Front, Search, Index, Links, Pathology, Molecules, Syndromes, Muscle, NMJ, Nerve, Spinal, Ataxia, Antibody & Biopsy, Patient Info

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   Pathology     Histology     Ultrastructure

Mitochondria: General³³

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

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

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

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

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

Mitochondrial DNA (mtDNA): General features

• Structure
  • Double-stranded, circular molecule: Except for D-loop which is triple stranded (Contains extra 7S DNA)
  • 16,569 nucleotide pairs
  • 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
• 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 link
• Inheritance of mtDNA
  • Maternal
    • Usual pattern
    • Sperm mtDNA is actively degraded
  • Paternal
    • Transmission of mtDNA in skeletal muscle (but not in other tissues) reported³⁴:
    ND2 mutation
• Transcription & translation of mtDNA
  • Promoters: Controlled by nucleus
    • 3 Promoters
    • H1: H-strand; Produces complete symmetric transcription of heavy strand of mtDNA
    • L: L-strand; Produces complete symmetric transcription of light strand of mtDNA
    • H2: Synthesis of 2 rRNAs; Acts with factor, mTERF
    • Promoters started by: Mitochondrial RNA polymerase + Specificity factor (mtTFA)
    • Promoter location: D-loop; Only non-coding region of mtDNA
      • 7% of mtDNA length
      • Contains cis elements involved in mtDNA replication & transcription
  • Transcripts: Large
    • Produced by H1- & L-strand
    • Subsequently cleaved into individual genes
• Mitochondrial DNA variation
  • Normal: Homoplasmy; All copies of mtDNA are identical within coding region
  • Heteroplasmy: Single cells contain different mtDNA populations
    • Occurs with some mtDNA mutations
    • Due to presence of multiple mitochondria in one cell, each containing several mtDNA copies
    • Produces tissue variation
    • Post-mitotic tissues
      • Usually contain highest levels of mutated mtDNA
      • Neurons; Skeletal & Cardiac muscle; Endocrine tissue
      • Mutations in mtDNA
        • % vs normal in mtDNA can vary widely among tissues in an individual
        • Mutational loads may change over time
        • Tissues are differentially sensitive to levels of mtDNA mutations: ? Related to oxidative energy requirements
    • Pathogenic heteroplasmic mutations: Severity of related symptoms
      • Increase with higher proportion of mutated mtDNA
      • Relation to severity not necessarily linear
  • Frequency of mtDNA-related disorders: 6 to 17 per 100,000 population
• Differences from nuclear DNA
  • No introns
  • Small intergenic spacing: Coding sequences of most genes are contiguous or separated by 1 or 2 bases
  • Codon sequences
    • Different start, stop & arginine, tryptophan, isoleucine
    • Some mitochondrial genes lack termination codon: Insertion of UAA at the transcriptional level instead
  • Replication of mtDNA
    • Rapid rate
    • Lacks proofreading
    • Mutation rate 10 to 100x > than nuclear DNA
  • Mitochondria lack an adequate DNA-repair mechanism
  • Mode of inheritance: mtDNA inherited maternally
• mtDNA Replication: Asynchronic & asymmetric mechanism
  • DNA synthesis
    • Starts in origin of replication of heavy strand (O_H)
    • Procedes unidirectionally: To origin of replication of light strand (O_L)
      • 2/3 of way around genome
      • Between cluster of 5 tRNA genes
    • When O_L is single stranded mtDNA synthesis starts in opposite direction
  • Other factors in mtDNA replication
    • Primer for H-strand replication: Small RNA synthesized from L-strand promoter
    • Transition between mtDNA replication & transcription: Produced by ribonucleoprotein, RNase MRP
    • Polymerase for mtDNA replication: DNA polymerase γ (pol γ)
    • Mitochondrial single-stranded binding protein (mtSSB)
  • All factors involved in maintenance, replication & expression of mtDNA: Nuclear encoded
• External links
  • Mitochondrial structure & function
  • Mitochondrial replication
  • 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 deficiency     ATPase deficiency   Carnitine-acylcarnitine translocase deficiency   Carnitine deficiency       Primary deficiency       Secondary deficiency   Carnitine palmitoyl transferase   Protein import defects   Solute carriers Substrate utilization   Pyruvate disorders   β-oxidation defects (Fatty acid)   Ketone synthesis     HMG-CoA lyase     HMG-CoA synthase Citric acid (TCA) cycle   Aconitase deficiency   Lipoamide dehydrogenase   Fumarase deficiency Lipid membrane defect: Barth Fusion & Fission Oxidation-Phosphorylation coupling   ATP Synthase   Luft's disease Respiratory chain   Composition     I. NADH-CoQ Reductase     II. Succinate-CoQ Reductase       Succinate dehydrogenase     III. CoQ-Cytochrome C Reductase     IV. Cytochrome oxidase     V. ATP Synthase   Coenzyme Q10   Combined defects Lactate mtDNA mutations   Intergenomic communication     Multiple mtDNA deletions     mtDNA depletion   mtRNA Nuclear gene defects   Tissue-specific   Generalized   mtDNA depletion

