Leber's hereditary optic neuropathy (II) Kearns-Sayre syndrome (III) Chronic progressive external ophthalmoplegia (III) Others

Leber's hereditary optic neuropathy plus multiple system degeneration (II) Inherited exertional myoglobinuria (I) ADULTHOOD Malignant migraine (III)

Neuropathy, ataxia, retinitis pigmentosa syndrome (II)


Hypertrophic cardiomyopathy and myopathy (II) Mitochondrial myopathy (II, IV)

*Diseases are listed by order of most likely age presentation The molecular genetics class is given in parentheses.

before age 6 months; in a fourth, the onset is early in the second year of life. Males are predominantly affected. There is a juvenile and an adult form.

Clinical Features and Associated Disorders. The usual age at onset is before the age of 1 year, with death usually before 5 years. A previously healthy, normal infant exhibits a progressive encephalopathy, with an early characteristic central hypoventilation syndrome. Central hypotonia is prominent early and may later be followed by spasticity. Brain stem findings are shown as poor feeding, sucking, and swallowing and as nuclear or supranuclear ophthalmoplegia. There may be optic atrophy but also pigmentary degeneration of the retina. If the onset occurs after the infant has obtained some upright posture, ataxia becomes evident. Seizures occur in the early-onset form, particularly when due to PDHC deficiency or the NARP mt8993 mutation. Movement disorders may occur later in the course and consist often of multifocal myoclonus. Serial CSF lactate and pyruvate levels are elevated. The diagnosis can usually be made by the combination of a typical course, elevated CSF lactate and pyruvate, and typical lesions on MRI.

Figure 31-4 (Figure Not Available) Algorithm for general approach to the investigation of diseases of oxidative phosphorylaReproduced with permission from The McGraw-Hill Companies, from Scriver C, ed: The Metabolic and Molecular Bases of Inherited Disease, 7th ed., New York, McGraw-Hill, 1995, p 1579.

Differential Diagnosis. Included is any infantile onset chronic or subacute progressive encephalopathy, but particularly the organic acidurias that present as progressive encephalopathy: glutaricaciduria type 1, biotinidase deficiency, and biopterin-dependent phenylketonuria. Other mitochondrial disorders--lethal infantile mitochondrial disease, atypical peroxisomal disorder, and infantile neuraxonal dystrophy--should be considered.

Evaluation (Fig. 31-4 (Figure Not Available) ). In Leigh's disease blood amino acid screening may show nonspecific aminoaciduria. Blood and, more definitively, CSF lactate and pyruvate levels are elevated, with lactate:pyruvate ratios not always at 25:1. Blood ammonia and glucose values are usually normal, as are those of urine organic acids. Other useful tests include serum biotinidase determination, blood sampling for very long chain fatty acids and red blood cell catalase, and pipecolic acid determination for excluding peroxisomal disorders. On T2-weighted sequences of brain MR images, areas of increased intensity are seen in brain stem, cerebellum, and basal ganglia symmetrically. An electroencephalogram may show only background slowing consistent with a nonfocal encephalopathy. Nuclear MR spectrometry, if available, may show a decreased phosphocreatine-to-phosphate ratio in affected brain areas. Specific cause is investigated by enzyme analysis for COX and pDhC activity in cultured skin fibroblasts and/or muscle biopsy, and muscle biopsy is performed for mtDNA analysis (see Fig. 31-4 (Figure Not Available) ).

Management. Supportive and symptomatic management includes nasogastric tube or gastrostomy for feeding problems to prevent aspiration, tracheostomy and ventilatory support for respiratory failure, prompt treatment of infections, frequent changes of position in bedridden patients to prevent skin ulceration, and the use of antiepileptic and antispastic drugs when appropriate. Metabolic treatment can be attempted, even while waiting for a definitive diagnosis, by starting with broad-spectrum cofactor supplementation therapy. This assumes that if the patient has a treatable mitochondrial disease, it will respond to factors that increase mitochondrial ATP production. Biotin (50 mg/day or more) and thiamine (300 mg/day or more) can be given in megadoses, in combination with the multivitamins. At least a 2-month trial should be given to determine therapeutic efficacy, although this approach is difficult to assess because of the phenotypical and genetic heterogeneity of these diseases. Dichloroacetate is available for lowering of lactic acid levels in research protocols, and it is hoped that it will soon be approved by the Food and Drug Administration. Doses of 15 to 200 mg/kg/day have been used in infants and children, with about a 20 percent fall in lactic acid levels. Coenzyme Q10, vitamin K, and vitamin C may also be tried.

Prognosis and Future Perspectives. The prognosis for Leigh's disease is grave: death is inevitable. The course at times may spontaneously remit, and therapies may seem to arrest the disease for periods of time. Death usually occurs by respiratory failure or complications such as sepsis.

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