In the past, Alpers disease had been considered to be of unknown etiology. Studies of patients, however, have provided information that points to a metabolic basis for the condition. Familial cases have been reported, and the inheritance pattern has suggested an autosomal recessive disorder. The examination of tissues (including muscle and brain) has revealed the presence of abnormal mitochondria in some patients. Also, fatty infiltration of the liver has been noted in some children and is thought not to result from the effects of antiepileptic drug therapy but to be related to the primary disease.

Intermittent elevations in lactate and pyruvate levels have been found in the serum and, more important, in the cerebrospinal fluid (CSF) of some affected individuals. An increased ratio of lactate to pyruvate has been noted. The finding of increased concentrations of these metabolites in the CSF suggests an abnormality in the metabolism of pyruvate within the brain. The study of various tissues from involved patients has suggested various abnormalities in the metabolism of pyruvate. These abnormalities have included disturbances in the pyruvate dehydrogenase complex; in the second part of the citric acid cycle; and in oxidation of the reduced form of nicotinamide adenine dinucleotide, cytochrome aa₃, and pyruvate carboxylase. Thus, what previously was thought to be a degenerative disease of unknown etiology may represent an autosomal disorder associated with pyruvate dysmetabolism.

A hallmark of Alpers disease in the brain is status spongiosus, with neuronal degeneration and loss. Glial proliferation resulting in astrocytosis often is present, and capillaries appear prominent and dilated. The disease involves primarily the cerebral gray matter; little, if any, change is found in the white matter. In severe cases, the thalamus, hippocampus, and cerebellum also may be involved. In patients in whom the liver is affected, the findings are those of subacute hepatitis with massive fatty degeneration, hepatocyte loss, bile duct proliferation, and fibrous scarring with or without cirrhosis. Changes in the muscle have included lipid infiltration, type grouping of fibers, or evidence of mitochondrial or lipid myopathies. Electron microscopy has revealed abnormal mitochondria in some cases.

Two forms of Alpers disease—infantile and juvenile—have been described. The infantile form usually has its onset in children who are between 1 and 3 years of age and are either normal or have had previous mild developmental delays. The course is rapid, and death usually occurs when the child is between 2 and 6 years of age. The initial symptoms may be vomiting and failure to thrive; these symptoms are followed by a severe seizure disorder that often presents with bouts of status epilepticus. The seizures may be focal or generalized, and myoclonus also is noted. Once the epilepsy becomes manifest, psychomotor development stops and previously mastered skills are lost. Affected children often have hypotonia and paresis, which eventually may change to spasticity. Ataxia, visual disturbances, and deafness commonly develop. The clinical manifestations usually are exacerbated by intercurrent infections and stress. Clinical signs of liver disease, if they occur, develop late in the illness and may be manifest by hepatomegaly and ascites. Occasionally, the liver disease may progress rapidly and cause fatal hepatic failure.