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MITOCHONDRIAL DISORDERS

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
  Antibodies
Biochemical Pathways
  Fatty acid oxidation
  Oxidative phosphorylation

Mitochondria
  Complexes
    Disorders
  General features
  Mitochondrial DNA (mtDNA)
    Encoded proteins
    General Features
    Mutations
  Nuclear encoded proteins
    General Features
    Mutations
TCA cycle Beta-Oxidation Fatty acyl-CoA & Carnitine transport ATP ANT Glycolysis General mitochondrial functions Acetyl-CoA Pyruvate via PDHC to Acetyl-CoA Oxidative Phosphorylation


Mitochondria: General 33

Axon transport
Biogenesis
  Fission & Fusion
DNA
Functions
Origin
Proteins
Structure

Mitochondrial Origins Structural features of mitochondria: 4 Compartments Mitochondria-Related Genes
Mitochondrial DNA (mtDNA)

Mitochondrial disorders: Organs involved
Mitochondrial proteins 133

General
Biogenesis
Intermembrane space (IMS)
Matrix
Membrane
  Inner
  Outer
  Solute carriers
Mitoribosome
Submitochondrial
Other
  mtRNA-related
Mitochondrial Biogenesis: Skeletal muscle Mitochondria: Axon transport

Functions of mitochondria

Mitochondrial DNA (mtDNA): General features

Differences from Nuclear DNA
Inheritance
mtDNA variation
Mutations & Disorders
Pathogenic mechanisms
Replication
Structure
Transcription & Translation

Modified from: www.mitomap.org

Mitochondrial disorders: General pathogenic mechanisms 7


Mitochondrial Disorders: mtDNA-related mutations

General
Point mutations
  mtRNA
mtDNA Deletions
  Multiple
    IBM
    MNGIE
  Single, Large
Quantitiative changes
Specific disorders
2° to Nuclear mutations

External links: Mitochondrial DNA mutations

Nuclear encoded mitochondrial proteins


General clinical features of mitochondrial disorders


Laboratory evaluation of mitochondrial disorders

Imaging
Molecular genetics
Muscle biopsy
Serum
Urine


MITOCHONDRIAL DISORDERS: CLINICAL SYNDROMES
Adult onset
Alexander disease: GFAP; NDUFV1
Alpers
ALS-FTD: CHCHD10
Alzheimer/Parkinsonism
Amino Acid disorders: Nuclear mutations
Anemia
Ataxias
Barth: Tafazzins; Xp28
Cardiomyopathy
Carnitine disorders
Cartilage-Hair hypoplasia: RMRP; 9p21
CNS
  Infantile & Childhood onset
  Syndromes
Congenital MD: CHKB; 2q13
Cramps
Deafness
  Maternal (mtDNA): Point mutations
    Amino-glycoside induced: 12s rRNA
    Syndromic (HAM; MELAS; MERRF): tRNA
    Non-syndromic: 12s rRNA
  Nuclear mutations
    DIDMOAD: WFS1; 4p16
    Deafness-Dystonia: DDP protein; Xq22
Diabetes
Encephalopathies
Extrapyramidal
  Dystonia
  Huntington's chorea
  Parkinson's
Eye
  Blindness
    Gyrate atrophy
    Optic atrophy
      LHON (Leber): mtDNA, MTND
    Visual loss: SFXN4
  Ophthalmoplegia, External (PEO)
    Dominant: Multiple mtDNA deletions
    Maternal: mtDNA point mutations
    Recessive: mtDNA deplete; Mpl mtDNA del  
    Sporadic: Single mtDNA deletion
    ? Immune (HyperThyroid)
Fatigue & Exercise intolerance
Friedreich ataxia: Frataxin; 9q13
Functional defects
Gastrointestinal
HAM: mtDNA tRNA Ser
Hepatic
Hypoglycemia
Infantile CNS: mtDNA & Nuclear mutations
Inflammatory myopathies
  IM-VAMP
  Mitochondrial antibodies
Kearns-Sayre: Single mtDNA deletion
Leigh: mtDNA & Nuclear mutations
Leukodystrophy
Lipomatosis: mtRNA Lys & Nuclear
Longevity
Maple syrup urine disease
MEGDEL: SERAC1; 6q25
MELAS: mtRNA Leu + other
Menkes: ATPase 7a; Xq21
MERRF: mtRNA Lys & Ser
MILS
MLASA
  1: PUS1; 12q24
  2: YARS2; 12p11
  3: MTATP6; Mitochondrial DNA
MNGIE: Thymidine phosphorylase; 22q13
Myalgias
Myasthenia
Myoglobinuria
Myopathy syndromes
  Infantile myopathies
    Fatal: mtDNA depletion
    "Later-onset": mtDNA depletion
  Inflammatory myopathy
    Inclusion body myositis: Mpl mtDNA delete
    mtDNA depletion: "Later-onset"
    PM + COX- muscle fibers: Mpl mtDNA delete
  LGMD 1H
NARP/MILS: mtATP6
Neoplasms
Neuropathy
  Motor ± Episodic weakness: mtATP6 or 8
Occipital horn syndrome: ATPase 7a; Xq21
Pancreas
Paraganglioma
Pearson's: mtDNA deletion
Perrault
Rhabdomyolysis: mtDNA
SANDO
Selenium deficiency
Skeletal & Hair
Spastic paraparesis
Spinal muscular atrophy
Stuve-Wiedemann syndrome: 1p34
Sudden infant death
  MTTL1; MTND1; HADHB
Systemic disorders
Toxic
  Arsenic trioxide
  AZT (Zidovudine)
  Copper
  Germanium
  Trichloroethylene
  Valproate: Precipitates
    Liver failure in Alpers
    Seizures in MELAS
Wilson's disease: ATPase 7B; 13q14
Zellweger
  PEX12
  PEX16
Classifications of Mitochondrial Disorders
  Biochemical
  Clinical
  Genetic: mtDNA; Nuclear

