu mutation (T3250C)
  • Laboratory
    • Serum CK
      • Normal or high
      • Especially increased with tRNA^Met mutation
    • Lactate (serum): Increased at rest or after exercise
  • Muscle pathology
    • Myopathy
      • Fiber size variability
      • Connective tissue: Especially increased with tRNA^Met (U4409C) mutation
    • Mitochondrial proliferation: Ragged red fibers (GT stain); Dark SDH stain
    • Cytochrome oxidase - (COX-) muscle fibers
      • Frequency: Up to 50%; greater with increased age
      • Mutant DNA more abundant than in normal fibers
    • Electron microscopy
      • Abnormal mitochondrial morphology
      • Paracrystalline inclusions
      • Usually not diagnostically useful with normal light microscopic histochemistry
• Associated systemic syndromes
  • MELAS
  • MERRF
  • Encephalopathy
  • PEO and sudden death
  • Cardiomyopathy
  
  
• Cytochrome c Oxidase, Subunit II (COX II; MTCO2)(Complex IV)
  • Encoded by
    • Guanine-rich heavy (H) strand of mtDNA
    • Located between nucleotide pairs 7586 & 8294
  • COX II protein
    • Forms catalytic core of Cytochrome c oxidase with COX I & COX III subunits
    • Associated 10 nuclear subunits: Modify or stabilize complex; No mutations found
  • Clinical syndromes: General⁵⁴
    • Variable syndromes
    • High mutation load: Associated with Multi-organ involvement & Early onset
    • Severity: Less than with recessive mutations in nuclear encoded COX assembly genes
    • Myopathy
      • Onset: Childhood to Teens
      • Weakness: Distal or Proximal predominant
      • Fatigue & Exercise intolerance
      • May occur in isolation or with CNS signs
    • CNS: Ataxia; Retinopathy; Optic atrophy
  • Genetic associations
    • Mutations generally heteroplasmic
    • T7587C
      • Maternal inheritance
      • Myopathy + CNS
    • T7671A mutation
      • 90% of DNA in muscle; 5% in blood
      • Sporadic
      • Myopathy
      • Mechanism
        • Reduced Assembly of COX enzyme
        • Reduced Anchoring of COX II in mitochondrial membrane
    • G7970T mutation (E129X)
      • Myopathy
        • Many COX- fibers
          • Severe reduction in COX activity (10% to 20% residual)
        • Lipid in type I fibers
        • Fiber size: Mild variation
      • Cataracts
      • Hearing loss: Sensory-neural
      • Ataxia
      • Cardiac arrhythmia
      • Depression
      • Short stature
      • Lactic acidosis
    • G8009A: Somatic mutation found in colorectal cancer
  • Biochemistry
    • Lactate: Mildly increased in serum or CSF
    • Oxidative enzymes: Selective reduction in COX activity
  • Muscle pathology
    • COX deficiency in 97% of muscle fibers: All COX subunits reduced
    • Mitochondrial proliferation: Increased SDH stain, mild to moderate
  
  
• Myopathy, Deafness & CNS disorders⁴¹
  l Mitochondrial tRNA^Ser(UCN) (MTTS1) ; Sporadic
  • Genetics
    • Mutation: A7480G; Heteroplasmic
    • Other syndromes with tRNA^Ser(UCN) mutations
      • MELAS/MERRF overlap: T7512C; Heteroplasmic
      • 7472insC mutation: Several syndromes
        • Hearing loss, Ataxia & Myoclonus (HAM)
        • Encephalopathy with cytochrome c oxidase deficiency
        • Myoclonus, epilepsy, cerebellar ataxia & progressive hearing loss
        • Skeletal myopathy, isolated: With exercise intolerance; Teen onset
      • Muscle: G7497A mutation
        • Myopathy
        • Exercise intolerance
      • Keratoderma, palmoplantar, with deafness: A7445G
      • Sensorineural hearing loss: Maternal inheritance; T7510C, T7511C & T7445C; Heteroplasmic
  • Onset
    • Age: 8 years
    • Gait disorder: Weakness or contractures
  • Clinical
    • Weakness: Proximal
    • Fatigue: Exertional
    • Deafness: Sensorineural
    • Ataxia: Limb & Trunk
    • Cognitive impairment
    • Optic atrophy
  • Laboratory
    • CT scan: Generalized atrophy
    • EEG: Low voltage
    • EMG: Myopathy; Axonal sensory neuropathy
    • Lactate: High in serum & CSF
    • Muscle biopsy
      • Myopathy: Fiber size variation
      • Mitochondrial pathology: Proliferation; COX- fibers
      • Mitochondrial biochemistry: Complex I & IV reduced
      • May be normal early in disease course
  
  
• Myopathy, Ptosis & Dysphonia
  l Mitochondrial tRNA^Trp (MTTW) ; Sporadic
  • Mutation
    • G5521A
    • Heteroplasmic in muscle (98%)
    • Absent in leukocytes
  • Clinical
    • Onset: 50 years
    • Eyes: Ptosis; No ophthalmoplegia
    • Myopathy
      • Weakness: Proximal; Mild
      • Fatigue
  • Muscle
    • Histochemistry: SDH+, COX- muscle fibers
    • Biochemistry: Cytochrome c oxidase reduction
  
  
• Myopathy, Diabetes & CNS disorders⁴²
  l Mitochondrial tRNA^Glu (MTTE) ; Maternal
  • Genetics
    • Mutation: Missense; T14709C
    • Distribution of mutated mtDNA
      • Homoplasmic or Heteroplasmic
      • Most tissues
    • Clinical correlations
      • Symptoms in patients with mutation level > 80%
      • Some homoplasmic patients (blood) are asymptomatic
    • General: MTTE disorders
      • Mutations: Very high level of heteroplasmy or homoplasmy in skeletal muscle
      • Muscle: Constant & predominant involvement
    • Allelic with
      • Benign infantile mitochondrial myopathy with reversible cytochrome c oxidase (COX) deficiency
      • Diabetes-deafness syndrome
      • LHON: Helper mutation (A14692G)
      • Mitochondrial myopathy with respiratory failure (A14687G)
      • MELAS/LHON/DEAF: Helper mutation (A14693G)
      • Progressive Encephalopathy (A14696G)
      • Encephalomyopathy + Retinopathy (G14740A)
      • Leukoencephalopathy (G14724A)
      • Exercise intolerance (G14739A)
  • Clinical
    • Onset
      • Age: Teens or Adult; Occasional congenital
      • Fatigue
      • Weakness
    • Myopathy
      • Weakness
        • Proximal
        • Orbicularis oculi
        • Late: Respiratory failure
        • Some patients described with FSH phenotype
        • Progression: Slow
      • Fatigue
    • Polyneuropathy: Sensory-Motor; Mild
    • CNS: Some patients
      • Cerebellar: Ataxia; Nystagmus
      • Congenital encephalopathy
    • Diabetes
  • Laboratory
    • EMG: Myopathy
    • NCV: Sensory-motor axonal neuropathy
    • Muscle
      • Myopathy: Endomysial fibrosis; Varied fiber size
      • Mitochondrial morphology: Proliferation; COX- muscle fibers
      • Biochemistry: Reduced Complex I & IV activity
    • Cardiac muscle: Focal COX reductions, especially in left ventricle
  • Other Mitochondrial tRNA^Glu (MTTE) mutations
    • C14680A
      • Age: 14-year-old boy
      • Clinical
        • Myopathy: Exercise intolerance, Weakness (Face & Proximal)
        • Ataxia
      • Laboratory
        • Lactic acidosis
        • Serum CK: High
        • Muscle biopsy: SDH+ & COX- muscle fiberw
        • Mitochondrial oxidative enzymes: Complexes I, III & IV with reduced activity
        • Mutant load: Highest in urine sediment & cheek mucosa
    • T14687C
      • Age: 16-year-old boy
      • Clinical: Retinopathy, Severe myopathy with respiratory failure
    • G14710A
      • Age: 41-year-old woman
      • Clinical: Ptosis, PEO, Pigmentary retinopathy, Migraine, Life-long exercise intolerance
    • G14724A
      • Age: 4-year-old boy
      • Clinical: Mitochondrial myopathy, Leukodystrophy

Mitochondrial Myopathy: Autosomal Recessive disorders

• Fatal infantile myopathy with severe mtDNA depletion
• Benign "later-onset" myopathy with moderate reduction in mtDNA
• Cytochrome c Oxidase I
• Congenital muscular dystrophy with mitochondrial structural abnormalities
• Glutaricaciduria IIA (MADD)
• Coenzyme Q10 deficiency
• Hydroxyacyl-CoA Dehydrogenase/3-Ketoacyl-CoA Thiolase/Enoyl-CoA Hydratase
  
  • Alpha subunit (HADHA): Trifunctional protein, alpha subunit
  • Beta subunit (HADHB): Trifunctional protein, beta subunit
• Succinic Dehydrogenase deficiency: Biochemical defects
  • SDH (Complex II) deficiency
  • Succinic Dehydrogenase + Aconitase (Chromosome 12)
• Multiple mtDNA deletions
• Myopathy with lactic acidosis & sideroblastic anemia (MLASA)
  • PUS1
  • YARS2
• mtDNA depletion syndromes
  • MNGIE
  • Fatal infantile
  • Later-onset
  • Myopathy
• Recurrent myoglobinuria
  • Multiple mtDNA deletions
  • Cytochrome c Oxidase deficiency, Subunit III: Complex IV
    
• Familial myalgia syndrome : Cytochrome b (MTCYB; Complex III)
• Myopathy with Cataracts & Combined Respiratory-Chain Deficiency
• Myopathy with abnormal mitochondrial translation
• Ornithine aminotransferase deficiency

