I. Defects proximal to respiratory chain (substrate transport and utilization); e.g. pyruvate dehydrogenase complex defects (see p. 706 >>), pyruvate carboxylase deficiency (see p. 722 >>), citric acid cycle defects.
lipid metabolism disorders could be considered "mitochondrial" dysfunctions, but do not have structural defects of mitochondria or "mitochondrial myopathy" phenotype.
II. Defects within respiratory chain - cause disorders of oxidative phosphorylation (classic mitochondrial disorders)
identified syndromes involve enzyme complexes I, III, IV. see p. 709-715 >>
N.B. complex II proteins are encoded entirely by nuclear DNA; other complexes – both nuclear DNA and mtDNA.
marked clinical, biochemical, and genetic heterogeneity - each enzyme complex is composed of 1multiple subunits encoded by different genes (some mitochondrial, some nuclear); 2some subunits are tissue specific.
most common form of complex IV deficiency -Leigh syndrome.
Molecular genetic classification
class I - nuclear DNA mutations(mendelian autosomal or X-linked inheritance):
CPEO, autosomal dominant (nuclear mutation causes multiple mtDNA deletions)
see p. Eye64 >>
lethal infantile mitochondrial disease
mitochondrial DNA depletion syndrome
inherited exertional myoglobinuria
mitochondrial myopathies: benign infantile mitochondrial myopathy, benign infantile mitochondrial myopathy and cardiomyopathy, lethal infantile cardiomyopathy, X-linked or Barth syndrome
succinate dehydrogenase deficiency
class II - mtDNA point mutations (nonmendelian maternal inheritance):
Leber hereditary optic atrophy (± infantile bilateral striatal necrosis, multiple system degeneration) see p. Eye62 >>
Clinical phenotype depends on: percentage of mutant mtDNAs (heteroplasmy)
tissue energy requirements and reserve.
each tissue requires different minimum level of mitochondrial ATP production to sustain normal cell function (threshold expression).
in family with heteroplasmic mtDNA mutations, different family members can inherit different percentages of mutant mtDNAs (due to replicative segregation) → different clinical symptoms.
complete phenotypes are rarely exhibited!
N.B. heteroplasmy and threshold expression are main factors that may cause asymptomatic carriers to exist!
cells with lowest potential to replicate (e.g. neurons) are most susceptible to degenerative changes in proteins, lipids, nuclear DNA, and mtDNA.
mtDNA mutations accumulate in proportion to metabolic rate.
clinical phenotype ranges from mild, slowly progressive weakness of extraocular muscles to severe, fatal infantile myopathies and multisystem encephalomyopathies*.
*clinical syndromes primarily cerebral, but defining histology muscular.
N.B. clinical syndromes are so diverse that it is difficult to discern unifying theme other than maternal inheritance; even lactic acidosis, feature of many syndromes, is not invariant.
Most often involved organs (high energy requirements of these organs make them dependent on efficient function of respiratory chain):
mitochondrial myopathy may be sole presentation of mitochondrial disorder.
slowly progressive weakness of limb-girdle or external ocular and other cranial muscles.
N.B. fraction of mitochondrial volume is greatest in extraocular muscles! – chronic progressive external ophthalmoplegia is clinical hallmark of mitochondrial disease!
abnormal fatigability on sustained (!) exertion.
recurrent myoglobinuria provoked by exercise is uncommon, but exists in some genetically heterogenous mitochondrial myopathies.
CNS has very high energy requirements and limited capacity to use other substrates than glucose for ATP synthesis.
CNS energy reserves are small (brief deprivation of either glucose or oxygen → irreversible cellular damage).
40% of all energy consumption in CNS is used to maintain Na-K gradient across cell membrane.
brain areas most susceptible to accumulation of mtDNA damage:
cerebral cortex (high glucose utilization rate), vs. white matter;
basal ganglia (dopaminergic neurons generate H2O2 and oxygen radicals).
Calcification of basal ganglia is seen in all syndromes but in minority of patients with any syndrome!
Other prevalent clinical manifestations - short stature, hearing loss, diabetes mellitus, visual dysfunction (retinopathy, optic atrophy).
Most likely age at onset (as rule, symptoms begin in infancy or childhood, when metabolic demands of growth and development are greatest):
Lethal infantile mitochondrial disease
Hypertrophic cardiomyopathy and myopathy
Infantile bilateral striatal necrosis and Leber hereditary optic neuropathy
Benign infantile mitochondrial myopathy
Benign infantile mitochondrial myopathy and cardiomyopathy
Lethal infantile cardiomyopathy, X-linked or Barth syndrome
PEO, autosomal dominant
Kearns-Sayre syndrome, autosomal dominant
Myo-neuro-gastrointestinal disorder and encephalopathy
Leber hereditary optic neuropathy plus multiple system degeneration
Inherited exertional myoglobinuria
Hypertrophic cardiomyopathy and myopathy
Diagnosis Congenital lactic acidosis (in blood and CSF).
Modestly elevated serum CK.
Muscle biopsy - ragged red fibers. see p. D30 >>
PET - reduced cerebral metabolic rates for oxygen but normal glucose utilization.
CT / MRI – infarct-like lesions (in cortex or basal grey matter), which are not in typical distribution of major arteries; sometimes reversible.
impaired respiration in biochemical tests of oxidative phosphorylation.
heteroplasmy can be recognized on Southern blot analysis.
enzyme analysis in cultured skin fibroblasts and/or muscle biopsy.
demonstration of mutation in muscle biopsy or blood WBCs.
absence of mutant mtDNA reflects both mitotic segregation early in embryogenesis and selection against mutant cell line in rapidly dividing tissue (but not in postmitotic myocytes)
No effective treatment!
Metabolic treatment can be attempted (even while waiting for definitive diagnosis) - at least 2-month trial of broad-spectrum cofactor supplementation therapy* (factors that increase mitochondrial ATP production):
*in combination with multivitamins
ubiquinone(Coenzyme Q10) up to 300 mg/day; idebenone (novel quinone)
biotin (50 mg/day or more)
thiamine (300 mg/day or more)
vit. K3 (menadione)
Dichloroacetate (15-200 mg/kg/day intravenously or orally) - for lowering of lactic acidosis.
drug crosses blood-brain barrier and inhibits pyruvate dehydrogenase specific kinase → pyruvate dehydrogenase activation.
X-linked or autosomal recessive nuclear DNA mutation
most commonly reported - ATPase 6 gene at mtDNA (same gene defect also causes NARP)
Several enzyme complexes involved (singly or in combination) - all lie in mitochondrial pathway for converting pyruvate to ATP: complexes I and IV, pyruvate dehydrogenase complex, pyruvate carboxylase.
Primarily affected areas: basal ganglia (putaminal involvement is characteristic)