Key Points
Disease summary:
Dysfunction of the electron transport chain (ETC) causes a group of multisystem disorders which can present in any age group. Mitochondrial disorders should be suspected in patients with diffuse involvement of several organ systems that does not conform to an established pattern of conventional disease, particularly in the presence of myopathy or neurologic symptoms.
The major clinical features of mitochondrial diseases include stroke or stroke-like events, dementia, seizures, myopathy, external ophthalmoplegia, pigmentary retinopathy, optic atrophy, hearing loss, cardiomyopathy, cardiac conduction abnormalities, hepatopathy, severe gastrointestinal (GI) dysmotility, autonomic dysfunction, and endocrinopathies.
Clinical features most specific to mitochondrial disorders include strokes that do not follow vascular territory, external ophthalmoplegia, unexplained lactic acidosis, and maternal inheritance pattern. The most common symptoms reported by patients include migraine, fatigue or exercise intolerance, heat intolerance, dyspnea, and GI dysmotility.
While many patients develop clusters of symptoms that fall into discrete clinical syndromes (Table 166-1), most affected individuals do not fit neatly into any particular syndromic category.
Hereditary basis:
Mitochondrial disease can result from mutations of both nuclear and mitochondrial genes.
Nuclear mutations can be inherited in autosomal dominant, autosomal recessive, or X-linked patterns.
Mutations of the mitochondrial DNA (mtDNA) are inherited through the maternal lineage. Each cell carries multiple copies of the mitochondrial genome and deleterious mutations usually affect some but not all copies of the mitochondrial genome (heteroplasmy). The expression of mitochondrial disease due to mtDNA mutations depends on the relative proportions of normal and abnormal mtDNA.
| Syndrome | Gene Symbol | Clinical Phenotype |
|---|---|---|
MELAS | MT-TL1, MT-ND5, MTTQ, MTTH, MTTK, MTTS1, MTND1, MTND5, MTND6, MTTS2 | The cardinal feature of MELAS is recurrent stroke-like episodes with resultant transient hemiparesis, hemianopsia, or cortical blindness. Repeated stroke-like episodes lead to impairment of cognitive, motor, and visual abilities. Seizures, recurrent headaches, exercise intolerance, weakness, and sensorineural hearing loss are commonly seen. |
MERRF | MTTK, MTTL1, MTTH, MTTS1, MTTS2, MTTF, MTND5 | MERRF is characterized by myoclonic seizures, proximal myopathy, ataxia, and cognitive decline. Other common findings include cardiomyopathy, Wolff-Parkinson-White (WPW) syndrome, optic atrophy, hearing loss, and short stature. Multiple symmetrical lipomatosis (Madelung disease) has been described in some patients. |
NARP | MTATP6 | The cardinal features of NARP are sensory motor neuropathy, cerebellar ataxia, and retinitis pigmentosa. Other common findings include dementia, seizures, proximal muscle weakness, and hearing loss. Usually there is no histologic evidence of mitochondrial myopathy. |
LHON | MTND1, MTND4, MTND6 | LHON is characterized by bilateral painless visual loss and usually presents in young adults. Males are approximately four times more likely to be affected. Other features include cardiac arrhythmias, myopathy, peripheral neuropathy, dystonia and WPW syndrome. A minority of female LHON carriers develop clinical and neuroimaging features indistinguishable from multiple sclerosis. |
MIDD | MTTL1, MTTE, MTTK | Hearing loss develops in early adulthood and frequently precedes the diagnosis of diabetes. Other features include basal ganglia calcification, cerebral or cerebellar atrophy, visual loss and night blindness, proximal myopathy, left ventricular hypertrophy, WPW syndrome, atrial fibrillation, and short stature. Patients may also develop end-stage renal disease which may precede the diagnosis of diabetes or deafness. Men are more commonly affected. |
Progressive external ophthalmoplegia (PEO) | Multiple mtDNA deletions; nuclear: POLG, C10orf2, SLC25A4, OPA1 | PEO is characterized by ptosis, paralysis of the extraocular muscles (ophthalmoplegia), and proximal limb weakness. Patients usually experience bilateral, symmetrical, progressive ptosis, followed by ophthalmoparesis. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. Both autosomal dominant and autosomal recessive inheritance can occur. |
Kearns-Sayre syndrome | mtDNA deletion | Kearns-Sayre syndrome consists of ophthalmoparesis, pigmentary retinopathy and onset before 20 years. Other clinical features include sensorineural hearing loss, renal tubular acidosis, cardiac conduction blocks, cerebellar ataxia, proximal myopathy, and short stature. Patients often have multiple endocrinopathies including diabetes mellitus, hypoparathyroidism, and Addison disease. Cerebrospinal fluid (CSF), protein of greater than 100 mg/dL is frequently seen. |
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) | POLG | An autosomal recessive systemic disorder resulting from mitochondrial DNA depletion which is characterized by adult onset of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. Other clinical features include myopathy, seizures, hearing loss, gastroparesis, cardiomyopathy, migraines, and depression. |
MNGIE | TYMP | Clinical features include nausea, early satiety, episodic abdominal pain, diarrhea, gastroesophageal reflux, postprandial emesis, progressive gastrointestinal dysmotility, dysphagia, and progressive cachexia. Other features include ophthalmoparesis, hearing loss, peripheral neuropathy, and distal muscle weakness. |
Diagnostic Criteria and Clinical Characteristics
When a patient presents with a classic mitochondrial syndrome, or with typical clinical features and a family history of maternal inheritance, molecular genetic testing often establishes the diagnosis of mtDNA-associated disease. A definite molecular genetic diagnosis, particularly in those with presumed nuclear DNA (nDNA) etiology, is difficult to establish in most patients. A variety of diagnostic criteria have been proposed and include the following:
Clinical evidence of myopathy including proximal myopathy, cardiomyopathy, rhabdomyolysis, or abnormal electromyography (EMG).
Clinical evidence of central nervous system (CNS) involvement including strokes, cortical blindness, seizures, developmental delay, or complex migraines.
Progressive external ophthalmoplegia.
Evidence of unexplained multisystem disease including loss of vision, hearing loss, GI dysmotility, autonomic dysfunction, endocrine disorders, nephropathy, or hepatic dysfunction.
Elevated lactate or alanine levels in plasma or cerebrospinal fluid (CSF), or elevated lactate by magnetic resonance (MR) spectroscopy of the brain.
MR imaging (MRI) evidence of metabolic strokes or Leigh disease.
Muscle biopsy showing ragged red fibers, subsarcolemmal accumulation of mitochondria, or crystalline inclusions, abnormal COX or SDH histochemical staining or decreased ETC enzymatic activity.