  TCA cycle

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

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

  Intense SDH staining of a muscle fiber with mitochondrial proliferation

• rRNA/tRNA
• Control regions
• Mitomap: General

Nuclear encoded mitochondrial proteins

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

General clinical features of mitochondrial disorders

• Onset
  • Infancy: Infantile with COX- Fibers; Encephalopathy; Leigh's
  • Childhood
    MELAS; MERRF; Leigh's; Myopathy & cardiomyopathy; Kearns-Sayre
  • Adult: CNS; PEO
• CNS
  • Ataxia
    • MELAS, MERRF; NARP; Deafness; Leukodystrophy; Leigh's; HAM; Friedreich ataxia
    • Other
  • Seizures: MELAS; MERRF; MILS; Myoclonic epilepsy
  • Movement disorders
    • Myoclonus: MERRF; HAM
    • Dystonia: MELAS; Leber's; Deafness-Dystonia
  • Spinal
    • SPG7
    • SPG13
    • SPG31
    • HHH syndrome
    • Spastic dystonia
    • Mitochondrial tRNA Ile
    • Leber's
    • Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL)
  • Migraine: MELAS; Myopathy
  • Cognitive disorders
    • Striatal necrosis: ATPase 6 (Leigh's) mutation
    • Retardation: Leigh's, Maternal (MILS)
    • Psychomotor regression: MELAS; Kearns-Sayre; Infantile encephalopathies
    • Dementia: MELAS; MERRF; Kearns-Sayre; PEO 3; Cytochrome b; ND3
    • Episodic encephalopathy: MELAS; MERRF; Myopathy; Infantile; Leigh's
  • Septo-optic dysplasia
• Myopathy
  • Weakness
  • Rhabdomyolysis: Recessive syndromes
  • Fatigue: Associated with high serum lactate at rest in PEO
• Polyneuropathy
  • Mitochondrial DNA: NARP; MNGIE; MERRF; Myopathy + Diabetes
  • Autosomal: HADHA; CMT 2A (MFN2); CMT 4A; Friedreich ataxia; SCO2 (Motor); POLG1; Sensory ataxic; Alpers-Huttenlocher
• Autonomic: MNGIE; Wolfram
• 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
• Neoplasms
  • Paraganglionoma: SDH subunits B, C, D
  • Leiomyomatosis: Fumarate hydratase
  • Renal cell cancer: Fumarate hydratase
  • B-cell lymphoma: BCL2 overexpression