Neuropathy; Ataxia; Retinitis Pigmentosa (NARP)

  ATP synthase 6 (MTATP6) (Complex V); Mitochondrial

MELAS

Clinical
Genetics
Laboratory
  • Nosology: Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke)
  • Epidemiology
    • Incidence 1:4,000
  • Genetics
    • General
      • Common causes: mtDNA point mutations in mtRNA genes
      • Heteroplasmic mutations: Mutant mtDNA proportion ~ 56% to 95%
    • 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
    • Pathogenesis: mtDNA mutation leads to disordered mtDNA synthesis & function
    • Genes
    • Genetic counseling: A3423G mutation
      • % of affected offspring higher: Higher mutant % 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 Syndrome 80
    • Possible trigger: Metformin 312
    • 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
        • Cognitive: Dementia or Mental retardation (50%-60%)
      • Focal events ("Strokes")
        • Onset
          • Typical: < 15 years
          • Usual: < 40 years
          • Range: Infancy to Late adulthood
        • Distribution in brain: Do not conform to single vascular territories
        • Cortical visual defect
          • Often 1st focal manifestation
          • Distribution: 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
        • Respiratory dysfunction: Early, episodic in some 264
      • 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
      • Headache, cluster
      • Extrapyramidal
        • Chorea
        • Parkinsonism
        • Basal ganglia calcification
      • Ataxia
    • Systemic features
      • Hearing loss (25% to 60%)
        • Sensorineural
        • May be subclinical
        • Cochlear > Retrocochlear
      • 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
          • Isolated syndrome: Asians > Caucasians
          • With Deafness
        • 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: More with MERRF
        • 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
      • General anesthesia: May deteriorate
    • Possible treatments 44
      • Dichloroacetate
      • L-arginine (0.5 g/kg): For acute stroke-like episodes
      • Citrulline (10 g/m2 over 2 days): May reduce lactate levels
      • Stroke Treatment: Taurine 241
        • Dose: 9 to 12 grams/day
        • Effect: Reduction in frequency of stroke-like episodes (2.2 to 0.72 per year)
        • Postulated mechanism
          • Restores taurine modification Δ in mutant mitochondrial tRNALeu(UUR)
  • 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: Reduced diffusion coefficient
      • White matter lesions: Some patients
        • Diffuse
        • Often in 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%)
    • Pathology (A3243G mutation) 6
      • Muscle: Abnormal in 72%
        • Ragged red fibers (RRF)
          • COX + & SDH + fibers: More than in most mitochondrial myopathies
          • COX - fibers: More common 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
2 common mtDNA mutations 278
mtRNALeu[UUR]
A3243G
mtRNALys
A8344G
Clinical Features: Comparative
Hearing Δ 50% - 85% 30% - 70%
Stroke-like
  Episodes
5% - 45% 5%
Cognitive Δ 13% - 35% 8%
Diabetes/
  Glucose Δ
38% - 53% 8%
Ataxia 12% - 42% 18% - 68%
Psychiatric 10% - 40% 5% - 50%
Seizures 12% - 40% 30% - 60%
Migraine 20% - 33% 6% - 53%
PEO 15% - 33% 12% - 27%
Respiratory Δ 7% - 28% 4% - 43%
Gastrointestinal 20% - 78% 37%
Cardiac Δ 10% - 35% 15% - 18%
Myopathy/
  Fatigue
7% - 42% 38% - 58%
Myoclonus 7% 20% - 57%
Lipomas 0% 17% - 28%
mtDNA: Disease Features
Heteroplasmy Yes: ↑ % Related to ↑ Disease severity
Varied % among tissues
Blood: ↑ Age → ↓ %
Muscle: All ages Same %
Same %
  All tissues
Mutation
  Effects
Protein Synthesis & Stability
Impaired recognition of
  UUA & UUG codons
Full length proteins
  Unstable
Truncated &
  Full proteins
    Unstable
Modifier Δ
mt-tRNALeu taurine
2-methylthiolation (ms2)
mt-tRNALys
  Wobble base
Mitoribosome
Stress response (ISRmt) ↑ →
  ↑ Serum FGF21 & GDF15

