Last updated: September 5, 2017
Chronic progressive external ophthalmoplegia → see p. Eye64 >>
Malignant migraine → see p. S25 >>
Reye syndrome → see p. 265 (1) >>
Mitochondrial DNA → see p. 586 (1) >>
CPEO = chronic progressive external ophthalmoplegia
KSS = Kearns-Sayre syndrome
MEPOP = mitochondrial encephalomyopathy with polyneuropathy, ophthalmoplegia, pseudoobstruction
MELAS = mitochondrial encephalomyopathy, lactic acidosis, stroke
MERRF = myoclonus epilepsy with ragged-red fibers
MNGIE = mitochondrial neuromyopathy, gastrointestinal encephalomyopathy
NARP = neuropathy, ataxia, retinitis pigmentosa.
POLIP = polyneuropathy, ophthalmoplegia, leukoencephalopathy, intestinal pseudo-obstruction
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 >>
CPEO, maternally inherited
Leigh disease, maternally inherited
maternally inherited adult-onset myopathy
maternally inherited cardiomyopathy
maternally inherited aminoglycoside-induced deafness
fatal infantile myopathy
hypertrophic cardiomyopathy and myopathy
class III - mtDNA deletions, duplications, large-scale rearrangements (nonmendelian maternal inheritance):
Pearson marrow-pancreas syndrome
maternally inherited diabetes and deafness (DAD)
MNGIE / MEPOP / POLIP
class IV - genetics not yet defined:
myo-neuro-gastrointestinal disorder and encephalopathy
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
Luft disease (nonthyroid hypermetabolism) with generalized myopathy
Leber hereditary optic atrophy
Leber hereditary optic neuropathy plus multiple system degeneration
Inherited exertional myoglobinuria
Hypertrophic cardiomyopathy and myopathy
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.
Leigh disease (Subacute Necrotizing Encephalomyelopathy)
- relatively common neurometabolic disease:
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)
brain stem (periaqueductal-periventricular region)
less involved - cerebral cortex, retinal pigment.
Pathology – necrotizing spongy degeneration, demyelination, gliosis, capillary proliferation.
lesions resemble Wernicke encephalopathy, but hypothalamus and mammillary bodies are spared.
≈ 50% are diagnosed in 1st year of life (usually before age 6 months); in 25%, onset is early in 2nd year of life:
males > females.
previously healthy, normal infant → subacute progressive encephalopathy:
characteristic central hypoventilation syndrome (with associated sighing or sobbing).
central hypotonia → spasticity.
poor feeding, sucking, swallowing → vomiting → arrest of psychomotor development.
(supra)nuclear ophthalmoplegia; nystagmus is common.
± optic atrophy, pigmentary retina degeneration.
ataxia (if onset occurs after infant has obtained some upright posture).
seizures in early-onset form
multifocal myoclonus later in course.
inevitable death before 5 years (respiratory failure, sepsis).
blood and, more definitively, CSF lactate & pyruvate↑
MRI - symmetrically increased intensity areas in brain stem, cerebellum, and basal ganglia.
blood amino acid screening - nonspecific aminoaciduria; ammonia and glucose values normal.
EEG - only background slowing (nonfocal encephalopathy).
nuclear MR spectrometry - phosphocreatine-to-phosphate ratio↓ in affected brain areas.
although muscle may show ragged red fibers, CNS abnormalities overshadow neuromuscular abnormalities.
Supportive & symptomatic + metabolic cofactor therapy.
Alpers disease (Progressive Infantile Cerebral Poliodystrophy)
genetic abnormality and inheritance pattern unknown (relation to mitochondrial dysfunction is at best uncertain!); prion disease?
histopathology ≈ Leigh's disease or Creutzfeldt-Jakob disease.
affected CNS locations (same as in Leigh's disease, but in reverse order): most severe in cerebral cortex, then cerebellum, basal ganglia, and brain stem.
biochemical abnormalities not specific (pyruvate dehydrogenase↓, utilization of pyruvate and NADH↓, citric acid cycle dysfunction).
onset and duration ≈ Leigh's disease.
signs & symptoms ≈ Leigh's disease; differences:
psychomotor delay before abrupt onset of seizures.
40% have hepatic dysfunction.
course is rapidly progressive after onset of seizures → death.
- of exclusion (no pathognomonic clinical sign or laboratory study!).
EEG - marked diffuse encephalopathy; characteristic high-voltage, very slow delta waves mixed with low-voltage polyspikes.
CT, MRI - progressive marked cortical atrophy.
Management - see Leigh's disease >>
N.B. avoid valproic acid - risk of accelerating course and resultant fatal toxic hepatitis!
Almost never familial! - most cases are sporadic!
mutations take place in fertilized ovum;
physical impediments affect personal interactions, and patients are not expected to have children.
single large mtDNA deletion (same as in sporadic CPEO).
deleted mtDNAs localize to distinct regions along muscle fiber, whereas normal mtDNAs are evenly distributed → periodic respiratory deficiency along muscle fiber.
Chronic progressive external ophthalmoplegia before age 20 yrs*.
*if after 20 yrs – it is just chronic progressive external ophthalmoplegia (CPEO) with autosomal dominant inheritance due to nuclear mutation causing multiple mtDNA deletions. see p. Eye64 >>
if coupled with wide variety of other manifestations = CPEO-plus
Atypical retinitis pigmentosa
At least one of following:
Cardiac conduction defects - may result in sudden death! (H: implanted cardiac pacemaker!!!)
Cerebellar syndrome (may be disabling)
CSF protein↑ (> 1 g/L).
Possible other features:
Sensorineural hearing loss
Endocrine dysfunction (short stature, diabetes, hypothyroidism).