• Fatal infantile myopathy with severe mtDNA depletion : General features
  • Inheritance: Usually recessive
  • Specific syndromes
    • TK2: Onset 8 to 24 months
    • DGUOK (Hepatocerebral syndrome): Onset 0 to 6 months
    • Succinyl-CoA synthase (SUCLA2)
  • Clinical
    • Onset: birth to 14 months
    • Death: 60% < 1 year
    • Clinical: Weakness & hypotonia
    • Family history positive in 50%
    • Lactic acidosis in more severe cases
    • Serum CK: Mildly, or Prominently elevated to > 1,000
    • Some with renal dysfunction
  • Muscle
    • Ragged red fibers in 88%
    • Cytochrome oxidase
      • Activity: Very reduced or absent in extrafusil fibers
      • Normal in spindles & arteries
      • Most mitochondrial peptides absent
      • COX VIIa,b selectively reduced
      • Other nuclear-encoded mitochondrial enzymes normal
  • Differential diagnosis
  
  
• Mitochondrial DNA depletion myopathy
  l Thymidine kinase, mitochondrial (TK2) ; Chromosome 16q22; Recessive
  • Epidemiology
    • Geography: Moslem; Ashkenazi Jewish; Hispanic
    • Frequency of TK2 mutation in mtDNA depletion syndromes: 11%
  • TK2 Mutations
    • Missense: His90Asn; Ile181Asn; Ile22Met; Thr77Met; Asp11Gly
    • Exon 5: Hotspot for mutations
    • ~22 mutations described
  • TK2 protein
    • Location: Mitochondria
    • Tissue expression: Ubiquitous
    • Phosphorylates nucleotides
      • Deoxythymidine, deoxycytidine & deoxyuridine to monophosphate form
      • Phosphate source: ATP
  • Onset
    • Age: Mean 11 months; Range 8 to 24 months
    • Motor: Gait impairment; Hypotonia; Proximal weakness
  • Clinical
    • Hypotonia
    • Weakness
      • Proximal > Distal
      • Progressive
        • Severe cases: Complete paralysis by 12 to 36 months
        • Death: Childhood; Mean 3.5 years
    • Respiratory failure: By 2 to 3 years
    • Normal: EOM; Face; Cognition
    • No involvement of systems other than muscle & nerve
  • Laboratory: Myopathy & SMA-like changes
    • Serum CK: High; 900 to 4,000
    • Muscle histology
      • Partial denervation, chronic: Grouped atrophy (SMA-like)
      • Myopathy: Active; Some patients
      • Reduced COX staining: May vary among muscle fibers
      • SDH+, COX- muscle fibers
    • Mitochondrial changes in muscle
      • Low activity: Complex I, III, IV, V
      • Normal activity: Complex II
      • mtDNA depletion: 16% to 22% of control levels
    • Plasma lactate: Normal or Elevated
    • EMG
      • Myopathic: Early in course
      • Denervation changes: Develop in occasional patient²⁷
  • Variant TK2 syndromes
    • Milder clinical course: Normal mtDNA amount
    • Spinal muscular atrophy syndrome
    • Rigid spine syndrome
    • Severe myopathy with motor regression
  
  
• Benign infantile mitochondrial myopathy with reversible cytochrome c oxidase (COX) deficiency ¹⁰³
  l mt-tRNA^Glu (MTTE) ; Maternal
  • Epidemiology: 12 familes
  • Genetics
    • Mutation: T14674C
    • Homoplasmic
    • Maternally inherited
    • General: MTTE disorders
      • Mutations: Very high level of heteroplasmy or homoplasmy in skeletal muscle
      • Muscle: Constant & predominant involvement
    • T14674C mutation: Only reversible phenotype
    • Allelic disorders
      • Myopathy, mitochondrial, with diabetes mellitus (T14709C)
      • Diabetes-deafness syndrome
      • LHON: Helper mutation (A14692G)
      • Mitochondrial myopathy with respiratory failure (A14687G)
      • MELAS/LHON/DEAF: Helper mutation (A14693G)
      • Progressive Encephalopathy (A14696G)
      • Encephalomyopathy + Retinopathy (G14740A)
      • Leukoencephalopathy (G14724A)
      • Exercise intolerance (G14739A)
  • Clinical
    • Onset
      • Age: Usually 1st weeks to 2.5 months
      • Muscle weakness & Hypotonia
    • Weakness
      • Proximal > Distal; Hypotonia
      • Respiratory failure
      • Dysphagia
      • ± Ophthalmoplegia
    • Neuropathy (40%): Axonal ± Demyelinating; Sensory > Motor; May be subclinical
    • CNS: Seizures; Encephalopathy
    • MRI: Delayed myelination; Variable other changes
    • Course
      • Spontaneous improvement: Common
        • Begins at 5 to 20 months
        • Normal by 2 to 3 years
      • Residual features: Mild myopathy in some patients
      • Survival: > 26 years; Pneumonia; Respiratory failure
  • Laboratory
    • Lactic acidosis: All
    • Serum CK: High in 60% to 1400
    • Muscle pathology
      • Ragged red fibers: SDH+; Early COX-; Later some COX+
      • Cytochrome oxidase
        • Early (1 to 4 months)
          • COX activity 6% to 66%: Diagnostic < 30% of control
          • COX VIIa,b & COX II selectively reduced
        • Reduced in mosaic pattern
        • Late: COX activity returns toward normal
      • Complex I: Reduced activity in some patients
      • Fiber size: Variable
      • Other: Increased lipid or glycogen in muscle fibers
      • Occasional: Degeneration & Regeneration; Inflammation; Lipid droplets in fibers
      • mtDNA: Moderate reduction
  
  

• Myopathy + Exercise intolerance ⁷⁸
  l Iron-Sulfur Cluster Scaffold Protein (ISCU) ; Chromosome 12q24.1; Recessive
  • Epidemiology: Northern Swedish families
  • Mutation
    • Homozygous
    • Intronic
    • g.G7044C
    • Induces abnormal gene splicing
      • ISCU transcripts with exon 4A more abundant in muscle
      • Reduction of normal mitochondrial isoform (m-ISCU)
  • ISCU protein
    • Primary scaffold on which iron-sulfur clusters are assembled
    • 2 isoforms in humans: Cytosolic & Mitochondrial
    • Regulation of cellular iron trafficking
    • Other iron-sulfur-cluster assembly proteins in human disease
      • Frataxin: Friedreich ataxia
      • Glutaredoxin 5 : Sideroblastic anemia
  • Clinical features
    • Onset: Life long
    • Fatigue
    • Episodes: After minor exertion
      • Shortness of breath
      • Tachycardia
      • Weakness
      • Rhabdomyolysis
      • Muscle swelling & Pain
  • Exercise physiology
    • Low maximal muscle oxygen extraction
    • Exaggerated circulatory responses
    • Exercise: Cardiac output/Oxygen utilization 4 to 4 times normal
  • Biochemical defects
    • SDH (Complex II) deficiency
    • Succinic Dehydrogenase + Aconitase : Reduced
    • Abnormality of muscle mitochondrial iron-sulfur cluster-containing proteins
      • Mature Rieske iron-sulfur protein of complex III
      • Several subunits of Complex I
  • Pathology
    • SDH staining: Variably reduced in muscle fibers
    • Increased iron staining in SDH deficient muscle fibers
    • Mitochondrial inclusions: Electron dense, Iron-rich
  
  
• Myopathy + Cataracts & Combined Respiratory Chain Defects ⁹¹
  l Growth Factor, augmenter of liver regeneration ERV1-Like (GFER) ; Chromosome 16p13.3-p13.12; Recessive
  • Epidemiology: Moroccan family, consanguineous, 3 siblings
  • Genetics
    • Mutation: Missense; R194H
  • GFER protein
    • Function: Mitochondrial Disulfide Relay System
    • ERV1/ALR protein family
    • Expression: Ubiquitous; Low in muscle; High in testes & liver
    • Small cysteine-containing
    • Localization
      • Long isoform: Intermembrane mitochondrial space (IMS)
      • Short isoform: Nucleus
    • Intramitochondrial import
      • Requires cooperation of translocase of mitochondrial outer membrane (TOM) complex
      • With Mia40-Erv1 disulfide relay system (DRS)
    • Sulfhydryl oxidases
    • Mutation effects in muscle & fibroblasts
      • Reduction in activity of Complexes I, II, and IV activity
      • Lower cysteine-rich protein content
      • Enlargement of the IMS space
      • Accelerated time-dependent accumulation of multiple mtDNA deletions
      • Reduced co-localization with COX17, TIMM13 & COX6B1
  • Clinical
    • Onset: 1st month
    • Cataract, congenital
    • Motor
      • Hypotonia
      • Developmental delay
      • Muscle smallness
    • Tendon reflexes: Reduced
    • Hearing loss: Sensorineural
  • Laboratory
    • Muscle
      • COX- muscle fibers, scattered
      • SDH+ muscle fibers, scattered
      • Complex IV or I, II & IV reduced activity by 33% to 50%
    • Serum lactate: High
    • Serum CK: Mildly elevated
    • Brain MRI: Thin corpus callosum
    • Serum ferritin: Low
    • Serum amylase: High
  
  
• Familial myalgia syndrome
  l Cytochrome b (MTCYB; Complex III)
  
  
• Myopathy with abnormal mitochondrial translation²⁴
  l Autosomal
  • Epidemiology: Two sporadic patients
  • Onset
    • Childhood
    • Motor: Weakness or Fatiguability
  • Clinical
    • Weakness
      • Proximal > Distal
      • Fatiguability
      • Course: Slowly progressive
    • Hypotonia
    • Ocular (50%): Ptosis & Ophthalmoplegia
    • Short stature (50%)
  • Laboratory
    • Sideroblastic anemia (50%)
  • Muscle
    • Mitochondrial proliferation: All muscle fibers
    • COX activity: Severely reduced
    • Biochemistry: Complexes I and IV (5% of control); Complex II+III (41% of control)
    • Immunoblot: Complexes I, III and IV 90% reduced; Nuclear complexes II and V normal
    • Mitochondrial translation defect: Generalized