MERRF 66

(Myoclonic Epilepsy; Ragged Red Fibers)

MNGIE (MTDPS1) 10

(Myopathy and external ophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy)
  Thymidine phosphorylase (TP; TYMP; Endothelial cell growth factor 1 (ECGF1)) ; Chromosome 22q13.33; Recessive

Clinical
Genetics
Laboratory
  mtDNA
TP protein
Variants
  Late onset
MNGIE syndromes: Other
  LIG3
  MTDPS4B: POLG
  No encephalopathy
  mtRNA Trp
  mtRNA Val
  PEO + Myopathy: MGME1


Leber's Hereditary Optic Neuropathy (LHON) 30

Epidemiology
Genetics
  Mitochondrial
    MTND1
    MTND4
    MTND6
  Recessive (LHONAR)
    1: DNAJC30
    2: NDUFS2
  Other
Clinical
Laboratory

Optic neuropathy
  Other
  Also see: LHON, Recessive

Single, Large-Scale Mitochondrial DNA Deletions (SLSMD) 302, 314

SLSMD: General Features
Clinical Syndromes
  Kearns-Sayre (KSS)
  Pearson's Marrow Syndrome
  Progressive External Ophthalmoplegia (PEO)

Kearns-Sayre Syndrome "Spectrum" (KSS)

PEO + (Progressive External Ophthalmoplegia)

PEO: General features
Dominant PEO
  Mitochondrial DNA Δ
    Multiple mtDNA deletions
  Nuclear DNA mutations (PEOA)
    POLG (PEOA1): 15q25
      SANDO
      MIRAS
      MSCAE
      Alpers
      Parkinsons
    ANT1 (PEOA2): 4q35
    Twinkle (PEOA3): 10q23
    POLG2 (PEOA4): 17q
    RRM2B (PEOA5): 8q23
    DNA2 (PEOA6): 10q21
    GMPR: 6p22
    OPA1: 3q28
    POLRMT: 19p13
    RRM1: 11p15
    Hypogonadism
    SCA28: AFG3L2; 18p11
Recessive PEO
  Mitochondrial DNA Δ
      mtDNA depletion, or
      Multiple mtDNA deletions
  Nuclear DNA mutations (PEOB)
    ENDOG: 9q34
    Leigh, PEO, OA: c12orf65; 12q24
    MNGIE: TYMP; 22q13
    POLG1: 15q26
      HSN + PEO (SANDO)
      PEOB1
      PEO + Cardiomyopathy
    PEO+
      CNS
        PEOB2: RNASEH1; 2p25
        PEOB4: DGUOK; 2p13
        PEOB5: TOP3A; 17p11
        PEOB6: RRM1; 11p15
        POLRMT: 19p13
      Myopathy
        MGME1; 20p11
        PEOB3; TK2 16q21
        TEFM: 17q11
      Cardiomyopathy
        Cardiomyopathy
        POLG1
        C1QBP
      Myopathy & Parkinsonism
      Sensory neuropathy
    SPG7 variant: Paraplegin; 16q24
Maternal PEO
  Mitochondrial DNA Δ
    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
Sporadic PEO
  Mitochondrial DNA changes
    Single, Large mtDNA deletion, or
    Multiple mtDNA deletions
  Kearns-Sayre: Large mtDNA deletion
  PEO + Proximal myopathy
  Sensory ataxic neuropathy
  ? Immune (HyperThyroid)