No trunk / extremities weakness, no dysphagia!
most patients die in 3-4th decade.
asymptomatic blood and CSF lactate & pyruvate!
CT/MRI - spongy degeneration (leukoencephalopathy), may be calcification of basal ganglia.
muscle biopsy (ragged red fibers are found in all cases!)
Pearson marrow-pancreas syndrome
- disorder of infancy (single mtDNA deletions):
refractory sideroblastic anemia
exocrine pancreatic dysfunction
may develop features of KSS in adolescence.
MERRF (Myoclonic Epilepsy and Ragged Red Fibers Syndrome)
mtDNA point mutation in tRNALys gene → protein synthesis defects (primarily complexes I, IV - have greatest number of mtDNA coded subunits).
familial occurrence with maternal inheritance, usually before age 20, is rule.
neuropathology – (spongy) degeneration of cerebellar cortex, substantia nigra, dentatorubral and pallidoluysian systems, locus ceruleus, inferior olivary nucleus, and pontine tegmentum.
Cerebral cortex & white matter are usually normal!
symptoms & signs (overlap with MELAS) - classically in late childhood:
progressive myoclonic epilepsy
mitochondrial myopathy (weakness and hypotonia); extraocular movements are normal
less common signs - progressive dementia, hearing loss, optic atrophy.
course is slowly progressive (death in 3-4th decade with severe mental deterioration).
all maternal relatives must have blood analyses for mutant DNA.
prenatal diagnosis (amniocentesis or chorionic villus sampling for mtDNA mutations) is unreliable - may not reflect embryo's muscle and brain genotype.
for seizures – clonazepam, valproate (watching for carnitine deficiency); for refractory myoclonic epilepsy - ketogenic diet, ACTH / corticosteroids, L-5-hydroxytryptophan plus carbidopa.
MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like Episodes)
mtDNA point mutation in tRNALeu(UUR) gene.
nonvascular cerebral infarcts (due to transient dysfunction of oxidative phosphorylation) → areas of neuron loss, demyelination, and astrocytic proliferation.
most cases occur before age 20 (normal early development → delayed motor and cognitive developmental milestones):
strokelike episodes (hemiplegia*, sudden cortical blindness, hemianopia, episodes of confusion and hallucination with fever, vomiting, aphasia, migraine headaches, seizures, etc) → encephalopathy with progressive dementia.
*can alternate from side to side
mitochondrial myopathy; extraocular movements are normal.
course is progressive (full expression leads to dementia, bedridden state, and death before age 20).
CT / MRI - cortical infarcts that are not wedge shaped but cut across several vascular territories; basal ganglia calcifications, ventricular dilation & cortical atrophy.
NARP (Neuropathy, Ataxia, Retinitis Pigmentosa Syndrome)
mtDNA point mutation in ATPase 6 gene (same gene defect also causes Leigh disease).
rare, functionally recessive, with variable systemic expression, adult-onset progressive disease:
neuropathy (neurogenic weakness)
pigmentary retinopathy (nyctalopia → loss of peripheral vision).
metabolic and muscle investigations are usually normal (only lactic acidemia in more severe cases).
MNGIE, s. MEPOP, POLIP
MNGIE = Mitochondrial Neuropathy, Gastrointestinal Encephalopathy
MEPOP = Mitochondrial Encephalomyopathy with Polyneuropathy, Ophthalmoplegia and Pseudo-Obstruction
POLIP = Polyneuropathy, Ophthalmoplegia, Leukoencephalopathy, and Intestinal Pseudo-Obstruction
multiple mtDNA deletions (similar to autosomal dominant PEO).
starts in childhood:
sensorimotor polyneuropathy - distal as well as proximal weakness
chronic progressive external ophthalmoplegia with prominent ragged-red fibers
leukoencephalopathy (seen on MRI)
chronic intestinal pseudo-obstruction, malabsorption.
Lethal Infantile Mitochondrial Disease
- oxidative phosphorylation defects* associated with extreme neonatal lactic acidosis (congenital lactic acidosis).
*defects in multiple complexes (mostly complex I and IV but also III) and various cytochromes.
several genetic mechanisms:
tissue-specific mtDNA depletions (maternal or mendelian inheritance) see below >>
presentation in (or shortly after) neonatal period – severe congenital lactic acidosis: marked hypotonia and weakness, failure to thrive, respiratory difficulty; brain itself is rarely involved.
Before serum [lactate] is known, clinical picture resembles urea cycle defects.
death by ≈ 5 months (uncorrectable lactic acidosis with hepatic and renal dysfunction, myocardiopathy).
- first human disease attributed to mitochondrial dysfunction - uncoupling of oxidative phosphorylation → hypermetabolic state (thyroid function normal) + generalized mitochondrial myopathy
mtDNA depletion syndrome
- abnormally low number of mtDNA genomes due to:
mutations in nuclear DNA that controls mtDNA replication and copy number!!!;
mtDNA point mutation - interacts with specific nuclear alleles, so replication is impaired.
abnormal timing of mtDNA replication (delayed) in embryogenesis;
histology - many cytochrome-c oxidase-negative fibers as well as ragged-red fibers.
presents at birth (or shortly afterward); depletion severity correlates with clinical severity:
generalized hypotonia and weakness.
cardiomyopathy, respiratory failure
renal tubular defects
lactic acidosis, serum CK↑↑
many die within first year of life (benign infantile form exists - hypotonic infants survive and appear normal by age 2 or 3 years).
Disorders of Citric Acid Cycle
Onset at birth or early infancy:
congenital lactic acidosis
failure to thrive, hypotonia, seizures, microcephaly, optic atrophy.
Diagnosis - analysis of urinary organic acids (patterns distinctive for each enzyme defect).
No effective treatment!
Bibliography for ch. “Metabolic Disorders” → follow this link >>
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