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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 Mitochondrial disorders   Biochemical classification   Clinical syndromes   Evaluation     Clinical Signs     Laboratory   General mechanisms     Mutation types       Mitochondrial       Nuclear encoded proteins     Functional defects     Secondary effects       mtDNA depletion       Multiple mtDNA deletions   Pathology     Histology       Differential diagnosis     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
        • 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
    • Disorders: Mitochondrial-encoded peptides
      • Mutations in most can produce: LHON
      • Various other different syndromes associated with mutations in individual peptides
  • 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)
        • DIABLO (SMAC)
    • 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
  • IMS protein disorders
    • Deafness
      • AK2
      • DIABLO
      • PNPT1 (DFNB70)
    • Muscle +..
      • Encephalomyopathy: GATM (AGAT)
      • Myopathy + Cataracts: GFER
    • Basal ganglia
      • Parkinson disease 13: HTRA2
      • Neurodegeneration: PANK2
      • Encephalomyopathy: PNPT1
    • Intellectual disability & Multisystem disorders: CEP89
    • Porphyria, variegate: PPOX
• 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
  • Matrix proteins: Disorders

    AARS2: Cardiac ACAD8 ACAD9: Fatigue ACADM: Fatigue + CNS ACADS: CNS; PEO ACADSB ACAT1 : Ketoacidosis ALAS2: Anemia ALDH2 : EtOH sensitive ALDH4A1 : Seizures ALDH5A1 : Encephalopathy ALDH6A1 AMT : Encephalopathy ATPAF2: Dysmorphic, Cardiac AUH BCAT2 BCKDHA BCKDHB: Maple syrup urine BCS1L: GRACILE c8orf38: Leigh c10orf2: PEO: SANDO c12orf65: Leigh+ c20orf7: Leigh+ CLPP : Perrault COA5: Cardiomyopathy COX10: Encephalopathy COX15: Leigh+ COX20 (FAM36A): Ataxia CPS1 D2HGDH DARS2: LBSL

    DBT DECR1 DGUOK: Hepatocerebral DLD: Encephalopathy DLAT: Encephalopathy DMGDH DNA2: Myopathy + PEO EARS2: Leukoencephalopathy ETFA: Myopathy ETFB: Glutaricaciduria ETFDH: Myopathy FARS2: Alpers FH: Encephalopathy FOXRED1: Leigh GCDH GCSH GFM1: Hepatoencephalopathy GLUD1 HADH HARS2: Perrault 2 HIBCH HMGCS2: Encephalopathy HMGCL HSD17B10: Retardation HSPD1: SPG13 IDH2 IDH3B ISCU: Myopathy IVD KARS: Neuropathy

    LARS2: Diabetes; Perrault MARS2: Spastic ataxia MCCC1 MCCC2 MCEE ME2 MGME1: PEO + Myopathy MRPL3: Cardiomyopathy MRPL44: Cardiomyopathy MRPS16: Acidosis MRPS22: Cardiomyopathy MTFMT: Leigh MTPAP: SPAX4 MUT NAGS NDUFAF1: Cardiomyopathy+ NDUFAF2: Leukoencephalopathy NDUFAF3: Encephalopathy NDUFAF4: Encephalopathy NUBPL: Encephalomyopathy OAT: Gyrate atrophy OGDH OTC OXCT1 PC: Ataxia+ PCCA: Biotinidase deficiency PCCB PCK2 PDHA1: Encephalopathy

    PDHB: Encephalopathy PDHX: Leigh PDK3: CMTX6 PDP1: Encephalopathy POLG: PEO POLG2: PEO PYCR1 RARS2: PCH6 RMRP: Cartilage-hair hypoplasia SARDH SARS2: Metabolic SCO1: Hepatoencephalopathy SCO2: Cardioencephalomyopathy SDHAF1: Leukoencephalopathy SDHAF2: Paraganglioma 2 SOD2 SUCLA2: Encephalomyopathy SUCLG1: Neonatal lactic acidosis SURF1: Leigh TACO1: Leigh TK2: Myopathy TMEM70: Encephalocardiomyopathy TRMU: Hepatic failure TSFM: Cardioencephalomyopathy TTC19: Ataxia & Encephalopathy TUFM: Encephalopathy UNG XPNPEP3 YARS2: Myopathy + Anemia

• 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
  • Outer membrane protein disorders
    • Macular degeneration 7 : ARMS2
    • Neoplasms
      • B-cell Lymphoma: BCL2 overexpression
      • Pheochromocytoma & Neuroblastoma susceptibility : KIF1B
    • Encephalopathy
      • CPT1A deficiency : CPT1A
      • DNM1L
      • Glycerol kinase (GK) deficiency : GK
    • Glycemic disorders : Glucokinase (GCK)
    • Brunner syndrome : MAOA
    • Parkinson disease 6 : PINK1
• Inner membrane: Proteins+
  • Disorders
    

    ABCB7: Ataxia + Anemia ACADVL: Myopathy ADCK3: SACR9 AGK: Sengers ATP5A1: Encephalopathy, neonatal ATP5E: Retardation + Neuropathy BRP44L: Encephalopathy c12orf62: Encephalocardiomyopathy Cardiolipin: Barth COX4I2: Pancreas + Anemia COX6B1: Encephalomyopathy CPT2: Myopathy CRAT: Encephalomyopathy CYCS CYP11A1 CYP11B1 CYP11B2 CYP24A1 CYP27A1: Cerebrotendinous Xanthomatosis CYP27B1 DHODH DNAJC19: Cardiac + Ataxia FASTKD2: Encephalomyopathy GPD2 HADHA: Multisystem; Myopathy

    HADHB: Encephalomyopathy HCCS: MIDAS L2HGDH: Encephalopathy MMAA MPV17: Hepatocerebral NDUFA1: Encephalopathy NDUFA2: Leigh + Cardiac NDUFA9: Leigh NDUFA10: Leigh NDUFA11: Encephalocardiomyopathy NDUFA12: Leigh NDUFA13 NDUFB3: Lethal infantile NDUFB9: Encephalopathy NDUFV1: Encephalopathy NDUFV2: Encephalopathy + Cardiac NDUFS1: Leukodystrophy NDUFS2: Encephalopathy + Cardiac NDUFS3: Dystonia NDUFS4: Encephalopathy NDUFS6: Lethal infantile NDUFS7: Encephalopathy NDUFS8: CNS + Cardiac OPA1: Optic atrophy

    OPA3: Optic atrophy PDSS1: Coenzyme Q10 deficiency SDHA: Leigh; Cardiac; Paraganglioma SDHB: Paraganglioma SDHC: Paraganglioma SDHD: Paraganglioma SLC25A carriers   SLC25A1: Epileptic encephalopathy   SLC25A3: Cardiac; Exercise intolerance   SLC25A4: PEOA2   SLC25A12: Hypomyelination   SLC25A13: Citrullinemia   SLC25A15: HHH   SLC25A19: Microcephaly   SLC25A20: Encephalocardiomyopathy   SLC25A22: Myoclonic epilepsy   SLC25A38: Anemia Paraplegin: SPG7 TIMM8A: Deaf-Dystonia-Dementia UCP1 UCP2 UCP3 UQCRB: Hypoglycemia, Hepatic UQCRC2: Episodic metabolic encephalopathy UQCRQ: Encephalopathy