Mitochondrial Myopathy: Autosomal Dominant

• Myopathy with focal depletion of mitochondria
• Mitochondrial DNA breakage syndrome: PEO + Myopathy
• LGMD 1H
• Mitochondrial myopathy: Lipid type
  • Myopathy: Facioscapulohumeral (FSH) distribution
  • Cerebellar disorder
  • Diabetes
• Mitochondrial myopathy with exercise intolerance¹⁹
  • Onset
    • First decade
    • Exercise intolerance
    • Leg weakness
  • Clinical
    • Weakness
      • Early: Proximal; Legs > Arms
      • 2nd decade: Neck flexor; Shoulder; Distal legs
      • 3rd & 4th decade: Mild face weakness
      • Pulmonary function: Restrictive deficits
      • Progression: Slow
      • Subjective improvement with methylprednisolone treatment
    • EOM: Unaffected
    • CNS: Normal cognition, sensation, cerebellar
    • Systemic: Short stature
  • Laboratory
    • Serum CK: 287 to 984
    • Serum lactate: High
    • Serum pyruvate: High
    • EMG: Myopathic
  • Muscle pathology
    • Ragged red fibers
    • Biochemistry
      • Cytochrome c oxidase (Complex IV): Reduced
      • Succinate cytochrome c reductase (Complex II & III): Reduced
      • NADH dehydrogenase (Complex I): Normal
• Also see: Progressive External Ophthalmoplegia, Dominant

Systemic Mitochondrial Syndromes

• Fatal multisystemic complex I deficiency: NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (NDUFS4)
• Finnish neonatal metabolic syndrome: BCS1L; 2q33
• Fumarate hydratase
• Lipoamide dehydrogenase deficiency (α-ketoglutaric dehydrogenase)
• Pyruvate dehydrogenase
• Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH syndrome)
• Leigh's
• Also see: Infantile disorders

• Cardiomyopathy: Mitochondrial DNA mutations
  • General
    • Often infantile onset
    • Skeletal Muscle Pathology with mtRNA mutations: Ragged red fibers (COX -)
    
    
  • Noncompaction of left ventricular myocardium ± congenital heart defects (LVNC)
    
    
  • Fatal cardiomyopathy, infantile onset
    l mtRNA Ile
    • Genetics
      • Mutation: A4317G; A4269G
      • Also see: Other tRNA Ile mutations
    • Onset: Neonatal
    • Clinical
      • Heart: Dilated & Hypertrophic
      • Other: Some features of MELAS; Short stature; Deafness
      • Death due to cardiac failure: Childhood to 18 years
    • Other tRNA Ile syndromes
      • Familial hypertrophic cardiomyopathy (A4295G; A4300G)
        • Homoplasmic
        • Maternal inheritance
        • Cardiac muscle: Low mitochondrial oxidative enzymes
      • Familial progressive necrotizing encephalopathy (T4290C)
        • Homoplasmic
        • Onset age: 6 to 16 years
        • Lab: Impaired glucose tolerance, Hyperlipidemia, Hyperuricemia
        • Muscle: No mitochondrial changes
      • Spastic paraparesis; Ataxia; PEO; Retardation (G4284A)
        • Heteroplasmic: Mutation load 55% to 90%
        • Variable syndromes within family
          • Spastic paraparesis: Isolated
          • Cardiomyopathy + Multisystem disorders
          • Ataxia, Hearing loss, Mental regression, PEO, Diabetes mellitus
        • Muscle biopsy: Normal histology
      • Hypomagnesemia, hypokalemia, hypertension, & hypercholesterolemia, Mitochondrial (T4291C)
        • Maternal inheritance
        • Homoplasmic mutation
        • Variable phenotype: ~50% penetrance of each feature; More signs with increasing age
        • Increased prevalence of migraine headache, sensorineural hearing loss & hypertrophic cardiomyopathy
        • Muscle biopsy: Fibers with increased SDH staining
  • Cardiomyopathy (Hypertrophic)
    l mtRNA Lys
    • Genetics
      • Mutation: A8296G (Also found in Diabetes)
      • Other tRNA Lys mutations: See MERRF
    • Onset: Neonatal
    • Death in infancy
    • Lab: High serum Lactate & Pyruvate
    
    
  • Cardiomyopathy (Hypertrophic)
    l mtRNA Leu (MTTL1)
    • Mutations: A3243G; A3260G; C3303T
    • Up to 10% of hypertrophic cardiomyopathy
    • Other MTTL1 mutations
      • Barth-like syndrome: Dilated cardiomyopathy
      • MELAS
    
    
  • Cardiomyopathy (Dilated)
    l mtRNA Leu (MTTL2)
    • Mutation: C12297T
    • Cardiomyopathy: Adult onset; Dilated
    • Other MTTL2 mutations
      • Myopathy: A12320G mutation in skeletal muscle
      • Encephalomyopathy: PEO+; G12315A mutation, heteroplasmic
    
    
  • Cardiomyopathy (Dilated)
    l mtRNA His (Histidine)
    • Genetics
      • Mutations: G12192A ± A16318T substitutions
      • Homoplasmic
    • Clinical syndromes
      • Cardiomyopathy
        • Dilated or Hypertrophic
        • Onset age: Adult
      • Pigmentary retinopathy & Sensorineural deafness: G12183A
      • MERRF/MELAS overlap: G12147A
    
    
  • Cardiomyopathy (Hypertrophic)
    l mtRNA Gly
    
    • Genetics
      • Mutation: T9997C
      • Heteroplasmic: Correlates with severity of cardiomyopathy
    • Clinical syndromes
      • Nonobstructive hypertrophic cardiomyopathy
        • Onset age: Neonatal to childhood
        • Enzyme deficiencies: Complex IV & Complexes II + III
      • Exercise intolerance: T10010C
      • Sudden death: A10044G
    
    
  • Cardiomyopathy (Apical hypertrophic) + Neuropathy⁷⁵
    l ATP synthase 8 (MT-ATP8) ; Mitochondrial
    • Epidemiology: Sporadic; Caucasian male
    • Genetics
      • Encoding: mtDNA nucleotides 8366-8572
      • Mutation
        • Nonsense mutation: G8529A (Trp55X)
        • Homoplasmic
      • Other MT-ATP8 mutations
        • C8393T: Valproate-induced encephalopathy
    • MT-ATP8 protein: Complex V
    • Clinical
      • Onset
        • Age: Infancy
        • Motor development: Slow
      • Motor
        • Delayed milestones
      • Cerebellar
        • Gait & Balance disorder
        • Speech: Dysarthric
      • Reflexes
        • Tendon: Reduced
        • Plantar: Extensor
      • Eyes: External ophthalmoplegia, mild
      • Cardiomyopathy
        • Exercise intolerance
        • Shortness of breath (dyspnea) during exercise
        • Angina
        • Left ventricular hypertrophy, apical
      • Neuropathy
    • Laboratory
      • Muscle
        • Complex V: Reduced activity & protein complex
      • Lactate: High in CSF; Normal in serum
      • NCV
        • SNAPs: Absent in legs
        • CMAPs: Reduced amplitude in legs
    • Variant syndrome: Valproate-induced encephalopathy
      • Mutation: C8383T
      • Course: Reversible
    
    
  • Infantile histiocytoid Cardiomyopathy
    l Mitochondrial cytochrome b (MTCYB) ; Often sporadic
    • Genetics
      • Mutation: G15498A (Gly251Asp)
      • Other disorders with MTCYB mutations
        • Exercise intolerance
        • Myopathy
        • Leber optic atrophy
        • Colorectal cancer
        • Encephalomyopathy
        • Parkinsonism
        • Obesity, susceptibility
    • Onset: < 2 years
    • Females > Males
    • Clinical
      • Cardiac
        • Dysrhythmia
        • Cardiac arrest
      • CNS & Eye anomalies
      • Course
        • Usually fulminant
        • May simulate sudden infant death syndrome
      • Treatment: Cardiac transplantation
    • Pathology
      • Pale granular foamy histiocyte-like cells in myocardium
      • Mitochondrial proliferation
    • Biochemistry: Isolated complex III deficiency
    
    
• Infantile onset cardiomyopathy: Nuclear DNA mutations
  • Cardioencephalomyopathy with cytochrome c oxidase deficiency
    l SCO2 ; Chromosome 22q13; Recessive
    • Mutations
      • Types: Missense & Nonsense
      • Many patients heterozygous for E140K mutation: Severe disease
      • Some patients homozygous for E140K mutation: Modreately severe disease
    • SCO2 protein
      • COX assembly gene: Enables incorporation of subunits 1 and 2 into holoprotein
      • Complex IV
      • Mutated protein: Impaired copper incorporation into holoenzyme
    • Clinical: Heterozygous for E140K mutation; Fatal infantile
      • Onset: Infantile (1st 3 months); Male = Female
      • Motor: Hypotonia; Respiratory failure
      • Cardiomyopathy: Hypertrophic; COX deficiency
      • Encephalopathy
      • Course: Fatal by 6 months
    • Clinical: Homozygous for E140K mutation¹⁸
      • Onset age: 3 to 10 months
      • Motor
        • Hypotonia
        • Respiratory
          • Insufficiency
          • Inspiratory stridor
        • Limb spasticity
        • Muscle: Denervation
      • Cardiomyopathy: Hypertrophic
      • CNS
        • Leigh-like syndrome
        • Psychomotor retardation
        • Seizures
      • Ocular
        • Ptosis
        • Ophthalmoplegia
      • PNS
        • ? Motor neuropathy
        • EMG: Denervation in some patients
      • Encephalopathy: Especially white matter lesions
      • Survival: 4 to > 24 months
      • Residual COX activity: 0% to Normal
    • Laboratory
      • Muscle
        • COX deficiency (Moderate to Severe)
          • COX (Complex IV) activity: Low or Normal; 0% to Normal
          • More reduction in mitochondrial COX I & II; than nuclear COX IV & Va
          • Other complexes & SDH: Normal
          • COX staining: Reduced
        • Morphology: Atrophic muscle fibers; Denervation (SMA-like)
        • May have denervation pattern similar to SMA
      • CNS pathology: Gliosis
      • Biochemistry
        • Lactic acid: High or Normal in serum or CSF
        • Increased copper uptake by fibroblasts
      • Neutropenia
    