EOM pathology


Progressive External Ophthalmoplegia (PEO): General Features 257
Sporadic PEO
  • Syndromes with severe ophthalmoplegia
  • Chronic PEO with few systemic features
    • Genetics: Mutation
    • Clinical
      • Onset age: Childhood to Late Adult
      • Ophthalmoplegia & Ptosis
      • Limb strength: Usually normal
      • Other features: Some patients
        • Exercise intolerance (50%)
        • Dysphagia (50%)
        • Myalgia (40%)
        • Systemic: Heart block (Rare)
      • Course: No, or rare, progression to Kearns-Sayre
    • Muscle biopsy
      • COX- muscle fibers: Most patients
      • SDH+ muscle fibers: some patients; Less than Kearns-Sayre
      • Muscle fiber morphology: Varied sizes or Normal
    • Serum CK: Usually normal
  • PEO + Sensory ataxic neuropathy 8
    • Also see: Sensory neuropathy, Recessive with POLG mutations
    • Clinical features
      • Onset
        • Age: 10 to 31 years
        • Gait unsteadiness
      • Polyneuropathy
        • Sensory loss
          • Large fiber modalities: Joint position; Vibration
          • Small fiber modalities (Mild): 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: Axon loss
          • SNAPs: Reduced amplitude or absent, 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

From: R Bucelli
CPEO with mtDNA deletion (9516-13058)
Medial & Lateral rectus muscles: Atrophy

Maternal PEO

PEO: Autosomal Dominant

Autosomal Dominant PEO: Clinical features

Ophthalmoplegia

Triple furrowed tongue
Differential diagnosis



PEO: Autosomal Recessive

Myopathy, Myoglobinuria & Fatigue: Mitochondrial Disorders

Autosomal Dominant
Autosomal Recessive
Maternal
Sporadic

Myoglobinuria


Mitochondrial disorders: Sporadic Myopathy & Fatigue syndromes

Specific sporadic mitochondrial myopathy syndromes

Mitochondrial myopathy: Maternal; mtDNA Point Mutations

Cytochrome c Oxidase: Subunit 2
Mitochondrial tRNA mutations

Sporadic myopathies

Mitochondrial Myopathy: Autosomal Recessive disorders


mtDNA Depletion Syndromes Other recessive mitochondrial syndromes

Mitochondrial Myopathy: Autosomal Dominant


Systemic Mitochondrial Syndromes

Adult onset
Anemia
Ataxia
Cardiac
Deafness
Diabetes
Infantile encephalopathies
Multiple symmetric lipomatosis
Optic atrophy



Infantile encephalopathies: Mitochondrial disorders


Cardiomyopathy: Mitochondrial disorders

Mitochondrial DNA  
  mtRNA
    MTTG (Gly)
    MTTH (His)
    MTTI (Ile)
    MTTK (Lys)
    MTTL1 (Leu)
    MTTL2 (Leu)
  Other
  Respiratory chain
    Complex I
      MTND1
      MTND2
      MTND4
      MTND5
      MTND6
    Complex III
      MTCYB
    Complex IV
      MTCO1
      MTCO2
      MTCO3
    Complex V
      MT-ATP8

Selenium deficiency

Cardiomyopathy
  Autosomal
Nuclear DNA
  Infant onset
    CEMCOX
      1: SCO2; 22q13
      2: COX15; 10q24
      3: COA5; 2q11
      4: COA6; 1q42
  Respiratory chain
    Complex I
      NDUFV1
      NDUFV2
      NDUFS1
      NDUFS2
      NDUFS3
      NDUFS4
      NDUFS6
      NDUFS7
      NDUFS8
      NDUFA1
      NDUFAF1
      NDUFAF2
      NDUFAF4
      NDUFAF5
      NDUFA2
      NDUFA10
      NDUFA11
      NDUFAF3
      NDUFA10
      NDUFB3
      NDUFB9
      NDUFB10
      NUBPL
      FOXRED1
      ACAD9
    Complex II
      SDHA
      SDHD
    Complex III
      UQCRFS1
    Complex IV
      COX6B1
      COX8A
      COX10
      COX11
      COX14
      COX15
      COX16
      COX20
      SCO1
      SCO2
      COA3
      COA5
    Combined Cpx
      C1QBP
      OPA1
      COXPD20