Laboratory evaluation of mitochondrial disorders

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

NARP

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

MELAS

• Inheritance
  • Maternal
  • Occasional sporadic & non-inherited mutation (tRNA Leu)
  • Clinical heterogeneity
    • Rare to find more than 1 fully expressed MELAS in same family
    • Maternal relatives often oligo- or asymptomatic
  • Nuclear mutation (Rare): POLG1
• mtDNA point mutations
  • Heteroplasmic: Mutant mtDNA proportion ~ 56% to 95%
  • Genes
    • mtRNA Leu (MTTL1)
      • Common mutation
      • A3243G mutation: 80% of MELAS syndromes
      • Other MELAS mutation loci
        • T3271C
          • More common in Japan
          • Later age of onset
          • Associated with Distal arthrogryposis
        • 3291
      • Other syndromes with tRNA Leu (MTTL1) mutations
        • Riboflavin sensitive myopathy (T3250C)
        • Isolated cardiomyopathy (A3243G; A3260G)
        • Diabetes (A3243G; C3256T)
        • Sudden infant death (SIDS)
        • MERRF-like with diabetes, optic neuropathy & retinopathy (C3256T)
        • Fatigue
        • Rhabdomyolysis (A3243G)
    • mtRNA Leu 2 (MTTL2; CUN) : Also cardiomyopathy, PEO, sideroblastic anemia
    • Cytochrome c Oxidase (Subunit 3 of Complex IV) : COX reduced; Few SDH + fibers
    • mtRNA Val (G1642A) : Also Leigh syndrome
    • mtRNA Ser (MTTS1) : MERRF/MELAS overlap
    • mtRNA Phe (MTTF)
      • Mutation: G583A
      • Other tRNA Phe syndromes
        • Myoglobinuria
        • Mitochondrial myopathy, late onset (G622A)
        • MERRF (G611A)
    • tRNA Lys (T8316C) : MERRF with other mutations
    • tRNA His (T12417G)
    • tRNA Gln (A4332G) : Atypical MELAS syndrome with deafness
    • NADH-Dehydrogenase Subunit 1 (MTND1) : MELAS, LHON or overlap phenotype
    • MTND5 (Complex I): MELAS + Leigh syndromes
    • MTND6 (Complex I): LHON is most common phenotype; Occasional early onset MELAS or Leigh with Complex I deficiency
    • Cytochrome b (Complex III): Myopathy is most common phenotype; Occasional MELAS
  • Genetic counseling: A3423G mutation
    • % of affected offspring: Increased with higher mutant load in maternal blood
    • Mutant load 1% to 19%: 20% chance of affected offspring
    • Mutant load > 20%: 50% chance of affected offspring
    • Full expression of phenotype in multiple family members: Rare
    • Partial expression in multiple family members: Common
• Clinical Syndrome⁸⁰
  • Onset
    • Mean = 10 years; Range = 2 to 40
    • Migraine-like attacks: Headache & Vomiting
    • Hearing loss
    • Occasional seizures
  • Encephalopathy: Often episodic
    • Generalized
      • Headache & vomiting (90%)
      • Loss of consciousness (85%)
      • Seizures (85%): May be precipitated by Valproate
      • Dementia or mental retardation (50%-60%)
    • Focal events ("Strokes")
      • Onset
        • Typical: < 15 years
        • Usual: < 40 years
        • Range: Infancy to Late adulthood
      • Distribution: Do not conform to single vascular territories
      • Cortical visual defect
        • Often 1st focal manifestation
        • Occipital blindness or hemianopia
      • Hemiplegia
      • Associated with
        • Neuronal hyperexcitability: Focal epileptiform discharges in acute period
        • Basal ganglia calcifications
      • MRI
        • T1-weighted hyperintense cortical signal
        • Compatible with cortical laminar necrosis & cytotoxic edema
        • Distribution: Do not conform to single vascular territories
        • Reduced diffusion
  • Myopathy
    • Clinical features in 50% with A3243G mutation
      • High incidence by 5th decade
      • Cumulative by 70 years: 77%
    • Weakness
      • Proximal
      • Symmetric
      • Mild to Moderate
      • Face: Some patients
    • Exercise intolerance
      • Some patients with no weakness
    • Ocular
      • Ptosis
      • External ophthalmoplegia
    • No association with inactivity
  • Polyneuropathy⁶¹
    • Clinical
      • Gait: Imbalance
      • Sensory: Paresthesias & Numbness; Distal
      • Tendon reflexes: Reduced
      • Legs > Arms
      • More common with: Myopathy, Increased age, Male
      • Asymptomatic in 50%
      • Exacerbated by dichloroacetate
    • Laboratory
      • NCV: Axonal, sensory neuropathy
      • Fasting glucose: May be abnormal
  • Other CNS
    • Hearing loss (25%): Sensorineural
    • Headache, cluster
    • Extrapyramidal
      • Chorea
      • Parkinsonism
      • Basal ganglia calcification
    • Ataxia
  • Systemic features
    • Eye
      • Pigmentary retinopathy (10% to 40%): More common in symptomatic relatives
      • Macular dystrophy
      • Optic atrophy
      • Visual field defects
      • Hypertelorism
    • Cardiomyopathy (15%)
      • Hypertrophic: More progression in diabetics
      • Left ventricular noncompaction
    • Short stature
    • Diabetes
      • May occur as isolated syndrome: More frequent in Asians than Caucasians
      • Maternally inherited (MIDD)
    • GI
      • Pancreatitis
      • Gastric dysmotility: Constipation; Diarrhea; Intestinal pseudoobstruction (ileus)
      • Nausea, cyclic or episodic vomiting
      • Dysphagia
      • Abdominal pain, epigastralgia
      • Sialoadenitis
    • Renal failure
      • Focal, segmental glomerulosclerosis
      • Renal cysts
      • Tubular dysfunction
      • Nephrotic syndrome
    • Endocrine
      • Multihormonal hypopituitarism, short stature
      • Hashimoto thyroiditis, goiter
      • Hypoparathyroidism
      • Addison's disease
      • Ovarian failure, abortion, miscarriage
    • Skin
      • Lipoma
      • Atopic dermatitis, local melanoderma
      • Asymmetric vascular dilatation
  • Course
    • Mean life span with full clinical syndrome ~ 2 to 4 decades
    • Causes of death: Cardiopulmonary failure; Status epilepticus; Pulmonary disease
    • May deteriorate after general anesthesia
• Laboratory
  • Lactic acidosis: Blood & CSF (85%)
  • EMG: Normal or Myopathic
  • Serum CK: Normal to 2x high (32%)
    • More commonly high with associated: Lactic acidosis; Diabetes; CNS disorders
  • EEG: Slowing, diffuse or focal
  • MRI: Strokes
    • Multifocal, mainly cortical lesions
    • Lesions not confined to vascular territories
  • 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 : A8344G (Frequent); T8356C; G8363A; G8361A
    • Syndromes: MERRF or MERRF/MELAS overlap
    • More likely inheritance: High mutation frequency in mother
    • Other mitochondrial mtRNA Lys syndromes
      • Cardiomyopathy (G8363A)
      • PEO with myoclonus (G8342A)
      • Deafness & Diabetes (A8296G)
      • Multiple Symmetric Lipomatosis (A8344G)
      • Leigh syndrome (A8344G)
      • Parkinson syndrome, Neuropathy & Myopathy (A8344G)
      • MELAS
      • MNGIE (G8313A)
  • mtRNA Ser (MTTS1)
    • Syndromes: MERRF/MELAS overlap; Epilepsia Partialis Continua; HAM
    • 7472-insertion mutation in tRNA^{Ser (UCN)}: May have MERRF or Pure myopathy
  • mtRNA Ser (MTTS2) : MELAS/MERRF overlap syndrome
  • mtRNA Leu
  • mtRNA Phe
• Onset: Late adolescence - Early adult
• Clinical syndrome: Also see HAM syndrome
  • CNS
    • Myoclonus (60%)
      • Treatment: Levetiracetam 1500 mg
    • Epilepsy (45%)
    • Cerebellar dysfunction
      • Ataxia
      • Gait disorder
    • Dementia
    • Optic atrophy (20%)
  • Polyneuropathy (20%)
    • Distal sensory loss (large fiber modalities)
  • Hearing loss (40%)
  • Myopathy
    • Weakness: Proximal
    • Muscle pain: Resting or Exercise-related
    • Cramps
    • Fatigue
  • Short stature (10%)
  • Lipomata (10%)
• Genetic counseling: G8344A mutation
  • Mutant load < 35% in maternal blood: Transmission risk < 5%
  • Prognosis: Related to mutant load in blood
• Laboratory
  • Serum CK: Normal
  • Lactic acidosis: Variable
  • Pathology of muscle
    • Ragged red fibers: SDH +, COX -
    • Muscle may be morphologically normal
    • Oxidative enzymes: Complexes I, III & IV may have reduced activity

