This is a familial or sporadically occurring mitochondrial disorder with a wide range of clinical manifestations. Only some of the cases display a maternal pattern of inheritance. The onset of neurologic difficulty in more than half of these patients is in the first year of life, mostly before the sixth month; but late-onset forms, with great heterogeneity of presentation as late as early adulthood, are also known. Neurologic symptoms often appear subacutely or abruptly, sometimes precipitated by a febrile illness or a surgical operation. It has seemed to us that this rapid onset is more characteristic of Leigh disease than it is of the other mitochondrial disorders and the disease could reasonably be designated as “acute necrotizing encephalomyelopathy” (ANE), a term applied to a similar entity in Japan and China.
In infants, loss of head control and other recent motor acquisitions, hypotonia, poor sucking, anorexia and vomiting, irritability and continuous crying, generalized seizures, and myoclonic jerks constitute the usual clinical picture. If the onset is in the second year, there is delay in walking, ataxia, dysarthria, psychomotor regression, tonic spasms, characteristic respiratory disturbances (episodic hyperventilation, especially during infections, and periods of apnea, gasping, and quiet sobbing), external ophthalmoplegia, nystagmus, and disorders of gaze (like those of Wernicke disease), paralysis of deglutition, and abnormal movements of the limbs (particularly dystonia but also jerky and choreiform movements). Mild cases, showing mainly developmental delay, have been mistaken for cerebral palsy. Peripheral nerves are involved in some cases (areflexia, weakness, atrophy, and slowed conduction velocities of peripheral nerves); in a few, autonomic failure is the most prominent feature. In some children the disease is episodic; in others it is intermittently progressive and quite protracted, with exacerbation of neurologic symptoms in association with nonspecific infections. The CSF is usually normal but the protein content may be increased.
The pathologic changes take the form of bilaterally symmetrical foci of spongy necrosis with myelin degeneration, vascular proliferation, and gliosis in the thalami, midbrain, pons, medulla, and spinal cord. In cases of acute onset there may be minor hemorrhagic change. The basal ganglia are characteristically but not invariably affected. Also, there may be a demyelinative type of peripheral neuropathy. In their distribution and histologic appearance, the CNS lesions resemble those of Wernicke disease (caused by a deficiency of thiamine) except that the lesions of Leigh disease are more extensive—sometimes involving the striatum—and they spare the mammillary bodies. The lesions, particularly those of the lenticular nuclei and brainstem, may be seen in CT and are strikingly demonstrated by MRI. The histochemical appearance of muscle is normal, although electron microscopy may show an increased number of mitochondria.
The clinical boundaries of Leigh disease have not been defined precisely. A familial disorder of infancy and early childhood, referred to as bilateral striatal necrosis and associated with dystonia, visual failure, and other neurologic defects, is probably a variant. The same may be true of an obscure adult-onset syndrome of progressive dementia, caused by thalamic lesions, in the form of necrosis, vascular proliferation, and gliosis. A resemblance to what has recently been termed acute necrotizing encephalomyelopathy, arising in children after an infectious illness, was alluded to earlier.