    
  • Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB)
        Trifunctional protein deficiency, type 2
    l Chromosome 2p23; Recessive
    • Cardiomyopathy
    • Myopathy
    • Liver dysfunction
    • Encephalopathy
    
    
  • Cardiomyopathy + Encephalomyopathy¹³
    l NADH-Ubiquinone oxidoreductase Fe-S Protein 2 (NDUFS2) ; Chromosome 1q23; Recessive
    • NDUFS2 Mutations: Missense; Homozygous
    • NDUFS2 protein: Complex I; Extramembranous near membrane domain; ? Role in protein transport
    • Onset
      • Age: Birth to 7 months
      • Hyoptonia or Failure to thrive
    • Clinical
      • Cardiomyopathy: Hypertrophic
      • Hypotonia: Axial
      • Pyramidal signs: Limb hyperreflexia
      • Ocular: Optic atrophy; Nystagmus
      • CNS: Progressive encephalopathy; Sleep apnea
      • Course: Death < 2 to 3 years
    • Laboratory
      • Lactate: High in CSF & Blood
      • Brain CT: Hypodensities in basal ganglia; Generalized atrophy
      • Exchocardiogram: Hypertrophic cardiomyopathy
      • Biochemistry: Selective Complex I deficiency
      • Riboflavin reverses adenosine triphosphate production deficit in fibroblasts
    
    
  • Mitochondrial phosphate carrier deficiency ⁶²
    l SLC25A3 ; Chromosome 12q23; Recessive
    • Epidemiology: 1 family
    • Genetics: Mutation
      • Missense; Gly72Glu
      • Located in Exon 3A with specific expression in heart and muscle
    • SLC25A3 protein
      • Import of inorganic phosphate into mitochondrial matrix: Functions in ATP synthesis
    • Clinical
      • Onset: 1st day of life
      • Cardiomyopathy: Hypertrophic; Progressive
      • Respiratory failure
      • Hypotonia
      • Course: death in 1st year
    • Laboratory
      • Serum lactate: High
      • Muscle biopsy
        • Lipid accumulation: More in type I muscle fibers
        • SDH & COX histochemistry: Abnormal mitochondrial network; No proliferation
        • Respiratory chain enzyme activities: No significant abnormalities
        • Defective ATP synthesis: Requires fresh tissue for measurement
    
    
  • Hypertrophic cardiomyopathy or Leigh syndrome
    l COX15 ; Chromosome 10q24; Recessive
    • Epidemiology: Single patient
    • Genetics
      • Mutation: Null allele (Exon 4 deletion) + Arg217Trp
      • Allelic syndrome: Leigh (Homozygous Arg217Trp)
    • Onset: Shortly after birth
    • Clinical
      • Seizures
      • Midface hypoplasia
      • Hypotonia
    • Laboratory
      • Lactic acidosis
      • Autopsy: Biventricular hypertrophic cardiomyopathy
    
    
  • Cardiomyopathy: Mitochondrial ATP synthase (Complex V) defects ⁶³
    • Genetics
      • Disorders of nuclear genetic origin
      • See: Other disorders of mitochondrial Complex V
    • General defect
      • Decreased content of structurally & functionally normal enzyme
      • Primary cause: Defect at early stage of enzyme assembly; Involves formation of F1 catalytic region
      • Gene defects
        • ATP12: 1 case
        • ATP synthase 8
        • Others undefined
    • Onset
      • Age: Neonatal
      • Low APGAR & Birth weight
      • Premature birth (50%)
    • Clinical
      • Hypertrophic cardiomyopathy (70%)
      • Hypotonia (90%)
      • Hepatomegaly (40%)
      • Head: Facial dysmorphism (30%); Microcephaly (30%)
      • Older patients: Psychomotor & Mental retardation
      • Course: 50% death in 1st weeks
      • Differs from features with Complex V disorders mitochondrial genes
        • See: NARP & MILS
    • Laboratory
      • Plasma lactate: High
      • 3-methyl-glutaconic aciduria
      • ATP synthase complex reduced on Western blot
    
    
• Infantile onset cardiomyopathy: Mutations, other
  • Cardiomyopathy (hypertrophic) & Cataracts (Sengers syndrome)
    • Hypotonia
    • Lactic acidosis
    • Death: Neonatal to early adult
    • Biochemistry
      • Complex I deficiency
      • Adenine nucleotide translocator 1 (ANT1): Levels in muscle reduced; No mutations
    
    
  • Encephalopathy
    l NDUFA11; Chromosome 19; Recessive
    
    
  • Leigh + Cardiomyopathy
    l NDUFA2; Chromosome 5q31; Recessive
    
    
  • Encephalopathy with Hypertrophic Cardiomyopathy
    l NDUFV2 ; Chromosome 18p11.31-p11.2; Recessive
    
    
  • Cardiomyopathy (hypertrophic); Brain swelling & Macrocephaly
    • Familial
    • Onset: 1st month
    • Lab: Complex I deficiency; High lactate
    • CNS Pathology: Small vessel proliferation & gliosis
  
  
• Cardiomyopathy: Autosomal, other
  • Cardiomyopathy with PEO
    • Dominant: Multiple mtDNA Deletions
    • Recessive
    
    
  • Dilated Cardiomyopathy with Ataxia (DCMA)
    
    
  • Cardiomyopathy + Mild Myopathy
    l Adenine nucleotide translocator 1 (ANT1; SLC25A4) ; Chromosome 4q35; Recessive
    • Epidemiology: Single sporadic patient
    • Genetics: Mutation
      • Missense: Ala123Asp
      • Homozygous
      • Allelic with: Autosomal dominant PEO (PEOA2)
    • ANT1 protein (SLC25A4)
      • Mutation: Causes loss of function
    • Clinical
      • Onset
        • Age: Childhood
        • Fatigue
        • Muscle pain
      • Cardiomyopathy: Hypertrophic
      • Myopathy
        • Mild
        • Exercise intolerance
        • No ophthalmoplegia
      • Headache episodes: Often with nausea & vomiting
      • Contractures: Ankle
    • Laboratory
      • Serum CK: Moderately high
      • Lactic acidosis
      • Muscle
        • Mitochondrial proliferation; SDH-positve muscle fibers
        • Ultrastructure: Abnormal mitochondria containing paracrystalline inclusions
        • Ox-Phos
          • Partial reductions in Complexes I, III, IV & V
          • Citrate synthase: High
      • EMG: Myopathic
      • NCV: Normal
    • Disease pathophysiology
      • May be related to excess of reactive-oxygen species (ROS)
    
    
  • Cardiomyopathy + Encephalopathy
    l NADH-Ubiquinone oxidoreductase 1 alpha subcomplex, assembly factor 1 (NDUFAF1; CIA30)
  
  
• Cardiomyopathy: X-linked
  • Barth syndrome: Allelic with Familial dilated cardiomyopathy 3A
  
  
• Dilated cardiomyopathy: Other
  • Right ventricular dilated cardiomyopathies (ARVD): ? Mitochondrial disorder
  
  
• Non-compaction of left ventricle
  
  
• Selenium deficiency

• Deafness: Maternal & Non-syndromic (mtDNA Point mutations)
  • 12s rRNA (MTRNR1)
    • Mutation: A1555G
    • Clinical: Aminoglycoside-induced & Non-syndromic deafness
    • May be more severe with associated mutants
      • GJB2 (Connexin 26) allele (heterozygous)
      • TRMU
  • MTTS1
    • Non-syndromic deafness
    • Aminoglycoside-induced deafness
  • MTCO1
    • Non-syndromic deafness
    • Aminoglycoside-induced deafness
• Deafness: Maternal ± Syndromic
  • Point mutations: Mitochondrial DNA
    • mtRNA^Leu (MTTL1) : Isolated hearing loss or Syndromic
      • Mutation: A3243G
      • Frequency
        • 7% of patients with matrilinear sensorineural hearing loss
        • Overall: 1%
      • More severe in males
      • Onset: Teens to 5th decade
      • Progression of deafness: Increases with age
      • Syndromic features
        • MELAS: Hearing loss present in many patients
        • Diabetes mellitus
        • Cardiomyopathy
      • A3243G: Mutation features
        • Heteroplasmic
        • Most commonly found in muscle or hair follicles
        • Less common in leukocytes with increasing age
    • MERRF
    • tRNA Ser (MTTS1)
      • A7445G mutation
        • Sensorineural hearing loss: May be homoplasmic
        • Palmoplantar keratoderma
      • 7472 insC (1 base pair insertion) & T7512C
        • Hearing loss; Ataxia; Myoclonus (HAM Syndrome)
        • Neurologic feature, other: Epilepsia partialis continua; With high levels of mutation
        • Pathology: COX deficiency; No ragged red fibers
        • Biochemistry: Complex IV deficiency
      • Disease mechanism: ? Mutations produce functional insufficiency of mitochondrial tRNA-Ser
      • Also related to MELAS/MERFF overlap syndrome
    • tRNA Ser (MTTS2)
      • Sensorineural hearing loss: Progressive
        • Recruitment: Distortion & physical discomfort as a result of loud noise
        • Persistent tinnitus
        • Similar to Usher syndromes, Type III but with maternal (dominant) inheritance
      • Retinitis Pigmentosa
      • Muscle: Mitochondrial proliferation
      • EKG: Right-axis deviation
      • Genetics
        • Mutation: C12258A; Same mutation produces Ataxia, Cataract & Diabetes syndrome
        • Other mutations in same gene produce
          • MELAS/MERRF overlap syndrome
    • tRNA Leu: with Diabetes
    • tRNA Lys : with Diabetes or Cardiomyopathy
    • tRNA Gln : Increased risk of sensorineural hearing loss & migraine¹⁴
  • Large (> 1 kb) heteroplasmic deletion: Kearns-Sayre ; PEO; Diabetes
  • Large (> 1 kb) heteroplasmic partial duplication: Kearns-Sayre; Diabetes; Ataxia; Tubulopathy
  • Wolfram syndrome: ? Mitochondrial form
• Sporadic syndromic deafness
  • Single large mtDNA deletion: with Optic Atrophy, Diabetes
  • Cytochrome c oxidase (COX) 1 (Complex IV)
    • Genetics
      • Mitochondrial DNA encoded
      • Mutations: G6930A, Stop codon; G6480A
      • Disrupts assembly of respiratory-chain complex IV
      • Biochemical correlates with the amount of mutant G6930A mtDNA
        • Differs from high threshold effect in mitochondrial tRNA point mutations
      • Other COX 1 mutations found in patients with sideroblastic anemia & Leber's
    • Clinical
      • Onset: 3 years; Cataracts
      • Hearing loss: 7 years; Sensorineural; Progressive
      • Myopathy
      • CNS: Ataxia; Myoclonic epilepsy
      • Ocular: Visual loss; Optic atrophy
    • Muscle biopsy
      • Mitochondrial enzymes: 90% reduction in COX; Normal SDH
      • No ragged red fibers
    • MRI
      • Cerebellar atrophy: Diffuse
      • Basal ganglia: Bilateral small symmetrical nodular hyperintensities
• Recessive syndromic deafness
  • Wolfram syndrome (DIDMOAD)
    • Major diagnostic features
      • Insulin-dependent diabetes mellitus
      • Optic atrophy: Progressive
    • Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness
    • Subtypes
      • Wolframin (WFS1): Chromosome 4p16
      • WFS2: Chromosome 4q22-24
      • ? Mitochondrial
    