• Submitochondrial (around mitochondria) protein disorders
  • CNS system disorders
    • SCA28: AFG3L2
    • Dyskinesia, Paroxysmal nonkinesiogenic 1 (PNKD1) : MR1
    • SPG31; HMN 5B: REEP1
    • Optic atrophy 7 (OPA7) : TMEM126A
    • Encephalopathy, Glycine : GLDC
    • MEGDEL: SERAC1
  • CoQ10 deficiency
    • COQ2
    • COQ6
    • COQ9
    • PDSS2
  • Systemic disorders
    • Anemia
      • Sideroblastic : Glutaredoxin 5 (GLRX5)
      • Sideroblastic + Myopathy: PUS1
    • Lipoid adrenal hyperplasia : STAR
  • Metabolic disorders
    • Hyperoxaluria 3 : DHDPSL (HOGA1)
    • Methylmalonic aciduria, cblB Type : MMAB
    • Homocystinuria : MMADHC
• Other mitochondrial proteins: Disorders
  • Encephalopathy
    • Encephalocardiomyopathy: MTO1
      
    • Encephalomyopathy: Apoptosis-inducing factor, mitochondrion associated (AIFM1)
    • Encephalopathy, ethylmalonic (EE): ETHE1
    • Encephaloneuropathy: RMND1
    • Encephalopathy, infantile: BOLA3
    • Encephalopathy, infantile: Iron-sulfur cluster scaffold protein (HIRIP5, NFU1)
    • Leigh syndrome: Leucine-rich PPR motif-containing protein (LRPPRC)
  • CNS system disorders
    • ALS/PD2: PARK7
    • AOA: Aprataxin (APTX)
    • Biotinidase deficiency: Holocarboxylase synthetase (HLCS)
    • Friedreich ataxia: Frataxin (FXN)
    • Parkinson disease, juvenile, type 2 : Parkin 2 (PARK2)
    • Parkinson disease 8 : Leucine-rich repeat kinase 2 (LRRK2)
    • Spastic ataxia: Alpha-methylacyl-CoA racemase (AMACR)
    • Spastic ataxia, Charlevoix-Saguenay: Sacsin (SACS)
    • SPG20 (Troyer): Spartin
  • CMT
    • 2K & 4A: Ganglioside-induced differentiation-associated protein 1 (GDAP1)
    • 2A2, V, VI & AR-CMT2: Mitofusin 2 (MFN2)
    • 2Q: DHTKD1
    • 4G & Anemia, hemolytic : Hexokinase 1 (HK1)
    • MT-ATP6
  • Systemic
    • Cardiac conduction defect, susceptibility : A kinase anchor protein 10 (AKAP10)
    • Cardiomyopathy + Acidosis : Malonyl-CoA decarboxylase (MLYCD)
  • Neoplasm
    • Colorectal cancer & T-cell acute lymphoblastic leukemia: Bcl-2 associated x protein (BAX)
    • Esophageal squamous cell carcinoma: WW domain-containing oxidoreductase (FOR, WOX1, WWOX)
  • Metabolic syndromes
    • Methemoglobinemia types I & II : Cytochrome b5 reductase 3 (CYB5R3)
  • Myopathy
    • CHCHD10
• 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
    • Pyruvate disorders
  • 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
    • 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: Different single cells contain varied 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
    • Pathogenic heteroplasmic mutations: Transmission
      • Initial variance among offspring: Prenatal germline without selection
      • Protein-coding genes: Purifying selection; Preferentially eliminated within a few generations
      • mtRNA genes: No oocyte selection over successive generations
      • Progressive accumulation of mutation occurs in some non-dividing post-mitotic tissues
  • 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
  • Disorders can produce
    • Multiple mtDNA deletions
    • Reduced amounts of mtDNA (mtDNA depletion)
• 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   Aconitase 2 deficiency   Fumarase deficiency   IDH3   Lipoamide dehydrogenase   SDH   SUCLA2 Other   Aminoacyl-tRNA synthetase (ARS)   Fusion & Fission   Lactate   Lipid membrane defect: Barth   Oxidation-Phosphorylation coupling     ATP Synthase     Luft's disease   Ribosome, mitochondrial 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 complex defect     COXPD     Iron-Sulfur cluster 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   Secondary effects     mtDNA depletion     Multiple mtDNA deletions

  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^Cys (MTTC) ; 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 (PEO) (sporadic types)
      • 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
      • Differential diagnosis
    • 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
  • External link: mtDNA Deletions
  
  
• 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
      • Acquired
        • Aging
        • Myositis: IM-VAMP
      • Hereditary
        • 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
      • Aminoacyl-tRNA synthetases (ARS) ¹⁵⁸
        • Disease mechanisms
          • ARSs provide specific attachment of amino acids to 3'-ends of their cognate tRNA
          • Mutations: Adversely affect mitochondrial translation with deranged synthesis of mitochondrial proteins
        • Genes: Mitochondrial
          • AARS2: Cardiomyopathy, Infantile
          • DARS2: Leukoencephalopathy
          • EARS2: Leukoencephalopathy
          • FARS2: Alpers fatal infantile encephalopathy
          • GARS: CMT 2D
          • HARS2 : Perrault syndrome 2 (Ovarian dysgenesis & Sensorineural hearing loss)
          • KARS: CMT-RIB
          • LARS2 : Diabetes, type 2, susceptibility; Perrault
          • MARS2: Portneuf spastic ataxia with leukoencephalopathy
          • RARS2: Pontocerebellar hypoplasia 6 (PCH6)
          • SARS2: Hyperuricemia, Pulmonary Hypertension, Renal Failure in Infancy and Alkalosis (HUPRA)
          • YARS2: Myopathy with lactic acidosis & sideroblastic anemia (MLASA2)
        • Also see
          • Cytoplasmic ARS syndromes
          • ARS autoantibodies
  • Other types of mitochondrial dysfunction caused by nuclear defects
    • Membrane structure: Barth syndrome
    • Protein importation into mitochondria: Deafness-Dystonia syndrome
    • Mitochondrial protein synthesis: Encephaloneuromyopathy
    • 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: CHKB; 2q13
      • Carnitine disorders
        
