Certain types of organic acidemia occurring in early infancy and of unproved genetic etiology have already been mentioned. Here reference is made to those few cases that are associated with deletions of mitochondrial DNA. The syndrome consists of psychomotor regression and episodic hyperventilation, hypotonia, and convulsions with intervening periods of normalcy. Choreoathetosis or progressive ophthalmoplegia have been added in a few cases. Probably most cases of this type are caused by disorders of the mitochondrial respiratory chain, particularly of the pyruvate-decarboxylase complex. Some children are dysmorphic, with a broad nasal bridge, micrognathia, posteriorly rotated ears, short arms and fingers, and other similar but mild dysmorphic features. De Vivo and colleagues have written a synopsis of this disease. Death usually occurs before the third year. The important laboratory findings are acidosis with high lactate levels and hyperalaninemia. The few cases that have been examined postmortem are found to have necrosis and cavitation of the globus pallidus and cerebral white matter, as in subacute necrotizing encephalomyelopathy (SNE). The diagnosis can be made by the finding of ragged red fibers in muscle or by measurement of enzyme activity. The process must be distinguished from the several diseases of infancy that are complicated by lactic acidosis.
This disease presents as progressive myoclonic epilepsy or myoclonic ataxia. As was noted in Chap. 5, these cases must be differentiated from several similar clinical entities, such as juvenile myoclonic epilepsy, Unverricht-
Lundborg disease, Lafora-body disease, Baltic myoclonus, and neuronal ceroid-lipofuscinosis, discussed earlier in this chapter. Tsairis and colleagues were the first to describe the connection between familial myoclonic epilepsy and mitochondrial changes in muscle, and numerous variants have been identified since their report.
Myoclonus in a child or young adult is the most typical feature and is elicited by startle or by voluntary movement of the limbs. The nature of the seizures varies but includes drop attacks, focal epilepsy, or tonic-clonic types, some of which are photosensitive. The ataxia tends to worsen progressively, replacing the myoclonus and seizures in some instances and remaining a minor feature in others. The myopathy usually produces inapparent or mild weakness, but the presence of mitochondrial muscle abnormalities is necessary for clinical diagnosis. To this constellation may be added any of the other elements of the mitochondrial diseases that have already been denoted, including deafness (present in our cases), mental decline, optic atrophy, ophthalmoplegia, cervical lipomas, short stature, or neuropathy.
Most cases are familial and display maternal inheritance, but the age of onset may vary and affected individuals have been reported with symptoms beginning as late as the sixth decade. Almost always the patients with later onset have the mildest disease, with only myoclonic epilepsy. Conversely, those with onset in the first decade tend to be more severely affected and die before the third decade. As with the other mitochondrial processes, the quantitative burden of mutant DNA bears some relationship to the time of onset and severity of the disease. Eighty percent of patients with MERRF have a point mutation of the mitochondrial genome at locus 8344, which codes for a transfer RNA and, conversely, most patients with this mutation will ultimately manifest some or all the clinical features of MERRF, including those with crossover features of the Leigh syndrome.
Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)