    
  • Wolfram syndrome 1
    l Wolframin (WFS1) ; WFS1; Chromosome 4p16; Recessive (or Semi-Dominant)
    
    • WFS1 gene mutations
      • ~24 mutations identified: Nonsense, Missense...
      • Most mutations in exon 8
      • Most patients compound heterozygotes
      • Carrier frequency: 1/350
    • mtDNA
      • Multiple mtDNA deletions common (up to 90%) in affected tissues such as brain
      • Few deletions in muscle or leukocytes
    • Wolframin protein
      • Endoglycosidase H-sensitive glycoprotein
      • Location
        • Subcellular: Transmembrane; Endoplasmic reticulum; Not in mitochondria
        • CNS (Neurons): Hippocampus CA1, Amygdaloid areas, Olfactory tubercle & Allocortex (Superficial layer)
      • Expressed in heart, brain, pancreas, liver, kidney, skeletal muscle
      • Mutations: Loss of function
    • Clinical
      • Prevalence: 1:100,000 to 1:700,000
      • Onset: 95% by age 15
      • CNS: > 60% by 4th decade
        • Deafness
        • Optic atrophy
          • Onset Mean 15 years, Range 6 weeks to 30 years
          • Usually begins after diabetes mellitus
        • Ocular: Occasional patient with Parinaud's
        • Cerebellar: Ataxia; Nystagmus (50%)
        • Myoclonus
        • Cortical
          • Seizures
          • Retardation
          • Psychiatric change: Depression; Psychosis; Organic brain syndrome
        • Central respiratory failure: Some patients
      • PNS
        • Autonomic dysfunction: Urinary tract atony
        • Polyneuropathy
      • Systemic
        • Diabetes mellitus
        • Diabetes insipidus (Onset 5 to 10 years)
        • Renal tract change: Distended bladder
      • Heterozygous carriers: Predisposition to
        • Psychiatric disease (?26x)
        • Diabetes
    • Lab
      • Hematology: Anemia; Low WBC; Low Platelets
      • Reduced
        • Vasopressin
        • Erythrocyte thiamine pyrophosphate activity
        • Thiamine pyrophosphokinase activity
    • MRI: Brain atrophy
    • CNS pathology
      • Optic nerve degeneration
      • Neuronal loss: Lateral geniculate; Basis pontis; Paraventricular & Supraoptic nuclei
      • Axonal dystrophy: Swellings; ? Frequency
    
    
  • Wolfram syndrome 2
    l CDGSH iron sulfur domain protein 2 (CISD2; ERIS; ZCD2) ; Chromosome 4q22-q24; Recesssive
    • Epidemiology: Jordanian consanguinous families
    • Genetics: Homozygous; E37Q
    • ERIS (Endoplasmic Reticulum Intermembrane Small protein)
      • Zinc finger protein
      • Localization: Endoplasmic reticulum
      • Expression: Pancreas, Brain & Other tissues
    • Typical features
      • Diabetes mellitus
      • Optic atrophy
      • Hearing loss: Sensory-neural
      • Urinary tract dilatation
    • Distinctive features
      • Diabetes insipidus: Milder or absent
      • Bleeding tendency: Defective platelet aggregation with collagen
      • Peptic ulcer disease
    
    
  • Wolfram syndrome
    l Mitochondrial form
    
    
  • Deafness-Dystonia-Dementia syndromes
    l DDP protein (TIMM8A) ; Chromosome Xq22; Recessive
    • TIMM8A gene mutations: Missense; Stop; Small deletion
    • DDP protein (Translocase of inner mitochondrial membrane 8)
      • Location: Mitochondrial intermembrane space
      • Homology to yeast Tim (Translocase of inner mitochondrial membrane) mitochondrial proteins
      • Function: ? Import of metabolite transporters from Cytoplasm to Mitochondrial inner membrane
      • ? Mutations cause defect in mitochondrial protein import system
      • Other TIM protein disorder: Dilated Cardiomyopathy with Ataxia (DCMA)
    • Clinical: Mohr-Tranebjaerg syndrome; Deafness-dystonia syndrome
      • Sensory-neural hearing loss: Progressive
      • Eye: Myopia; Reduced visual acuity; Constricted visual fields; Retinal change
      • CNS: Dystonia; Mental deficiency; Cortical blindness
    • Clinical: Jensen syndrome
      • Eye: Blindness; Optic atrophy
      • Ear: Sensorineural hearing loss
      • CNS: Dementia; CNS calcifications
      • Muscle: Wasting
    • Differential diagnosis: Other mitochondrial dystonia syndromes
      • LHON + Dystonia
      • Some patients: MELAS; NARP; POLG1; Leigh
      • Leukoencephalopathy with Complex II deficiency
    
    
  • Reticular dysgenesis
    l Adenylate kinase 2 (AK2) ; Chromosome 1p34; Recessive
    • Severe combined immunodeficiency
      • Early differentiation arrest in the lineage
      • Impaired lymphoid maturation
    • Sensorineural deafness, bilateral

• Mitochondrial DNA: Ataxia is usually single part of multi-component syndrome
  • Leukodystrophy: Sporadic; Single large mtDNA deletion
  • MELAS
  • MERRF
  • ATP synthase 6
    • NARP
    • Ataxia & Cognitive delay
  • HAM: MTTS1
  • Ataxia, Cataract & Diabetes mellitus: tRNA Serine 2 (MTTS2)
    • Same mutation produces: Progressive sensorineural deafness & retinitis pigmentosa
  • Cytochrome c Oxidase I (MTCO1)
  • Cytochrome c Oxidase II (MTCO2) : Ataxia; Distal weakness; Retinopathy & Optic atrophy
• Recessive
  • Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL)
  • MIRAS,MSCAE & SANDO (Sensory ataxia): POLG1
  • Friedreich ataxia: Frataxin
  • IOSCA: Twinkle
  • Coenzyme Q10 deficiency syndromes
    • Aprataxin
    • CABC1
  • COX10 (Heme A:farnesyltransferase)
  • Dilated Cardiomyopathy with Ataxia (DCMA): DNAJC19
  • Pyruvate dehydrogenase: Episodic ataxia; Leigh syndrome
• Dominant: Variable, or incomplete, connections between ataxia & mitochondrial disorders
  • SCA 28
  • Cerebellar ataxia, Deafness & Narcolepsy
  • OPA1: Occasional patients (ADOAD)
  • AD-PEO: Rare patients
• X-linked
  • Sideroblastic anemia & Spinocerebellar ataxia (XLSA/A)
• Other: Variable or Uncertain
  • Deafness: Usually recessive or mitochondrial
  • Leigh's: Usually recessive or mitochondrial
  • CAPOS
  • ? SCA7

• Diabetes
  • Myopathy: mtDNA Point mutation tRNA Glu: Heteroplasmic or Homoplasmic
  • tRNA Leu : See MELAS; A3243G mutation
    • Frequency: 0.9% in unselected DM; 2% to 5% in inherited
  • tRNA Lys
  • Kearns-Sayre
  • Single large mtDNA deletion
  • Large scale mtDNA tandem duplication: Maternally transmitted; Deafness
  • Wolfram syndrome
  • Friedreich ataxia
  • Ataxia, Cataract & Diabetes mellitus: tRNA Serine 2 (MTTS2)
  • Type 2 diabetes association: PPARG mutation
  • Metabolic syndrome in obesity
• Pancreas, Other
  • Pearson
  • Exocrine pancreatic insufficiency, Dyserythropoietic anemia & Calvarial hyperostosis

• E3: Lipoamide (α-ketoglutaric) dehydrogenase deficiency
• SCO1
• HADHA
• HMG-CoA lyase deficiency
• Deoxyguanosine kinase (DGUOK)
• 3-Hydroxy-3-methylglutaryl-CoA synthase 2
• Ubiquinol-cytochrome C reductase-binding protein