    • Encephalopathies
      • Leigh: SURF-1; NDUFS7; NDUFS8; NDUFV1; SDHA; Pyruvate carboxylase; PDHC
      • Infantile & Childhood
      • 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
    • Also see: Mitochondrial proteins
  • 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; SUCLG1
  • Spinal
    • Nuclear DNA
      • SPG7
      • SPG13
      • SPG20
      • SPG31
      • HHH syndrome
      • MTPAP
      • NBIA: PANK2; MPAN
      • Spastic dystonia
      • Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL)
      • Charlevoix-Saguenay spastic ataxia (ARSACS)
      • Portneuf spastic ataxia
      • MEGDEL: SERAC1
    • Mitochondrial DNA
      • MTCO3
      • Mitochondrial tRNA Ile
      • Leber's (MTND4)
      • MTATP6
  • 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
  • External ophthalmoplegia (PEO)
• Polyneuropathy
  • Mitochondrial DNA: NARP; MNGIE; MERRF; Myopathy + Diabetes
  • Autosomal: HADHA; CMT 2A (MFN2); CMT 2Q (DHTKD1); CMT 4A (GDAP1); Friedreich ataxia; SCO2 (Motor);
        KARS; GARS; POLG1; Sensory ataxic (SANDO); 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 of mitochondrial disorders
  • 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; MTCYB
    • SDH positive (Ragged red) muscle fibers with prominent lipid accumulation: Coenzyme Q₁₀ deficiency
  • Cytochrome oxidase (COX) stain changes
    • General
      • Usual pathologies
        • Absent or reduced staining of muscle fibers
          • Reduced COX activity distribution: May be diffuse or in scattered fibers
          • Degree of reduced COX activity in SDH+ fibers: Variable with multiple mtDNA mutations
        • Increased staining of fibers
          • Mitochondrial proliferation
          • Variably present depending on syndrome
      • May identify patients with mitochondrial disorders not detected by SDH stains
    • Scattered abnormal muscle fibers: Properties
      • COX-negative but normal SDH staining: Suggests
        • mtDNA mutation affecting mitochondrial protein synthesis
        • Mutations in COX I, COX II, or COX III genes
        • Heteroplasmic mutation
      • Both COX-positive & SDH increased fibers: 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
      • SDH-Increased, COX-negative fibers
        • May have 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
    • Diffuse change: COX reduction
      • 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
  • Antibody stains for OXPHOS complexes ¹⁴⁴
    • Antibody targets for OXPHOS complex identification
      • Complex 1: NDUFS7; NDUFB8
      • Complex 2: SDHB
      • Complex 3: UQCRC2
      • Complex 4: MTCO1 (mtDNA encoded)
      • Complex 5: ATP5A1, ATP5A2
    • Patterns of staining: Variable among fibers
      • Mosaic of variable staining for Complexes I & 4: Various mitochondrial disorders
      • Complex 1 & 4 negative: MERRF; Normal aging; Inclusion body myositis
      • Complex 1 negative & Complex 4 positive: MELAS
  • Gomori trichrome stain
    • Stains "Ragged red" muscle fibers
    • Much less specific & sensitive for mitochondrial proliferation than SDH
  • 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
  • Nile Red: Neutral lipid stained in muscle fibers
  • Inflammation
    • Uncommon in most mitochondrial disorders
    • Present with: Inclusion body myositis; PM/COX-
  • Muscle fiber necrosis & regeneration: Uncommon
  • Perimysial vessels, Intermediate-sized
    • SDH+ & COX+: MELAS; MTCYB
    • SDH+ & COX-: MERRF
  • Mitochondrial enzyme immunohistochemistry
    • mtDNA-encoded respiratory chain subunits
      • COX II (Subunit II of Complex IV)
      • ND1 (Subunit I of Complex I)
    • nDNA-encoded respiratory chain subunits
      • COX IV (Subunit IV of Complex IV)
      • FeS (Iron sulfur subunit of Complex III)
    • Anti-DNA antibodies
  • 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
  • MTATP6 mtDNA point mutations
    • Common: T8993G; T8993C
    • Other: G8989C; 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
  • Allelic disorders
• Disease mechanism
  • ? Inefficient coupling between proton transport & ATP synthesis
  • Reduced ATP synthesis rate
• Clinical
  • Severity: Intrafamilial variability
  • Onset
    • Age: Childhood (2nd decade) or Adult
  • Sensory neuropathy
    • Pan modal loss: Reduced vibration
    • Distal > Proximal
    • Legs > Arms
  • 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
    • Gait disorder
    • Dysarthria
  • Other CNS
    • Dementia
    • Seizures
      • More common with early onset NARP
      • Later: EEG abnormalities; Tonic-Clonic seizures
    • Developmental delay
    • Pyramidal signs
    • Dystonia
    • Hearing loss
  • Cardiac
    • Mostly with MILS syndromes: Infantile hypertrophic
• Laboratory
  • Serum lactate: Normal or Mildly elevated
  • Muscle pathology
    • No ragged red or COX- fibers
    • Denervation: Type groups; Atrophic angular muscle fibers
  • NCV: Axon loss, Sensory > Motor
  • Brain MRI
    • Cerebral: Atrophy; Periventricular white matter pathology
    • Cerebellar: Cortical atrophy; Dilation of 4th ventricle
    • Lenticular nuclei: High T2 signal
  • CNS pathology: Similar to Leigh syndrome ⁶⁴
    • Focal cystic necrosis
    • Pathways: Visual, Auditory & Olfactory pathways,
    • Cerebellar system: Inferior olive; Dentate nucleus
    • Striatum: Especially putamen
  • Electroretinogram: Rod or Cone dysfunction
• Variant syndrome: CMT Type 2, Mitochondrial Inheritance ¹⁴²
  • Nosology: Distal Hereditary Motor Neuropathy (dHMN) in some patients
  • Epidemiology: 4 families
  • Genetics
    • MTATP6 mutation
      • T9185C
      • High mutant loads (92%) to Homoplasmic
      • Lower mutant loads (< 64%): Often asymptomatic
      • Intermediate mutant loads (64% to 91%): Upper motor neuron features; No neuropathy
    • Allelic disorders
  • Clinical
    • Onset
      • Age: Usual 1st or 2nd decade
      • Gait disorder: Falling; Unsteadiness
    • Weakness
      • Distal
      • Legs > Arms
      • Proximal (Mild): 10%; May be early in course
    • Sensory loss: 30%; Distal; More with increasing age
    • Upper motor neuron: 30%
      • Tendon reflexes: Brisk
      • Plantar reflex: Extensor
    • Skeletal
      • Pes cavus: 50%
      • Kyphoscoliosis: 10%
    • Course
      • Progressive
      • Wheelchair: 2nd to 6th decade in some
      • Decompensation in affected individuals after viral or septic illness
  • Laboratory
    • NCV
      • Motor axon loss: Most
      • Sensory axon loss: Some
    • Complex V: Activity reduced; Unstable
  • Asymptomatic relatives: May have upper motor neuron signs