MNGIE¹⁰

• Thymidine phosphorylase genetics: MNGIE
  • Types
    • Missense mutations most common
    • Occasional insertions, deletions or splice acceptor change in intron
    • Location
      • > 12 Different mutations identified
      • More than 1 family with A3371C, G1419A
      • More in Exons 4 & 7
  • Loss of function of thymidine phosphorylase: Measured in leukocytes
    • MNGIE patients: All have absent, or nearly complete loss of, TP function
    • Carriers: ~ 35% of normal activity; Range 15% to 60%
• Thymidine phosphorylase protein (Endothelial cell growth factor, platelet derived (ECGF1))
  • Catalyzes phosphorolysis of thymidine to thymine & deoxyribose 1-phosphate
  • Plays role in homeostasis of cellular nucleotide pools
  • ? Has angiogenic effects
• Clinical features: Homogeneous
  • Onset
    • Age: Usually < 20 years (75%); Range 5 mo to 43 years
    • Signs: Gastric dysmotility (45%); Extraocular (26%)
  • Visceral neuropathy (100%)
    • Diarrhea
    • Obstipation
    • Episodic intestinal pseudo-obstruction & Gastroparesis
      • Nausea
      • Vomiting
      • Weight loss
      • Malabsorption
    • Borborygmi 96%
    • Early satiety
    • Diverticulae: In duodenum & jejunum
  • Ocular
    • External ophthalmoplegia (100%)
    • Ptosis (100%)
    • Retinal degeneration (6% to 25%)
  • Musculoskeletal
    • Thin body habitus & Cachexia: Weight loss (100%)
    • Short stature (70%)
  • Neuropathy (87%)
    • Sensory predominant: Distal loss; Pain
    • Weakness
      • Distal: Early
      • Proximal with disease progression
      • Symmetric
    • Areflexia (45%)
    • Axonal loss
    • Demyelinating features: Some patients³⁸
      • Conduction velocity: Reduced (<80% of lower limit of normal)
      • Conduction block & temporal dispersion in some patients
    • Course
      • Progression over months
      • Spontaneous fluctuations may occur
  • CNS
    • Hearing loss (60%)
    • Cognition: Normal intelligence; No dementia
    • Leukoencephalopathy (100%): Increased T2 signal on brain MRI
  • Disease course: Early death, Mean 38 years, Range 18 to 53 years
• Lab
  • Serum
    • Lactic acidosis (64%)
    • Plasma thymidine levels: Increased 20-fold
    • Plasma deoxyuridine levels: Increased
  • Abnormal EKG (18% to 35%)
  • CSF: High protein (89%)
  • EMG
    • Neurogenic only: 61%
    • Neurogenic + Myogenic: 39%
  • Muscle pathology
    • Mitochondrial changes in muscle fibers
      • Mitochondrial proliferation
      • COX - fibers (90%)
      • SDH + fibers (60%)
      • Oxidative enzyme levels: May be normal
      • Eye muscles: Myopathic changes
    • Neurogenic changes
  • mtDNA³⁵
    • Multiple deletions without duplications (62%)
      • Microdeletions occur at
        • Imperfectly homologous breakpoints (Similar but not identical mtDNA sequences)
        • Perfect direct sequence repeats
      • Five major species of mtDNA deletions
      • Hot-spot for mtDNA rearrangements
        • Nicotinamide adenine dinucleotide dehydrogenase 5 (ND5) gene
        • Occurs in 4 of 5 species of deletions
      • Deletions in tissue: Most prominent in skeletal muscle; Not present in intestine
    • Somatic point mutations: High frequency of 5’-ATT to 5’-GTT
    • mtDNA abnormalities may be produced by
      • Increased intracellular Thymidine & Deoxyuridine that may cause
      • Imbalances of mitochondrial nucleotide pools
      • Homologous recombination
    • mtDNA depletion: Variable
      • 6% to 20 % of normal total mtDNA, especially in liver
      • ? Secondary to mtDNA point mutations & multiple deletions
  • Biochemistry: Thymidine phosphorylase activity < 5% of normal in leukocytes
  
  
• MNGIE variant: 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
  
  