  Other
    mtDNA Depletion
      TYMP
    mtRNA Processing
      MTO1
    Ribosome
    CoQ10 depletion
      COQ2
      COQ4
      COQ6
      COQ7
      COQ9
      ADCK3
      PDSS1
      PDSS2
    3-MGA
      AGK
      DNAJC19
      TAZ
      TMEM70
    Organic aciduria
      HADHB
    Carrier protein
      SLC25A3
      SLC25A4
    Fe-S Cluster
      FXN
    ARS
      AARS2
    CFC1: BRAF
    ELAC2
    HCCS
    Pyrophosphatase 2
    SHMT2
    TRMT5



Deafness: Mitochondrial disorders

Autosomal Recessive inheritance, Syndromic
  Wolfram (DIDMOAD): WFS1; WFS2
  Deafness-Dystonia syndrome
Maternal (mitochondrial) inheritance
  Non-syndromic
  Syndromic
Sporadic syndromic



Ataxia: Mitochondrial disorders
Diabetes & Pancreas: Mitochondrial disorders


Hypoglycemia: Mitochondrial disorders
Anemia & Hematologic
Myopathy with lactic acidosis & sideroblastic anemia 1 (MLASA1)
  Pseudouridine synthase 1 (PUS1) ; Chromosome 12q24.33; Recessive

Myopathy with lactic acidosis & sideroblastic anemia 2 (MLASA2) 112
  Tyrosyl-tRNA Synthetase (YARS2) ; Chromosome 12p11.21; Recessive

Exocrine pancreatic insufficiency, Dyserythropoietic anemia & Calvarial hyperostosis
  Cytochrome c Oxidase, Subunit IV, Isoform 2 (COX4I2) ; Chromosome 20q11.21; Recessive

MTDPS19: Epileptic encephalopathy + Anemia + Complex I deficiency
  Solute Carrier Family 25 (Mitochondrial carrier), Member 10 (SLC25A10) ; Chromosome 17q25.3; Recessive

Hepatic: Mitochondrial


Acute Infantile Liver Failure (LFIT) 104
  tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) ; Chromosome 22q13.31; Recessive

COXPD46: Liver disease
  Mitochondrial Ribosoml Protein 23 (MRPS23) ; Chromosome 17q22; Recessive

COXPD47: Multisystem disorder + Liver disease
  Mitochondrial Ribosomal Protein 28 (MRPS28) ; Chromosome 8q21.13; Recessive

COXPD48: Encephalomyopathy
  NOP2/SUN RNA Methyltransferase family, member 3 (NSUN3) ; Chromosome 3q11.2; Recessive

Multiple symmetric lipomatosis



Optic neuropathy: Mitochondrial

Mitochondrial DNA
  LHON
Nuclear DNA
Syndromic
  Behr syndromes
  OA + Deafness
    FDXR; 17q25
  OA + Encephalopathy
    12: AFG3L2; 18p11
    NDUFA13; 19p13
    SDHA; 5p15
  OPA+
    1: OPA1; 3q28
    3: OPA3; 19q13
    7: TMEM126A; 11q14
    10: RTN4IP1; 6q21
    11: YME1L1; 10p12
    13: SSBP1; 7q34
  Neuropathy
    HMSN6B: SLC25A46; 5q22
    OPA1: OPA1; 3q28
    MFN2: 1p36
    NDUFS6; 5p15
  SPG7; 16q26
  SPG74: IBA57; 1q42
  Wolfram
    WFS1: 4p16
    WFS2: CISD2; 4q24
Non-syndromic
  OPA, Dominant
    1: OPA1; 3q28
    3: OPA3; 19q13
    4: 18q12
    5: DNM1L; 12p11
    8: 16q21
    14: MIEF1; 22q13
    SPG7; 16q26
  OPA, Recessive
    2: Xp11
    6: 8q21
    7: TMEM126A; 11q14
    9: ACO2: 22q13
    15: MCAT; 22q13
    16: MECR; 1p35
  LHON, Recessive
    DNAJC30; 7q11
    NDUFS2; 1q23

General

Optic atrophy (OPA): Other

Leigh Syndrome

Features
  Clinical
  Laboratory
Types
Causes of Leigh-like Syndrome 3
Defect Frequency (%)
mtDNA mutation18-34
PDHc10
Complex I25
Complex IV14
Complex II or III 5
CoQ10 2
Other 26