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)
        • MERRF/KSS overlap (A3251G; T3291C)
        • 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
        • Myopathy
          • MERRF (G611A)
          • Late onset (G622A)
          • Late onset, axial + Ataxia (C602T) ¹⁴¹
            • Paraspinal muscle atrophy: Camptocormia
            • Encephalopathy: Seizures
            • Ataxia
            • Muscle: SDH+ & COX- fibers
    • mtRNA Cys (A5814C)
      • Other mutation: Dystonia +... (A5816C)
    • 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
    • MTCOI
  • 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
  • Polyneuropathy ⁶¹
    • 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
      • Frequency: 15% to 40% with A3243G mutation
      • Hypertrophic: Left ventricular
        • Increased mortality & morbidity
        • More progression: Diabetics
      • Left ventricular noncompaction
      • Conduction defects: Wolff-Parkinson-White or Other
      • Hypertension
    • 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)
      • Myopathy (MIMECK) (A8291G)
      • ?? Madras MND (A8302)
  • 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 Ile (MTTI)
  • 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 -
    • Vacuoles in small fibers (A8344G mutation): Some patients
      • Rimmed or Autophagic
      • LC3 aggregates
    • 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
  • Type
    • Most common: Missense mutations
    • Occasional: Insertions, Deletions, Stop or Splice acceptor change in intron
    • > 50 Different mutations identified
  • Location
    • 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
    • Geographic
      • c.A866G Europe
      • c.T518G Dominican Republic
• Thymidine phosphorylase protein (Endothelial cell growth factor, platelet derived (ECGF1))
  • Thymidine phosphorylasethymine phosphorylase
  • 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
  • General
    • Often: Homogeneous
    • Intra- & inter-familial clinical variability: Reported
    • Poor genotype–phenotype correlation
  • Onset
    • Age
      • Often < 20 years (75%)
      • Mean 18 years; Range 5 mo to 53 years
      • Majority with 1st symptoms < 12 years
    • Signs
      • Gastric (57%)
        • Dysmotility (45%): Diarrhea; Nausea & vomiting
        • Abdominal pain & cramps
      • Extraocular (26%): Ptosis; External ophthalmoplegia
      • Polyneuropathy: Foot drop
  • 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
      • Sensory ataxia
    • 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
  • Myopathy
    • Proximal weakness (14%)
    • Exercise intolerance (8%)
  • CNS
    • Hearing loss (60%)
    • Cognition
      • Normal intelligence in most
      • Cognitive impairment or Dementia (9%)
    • Other occasional
      • Seizures
      • Headaches
  • Cardiac: Occasional; Incomplete right bundle branch block
  • Pancreas: Diabetes or Glucose intolerance; Amylase increase; Exocrine insufficiency
  • Neoplasms (3%)
  • Disease course
    • Progressive: Months to Years
    • Spontaneous fluctuations may occur: Associated with acute medical events
    • Early death
      • Ages: Mean 35 to 38 years, Range 18 to 53 years
      • Associated with infections + other systemic disorders
• Laboratory
  • Serum
    • Lactic acidosis (64%)
    • Plasma thymidine levels: Increased 20-fold
    • Plasma deoxyuridine & deoxythymidine levels: Increased
    • Hypokalemia: Tetany; Cardiac arrhythmia
  • 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 (80% to 90%)
      • SDH + fibers (60%)
      • Oxidative enzyme levels: May be normal
      • Eye muscles: Myopathic changes
    • Neurogenic changes
      • Grouped atrophy
      • Fiber type grouping
      • Target/targetoid fibers
  • 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 (MTDPS1 ): 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
          • Western: ND4 (G11778A) (69%), ND1 (G3460A) (13%), ND6 (T14484C) (14%)
          • Chinese: ND1 (G3460A; G3635A); ND5
      • 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
      • Mutation: T3394C ¹³⁶
        • Variable effects depending on haplogroup & environmental context
        • Complex I activity reduced: B4c & F1 haplogroups
        • Complex I activity increased: M9 haplogroup
        • Low altitude: Increased LHON risk
      • Other MTND1 mutations
        • LHON: G3635A; G3733A; C4171A⁵⁰
        • Familial Non-Arteritic Anterior Ischemic Optic Neuropathy (NA-AION): G4132A, Ala276Thr
        • MELAS
        • Exercise intolerance
        • SIDS
        • Dystonia
        • 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
      • tRNA Leu (MTTL1): T3291C; Adult onset MERRF/KSS overlap
  • 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 - & some 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 having a single large mtDNA deletion
  • Pearson's Syndrome
    • Sideroblastic anemia
      • Pancytopenic crises
      • Macrocytic
      • Bone marrow: Normal cellularity; Vacuolization
    • Pancreatic insufficiency
      • Exocrine: Malabsorption; Steatorrhea
      • Endocrine: Insulin-dependent diabetes; Later in disease course
    • Infancy: Low birth weight; Death; Metabolic & lactic acidosis
    • Course
      • Often fatal in early childhood
      • May precede development of Kearns-Sayre syndrome if survival past infancy
    • Treatment
      • Chronic transfusions
      • Replacement of pancreatic enzymes
    • Laboratory
      • mtDNA deletions often found in leukocytes
  • 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   Nuclear DNA mutations     POLG (PEOA1): 15q25     ANT1 (PEOA2): 4q35     Twinkle (PEOA3): 10q23     POLG2 (PEOA4): 17q     RRM2B (PEOA5): 8q23     DNA2 (PEOA6): 10q21     OPA1: 3q28     Hypogonadism Recessive   Mitochondrial DNA changes       mtDNA depletion, or       Multiple mtDNA deletions   Nuclear DNA mutations     Leigh, PEO & OA: c12orf65; 12q24     MNGIE: TYMP; 22q13     POLG: 15q25     DGUOK: 2p13     PEO + Myopathy: MGME1; 20p11     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 pathology
  • 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 POLG2: 17q RRM2B: 8q23 Hypogonadism   POLG: 15q25   Variants     SANDO     MIRAS     MSCAE     Alpers     Parkinsons

• Mitochondrial DNA breakage syndromes: Autosomal dominant PEO
  • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 (PEOA3; PEO 1)
    l Twinkle (C10ORF2) ; Chromosome 10q24.31; 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, Cortical 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 depletion (MTDPS7 ) ⁷⁴
      • Epidemiology: 2 siblings
      • Genetics (Twinkle; c10orf2)
        • 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
    
    
  • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 (PEOA2; PEO 2; PEO 2/PEO 3)
    l Adenine nucleotide translocator 1; (ANT1; SLC25A4) ; Chromosome 4q35.1; 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
    • Clinical
      • Onset age: 20 to 35 years
      • Ocular: Ophthalmoplegia & Ptosis
      • Severity: Milder than PEO-Twinkle
      • 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
    
    
  • Progressive external ophthalmoplegia with mitochondrial DNA deletions, Autosomal Dominant 1 (PEOA1; PEO 1) ²⁵ or Recessive
    l Polymerase, DNA, Gamma (POLG; POLG1) ; Chromosome 15q26.1; 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
        • Clinical syndromes
          • adPEO
          • PEO+ Demyelinating neuropathy
          • PEO + Distal myopathy
          • PEO + Hypogonadism
      • Recessive mutations (PEOB1 ): Usually missense
        • Homozygous: Ala467Thr; Leu304Arg; Arg3Pro; G848S
        • Compound heterozygotes: T251I & R309L; P587L & R853W; T251I+P587L & M603L; D1184N & N468D
        • Clinical syndromes
          • Alpers-Huttenlocher syndrome (AHS) (Severe phenotype)
          • Childhood myocerebrohepatopathy spectrum (MCHS)
          • Myoclonic epilepsy myopathy sensory ataxia (MEMSA; MSCAE)
          • Ataxia neuropathy spectrum (ANS): SANDO; MIRAS
          • Autosomal recessive progressive external ophthalmoplegia (arPEO)
          • MNGIE
          • Parkinsons
      • 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 (PEO AD1 )
      • 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
        • Onset age: 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 neuropathy ⁵⁸
      • 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
      

      MSCAE

      • 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
          • Simple partial: Motor; Involves arm or head
          • Complex partial
          • Secondary generalized epilepsy & Status epilepticus
          • Treatment
            • Sodium channel blocker + Benzodiazepine
            • NOT Valproate
            • Lamotrigine & Gabapentin: May increase myoclonus
        • Ataxia
          • Cerebellar; Nystagmus
          • 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 (MTDPS4A)
    • 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
    • Variant syndrome: MNGIE variant (MTDPS4B )
      • Recessive
      • POLG1 Mutations: Missense; P1073L; A467T; G848S
      • Congenital myopathy
      • Gastrointestinal pseudoobstruction
    • Variant syndrome: PEO + Hypogonadism
      l POLG1; Chromosome 15q26.1; 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
    • Variant syndrome: PEO + Cardiomyopathy
      l POLG1; Chromosome 15q26.1; Recessive
      • Clinical
        • Onset: 1st decade
        • PEO
        • Cardiomyopathy: Dilated
        • Proximal weakness
        • Course: Fatal in 2nd decade
      • Pathology: Multiple mtDNA deletions; Ragged red fibers
        