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
    • Penetrance
    • Dependence on a secondary mtDNA mutation for clinical expression
    • Tendency to recover from episodes of visual loss (4% to 40%)
    • Extraocular neural involvement
  • Mutations
    • General
      • 3 Mutations account for 96% of cases
        • All in Complex I genes
        • Mutations: ND4 (G11778A) (69%), ND1 (G3460A) (13%), ND6 (T14484C) (14%)
      • Mutation pattern
        • Most patient's mutations are homoplasmic
        • Some patients in each family may be heteroplasmic
    • NADH-Dehydrogenase Subunit 4 (MTND4) : Complex I
      • Mutation: G11778A
        • Missense: R340H
        • Most common LHON mutation
        • Mutation load in an individual's blood: Correlations
          • Higher mutation load: Frequency of blindness in males greater
          • Frequency of clinically affected sons: Related to mutant mtDNA in mother's blood
            • Mothers with < 80% less likely than Mothers with 100%
          • Changes in mutation load from one generation to the next
            • Largely determined by random genetic drift
        • Clinical features
          • Most severe syndrome
          • No light perception
          • Visual recovery in 4% after 36 months
          • Other occasional CNS
            • Ataxia syndrome: Adult-onset
            • Paraparesis: Spastic
    • NADH-Dehydrogenase Subunit 1 (MTND1) : Complex I
      • Mutation: G3460A
        • Missense: A52T
        • Moderate severity
        • Recovery in 22%
      • Mutation: G3376A
        • Clinical: LHON; MELAS; LHON/MELAS overlap
      • Other mutations
        • G3733A; C4171A⁵⁰
        • Familial Non-Arteritic Anterior Ischemic Optic Neuropathy (NA-AION): G4132A, Ala276Thr
        • MELAS
        • Exercise intolerance
        • SIDS
    • NADH-Dehydrogenase Subunit 6 (MTND6) : Complex I
      • Mutation: T14484C
        • Missense: M64V
        • Best prognosis
        • Recovery in 37% at 16 months
        • Common in French-Canadians: Introduced in 17th century introduction by female founder⁴⁸
      • 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 mutations
      • NADH dehydrogenase (Subunits 1 , 2 , 4 , 5 , or 6 ); Complex I
      • Cytochrome c Oxidase (Subunits 1 or 3 ); Complex IV
      • Cytochrome b; Complex III
      • ATP Synthase; 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
    • 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 :
      • NADH-Dehydrogenase Subunit 6 (MTND6, Complex I)
      • NADH-Dehydrogenase Subunit 1 (MTND1, Complex I)
      • NADH-Dehydrogenase Subunit 4 (MTND1, 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

Kearns-Sayre Syndrome

• Family history
  • Sporadic: Most patients
  • Familial cases: Rare; Mother to offspring³⁷
• Genetics
  • mtDNA mutation types
    • Single large mtDNA deletion (2 to 8 kb)
      • Most common mutation type (80%)
      • Identical deletions in Pearson syndrome & PEO
      • Common deletions
        • Most common: 4977 base pairs from 8488 to 13460; 13 base pair repeat at mutation break point
        • Thai patients: 3558 bp deletion; 10204 to 13761, or 10208 to 13765
      • Most deletions preserve
        • Promoters of transcription of heavy & light strands
        • 12S & 16S ribosomal RNA genes
        • Origin of heavy strand replication
      • Change in number of deletions over time
        • Increased in muscle
        • Reduced in rapidly turning over cells (hematopoetic)
    • Large scale tandem duplication
    • Also patients with NARP/T8993G mutation
  • Heteroplasmic distribution of mutations
• Clinical features
  • General
    • Characteristic signs: PEO; Pigmentary degeneration of retina; Heart block; Mitochondrial myopathy
    • Partial expression of signs common
  • Onset: < 20 years; Later onset patients may have only PEO
  • Ocular
    • External Ophthalmoplegia
      • Progressive
      • Limitation, or absence, of movement in all fields of gaze
    • Ptosis
    • Retinal Pigmentary Degeneration (Retinitis pigmentosa): Peripheral retina > Central
  • Dysphagia: 50% of adults symptomatic
    • Regurgitation of liquids
    • Problems with solids also
    • Weight loss
    • Most commonly associated with cricopharyngeal achalasia¹⁷
    • Treatment: ? Cricopharyngeal myotomy
  • Myopathy
    • Weakness (90%): Proximal > Distal; Symmetric
    • Occasional fatigue or pain on exertion
    • Course: Slowly progressive
  • Polyneuropathy (10%): Sensory-Motor
  • CNS
    • Respiratory drive: Reduced
    • Hearing loss (95%)
    • Ataxia (90%)
    • Dementia, or impaired intellect (85%)
    • Upper motor neuron: Spasticity; Increased Tendon reflexes
    • Stroke (8%)
  • Systemic features
    • Cardiac: Conduction Block; Sudden death
    • Endocrinopathies: Glucose Intolerance (15%); Hypothyroidism; Hypoparathyroidism (6%)
    • Skeletal: Short stature
  • Laboratory
    • Muscle pathology
      • Ragged red fibers (98%): COX + and COX -
      • Variation in muscle fiber size
    • Lactic acidosis (80%)
    • Head CT: Basal ganglia calcifications (5%)
    • CSF Protein: High
  • Prognosis: Death common in 3rd or 4th decade
• Related disorders
  • Pearson's Syndrome
    • Sideroblastic anemia: Pancytopenic crises
    • Pancreatic insufficiency: Insulin-dependent diabetes; Malabsorption
    • Infancy: Low birth weight; Death; Metabolic & lactic acidosis
    • May precede development of Kearns-Sayre syndrome if survival past infancy
  • 2-Oxoadipic aciduria & 2-Aminoadipic aciduria
    • Onset: 2 years
    • Organic acidemia
      • Episodes of ketosis & acidosis
      • Progressive to coma
      • Resolution of clinical & metabolic features
      • Kearns-Sayre syndrome may develop later in childhood

PEO + (Progressive External Ophthalmoplegia)