From: R Bucelli

From: R Bucelli



Quantitative errors in mtDNA (mtDNA depletion (MTDPS))
MTDPS (MDDS) syndromes
  1: TYMP; 22q13
  2: TK2; 16q22
  3: DGUOK; 2p13
  4A & 4B: POLG; 15q26
  5: SUCLA2; 13q14
  6: MPV17; 2p23
  7: Twinkle; 10q24
  8: RRM2B; 8q23
  9: SUCLG1; 2p11
  10: AGK; 7q34
  11: MGME1; 20p11

  12: SLC25A4; 4q35
  13: FBXL4; 6q16
  14: OPA1; 3q29
  15: TFAM; 10q21
  16: POLG2; 17q23
  17: MRM22; 7p22
  18: SLC25A21; 14q13
  19: SLC25A10; 17q25
  20: LIG3; 17q12
  SSBP1: 7q34
  ABAT: 16p13
MDDS
  Nucleotide salvage pathway
    ABAT
    DGUOK
    GMPR
    RRM1
    SUCLA2
    SUCLG1
    TK2

mtDNA: Qualitative errors

Qualitative errors in mtDNA (multiple mtDNA deletions)
Mitochondrial disorders: Drugs & Toxins

Arsenic trioxide: Myopathy
Copper: CNS
Doxorubicin: Cardiomyopathy
Germanium: Myopathy
Ixabepilone: Neuropathy
Nucleosides
  AZT: Myopathy
  Clevudine: Myopathy
  General
  Neuropathy
  Telbivudine: Neuropathy; Myopathy
Trichloroethylene (TCE): Neuropathy
Valproate: Myopathy; CNS

 
AZT

Inclusion Body Myositis
Paragangliomas: Non-chromaffin, Hereditary

PGL1: SDHD; 11q23
PGL2: SDHAF2; 11q13
PGL3: SDHC; 1q21
PGL4: SDHB; 1p36
PGL5: SDHA; 5p15
PGL6: SLC25A11;17p13
PGL7: DLST; 14q24
Other
  SDHAF3
  SDHAF4
  IDH2

Other Mitochondrial Syndromes & Mutations

Mitochondrial syndromes: Infantile & Childhood Onset

Complex deficiency,
  Combined
(COXPD)
    1: EFG1; 3q25
    2: MRPS16; 10q22
    3: EFTs; 12q13
    4: EFTu; 16p11
    5: MRPS22; 3q23
    6: AIFM1; Xq26
    7: c12orf65; 12q24
    8: AARS2; 6p21
    9: MRPL3; 3q22
    10: MTO1; 6q13
    11: RMND1; 6q25
    12: EARS2; 16p12
    13: PNPT1; 2p15
    14: FARS2; 6p25
    15: MTMFT; 15q22
    16: MRPL44; 2q36
    17: ELAC2; 17p12
    18: SFXN4; 10q26
    19: LYRM4; 6p25
    20: VARS2; 6p21
    21: TARS2; 1q21
    22: ATP5A1; 18q21
    23: GTPBP3; 19p13
    24: NARS2; 11q14
    25: MARS2; 2q33
    26: TRMT5; 14q23
    27: CARS2; 13q34
    28: SLC25A26; 3p14
    29: TXN2; 22q12
    30: TRMT10C; 3q12
    31: MIPEP; 13q12
    32: MRPS34; 16p13
    33: C1QBP; 17p13
    34: MRPS7; 17q25
    35: TRIT1; 1p34
    36: MRPS2; 9q34
    37: MICOS13; 19p13
    38: MRPS14; 1q25
    39: GFM2; 5q13
    40: QRSL1; 6q21
    41: GATB; 4q31
    42: GATC; 12q24
    43: TIMM22; 17p13
    44: FASTKD2; 2p23
    45: MRPL12; 17q25
    46: MRPS23; 17q22
    47: MRPS28; 8q21
    48: NSUN3; 3q11
    49: MIEF2; 17p11
    50: MRPS25; 3p25
    51: PTCD3; 2p11
    52: NFS1; 20q11
    53: c2orf69; 2q33
    54: PRORP; 14q13
    55: POLRMT; 19p13
    56: TAMM41; 3p25
    57: CRLS1; 20p12
    58: TEFM; 17q11
    59: MRPL39; 21q21
    APOO: Xp22
    ENDOG; 9p34
    FBXL4: 6q16
    HSD10: Xp11
    LETM1: 4p16
    TK2: 16q22
    TRNT1: 3p26
Complex I deficiency (MC1DN)
  Multisystem
    1 NDUFS4: 5q11
    8 NDUFS3: 11p11
    29 TMEM126B: 11q14
    30 NDUFB11: Xp11
  Encephalopathy
    4 NDUFV1: 11q13
    5 NDUFS1: 2q33
    10 NDUFAF2: 5q12
    12 NDUFA1: Xq24
    14 NDUFA11: 19p13
    15 C6ORF66: 6q16
    21 NUBPL: 14q12
    24 NDUFB9: 8q24
    28 NDUFA13: 19p13
    31 TIMMDC1: 3q13
    33 NDUFA6: 22q13
    37 NDUFA8: 9q33
  Encephalocardiomyopathy
    2 NDUFS8: 11q13
    6 NDUFS2: 1q23
    7 NDUFV2: 18p11
    11 NDUFAF1; 15q15
    20 ACAD9; 3q21
    39 NDUFB7; 19p13
    VARS2 (COXPD20): 6p21
  Leigh
    3 NDUFS7: 19p13
    13 NDUFA2: 5q31
    17 NDUFAF6: 5q12
    19 FOXRED1: 11q24
    22 NDUFA10: 2q37
    23 NDUFA12: 12q22
    26 NDUFA9: 12p13
    27 MTFMT: 15q22
    32 NDUFB8: 10q24
    34 NDUFAF8: 17q25
    36 NDUFC2: 11q14
  Lethal neonatal
    9 NDUFS6: 5p15
    16 C20orf7: 20p12
    18 NDUFAF3: 3p21
    25 NDUFB3: 2q33
    35 NDUFB10: 16p13
  LHON
    38: DNAJC30; 7q11