    • Variant syndrome: Distal myopathy, Cachexia & PEO ¹⁴³
      l POLG1; Chromosome 15q26.1; Dominant or Sporadic
      • Epidemiology: 2 patients
      • Mutations: Leu896Arg (de novo); Tyr951His
      • Clinical
        • Onset age: 3rd or 4th decade
        • Weakness
          • Distal predominant
          • Arms > Legs
          • Bulbar: Dysarthria; Dysphgagia
        • Cachexia: 1 patient
        • Eyes
          • Ptosis
          • Ophthalmoplegia
          • Cataracts
      • Laboratory
        • CK: Mildly high
        • EMG: Myopathic
        • NCV: Normal
        • Muscle: Ragged red & COX- muscle fibers
      • Other family members
        • No strong positive family history
        • 1 with cataracts
      
      
    • Differential diagnosis
      • Friedreich ataxia
      • IOSCA
    
    
  • Progressive external ophthalmoplegia with mitochondrial DNA deletions, Autosomal Dominant 4 (PEOA4; PEO 4)
    l POLG2 ; Chromosome 17q23.3; Dominant
    • Epidemiology: 2 generation family + Sporadic patient
    • Genetics: Mutations
      • Heterozygous
      • Gly451Glu (c.1352GrA/p.G451E); c.1207_1208ins24; Deletions; Missense
    • 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 + Systemic
      • Variable severity
      • Onset
        • Age: Infancy to 30 to 40 years
        • Ptosis
      • Ocular
        • Ptosis
        • External ophthalmoplegia
      • Muscle
        • Exercise intolerance
        • Pain
        • Weakness: Mild
          • Face
          • Limbs
      • CNS: Seizures & Hypotonia in younger onset patients
      • Course: Progressive
    • 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
        • Mitochondria: Abnormal morphology
      • CNS: Younger onset patients
        • Cerebellar atrophy
    
    
  • Progressive external ophthalmoplegia with mitochondrial DNA deletions, Autosomal Dominant (PEOA5) ¹⁵⁶
    l DNA replication helicase 2, yeast, homolog of (DNA2) ; Chromosome 10q21.3; Dominant
    • Epidemiology: 3 families
    • Genetics
      • Mutations: Arg284His; Lys313Glu; Val723Ile
    • DNA2 protein
      • Location: Mitochondria ? + other
      • Helicase/nuclease family
      • Interacts with: POLG1
      • Function: Probably involved in: mtDNA replication; Long-patch base-excision repair (LP-BER)
      • Contains ATPase domain
    • Clinical
      • Onset age: Childhood to 4th decade
      • Weakness: Proximal > Distal; Legs ± Arms
      • Muscle features, other: Hypotonia; Myalgia; Exertional dyspnea; Small size
      • Eye: Ptosis or Ophthalmoplegia (75%)
      • Lordosis
    • Laboratory
      • Muscle
        • COX- or SDH+ fibers (2% to 5%)
        • mtDNA deletions
        • Type 2 atrophy (1 patient)
      • Serum CK: Normal or Mildly high
    
    
  • PEO 2/3
    
    • Disorder mistakenly localized to Chromosome 3p
    • See PEO 2/3

• 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 15q26.1; 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; Sensory ataxia
      • 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 or Neuronopathy
      • SNAPs: Absent or Reduced amplitude
      • EMG
        • Denervation (90%): Distal ± Proximal
        • Myopathy (40%): Proximal
    • 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
    • CNS pathology ¹²⁷
      • Spinal cord: Posterior column atrophy
      • Dorsal root ganglia: Neuron loss
      • Mitochondrial DNA copy number: Reduced in affected neurons
      • Mitochondrial oxidative enzymes: Reduced activity of Complexes I & IV
  • 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
  
  
• PEO + Myopathy & Respiratory failure (MTDPS11) ¹⁵⁴
  l Mitochondrial genome maintenance exonuclease 1 (MGME1; c20orf72) ; Chromosome 20p11.23; Recessive
  
  • Epidemiology: 3 families, 6 patients
  • Genetics
    • Mutations: Trp152X; Tyr233Cys
  • MGME1 protein
    • Mitochondrial RecB-type exonuclease
    • PD–(D/E)XK nuclease superfamily
    • Cleaves single-stranded DNA
    • Processes DNA flap substrates
    • Essential for mitochondrial genome maintenance
  • Clinical
    • Onset
      • Age: < 20 years
      • Ptosis
    • Eye
      • Ptosis
      • Ophthalmoplegia, External
    • Muscle
      • Weakness
        • Proximal
        • Respiratory failure: With disease progression
        • Face
        • Dysphonia
        • Dysphagia
        • Course: Slow progression
      • Wasting
        • Progressive to emaciation
        • Scapular winging
    • CNS: Mental retardation; Memory defecits
    • Spinal deformities: Rigid; Lourdosis; Kyphosis
    • Cardiac: Myopathy or Arrythmias
    • Gastrointestinal (GI): Nausea, Flatulence, Abdominal fullness, Diarrhea - recurrent, Loss of appetite
  • Laboratory
    • Muscle
      • Histochemistry: SDH+ & COX- fibers
      • mtDNA
        • Multiple deletions: Larger size than with POLG1 mutations
        • Depletion: Reduced copy number
        • 7S DNA (single-stranded component of the mtDNA displacement loop (D loop)): Increased
      • Respiratory chain: Complex I or I+IV deficiencies
    • MRI: Cerebellar atrophy

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)} (G7497A; 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) ; Mitochondrial
  • 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: 5 amino acids, in frame
    • Insertion: 1 base pair
    • 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: 4 to 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: 1-base pair insertion (9537C)
  • 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
    • SDH positive fibers: Few; Many in patient with deletion
    • 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
    • Leigh-like: Homoplasmic m.C9537insC frameshift
    • Nonarteritic ischemic optic neuropathy (NAION)-Myoclonic epilepsy: Homoplasmic T9957C
  
  
• Myoglobinuria & Exercise intolerance
  l Cytochrome c Oxidase, Subunit I (MTCO1)(Complex IV) ; Mitochondrial
  • 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, Myopathy
    • Epilepsy partialis continua: C6489A
    • Motor neuron disease: m.6020del5
    • LHON
    • Myopathy, Cardiomyopathy, Stroke: Homoplasmic C6328T
    • MELAS-like: C6597A; G7023A
    • ? Myopathy: Proximal, Adult onset; Inflammation; A7222G, Only 24% Heteroplasmy
  
  
• Exercise intolerance, Proximal weakness ± Myoglobinuria
  l Cytochrome b (MTCYB; Complex III) ; Mitochondrial
  • 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)
    • MELAS
      • Migraine, Epilepsy, Polyneuropathy, Stroke-like episodes: T14864C, Heteroplasmic
      • Parkinsonism 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
  
  
• Myopathywith Episodic high Creatine Kinase (MIMECK) ¹⁴⁰
  l mtRNA Lys (MTTK) : A8291G
  
  • Epidemiology: Japanese patients
  • Genetics
    • Homoplasmic
    • A8291G mutation reported in few healthy controls
    • Patients all had other similar mtDNA polymorphisms
  • Clinical
    • Onset
      • Age: Adult; 15 to 69 years
      • May be acute or subacute
    • Myopathy
      • Weakness
        • Proximal
        • Symmetric
        • Mild
        • Dysphagia: Some
      • Myalgias: Episodic
  • Laboratory
    • Serum CK: High, episodic
      • Usual: 67 to 320
      • Episodic: 200 to 11,000
    • Muscle biopsy: SDH+ & COX- muscle fibers
  • Other MTTK mutations

