Patients with this syndrome have normal early development followed by poor growth, focal or generalized seizures, and recurrent acute episodes that resemble strokes or prolonged transient ischemic attacks. The stroke deficits often improve but in some cases lead to a progressive encephalopathy. Some have hemicranial headaches that cannot be distinguished from migraine, and others suffer repetitive vomiting or episodic lactic acidosis. If there is a characteristic feature it is the unusual clinical pattern of focal seizures, sometimes prolonged, which herald a stroke (see Pavlakis et al) and produce an unusual radiographic pattern of infarction involving the cortex and immediate subcortical white matter. The CT may also show numerous low- density regions that have no clinical correlates. Most patients have ragged red fibers in muscle but only rarely is there weakness or exercise intolerance.
Approximately 80 percent of MELAS cases are related to a mitochondrial mutation occurring at the 3243 site of the mitochondrial gene or, in a few instances, at an alternative locus that also codes for a segment of transfer RNA. Maternal inheritance is common but sporadic cases are well known. In the survey conducted by Hammans and coworkers, only half of the cases of the 3243 mutation were associated with the MELAS syndrome. The finding of an abnormal mitochondrial genome in the endothelium and smooth muscle of cerebral vessels has been suggested as a basis for the strokes and migraine headaches.
The Diagnosis of Mitochondrial Disorders
The characteristic neurologic signs of a mitochondrial disorder fall into certain broad groups: (1) combinations of ataxia, seizures, and myoclonus, typified by the MERRF syndrome; (2) migraine-like headaches, recurrent small strokes, and preceding seizures, represented by the MELAS syndrome; (3) combinations of ophthalmoplegia (progressive external ophthalmoplegia), retinitis pigmentosa, polyneuropathy, or deafness (Kearns-Sayre syndrome); (4) optic atrophy (Leber type); and (5) a myopathy that is slowly progressive or fluctuating in severity. These may be combined with dementia, lactic acidosis, short stature, diabetes, ptosis, and cardiac conduction defects as well as with multiple symmetrical lipomas. Peripheral nerve involvement, although common in these disorders, is usually asymptomatic; autonomic failure may be a rare manifestation. A panoply of visceral dysfunctions are at times associated with the neurologic features including bone marrow changes of sideroblastic anemia, renal tubular defects, endocrinopathies (mainly diabetes mellitus, but also hypothyroidism or deficiency of growth hormone), hepatopathy, cardiomyopathy, and recurrent vomiting with intestinal pseudoobstruction. Diabetes has been a marker in several of the early-onset MELAS and MERRF cases that we have seen, but less often when the first manifestations appeared in adulthood.