Complex II deficiency (MC2DN)
  1 Leigh/Encephalopathy: SDHA; 5p15
  2 Leukoencephalopathy: SDHAF1; 19q12
  3 Encephalopathy: SDHD; 11q23
  4 Leukoencephalopathy: SDHB; 1p36
  Iron-Sulfur (Fe-S) cluster disorders

Complex III deficiency (MC3DN)
  1 Leigh: BCS1L; 2q33
  2 Encephalopathy + Ataxia: TTC19; 17p12
  3 Hypoglycemia: UQCRB; 8q22
  4 Encephalopathy: UQCRQ; 5q31
  5 Encephalopathy: UQCRC2; 16p12
  6 Hyperglycemia: CYC1; 8q24
  7 Encephalopathy: UQCC2; 6p21
  8 Encephalopathy: LYRM7; 5q23
  9 Encephalopathy: UQCC3: 11q12
  10 Cardiomyopathy: UQCRFS1; 19q12
  11 Encephalopathy: UQCRH; 1p33
Complex IV deficiency (MC4DN)
  1 Leigh: SURF1; 8q34
  2 Cardioencephalomyopathy: SCO2; 22q13
  3 Spastic-Ataxia: COX10; 17p12
  4 Hepatic failure: SCO1; 17p13
  5 Leigh: LRPPRC; 2p21
  6 Leigh + Cardiac: COX15; 10q24
  7 Leukodystrophy: COX6B1; 19q13
  8 Leigh: TACO1; 17q23
  9 Cardiomyopathy: COA5; 2q11
  10 Encephalocardiomyopathy: COX14; 12q13
  11 Spastic ataxia: COX20; 1144
  12 Leigh: PET100; 19p13
  13 Cardiomyopathy: COA6; 1q42
  14 Neuropathy+: COA3; 17q21
  15 Leigh: COX8A; 11q13
  16 Encephalopathy: COX4I1; 16q24
  17 Leukodystrophy: APOPT1; 14q32
  18 Myopathy: COX6A2; 16p11
  19 Encephalopathy: PET117; 20p11
  20 Systemic: COX5A; 15q24
  21 Encephalopathy: COXFA4; 7p21
  22 Encephalopathy: COX16; 14q24
  23 Encephalopathy: COX11; 17q22
  Development & Multisystem: CEP89; 19q13
  Encephalomyopathy: FASTKD2; 2p23
  Encephalomyopathy: AIFM1; Xq25
  Encephalopathy: TOMM70; 3q12
  Leigh
  Leukoencepalopathy: AARS2; 6p21

Complex V deficiency: Disorders (MC5DN)
  1: ATP12 (ATPAF2); 17p11
  2: TMEM70; 8q21
  3 (MR & PN): ATP5E; 20q13
  4A (de novo): ATP5F1A; 18q21
  4B (Neonatal): ATP5F1A; 18q21
  5: ATP5F1D; 19p13
  6: ATP5MD (USMG5); 10q24
  7: ATP5PO; 21q22
  Cardiomyopathy + Neuropathy: mtATP8
  Leigh: mtATP6
  NARP: mtATP6