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: General ⁵⁴
    • Variable syndromes
      • High mutation load: Associated with Multi-organ involvement, MELAS & 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
    • Rhabdomyolysis: Some patients; T7989C
    • 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
        • Mutations: T7510C, T7511C & T7445C
        • Heteroplasmic
        • Some aminoglycoside induced: G7444A
  • 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

• ACAD9: Fatigue syndrome
• Benign "later-onset" myopathy with moderate reduction in mtDNA
• Congenital muscular dystrophy with mitochondrial structural abnormalities: CHKB; 2q13
• Cytochrome c Oxidase I
• Coenzyme Q10 deficiency
• Fatal infantile myopathy with severe mtDNA depletion
• Glutaricaciduria IIA (MADD)
• Hydroxyacyl-CoA Dehydrogenase/3-Ketoacyl-CoA Thiolase/Enoyl-CoA Hydratase
  
  • Alpha subunit (HADHA): Trifunctional protein, alpha subunit
  • Beta subunit (HADHB): Trifunctional protein, beta subunit
• mtDNA depletion syndromes
  • MNGIE
  • Fatal infantile
  • Later-onset
  • Myopathy
• Multiple mtDNA deletions
• Myalgia syndrome, Familial : Cytochrome b (MTCYB; Complex III)
• Myoglobinuria, Recurrent
  • Multiple mtDNA deletions
  • Cytochrome c Oxidase deficiency, Subunit III: Complex IV
    
• Myopathy with lactic acidosis & sideroblastic anemia (MLASA)
  • MLASA1: PUS1
  • MLASA2: YARS2
• Myopathy with Cataracts & Combined Respiratory-Chain Deficiency
• Myopathy with abnormal Mitochondrial Translation
• Ornithine aminotransferase deficiency
• Succinic Dehydrogenase deficiency: Biochemical defects
  • SDH (Complex II) deficiency
  • Succinic Dehydrogenase + Aconitase (Chromosome 12)

• 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 (MTDPS2) ¹⁵³
  l Thymidine kinase, mitochondrial (TK2) ; Chromosome 16q21; Recessive
  • Epidemiology
    • Geography: Moslem; Ashkenazi Jewish; Hispanic
    • Frequency of TK2 mutation in mtDNA depletion syndromes: 11%
  • TK2 Mutations
    • Missense: Asp11Gly; Ile22Met; Thr77Met; His90Asn; T108M; Ile181Asn
    • Exon 5: Hotspot for mutations
    • ~25 mutations described
    • Same mutations may produce pediatric or adult disease
  • TK2 protein
    • Location: Mitochondria
    • Tissue expression: Ubiquitous
    • Phosphorylates nucleotides
      • Deoxythymidine, deoxycytidine & deoxyuridine to monophosphate form
      • Phosphate source: ATP
  • Clinical
    • Disease severity: Intra-familial variability
    • Onset
      • Age: Mean 11 months; Range 8 to 24 months
      • Motor: Gait impairment; Hypotonia; Proximal weakness
    • Hypotonia
    • Weakness
      • Proximal & Axial > Distal
      • Respiratory failure: By 2 to 3 years
      • Bulbar & Facial
    • Normal: EOM; Face; Cognition
    • Course: Progressive
      • Severe cases
        • Complete paralysis by 12 to 36 months
        • Death: Childhood; Mean 3.5 years
      • Milder variants
        • Weakness onset in childhood or adult: Slow progression
        • Rapid worsening as adult
    • Involvement of systems other than muscle & nerve: Rare
      • Gynecomastia: 1 patient
  • Laboratory: Myopathy & SMA-like changes
    • Serum CK: High; 750 to 4,000
    • Muscle histology
      • Partial denervation, chronic: Grouped atrophy (SMA-like)
      • Myopathy: Active; Varied fiber size; Some patients
      • Reduced COX staining, diffuse: May vary among muscle fibers
      • SDH+ & COX- muscle fibers
    • Mitochondrial changes in muscle
      • Low activity: Complex I, III, IV, V
      • Normal activity: Complex II
      • Citrate synthase: High
      • mtDNA depletion (MPDPS2 )
        • Severe patients: 16% to 22% of control levels
        • Milder disease: 45% residual
      • mtDNA deletions: Multiple
    • 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 (MMIT) 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
      • Face
      • Respiratory failure
      • Dysphagia
      • ± Ophthalmoplegia
      • Hypotonia
      • Macroglossia
    • Neuropathy (40%): Axonal ± Demyelinating; Sensory > Motor; May be subclinical
    • CNS: Seizures; Encephalopathy
    • Liver: Hepatomegaly
    • 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
    • MRI: Delayed myelination; Variable other changes
    • 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 12q23.3; Recessive
  • Epidemiology: Northern Swedish families
  • Mutations
    • g.G7044C (IVS5 + 382G>C)
    • Homozygous
    • Intronic
    • Induces abnormal gene splicing
      • ISCU transcripts with exon 4A more abundant in muscle
      • Reduction of normal mitochondrial isoform (m-ISCU)
      • Highest levels of abnormal mRNA in muscle
    • Missense: Gly50Glu; Heterozygous with intronic splice mutation
    • ISCU knockout mouse: Embryonic lethal
  • ISCU protein
    • Primary scaffold on which iron-sulfur clusters are assembled
    • 2 isoforms in humans
      • Cytosolic (ISCU1): Full length
      • Mitochondrial (ISCU2): Exon 2 spliced out
    • Regulation of cellular iron trafficking
    • Iron-sulfur-cluster proteins
      • Iron-sulfur (Fe-S) clusters: Essential components of enzymes involved in
        • Maturation of subunits of complexes I, II & III
        • Synthesis of enzyme-bound cofactor lipoate in 2-oxoacid dehydrogenases
      • Iron-sulfur (Fe-S) cluster synthesis
        • Location: Occurs in mitochondrial matrix
        • Export of some clusters to form cytosolic & nuclear proteins
      • Fe-S cluster disorders
        • Muscle biochemistry: Complex II ± I or III deficiency
        • Fe-S cluster containing proteins
          • ISCU: Myopathy
          • Frataxin: Friedreich ataxia
          • Glutaredoxin 5 : Sideroblastic anemia
          • NFU1: Infantile encephalopathy with multiple mitochondrial dysfunctions 1
          • BOLA3: Infantile encephalopathy with multiple mitochondrial dysfunctions 2
        • Biosynthesis of mitochondrial iron-sulfur [4Fe-4S] proteins
          • IBA57: Encephalopathy
  • Clinical features: Homozygous splice site mutations
    • Onset: Life long
    • Fatigue
    • Episodes: After minor exertion
      • Shortness of breath
      • Tachycardia
      • Weakness
      • Rhabdomyolysis: Some patients
      • Muscle swelling
      • Myalgias
    • Cardiac: Mild hypertrophy
    • Course: Non-progressive
  • Exercise physiology
    • Low maximal muscle oxygen extraction
    • Exaggerated circulatory responses
    • Exercise: Cardiac output/Oxygen utilization 2 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
  • Serum lactate: High
  • Pathology
    • SDH staining in muscle fibers: Variably, but generally, reduced
    • COX staining in muscle fibers: Reduced in some
    • Iron: Increased (Prussian Blue) staining in SDH deficient muscle fibers
    • Mitochondrial inclusions: Electron dense, Iron-rich
    • ISCU protein: Severely reduced
  • Variant syndrome: Heterozygous splice site & missense mutations
    • Muscle weakness: Severe; Proximal > Distal
    • Exercise intolerance: Severe
    • Slowly progressive
    • Cardiomyopathy
    • EMG: Myopathic
    • Muscle biopsy
      • Internal nuclei
      • Endomysial connective tissue: Increased
      • ISCU protein: Moderately reduced
  