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

Maternal   Mitochondrial DNA changes       mtDNA point mutations       May be sporadic   tRNALeu(UUR)     MELAS     PEO   tRNALeu(CUN)   tRNAAsn   tRNAGln: PEO-plus   tRNAAla: PEO-plus   tRNATyr: PEO-plus   tRNALys: PEO-plus   tRNAIle

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

• Syndromes with severe ophthalmoplegia
  • Kearns-Sayre: Single large mtDNA deletion
  • PEO + Proximal myopathy
  • PEO
• Chronic PEO with few systemic features
  • Mutation
    • Single large mtDNA deletion
    • Heteroplasmic
    • Location: Less commonly in blood than with multisystem syndromes
  • Clinical
    • Onset age: > 20 years
    • Ophthalmoplegia
    • Systemic: Heart block in some patients
• PEO + Sensory ataxic neuropathy⁸
  • Also see: Sensory neuropathy, Recessive with POLG mutations
  • Onset
    • Age: 10 to 31 years
    • Gait unsteadiness
  • Clinical features
    • Polyneuropathy
      • Sensory loss: Joint position; Vibration; Mildly reduced pain & temperature
      • Gait disorder: Sensory ataxia; Romberg +
      • Motor: Normal in most; Late distal weakness
      • Tendon reflexes: Absent
    • Cranial nerve disorders
      • External ophthalmoplegia: Onset after neuropathy
      • Ptosis
      • Dysarthria
      • Facial weakness: Mild
    • Myopathy: Mild proximal weakness
    • Cerebellar: Normal
    • Progression: Slow over decades
  • Laboratory
    • Electrophysiology
      • Sensory NCV: Axonal loss (Reduced or absent SNAP amplitude, Legs > Arms
      • Motor NCV: Normal, or Low CMAP amplitude in legs
      • EMG: Distal denervation; Proximal normal or myopathy
    • Serum CK: Mildly elevated
    • Serum lactate: Normal or Mildly elevated
    • Muscle biopsy
      • Myopathic changes: Mild
      • Ragged red muscle fibers 50%
    • Nerve biopsy: Loss of large & Small axons
    • Mitochondrial DNA: Multiple deletions
  
  
• tRNA^Gln : PEO
  • Genetic
    • Case reported is sporadic
    • Mutation
      • 1 base-pair insertion, 4366A
      • Heteroplasmic
      • Most in skeletal muscle; Some in fibroblasts
  • Clinical
    • Onset: 5 years; Weakness; Ptosis
    • Cranial nerves
      • Facial weakness
      • Dysphonia; Dysphagia
      • Ptosis: Bilateral; Symmetric; Severe
      • Ophthalomoplegia
    • Weakness: Mild; Extremity
    • Tendon reflexes: Reduced
    • No signs of cardiac, cerebellar, or retinal disorders
  • Laboratory
    • NCV: Normal
    • EMG: Myopathic
    • Muscle pathology
      • Ragged red fibers
      • Many COX- muscle fibers (89%)
      • Impairment in mitochondrial protein synthesis
      • Mutated DNA: Skeletal muscle (87%); EOM (61%)
  
  
• tRNA^{Ala 16}: PEO
  • Genetics: T5628C mutation
  • Onset
    • 6th decade
    • Ptosis
  • Clinical
    • Family history: Negative
    • Eye movements: Decreased in horizontal direction
    • Weakness: Proximal; Symmetric; Mild
    • Dysphagia
  • Laboratory
    • Muscle
      • Many COX negative muscle fibers ± Mitochondrial proliferation
      • Biochemistry: Partial defect of Complex I
    • EMG: Myopathic
    • Serum CK: Normal
  
  
• tRNA^Leu(UUR) : PEO
  • Genetics: T3273C mutation
    • One of 13 reported mutations in tRNA^Leu(UUR) gene
    • Other tRNA^Leu(UUR) mutations causing PEO+: A3243G; A3251G; C3256T
    • Other tRNA^Leu(UUR) mutations in anticodon stem
      • A3260G: Myopathy & Cardiomyopathy; MELAS
      • T3271C: MELAS
  • 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
  
  
• tRNA^{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

• 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   POLG: 15q25   POLG2: 17q   Hypogonadism

• Mitochondrial DNA breakage syndromes: Autosomal dominant PEO
  • PEOA3 (PEO 1)
    l Twinkle (C10ORF2) ; Chromosome 10q23.3-q24.3; Dominant
    • Genetics
      • Gene mutations
        • Missense most common: Homozygotes (Ala359Thr) more severe than heterozygotes
        • Severe CNS phenotype with polyneuropathy: 39 bp duplication
        • Location: Cluster in region of protein involved in subunit interactions
        • 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
      • Allelic with: IOSCA
    • 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
      • 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
      • 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
    • Epidemiology: Multiple families with different ethnic origins
    • Clinical features
      • Onset: Average = early 20's to early 30's; Variable within families
      • Eye (100%): Bilateral ptosis; PEO
      • Myopathy
        • Weakness: Proximal
        • Cramps
        • Respiratory failure: Occasional
      • Occasional psychiatric disorders: Depression; Avoidant personality traits
      • Cataracts
      • Occasional
        • Bulbar weakness
        • Muscle pain
        • Ataxia
        • Polyneuropathy
        • Parkinsonism
    • Laboratory
      • Muscle Pathology: Ragged red fibers; COX- fibers
      • Mutant mtDNA: Brain > Muscle & Heart
      • Ketoacidosis: Occasional
    • Variant syndrome: SANDO with Ataxic sensory neuropathy⁵²
      • C10ORF2 mutation
      • Dominant
      • 2 siblings with missense Lys319Glu mutation
      • Also see: SANDO with POLG mutations
    • Variant syndrome: PEO + Parkinsonism⁷³
      • Mutation: R374Q
      • Some families with same mutation do not have Parkinsonism
    • Variant syndrome: Encephalopathy with mtDNA depletion⁷⁴
      • Epidemiology: 2 siblings
      • Genetics
        • Recessive
        • Compound heterozygous mutations: A318T & Y508C
      • Onset age: 5 to 6 months
      • Clinical
        • Hypotonia
        • Athetosis
        • Neuropathy: Sensory
        • Ataxia
        • Hearing deficit
        • Ophthalmoplegia,
        • Epilepsy: Intractable
      • Laboratory
        • Serum transaminases: High
        • mtDNA depletion: Liver & Brain > Muscle
        • Sural nerve: Reduced numbers of large myelinated axons
        • Spinal cord: Loss of axons in posterior columns
    
