The nature of this combined hepatic–cerebral degeneration leads to EEG abnormalities, progressive atrophy (particularly occipital) on the CT, loss of visual evoked potentials, and abnormal liver function tests. Despite the nuclear location of the POLG mutation, the main ultrastructural change is a depletion of mitochondria in brain, liver, and muscle. Neuropathologic examination shows marked atrophy of the cerebral convolutions and cerebellar cortex, with loss of nerve cells and fibrous gliosis (“walnut brain”). The cerebral white matter and basal ganglia are relatively preserved. In some cases, the spongiform vacuolization of the gray matter of the brain resembles that seen in Creutzfeldt-Jakob disease. Hypoglycemic, hypoxic, and hypotensive encephalopathies must always be considered in the diagnosis but can usually be eliminated by knowledge of the clinical circumstances at the onset of the illness.
A number of biochemical abnormalities have been identified in patients with Alpers disease, including pyruvate dehydrogenase deficiency, decreased pyruvate utilization, dysfunction of the citric acid cycle, and decreased cytochromes a and aa3, all similar to the mitochondrial defects of Leigh’s disease.
This uncommon disease of the neonatal period or early infancy has many biochemical etiologies. The symptoms have consisted of psychomotor regression and episodic hyperventilation, hypotonia, and convulsions, with intervening periods of normalcy. Choreoathetosis has been observed in a few cases. Death often occurs before the third year. The important laboratory findings are acidosis with an anion gap and high serum lactate levels and hyperalaninemia. Defects can be found in the pyruvate dehydrogenase complex of enzymes and the electron transport chain complexes, which function in the oxidative decarboxylation of pyruvate to acetyl coenzyme A (CoA), relating the disease to defects in the mitochondrial respiratory chain enzymes. Indeed, lactic acidosis is a feature of several of the mitochondropathies discussed later in this chapter. Cases examined postmortem have shown necrosis and cavitation of the globus pallidus and cerebral white matter. Possibly this is a variant of Leigh disease. It must be distinguished from the several diseases of infancy that are complicated secondarily by lactic acidosis, especially the organic acidopathies. Cases of benign transient infantile lactic acidosis have been reported, but their etiology is unclear.
Cerebrohepatorenal (Zellweger) Disease and the Peroxisomal Disorders (PEX1 and Other Mutations)
This disease, estimated to occur once in every 100,000 births, is inherited as an autosomal recessive trait. It has its onset in the neonatal period or early infancy and as a rule leads to death within a few months. Motor inactivity and hypotonia, dysmorphic alterations of the skull and face (high forehead, shallow orbits, hypertelorism, high arched palate, abnormal helices of ears, retrognathia), poor visual fixation, multifocal seizures, swallowing difficulties, fixed flexion posture of the limbs, cataracts, abnormal retinal pigmentation, optic atrophy, cloudy corneas, hepatomegaly, and hepatic dysfunction are the usual manifestations. Stippled, irregular calcifications of the patellae and greater trochanters are highly characteristic. Pathologically, there is dysgenesis of the cerebral cortex and degeneration of white matter as well as a number of visceral abnormalities— cortical renal cysts, hepatic fibrosis, intrahepatic biliary dysgenesis, agenesis of the thymus, and iron storage in the reticuloendothelial system.