  
• Myopathy + Cataracts & Combined Respiratory Chain Defects ⁹¹
  l Growth Factor, augmenter of liver regeneration ERV1-Like (GFER) ; Chromosome 16p13.3; 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
  
  
• Fatigue & Exercise Intolerance (Complex I) ¹¹⁶
  l Acyl-CoA Dehydrogenase family, member 9 (ACAD9) ; Chromosome 3q21.3; Recessive
  • Epidemiology: Few families
  • Genetics
    • Missense mutations: Arg532Trp; Arg127Glut; Arg469Trp
  • ACAD9 protein
    • Catalyzes initial rate-limiting step in β-oxidation of fatty acyl-CoA
    • Belongs to group of ACADs that act on fatty acids containing 14 to 20 carbons
    • Homodimer
  • Clinical
    • Onset age: 4 years
    • Fatigue syndrome
      • Exercise intolerance
      • Urge to vomit
      • Sense of mental slowness
      • Duration: 1 hour
    • Treatment: Riboflavin, high dose 300 mg/day
  • Laboratory
    • Muscle: Complex I activity reduced (6% to 40%)
    • Serum lactate: High
  • Variant
    • Episodic hepatic dysfunction
      • Precipitated by minor illnesses
      • Cardiomyopathy: Some patients

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 intolerance
  l Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial (CHCHD10) ; Chromosome 22q11.23; Dominant ¹⁹
  • Mutations: 2 mutations on one chromosome
  • CHCHD10 protein: Mitochondrial
  • 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 (MTTI)
    • 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
    • mtRNA Ile syndromes
      • Cardiomyopathy
        • Familial hypertrophic cardiomyopathy (A4295G; A4300G)
          • Homoplasmic
          • Maternal inheritance
          • Cardiac muscle: Low mitochondrial oxidative enzymes
        • Fatal cardiomyopathy, infantile onset
      • Encephalopathy, Familial progressive necrotizing (T4290C)
        • Homoplasmic
        • Onset age: 6 to 16 years
        • Lab: Impaired glucose tolerance, Hyperlipidemia, Hyperuricemia
        • Muscle: No mitochondrial changes
      • Myoclonus epilepsy, Progressive (MERRF)
        • Mutation: m.4279A>G
        • Onset age: 4th decade
        • Muscle: Ragged red fibers
      • 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
      • Rhabdomyolysis
    
    
  • 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
    • Morbidity & Mortality: High
    • Onset age: 24 to 40 years; Mean 30 years
    • Other MTTL1 mutations
      • Barth-like syndrome: Dilated cardiomyopathy
      • MELAS
      • Left ventricular noncompaction
      • Conduction defects: Wolff-Parkinson-White or Other
    
    
  • 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 (CEMCOX1)
    l SCO2 ; Chromosome 22q13.33; 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
    
    
  • Encephalocardiomyopathy with cytochrome c oxidase deficiency: Fatal neonatal lactic acidosis ¹³⁰
    l c12orf62 ; Chromosome 12q13.12; Recessive
    • Epidemiology: Portuguese family
    • Mutation: Homozygous; Missense; Met19Ile
    • c12orf62 protein
      • Cell localization: Mitochondria, Integral membrane
      • Interacts with: EFTu, LRPPRC, SLIRP
      • Function: COX I assembly & Coupling with assembly of nascent subunits into COX holoenzyme complex
      • Mutation: Protein absent
    • Clinical
      • Prenatal: Oligoamnios; Septum-lucidum cysts
      • Dysmorphism: Hypotelorism, Microphthalmia, Ogival palate, Single palmar crease
      • Cardiomyopathy: Hypertrophic
      • Hepatomegaly
      • Renal: Hypoplasia
      • Adrenal: Hyperplasia
    • Laboratory
      • Lactic acidosis: Blood; CSF
      • Brain pathology
        • Hypertrophy, diffuse alteration
        • White-matter myelination: Diffuse pathology, and numerous
        • Cavities: Parieto-occipital, Brainstem, Cerebellum
      • COX
        • Activity: 30% to 40% of control fibroblasts
        • Fully assembled complex: Reduced
        • COX assembly defect: Reduced levels of COX I, II & IV
    
    
  • Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB)
        Trifunctional protein deficiency, type 2
    l Chromosome 2p23.3; Recessive
    • Cardiomyopathy
    • Myopathy
    • Liver dysfunction
    • Encephalopathy
    
    
  • Cardiomyopathy + Encephalomyopathy¹³
    l NADH-Ubiquinone oxidoreductase Fe-S Protein 2 (NDUFS2) ; Chromosome 1q23.3; Recessive
    • NDUFS2 Mutations: Missense; Homozygous
    • NDUFS2 protein: Complex I; Extramembranous near membrane domain; ? Role in protein transport
    • Onset
      • Age: Birth to 7 months
      • Hypotonia 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
      • Echocardiogram: Hypertrophic cardiomyopathy
      • Biochemistry: Selective Complex I deficiency
      • Riboflavin reverses adenosine triphosphate production deficit in fibroblasts
    
    
  • Mitochondrial phosphate carrier deficiency ⁶²
    l SLC25A3 ; Chromosome 12q23.1; Recessive
    • Epidemiology: 2 families
    • Genetics: Mutations
      • Missense Gly72Glu; Intronic c.158-9A>G
      • Located in, or near, Exon 3A with specific expression in heart and muscle
    • SLC25A3 protein
      • Mitochondrial solute carrier
      • Import of inorganic phosphate into mitochondrial matrix
      • Functions in ATP synthesis
      • Other causes of: TPP deficiency
    • Clinical
      • Onset: 1st day of life
      • Cardiomyopathy: Hypertrophic; Progressive
      • Respiratory failure
      • Hypotonia
      • Course
        • Death in 1st year: Some patients
        • Survival to adulthood: Exercise intolerance; Proximal weakness
    • 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
        • Mitochondrial phosphate carrier: Reduced
    
    
  • Hypertrophic cardiomyopathy, Fatal infantile or Leigh syndrome (CEMCOX2)
    l COX15 ; Chromosome 10q24.2; 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
      • Death: < 1 month
    • Laboratory
      • Lactic acidosis
      • Autopsy: Biventricular hypertrophic cardiomyopathy
    
    
  • Cardiomyopathy (Complex IV defects ) ¹²¹
    l Cytochrome c oxidase assembly factor 5 (COA5; C2orf64) ; Chromosome 2q11.2; Recessive
    • Epidemiology: Turkish family; 2 siblings
    • Genetics: Ala53Pro mutation; Homozygous
    • C2orf64 protein
      • Mitochondrial intermembrane
      • Twin Cx₉C motif protein
      • Early step of Complex IV assembly process
    • Clinical
      • Onset age: < 1 month or in utero
      • Cardiomyopathy: Hypertrophic restrictive
      • Brain: Normal
    • Muscle
      • Lipid droplets
      • Mitochondrial proliferation
      • Complex IV deficiency
    