    
  • PEOA2 (PEO 2/PEO 3)
    l Adenine nucleotide translocator 1; (ANT1; SLC25A4) ; Chromosome 4q35; Dominant
    • Genetics mutations
      • Mutation type: Missense
      • Familial patients: Ala114Pro; Leu98Pro
      • Sporadic patient: Val289Met
      • Mutation effects
        • Structural: Alter α-helix of protein
        • Alters oxidative metabolism
        • mtDNA mutations
      • Other disease associations
        • Allelic with: Cardiomyopathy + Myopathy, Recessive
        • FSH dystrophy
          • Gene location: Near FSH locus on 4q35
          • Over-expression of ANT1 in FSH dystrophy muscle
    • SLC25A4 protein
      • Class: Mitochondrial solute carrier
      • Adenine nucleotide translocator (ANT1)
      • Most abundant protein in inner mitochondrial membrane
    • Epidemiology: Italian & Greek families
    • Onset: 20 to 35 years
    • Clinical
      • Ocular: Ophthalmoplegia & Ptosis
      • Severity: Milder than 10q linked PEO
      • Weakness: Variable
        • Some patients: No fatigue or generalized muscle weakness
        • Occasional: Dysphagia, Dysphonia, Face, Proximal & Respiratory
      • Cataracts: After 40 years
      • Other changes in some patients
        • Sensorineural hypoacusia
        • Goiter
        • Dementia
        • Bipolar affective disorder²⁸
    • Laboratory
      • Serum: High lactic acid
      • Muscle mtDNA: Multiple deletions
      • Respiratory-chain enzymes with mtDNA-encoded subunits: Mild deficiency of some
    