• Sideroblastic anemia & Ataxia: ABCB7; Xq13
• MELAS: MTTL2
• Pearson's syndrome: Single large mtDNA deletion
• Myoglobinuria & Exercise intolerance: MTCO1
• Myopathy with lactic acidosis & sideroblastic anemia: PUS1; 12q24.33
• Myopathy with abnormal mitochondrial translation
• Syndromic deafness: WFS1; 4p16
• Exocrine pancreatic insufficiency, Dyserythropoietic anemia & Calvarial hyperostosis: COX4I2; 20q11.21
• Sideroblastic anemia, congenital, non syndromic
    l SLC25A38 ; Chromosome 3p22.1; Recessive
    l δ-Aminolevulinate synthase 2 (ALAS2) ; Chromosome Xp11.21; Dominant
  

• Epidemiology: Jewish families of Iranian extraction
• Genetics
  • Mutation: Missense; Arg116Trp
• Mutation effect: Reduced tRNA pseudouridylation
• Clinical
  • Onset
    • Age: Childhood & Teens
    • Weakness
  • Myopathy
    • Weakness: Progressive
    • Exercise intolerance: Fatigue; Nausea & Vomiting
    • Ptosis: Mild; Occasional patient
  • Short stature
• Laboratory
  • Anemia: Sideroblastic; Blood transfusions may be necessary
  • Lactic acidosis: At rest
  • Muscle
    • Histology: Varied fiber size; No SDH+ or COX- muscle fibers
    • Biochemistry: Reduced mitochondrial oxidative enzyme activities

• Epidemiology: 2 Lebanses families
• Genetics
  • Mutation: Homozygous; Missense; F52L
• YARS2 protein
  • Catalyzes covalent binding of tyrosine to its cognate tRNA
• Clinical
  • Onset
    • Age: Infancy or childhood
    • Sideroblastic anemia
    • Delayed milestones
  • Weakness
    • Dysphagia
    • Respiratory failure
    • Fixed weakness: Mild
    • Exercise intolerance
  • Short stature
  • Cognition: Normal
• Laboratory
  • Sideroblastic anemia
  • Serum lactate: High
  • Muscle
    • Lipid storage
    • SDH+ muscle fibers
    • COX reduced
    • Oxidative enzymes
      • Reduced: Complex I, III, & IV activity & protein complex
      • Increased: Complex II & Citrate synthase

• GI: Exocrine pancreatic insufficiency
  • Steatorrhea
  • Malabsorption of lipid-soluble vitamins
• Skeletal: Calvarial hyperostosis
• Blood: Dyserythropoietic anemia

• Epidemiology: Yemenite Jewish patients
• Genetics
  • Common mutation: Homozygous Y77H
  • Other mutations: Missense & Deletions
  • Allelic with
    • Mutations aggravating deafness with homoplasmic A1555G mutation in MTRNR1
• TRMU protein
  • Mitochondria-specific
  • tRNA-modifying enzyme
  • Role in mitochondrial translation
  • Mutation effect: Amount of thio-modified mitochondrial tRNAs is severely reduced
• Clinical
  • Onset
    • Age: 1 to 4 months
    • Irritability, Poor feeding, Vomiting
  • Hepatic failure
    • Jaundiced sclerae
    • Distended abdomen
    • Hepatomegaly
    • Lethargy
  • Course
    • Death during acute episode, or
    • Resolution without recurrence
      • Improvement starts: After 2 to 3 weeks
      • Liver functions normal: After 3 to 4 months
      • Liver size normal: 3 months to 3 years
• Laboratory
  • Coagulopathy: Low factor 5 & 11; Not corrected by vitamin K supplementation
  • Albumin: Low
  • Direct hyperbilirubinemia
  • Metabolic acidosis
  • Hyperlactatemia,
  • α-fetoprotein: High
  • Blood ammonia: Normal or Slightly elevated
  • Plasma amino acids: High phenylalanine, tyrosine, methionine, glutamine & alanine
  • Urinary organic acids: High lactate, phenylalanine & tyrosine metabolites; Ketotic dicarboxylic & 3-hydroxydicarboxylic aciduria
  • Liver biopsy
    • Histology: Abnormal
    • Enzyme analysis: Complexes I, III & IV low; Complex II normal
  • Serum CK: Normal
  • EMG: Normal
  • Muscle biopsy: Normal histology
• Differential diagnosis: Hepatic failure + Hyperlactatemia
  • DGUOK
  • POLG: Alpers
  • MPV17: Navajo

• Leber's (LHON)
  • Genetics: Various mitochondrial gene mutations
  • Onset age: Mid-adult
  • Clinical: Subacute loss of vision; Central scotoma
  
  
• Optic atrophy (OPA1) ⁷⁶
  l OPA1 protein ; Chromosome 3q28-q29; Dominant
  • OPA1 mutations
    • > 100 different mutations
    • ~50% cause premature truncation
    • Spread throughout the gene coding sequence
    • Most localized in: GTPase domain (exons 8-16); 3’ end of the coding region (exons 27-28) (GED domain)
    • Relative paucity of mutations in exons 1 to 7
    • Missense mutations: Linked to
      • Mitochondrial DNA (mtDNA) instability
      • Accumulation of multiple mt DNA deletions in skeletal muscle
    • Truncation mutations: Cause reduced levels of OPA1 in tissues
    • Disease mechanism: ? Haploinsufficiency of OPA1 protein
    • External link: Mutation data base
  • OPA1 protein
    • Cellular location: Mitochondrial
      • Anchored to inner membrane facing intermembrane space
    • Tissue location: Widely expressed; Most abundant in retina; Also brain, testis, heart, skeletal muscle
    • Functions
      • Maintenance & stability of mitochondrial DNA
      • Required for mitochondrial fusion
      • Regulation of mitochondrial dynamics & maintenance of structural integrity of cristae
      • Regulating apoptotic process through control of cytochrome c redistribution
    • Dynamin-related GTPase
    • OPA1 directly interacts with: Subunits of complexes I, II & III; Apoptosis inducing factor
    • 8 isoforms from alternative splicing
    • Processing associated with m-AAA protease AFG3L2
    • Mutation effects
      • Oxidative phosphorylation defect at level of complex I: Similar to LHON mutations
      • Impairment in mitochondrial ATP synthesis driven by complex I substrates
      • OPA1 mutant fibroblasts: More prone to cell death
      • Abnormal mitochondrial morphology
  • Clinical: Heterogeneous
    • Onset
      • 60% < 10 years
      • Common ages: 18-35 yrs
      • Sudden onset of visual loss
      • Both eyes: Asynchronously
    • Visual acuity: Variably reduced
      • Progressive decrease in visual acuity
      • Color vision defect: Blue-yellow hues
      • Loss of sensitivity in central visual field
      • Optic nerve pallor
    • Deafness: R445H & G439V mutations
    • Ataxia: G439V mutation
  • Pathology & Biochemistry
    • Retinal ganglion cells: Degeneration
    • Muscle
      • Impaired oxidative phosphorylation
      • Reduced ATP synthesis
  • Variant syndrome: Complex phenotype with R445H mutation (ODOAD)
    • Dominant inheritance
    • Optic atrophy: Visual loss
    • Sensorineural deafness
    • Myopathy: Some patients
      • Ptosis
      • External ophthalmoplegia: Progressive
  
  
• Optic atrophy 3 (OPA3)
  l OPA3 ; Chromosome 19q13.2-q13.3; Recessive
  • Nosology: 3-Methylglutaconic aciduria, Type III; Iraqi-Jewish 'Optic atrophy plus'
  • OPA3 expression: High in muscle
  • Clinical
    • Eye
      • Optic atrophy
      • Cataracts
    • Extrapyramidal: Chorea; Early onset
    • Spastic paraparesis: 50%; Onset 2nd decade
    • Ataxia: Mild
    • Cognitive defects: Mild
  • Laboratory
    • 3-Methylglutaconic aciduria: Also see Encephalocardiomyopathy
  
  
• Optic atrophy, non-syndromic ⁸⁹
  l TMEM126A ; Chromosome 11q14.1; Recessive
  • Epidemiology: Algerian & Maghreb families
  • Mutation: Arg55X
  • TMEM126A protein
    • Mitochondrial: Co-localizes with SDHA; MTCO1; ATP5A; ATP5B
    • Transmembrane
    • Expressed in brain, muscle, retina
    • ? Mitochondria-localized mRNA (MLR) protein
    • TMEM70 mutation: Encephalocardiomyopathy
  • Clinical
    • Onset age: 4 to 6 years
    • Visual loss: Severe; Bilateral; Central scotoma; Peripheral fields spared
    • Optic disc: Pallor
    • Other occasional features
      • Hypertrophic cardiomyopathy
      • Hearing loss
  • Laboratory
    • Complex I activity: Reduced in fibroblasts in 1 patient

• OPA2
  l Chromosome Xp11.4-p11.21; Recessive
  • Epidemiology: Dutch & Idaho families
  • Onset: early childhood
  • Clinical
    • Visual acuity: Reduced; 20/30 to 20/100
    • Optic nerve pallor
    • Progresion: Slow
  
  
• OPA4
  l Chromosome 18q12.2–q12.3; Dominant
  
  
• OPA5
  l Chromosome 22q12.1-q13.1; Dominant
  • Epidemiology: French families
  • Clinical
    • Optic nerve pallor
    • Visual acuity: Decreased slowly, Central scotoma
    • Color vision: Moderately impaired; Varies from normal to blue-yellow dyschromatopsia
  
  
• OPA6
  l Chromosome 8q21-q22; Recessive
  • Epidemiology: French family
  • Clinical
    • Onset age: 2 to 6 years
    • Optic atrophy
    • Visual acuity: Decreased slowly
    • Color vision: Dyschromatopsia for red-green
    • Photophobia

• Clinical features

  Causes of Leigh-like Syndrome3
  Defect	Frequency (%)
  mtDNA mutation	18
  PDHC	10
  Complex I	19
  COX deficiency	14
  Complex II + Other	39