Multiple Mitochondrial (MMDS)
  1: NFU1; 2p13
  2: BOLA3; 2p13
  3: IBA57; 1q42
  4: ISCA2; 14q24
  5: ISCA1; 9q21
  6: PMPCB; 7q22
  7: GCSH; 16q23
  MMDS: FBXL4; 6q16
  + Myopathy
    MRPS25: 3p25
    PNPLA8: 7q31

Other
Alexander: GFAP; 17q21
Alpers: 1; 2
Ataxia: COX10; 17p13
Brain Iron Accumulation (NBIA)
  c19orf12; 19q12
  PANK2; 20p13
Cardiomyopathy
CODAS: LONP1; 19p13
Coenzyme Q10 deficiency
  COQ2: 4q21
  COQ4: 9q34
  COQ7: 16p12
  PDSS2: 6q21
DLD deficiency: DLD; 7q31
EIEE3: SLC25A22; 11p15
Encephalopathy
  CA5A: 16q24
  + Cardiomyopathy: TMEM70; 8q21
  + Dystonia: HTRA2; 2p13
  Epileptic: TIMM50; 9q13
  Ethylmalonic: ETHE1; 19q13
  IIAE3 (ANE1): RANBP2; 2q11
  IMMT; 2p11
  Lethal: TRAK1; 3p22
  MDH2: 7q11
  MICU2; 13q12
  NADK2: 5p13
  PMPCB: 7q22
  POLRMT: 19p13
  YOBELN: OGDHL; 10q11
  TMEM65: 8q24
  WARS2: 1p12
FMRD: FH; 1q42
GRACILE (Finnish): BCS1L; 2q33
HADHA: 2p23
Hepatocerebral syndromes
  Hepatoencephalopathy: EFG1; 3q25
  mtDNA depletion
    DGUOK: 2p13
    MPV17: 2p21-p23
HHH: SLC25A15; 13q14
HMGCS2 deficiency: 1p13
HUPRA: SARS2; 19q13
IMNEPD: PTRH2; 17q23
Leigh
Leukodystrophy & Leukoencephalopathy
  AARS2
  c2orf69
  COX6B1
  COX10
  COXPD4
  DARS2
  EARS2
  HLD4
  HLD10
  HSP60
  NDUFS1
  mtDNA deletion, Single large
  SDHAF1
  SDHB
  SURF1
  tRNAGlu
Linear Skin Lesions
  Microphthalmia + : HCCS; Xp22
  Microcephaly +: COX7B; Xq21
  MLS: NDUFB11
MADD: ETFA; 15q23
MEGDEL: SERAC1; 6q25
Menkes & Occipital horn: ATPase 7; Xq21
Mitochondrial ATPase deficiency
Mitochondrial fission defect: DNM1L; 12p11
MTDPS
NEDCASB: SHMT2
Ponto-Cerebellar hypoplasia 6: RARS2; 6q15
Pyruvate dehydrogenase complex
  PDHA1: Xp22
  PDHB: 3p21
  PDHX: 11p13
  PDP1: 8q22
  DLD: 7q31
  Pyruvate dehydrogenase E2: DLAT; 11q23
  LIAS: 4p14
  TPK1: 7q35
Pyruvate: Other
  Pyruvate carboxylase: 11q13
  Pyruvate transporter (MPC1): 6q27
SCO1: 17p13
Severe neonatal lactic acidosis: SUCLG1; 2
Sudden infant death

Mitochondrial syndromes: Childhood Onset
Mitochondrial syndromes: Adult onset CNS
Parkinsonism & Polyneuropathy (PKNPY) 258
  Ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) ; Chromosome 3p21.31; Dominant
Movement disorder & Spastic Ataxia, Childhood onset 236
  Vacuolar protein sorting 13, yeast, homolog of, D (VPS13D) ; Chromosome 1p36; Recessive
Migraine & Encephalopathy (MC1DM1)
  Complex I, Subunit 3 (MTND3) ; Mitochondrial DNA

Germanium myopathy

Arsenic trioxide myopathy 148

Mitochondrial Solute Carriers (SLC25A family & Others)

Inner mitochondrial membrane Outer mitochondrial membrane
Return to Neuromuscular Home Page
Return to Neuromuscular Syndromes

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