    
  • PEOA1 (PEO²⁵)
    l Polymerase, DNA, Gamma (POLG; POLG1) ; Chromosome 15q25; Dominant or Recessive
    • Genetics
      • Dominant mutations
        • Tyr955Cys: Most common mutation
        • Other: G923D; R943H; Arg953Cys; A957S; Asn468Asp; Ala1105Thr; S1176L; G268A; R1146C
        • Some dominant mutations (G923D; A957S) may have
          • Low penetrance
          • Severe phenotype & more mtDNA mutations if homozygous
      • Recessive mutations (PEOB1 ): Usually missense
        • Homozygous: Ala467Thr; Leu304Arg; Arg3Pro; G848S
        • Compound heterozygotes: T251I & R309L; P587L & R853W; T251I+P587L & M603L; D1184N & N468D
      • Other mutations
        • Absence of ten-repeat polyglutamine tract encoded by CAG repeat: Associated with male infertility
      • External link: Mutation database
    • POLG protein
      • Catalytic subunit of mitochondrial DNA polymerase
      • Function
        • Required for mitochondrial DNA replication and repair
        • C-terminal domain: DNA polymerase responsible for mtDNA replication
        • N-terminal exonuclease (exo) domain: Increases the fidelity of mtDNA replication
      • Location: Diffusely in mitochondria
      • Accessory subunit of DNA polymerase: POLG2
    • Epidemiology
      • Common (45%) cause of familial PEO with multiple mitochondrial DNA deletions
    • Clinical features: PEO syndrome
      • Onset: 16 to 39 years
      • Ophthalmoplegia, Progressive external
      • Muscle
        • Weakness: Proximal
        • Exercise intolerance
      • Neuropathy
        • Sensory loss: Vibration
        • Tendon reflexes: Often absent
      • Endocrine
        • Poorly formed 2° sex characteristics: Breasts; Pubic hair
        • Early menopause: < 35 years
        • Testicular atrophy
      • Parkinsonism⁴⁵
        • Increased association with POLG pol-domain mutations
        • Onset: After PEO
        • Oset: 4th to 8th decade
        • PET scan: Dopaminergic neuron loss
        • Levodopa responsive
      • Severe disease
        • Proximal weakness & wasting: May be severe
        • Cranial nerves: Dysphagia; Dysphonia; Facial diplegia
        • Abnormal gait: Due to spinal ataxia or distal weakness
        • Depression,
        • Extrapyramidal syndrome: Also seen in recessive syndrome
    • Pathology
      • Muscle
        • Ragged red fibers
        • COX- & SDH + fibers: Numerous
        • Multiple mtDNA deletions
      • Normal mtDNA copy number in affected tissues
    • Laboratory
      • Serum CK: Mildly high
      • Serum Lactate: Mildly elevated
      • EMG
        • Denervation: Distal
        • Myopathy: Proximal
    • Variant syndrome: Sporadic mitochondrial myopathy syndromes with multiple mtDNA deletions
      • Onset: 20 to 62 years
      • PEO: All patients
      • Myopathy: Most patients
      • Dysphagia: 2 patients
      • Neuropathy: Sensory-Motor; 1 patient
      • MNGIE-like syndrome
    • Variant syndrome: SANDO (Hereditary sensory neuropathy)
      • Sensory Ataxic Neuropathy, Dysarthria & Ophthalmoparesis
      • Recessive inheritance
      • POLG1 mutations in exo-domain: Lys319Glu⁴⁷; W748S; A467T
      • Ataxic sensory neuropathy
      • No Parkinsonism
    • Variant syndrome: Sensory neuropathy, PEO & Tremor
      • Dominant inheritance
    • Variant syndrome: PEO + Severe axonal and demyelinating sensory–motor neuropathy⁵⁸
      • Genetics
        • Mutation: Homozygous G763R
        • Inheritance: Recessive
      • Clinical
        • Onset: 2nd decade
        • Weakness: Distal > Proximal; Face
        • Sensory loss: Distal legs; Panmodal
        • Tendon reflexes: Absent
        • PEO + Ptosis
        • Bulbar: Dysphonia; Dysphagia
      • Laboratory
        • NCV: Axonal loss
        • Nerve pathology: Axonal loss; Thin myelin sheaths
        • Muscle: Ragged red fibers; COX- fibers
        • Mitochondrial (Muscle): Complexes I, III & IV partially reduced
    • Variant syndrome: MIRAS⁵¹
      • Mitochondrial recessive ataxia syndrome
      • Epidemiology: Common in Finland (Carrier frequency 1:125) & Europeans
      • POLG1 mutations
        • W748S + E1143G in cis
        • Homozygous W748S or A467T
        • Similar seen in MSCAE
      • Recessive inheritance: Many sporadic cases
      • Onset
        • Age: Range 5 to 38 years
        • Balance disorder
        • Epilepsy
      • Clinical: Hetergeneous
        • Ataxia: Gait & Limb; Dysarthria; Nystagmus (60%)
        • Polyneuropathy
          • Tendon reflexes in legs: Reduced or Absent
          • Vibration sense: Reduced
          • Pain: Some patients
          • Electrodiagnostic changes (100%): Sensory neuropathy; Axonal loss
        • Muscle: Strength reduced (30%); Cramps (25%)
        • Epilepsy (50%)
        • Cognitive impairmnent (80%): Mental retardation; Psychiatric
        • Involuntary movements: Athetosis; Tremor
        • Obesity (70%)
        • Eye movement disorders: Mainly CNS; No PEO
      • Laboratory
        • MRI: Cerebellar atrophy & white matter changes
        • Muscle: Denervation; Mitochondrial changes rare
        • EEG: Abnormal background
      • Carriers
        • No prominent clinical phenotype
        • Subclinical: Sensory polyneuropathy in majority
    • Variant syndrome: SCA + Epilepsy (MSCAE)⁷⁷
      • POLG1 genetics
        • Recessive
        • Homozygous: A467T; Gln497His; W748S
        • Similar seen in MIRAS
      • Onset: 2nd & 3rd decade
      • Clinical
        • Migraine
        • Myoclonus or Myoclonic seizures
        • Seizures
          • Often presenting symptom
          • Occipital lobe: Scotomas; Flickering; Visual loss; Visual hallucinations; Nystagmus
          • Simple partial: Motor; Involves arm or head
          • Complex partial
          • Secondary generalized epilepsy & Status epilepticus
          • Treatment
            • Sodium channel blocker + Benzodizepine
            • NOT Valproate
            • Lamotrigine & Gabapentin: May increase myoclonus
        • Ataxia
      • Laboratory
        • EEG: Occipital seizure activity
        • MRI T2 high signal: Thalamus; Occipital cortex; Cerebellum
    • Variant syndrome: Alpers
      • Genetics
        • Recessive
        • Mutations
          • Glu873Ter & A467T
          • Similar seen in MIRAS & MSCAE
      • POLG protein: Very low residual POLG activity
      • Clinical
        • Progressive neurological disorder
        • Liver failure
      • Laboratory
        • mtDNA depletion in some patients
    • Variant syndrome: Parkinsonism without External ophthalmoplegia⁵⁷
      • Epidemiology: 2 Sisters
      • Genetics
        • Recessive
        • Mutations: Heterozygous; G737R & R853W
      • Onset
        • Age: 3rd decade
        • Extrapyramidal: Parkinsonism or Dystonia
      • Clinical
        • Parkinsonism
        • Weakness (50%): Distal, Mild
        • EOM: Full
      • Laboratory
        • Serum Lactate: High in one patient
        • Serum CK: Normal
        • Muscle
          • COX- muscle fibers
          • Oxidative metabolism: Reduced (50%) enzymes with mitochondrial subunits
        • Nerve conduction studies: Polyneuropathy
          • Axonal
          • Sensory > Motor
        • MRI: Moderate generalized cerebral & cerebellar atrophy