  • Onset: 1^st year, or occasionally later
  • Hypotonia
  • Episodic
    • Vomiting
    • Ataxia
    • Choreoathetosis
    • Hyperventilation
  • Encephalopathy: Loss verbal milestones
  • Motor: Spasticity; Abnormal breathing rhythm
  • Brainstem & Basal ganglia signs
    • Hearing loss
    • Cerebellar: Ataxia; Nystagmus
    • Dystonia
  • Ophthalmologic: Visual loss; Ophthalmoparesis
  • Peripheral neuropathy
    • Often subclinical: Prevalence by nerve conduction testing: 45%
    • Pathology: Reduced Myelinated & Unmyelinated axons; ? Demyelination
  • Clinical signs may become manifest with
    • Stress: Intercurrent infection
    • Carbohydrate intolerance
  • Course
    • Progression: Motor & Intellectual regression
    • Death often within 2 years of onset
• Lab
  • Lactate: High in CSF > blood
  • Muscle biopsy
    • Normal histology
    • COX deficiency: All subunits, nuclear & mitochondrial encoded
  • MRI
    • Most common: High T2 signal in lentiform & caudate nuclei
    • Other common abnormalities in: Thalamus, Periaquiductal gray, tegmentum, red & dentate nuclei are also
    • White matter: Generally preserved
    • SURF1: Lesions in Brain stem & Subthalamic nuclei
  • CNS pathology
    • Focal, bilaterally symmetric spongiform lesions
    • Location: Especially in thalamus and brain stem
    • MRI: Symmetrical hyperintense lesions on T2
  • Common genetic cause of typical Leighs: SURF1 mutations
• General pathophysiology: Severe deficiency in mitochondrial ATP production
• Leigh syndrome (LS) & Infantile encephalopathies (IE): Genetically defined types
  
  

  Mitochondrial mutations   MILS (LS): ATPase 6   MTND2   MTND5   MTND6   tRNAs   COX III   mtDNA deletions (LS) Nuclear mutations   Complex I     NDUFA11: 19     NDUFS3 (LS): 11p11     NDUFS4 (LS & IE): 5q11     NDUFS7 (LS): 19p13     NDUFS8 (LS): 11q13     NDUFV1 (LS): 11q13     C8orf38 (LS): 8   Complex II     SDHA (LS): 5p15   Complex III     BCS1L (LS): 2q33   Complex IV     LRPPRC (LS): 2p16     Surfeit-1 (LS): 9q34     SCO2 (IE): 22q13     TACO1: 17q23   Pyruvate metabolism     Pyruvate carboxylase (LS): 11q13     Pyruvate decarboxylase (LS)     Pyruvate dehydrogenase       Pyruvate dehydrogenase E1-α (LS): Xp22       Dihydrolipoyl transacetylase E2 (IE): DLAT; 11q23       Lipoamide dehydrogenase E3 (LS): 7q31       Protein X       Phospho-E phosphatase Infantile encephalopathies: Other

  
  
  • Leigh syndrome: Maternal inheritance (MILS) & other mitochondrial DNA disorders
    • mtDNA point mutations
      l ATP synthase 6 (MTATP6) (Complex V)
      • Encoding: mtDNA nucleotides 8527-9207
      • Mutations: Also found in
        • NARP
        • Leber's
        • Familial bilateral striatal necrosis
        • Ataxia & Cognitive delay (T9035C)¹⁰¹
      • Motor: Hypotonia; Developmental delay 50% to 90%
      • Peripheral neuropathy 30%
      • T8993G mutation
        • Onset: 4 to 5 months
        • Frequency: Common
        • Seizures 67%
        • Retinitis pigmentosa or optic atrophy 33%
        • Increased severity
      • T8993C mutation
        • Onset: Median = 4 years; Range = 0.5 to 56 years
        • Frequency: Rare
        • Ataxia 90%
        • Juvenile Leigh's with respiratory failure
      • T9176C mutation: Variable presentation
        • Leigh syndrome
        • Later onset: Bilateral striatal necrosis
      • Severity also dependent on level of mutant DNA (heteroplasmy)
      
      l Mitochondrial tRNAs
      • Lys (A8344G); Trp ; Val ; Leu ; Ser
        
      
      l MTND2 (Leigh with Complex I deficiency)
      
      • Genetics
        • ND2 encoding
          • Guanine-rich heavy (H) strand of mtDNA
          • Located between nucleotide pairs 4470 & 5511
        • Mutation: Leu71Pro
      • Clinical: Leigh syndrome
        • Encephalomyopathy, progressive
        • Died: Age 10 years; Respiratory failure
      • ND2 mutations also cause
        • LHON
        • Exercise intolerance ± Mild weakness
      
      l MTND5 (Leigh with Complex I deficiency)
      • Genetics
        • ND5 encoding
          • Guanine-rich heavy (H) strand of mtDNA
          • Located between nucleotide pairs 12337 & 14148
        • Mutation: 13730A
        • Hotspot for mtDNA mutations
      • Clinical: Leigh syndrome
        • Mutation: A13084T
        • Combined features of Leigh & MELAS
        • Course: Progressive
      • Muscle pathology
        • Some biopsies have muscle fibers with mitochondrial proliferation: All SDH+ & COX+
        • Complex I deficiency
      • MTND5 mutations also found in
        • General: Mutations in ND5 often cause multisystem disorders that involve muscle
        • Atypical MELAS syndrome
        • MNGIE
        • MERRF
        • LHON
        • Parkinson's disease (Modifier)
      
      l MTND6 (Leigh with Complex I deficiency)
      • ND6 encoding
        • Cytosine-rich light (L) strand of mtDNA
        • Located between nucleotide pairs 14149 & 14673
      • Mutation
        • T14487C (M63V)
        • Heteroplasmic
      • Clinical: Leigh syndrome
        • Onset: 4 months to 6 years
        • Clinical
          • Tonic-clonic seizures
          • Motor retardation
          • Hypotonia
          • Deafness
          • Pyramidal features
          • Extrapyramidal signs: Dystonia
          • Course
            • Episodic: Brainstem events with oculomotor palsies, strabismus & recurrent apnea
            • Progressive
      • Laboratory
        • Lactic acidemia
        • Basal ganglia lesions
      • MTND6 mutations also found in
        • Leber optic atrophy
        • MELAS
      
      l COX III (MTCO3) (Complex IV)
      • COX III encoding
        • Guanine-rich heavy (H) strand of mtDNA
        • Located between nucleotide pairs 9207 & 9990
      • Leigh syndrome
        • Onset: 4 years
        • Spastic paraparesis + Ophthalmoplegia
        • Lactic acid: High in serum
        • Muscle: Isolated COX defecit
        • MRI: Leigh-like lesions in putamen
      • Mutations also found in
        • Leber optic atrophy
        • Myopathy with exercise intolerance
        • Rhabdomyolysis: 15 bp in-frame deletion
        • Episodic encephalopathy
      
      
    • mtDNA deletions
    
    
  • Nuclear mutations: Leigh
    

    Complex I Complex II Complex III Complex IV Other

    • Complex IV
      • Cytochrome oxidase deficiency (Complex IV)
        l Surfeit-1 (SURF-1) protein ; Chromosome 9q34; Recessive
        • Genetics: SURF-1 mutations
          • Small rearrangements: All predict loss of function of SURF-1 gene
          • Occur in 75% of typical Leigh syndrome in Caucasians
          • Rarely occur in atypical Leigh syndromes
        • Protein
          • Located in inner mitochondrial membrane
          • Involved in biogenesis of COX complex
          • Biochemistry in disease: Reduced COX activity to ~10% of controls in fibroblasts > muscle
        • Clinical: Specific for typical Leigh syndrome
          • Early onset
          • Encephalopathy: Rapidly progressive psychomotor regression
          • Generalized hypotonia
          • Tendon reflexes: Brisk
          • Ataxia: Truncal
          • Oculomotor disorders: Slow saccades; Ophthalmoparesis; Irregular EOM
          • Respiratory: Episodic apnea & Irregular hyperpnea
          • Death: Central ventilatory failure
        • Laboratory
          • Lactate: High
          • MRI: Symmetric lesions; Scattered from basal ganglia to brain stem
          • Muscle histochemistry: COX staining reduced; Lipid increased in muscle fibers
          • Fibroblasts & Muscle biochemistry: Complex IV deficiency
        
        
      • Cytochrome oxidase deficiency: French-Canadian type ³¹ (Complex IV)
        l LRPPRC ; Chromosome 2p16; Recessive
        • Mutations
          • Type: Missense in most; 1 deletion
          • Commonly homozygous for A354V
        • Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC)
          • mRNA-binding protein
          • Likely involved with mtDNA transcript processing
        • Epidemiology: Quebec families (Saguenay-Lac-Saint-Jean)
        • Clinical
          • Onset: Developmental delay; Hypotonia
          • Facial dysmorphism: Mild
          • Leigh syndrome
          • Mortality: Due to episodes of severe acidosis and coma
        • Laboratory
          • Congenital lactic acidosis
          • Metabolic acidosis: Mild, Chronic, Well-compensated
          • Low COX activity: Especially in Brain & Liver
          • Pathology
            • CNS: Leigh disease
            • Liver: Microvesicular steatosis
        
        
      • Leigh syndrome: Late onset ⁹⁸ (Complex IV)
        l Translational activator of COX I (TACO1; CCDC44) ; Chromosome 17q23.3; Recessive
        • Epidemiology: Single family
        • Mutation: Homozygous; 472insC
        • TACO1 protein
          • Mitochondrial translational activator
          • Mutant: Impaired synthesis of COX subunit I
        • Clinical: Leigh syndrome
          • Childhood onset
          • Slowly progressive
        • Biochemistry
          • Complex IV deficiency: Isolated
        