    
  • Cardiomyopathy (Complex I & Complex IV defects) ¹²²
    l Alanyl-tRNA Synthetase 2 (AARS2) ; Chromosome 6p21.1; Recessive
    • Epidemiology: Finnish patients
    • Combined oxidative phosphorylation deficiency 8 (COXPD8)
    • Mutation: Leu155Arg; Arg592Trp
    • AARS2 protein
      • Location: Mitochondria
      • Amino acid tRNA synthetase
      • Mutation: Deficiency of respiratory complexes
    • Clinical
      • Onset: Infantile
      • Cardiomyopathy: Dilated & hypertrophic
      • Death: < 1 year
    • Laboratory
      • Muscle
        • COX- & SDH+ muscle fibers
        • Fiber size: Varied
        • Oxidative enzymes: Multiple defects
      • Serum CK: Normal
    
    
  • COXPD10: Cardiomyopathy, Hypertrophic & Lactic Acidosis (Complex I & Complex IV defects) ¹³⁷
    l Mitochondrial translation optimization 1 homolog (MTO1) ; Chromosome 6q13; Recessive
    • Epidemiology: 2 Italian children
    • Genetics
      • Mutations: Frameshift (Arg620Lysfs*8) & Missense (Ala428Thr)
    • MTO1 protein
      • Mitochondrial-tRNA modifier
      • Location: Tissues with high metabolic rate; Skeletal muscle, Liver, Heart
    • Clinical
      • Onset: Birth or Prenatal
      • Oligohydramnios
      • Hypotonia
      • Cardiomyopathy: Hypertrophic
      • Death: < 2 months
    • Laboratory
      • Hypoglycemia
      • Metabolic acidosis
      • Serum Lactate: High
      • Oxidative enzymes: Moderately reduced Complex I & IV activity
    • MTO1 variant syndrome: Encephalomyopathy, Recessive ¹³⁸
      
      • Epidemiology: 1 patient
      • Genetics
        • Mutations: Missense; Gly59Ala, Thr308Ala
      • Clinical
        • Onset
          • Age: 3 months
          • Seizure
        • CNS
          • Infantile spasms: Poor response to treatment
          • Delayed development: Motor & Cognitive
          • Tone: Distal increased; Axial hypotonia
          • Chorio-Athetoid movements
      • Laboratory
        • Muscle
          • COX negative muscle fibers
          • Complex IV deficiency
          • Lipid increased
        • Brain MRI: Normal
    
    
  • 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 in mitochondrial genes
        • See: NARP & MILS
    • Laboratory
      • Plasma lactate: High
      • 3-methyl-glutaconic aciduria
      • ATP synthase complex reduced on Western blot
    
    
  • Cardiomyopathy (Complex I & Complex IV defects) ¹⁵⁵
    l Mitochondrial ribosomal protein L44 (MRPL44) ; Chromosome 2q36.1; Recessive
    • Epidemiology: 1 Finnish family, 2 patients
    • Genetics: Homozygous missense mutation, L156R
    • MRPL44 protein
      • Structural subunit of mitochondrial large (39S) ribosomal subunit
      • Role in assembly & stability of subunit
      • Other mitochondrial ribosomal subunit disorders
        • Small subunit: MRPS16, MRPS22; Early death; Lactic acidosis, severe
        • Large subunit: MRPL3; Cardiomyopathy & Mental retardation
    • Clinical
      • Onset age: 3 top 6 months
      • Cardiomyopathy: Hypertrophic
      • Liver: Steatosis
      • Course: Variable
        • Infantile death: 1 patient
        • Stable in teens: 1 patient
    • Laboratory
      • Liver transaminases: High
      • Serum lactate: Normal or high
      • Muscle
        • COX staining: Normal or Mildly reduced
        • Assembled respiratory chain complexes in muscle: I & IV reduced
      • Fibroblasts: Complex IV deficient
    
    
  • PEO + Myopathy: MGME1
  
  
• Infantile onset cardiomyopathy: Mutations, other
  
  
  • Sengers syndrome: Cardiomyopathy, Hypertrophic & Cataracts (MTDPS10) ¹³¹
    l Acylglycerol Kinase (Multisubstrate lipid kinase) (AGK; MULK) ; Chromosome 7q34; Recessive
    
    • Epidemiology: 10 families
    • AGK mutations: Missense, Splicing or Stop
    • AGK protein
      • Mitochondrial
      • Phosphorylates diacylglycerol, ceramide & 1-acylglycerol
      • Assembly of ANT & Respiratory chain complexes
    • Clinical
      • Onset age: 1 week to 4 years
      • Hypotonia
      • Cardiomyopathy: Hypertrophic
      • Exercise intolerance
      • Mental development: Normal
      • Cataracts
      • Death
        • Age: Neonatal to 4th decade
        • Cardiomyopathy
    • Muscle: Skeletal & Cardiac
      • Lipid: Small droplets
      • Glycogen: Increased
      • AGK protein: May be absent
    • Biochemistry
      • Lactic acidosis
      • OXPHOS
        • Complex I, II, III, II+III & IV deficiency
        • Citrate synthase: High
        • Some patients normal
      • mtDNA levels: Reduced
      • Adenine nucleotide translocator 1 (ANT1): Levels in muscle reduced; No mutations
    
    
  • Encephalopathy
    l NDUFA11 ; Chromosome 19p13.3; Recessive
    
    
  • Leigh + Cardiomyopathy
    l NDUFA2 ; Chromosome 5q31.3; Recessive
    
    
  • COXPD5
    l MRPS22 ; Chromosome 3q23; Recessive
    
    
  • Encephalopathy with Hypertrophic Cardiomyopathy
    l NDUFV2 ; Chromosome 18p11.22; Recessive
    
    
  • Cardiomyopathy + Mental retardation (COXPD9)
    l Mitochondrial ribosomal protein, Large 3 (MRPL3) ; Chromosome 3q22.1; 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 4q35.1; Recessive
    • Epidemiology: Sporadic patient; Mennonite family
    • Genetics
      • Mutations
        • Missense (Ala123Asp) or Null (c.523delC)
      • U mtDNA haplogroup: Disease severity worse ¹⁵⁷
        • More rapid & severe cardiomyopathy than haplogroup H
        • Creatine kinase MB & Troponin I higher
      • Allelic with: Autosomal dominant PEO (PEOA2)
    • ANT1 protein (SLC25A4)
      • Mutations: Causes loss of function
    • Clinical
      • Onset
        • Age: Childhood
        • Fatigue
        • Muscle pain
      • Cardiomyopathy: Hypertrophic, symmetric & concentric
      • Myopathy
        • Mild
        • Exercise intolerance
        • No ophthalmoplegia
      • Headache episodes: Often with nausea & vomiting
      • Contractures: Ankle
    • Laboratory
      • Serum CK: Moderately high
      • Lactic acidosis
      • Hyperalaninemia
      • 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
      • Cardiac
        • Hypertrophy
        • Cardiomyocyte degeneration
        • Mitochondria: Overabundant & Structurally abnormal
        • Subendocardial interstitial fibrosis
        • Arteriolar smooth muscle: Hypertrophy
    • 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); Chromosome 15q15.1
  
  
• 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