        
      • COX15 mutation
      
      
    • Complex I
      • NDUFS4
        
        
      • NADH-Ubiquinone oxidoreductase Fe-S protein 3 (NDUFS3)
        l Chromosome 11p11.11; Recessive
        • Epidemiology: Single patient
        • Genetics: Compound heterozygote; Thr145Ile & Arg199Trp
        • Clinical
          • Onset: 9 years
          • Dystonia: Axial; Pharyngeal
          • Optic nerve: Atrophy
          • Motor: Tetraparesis; Respiratory insufficiency
          • Progression: Rapid; Multisystem disorder
        • Laboratory
          • Cerebral MRI: High T2 signal in putamen, white matter, brain stem
          • CSF lactate: High
          • Muscle biochemistry: Complex I deficiency
        
        
      • NADH:ubiquinone oxidoreductase 23-kD subunit (NDUFS8) protein
        l Chromosome 11q13; Recessive
        • Clinical
          • Onset: Birth
          • Neural: Hypotonia; Brisk tendon reflexes; Seizures; Drowsiness
          • Cardiomyopathy
        • Laboratory
          • Lactate: Increased in blood & CSF
          • MRI: Hypodensity of white-matter, Putamen & Mesencephalon
          • Muscle biopsy
            • Histochemistry: Few Type I fibers; No ragged red fibers
            • Biochemistry: Complex I deficiency
        • Brain pathology
          • Spongiform changes
          • Capillary proliferation & endothelial swelling
          • Demyelination
          • Gliosis
        
        
      • NADH:ubiquinone oxidoreductase Fe-S Protein 7 (NDUFS7)
        l Chromosome 19p13; Recessive
        • Clinical
          • Onset: 1st year; Repeated vomiting
          • Neural: Hemiparesis; Hypotonia; Hyperactive tendon reflexes
          • Death: 1st decade
        • Laboratory
          • Pyruvate & Lactate: Normal in serum urine & CSF
          • MRI: Symmetric lesions in caudate, putamen & dentate
          • Mitochondrial oxidative enzymes: Complex I deficiency
        
        
      • NADH-Ubiquinone Oxireductase Flavoprotein 1 (NDUFV1) (Complex 1) deficiency
        l Chromosome 11q13; Recessive
        • Protein: NADH- and FMN-binding site of complex I
        • Clinical
          • Onset: 5 months
          • Repeated vomiting
          • Strabismus
          • Hypotonia
          • Encephalopathy: Myoclonic epilepsy; Psychomotor regression
        • Biochemistry: Complex I deficiency
        • Variant: Some patients with Alexander disease
        
        
      • C8orf38 (Complex 1) deficiency⁸⁵
        l C8orf38 Chromosome 8q22.1; Recessive
        • Epidemiology: Lebanese family
        • Mutation
          • Missense: Gln99Arg
        • Clinical
          • Onset age: 7 to 10 months
          • Seizures: Focal right-hand
          • Movement & Strength
          • Ataxia
          • Rigidity
          • Death: Childhood
        • Laboratory
          • Lactic acidosis
          • Biochemistry: Complex I deficiency
          • Neuroimaging: consistent with Leigh syndrome
      
      
    • Complex II: Succinate dehydrogenase, subunit A, Flavoprotein (SDHA; Fp) ²⁹
      l Chromosome 5p15; Recessive or Dominant
      • Genetics
        • Mutations: Missense
      • Epidemiology: 4 patients described
      • Clinical: Variable syndromes
        • Late onset: Dominant
          • Mutation: Arg451Cys
          • Onset: 4th decade
          • Cardiopathy: Hypertrophic
          • Skeletal muscle: Myopathy
          • Cerebellar ataxia
          • Optic neuropathy
        • Leigh syndrome: Recessive
        • Mutations
          • Commonly in region of amino acids 524-555
          • Action: ? Interfere with Fp-Ip molecular interaction
          • Cause partial reduction in complex II activity
        • Onset: 9 months with psychomotor delay
        • Truncal ataxia: Delayed walking
        • Lactate: Mild increase in serum & CSF
        • MRI: Necrotic lesions in basal ganglia
        • Dilated cardiomyopathy: Recessive²⁹
          • Epidemiology: Bedouin family
          • Mutation: G555E
            • Same mutation reported in severe & mild Leigh syndromes
            • Patient reported with non-penetrance of mutation
          • Onset age: Neonatal; Prenatal to 8 months
          • Cardiomyopathy
            • Dilated
            • Severe
            • Noncompaction of left ventricle
            • Complex II activity: Reduced in heart; Normal in skeletal muscle
      • Biochemistry of early onset disorders
        • Complex II activity
          • Reduced to 50% to 75% of lower limit of normals
          • Other complexes normal
        • Carnitine: High free & total
        • Lactate & Pyruvate: High
        • Krebs cycle intermediates high: Succinate > Fumarate & Malate
        • Ketone: High in urine
      
      
    • Leigh-like syndrome, Optic atrophy & Ophthalmoplegia ¹¹³
      l c12orf65 ; Chromosome 12q24.31; Recessive
      
      • Epidemiology: 2 families, Turkish & Dutch
      • Genetics
        • Mutations: Homozygous 1 bp deletions
      • c12orf65 protein
        • Class I peptide release factor
        • ? Recycling abortive peptidyl-tRNA species released from ribosomes during elongation phase of translation
        • Mutations
          • Mitochondrial translation deficiency
          • Reduced synthesis of mtDNA encoded peptides
      • Clinical
        • Onset age: 1 to 3 years
        • Psychomotor retardation
        • Ataxia
        • Eye
          • Ptosis
          • Ophthalmoplegia
          • Nystagmus
          • Optic atrophy
          • Reduced vision
        • Muscle
          • Atrophy: Diffuse
          • Face weakness
          • Bulbar: Difficulty chewing; Dysarthria
          • Hypotonia
          • Weakness: Distal > Proximal
        • Sensory: Distal loss
        • Tendon reflexes: Absent
        • GI: Ileus late in course
        • Course
          • Slower than typical Leigh
          • Death in 3rd decade
          • Similar to TACO1
      • Laboratory
        • Serum lactate: Variably elevated
        • Oxidative enzymes
          • Mixed defect
          • Reduced Complex I, III, IV & V activity
        • Brain MRI: Leigh-like
          • Bilateral lesions in thalami, brain stem & medulla
        • NCV: Axonal neuropathy
      
      
    • Pyruvate carboxylase deficiency
      l Chromosome 11q13.4-q13.5; Recessive
      • Neonatal type
        • Onset: Neonatal
        • Delayed neurologic development
        • Ataxia
        • Chronic lactic acidemia
          • Normal lactate:pyruvate ratio
      • Less severe phenotype
        • Later infantile onset
        • Increased lactate:pyruvate & acetoacetate to 3-hydroxybutyrate ratios
      
      
    • Pyruvate dehydrogenase complex (PDHC)
      • Pyruvate dehydrogenase complex: General
        • Structure
          • Nuclear-encoded mitochondrial matrix multienzyme complex
          • Composed of multiple copies of 3 enzymes
            • E1 (PDHA1)
              • Heterotetramer of 2 alpha and 2 beta subunits
              • E1-alpha subunit contains E1 active site
            • Dihydrolipoyl transacetylase (DLAT)
            • Dihydrolipoyl dehydrogenase (DLD)
        • Function: Link between glycolysis and the tricarboxylic acid (TCA) cycle
        • Action: Catalyzes irreversible conversion of pyruvate into acetyl-CoA
      
      
    • Pyruvate dehydrogenase E1-α deficiency (Pyruvate decarboxylase deficiency)
      l Pyruvate dehydrogenase E1-α (PDHA1) Chromosome Xp22.2-p22.1; Recessive
      • Onset: Early childhood
      • Clinical
        • Seizures
        • Hyperventilation
        • Cerebellar ataxia: Episodic
        • Chorioathetosis
        • Males: Presentation depends on the functional severity of E1-α mutation
        • Females: Clinical presentation may depend on pattern of X-inactivation in brain
        • Treatment: ? Thiamine
      • Laboratory
        • Lactic acidosis
        • Carbohydrate intolerance
        • Serum pyruvic acid: High
        • Serum alanine: High
        • E1-alpha protein: Low
      • Variant syndromes
        • Neonatal: Severe lactic acidosis
        • Infantile
          • Most common
          • Hypotonia
          • Lethargy
          • Seizures
          • Dystonia
          • Psychomotor retardation
          • Leigh-like lesions
          • Hyperlactataemia: Mild to Moderate
      
      
    • Dihydrolipoamide dehydrogenase (DLD) deficiency
      l DLD; Chromosome 7q31-q32; Recessive
      • Genetics
        • Mutations: Missense or Truncating
        • G229C mutation in Ashkenazi Jews
        • Allelic with: Maple Syrup Urine disease III
      • DLD protein
        • Component of
          • Pyruvate dehydrogenase complex
          • α-ketoglutarate dehydrogenase complex
          • Branched-chain alpha-keto acid dehydrogenase complex
          • Mitochondrial glycine cleavage system
        • DLD Mutations
          • DLD activity: < 5% of control values,
          • Western blot: DLD protein levels 40% of controls
      • Clinical
        • Onset
          • Age: Infancy to Adulthood
          • More severe with earlier onset
        • Recurrent
          • Vomiting & Abdominal pain
          • Stroke-like episodes
        • Hypothermia
        • Motor retardation
        • Myoglobinuria: Occasional
        • Exertional fatigue: Between episodes
        • Treatment: ? Lipoic acid (Oral); Reduced Branched chain amino acids in diet
      • Laboratory
        • Lactic acidosis
        • High pyruvate, lactate, α-ketoglutarate, Branched-chain amino acids
        • Hypoglycemia: Intermittent
        • MRI: Symmetric basal ganglia signal
      
      
    • Pyruvate dehydrogenase phosphatase deficiency
      
      
    • Pyruvate dehydrogenase E3-binding protein deficiency
      l Pyruvate dehydrogenase complex, component X (PDHX) ; Chromosome 11p13; Recessive
    
    
  • Also see: Infantile encephalopathies