The prevalence of the disease cannot be stated exactly, but is on the order of 1 per 50,000 to 1 per 100,000 of the general population. The disease is transmitted as an autosomal recessive trait. The gene, called ATP7B (homologous with the ATP7A gene, which is defective in Menkes disease), codes for a membrane-bound, copper-binding ATPase. One of the curious aspects of the genetics of the disease is the multitude of mutations within this gene that give rise to the disease and no one mutation accounts for more than 30 percent of cases. Inadequate functioning of the ATPase enzyme in some way reduces excretion of copper in the bile. As noted further on, liver transplantation halts progression of the disease, indicating that the primary biochemical effect of the mutation is in the liver rather than the nervous system.
The mutation gives rise to two fundamental disturbances of copper metabolism: (1) a reduced rate of incorporation of copper into ceruloplasmin and (2) a reduction in biliary excretion of copper. The deposition of copper in tissues is the cause of virtually all the manifestations of the disease—cirrhosis, hemolytic anemia, renal tubular changes, Kayser-Fleischer rings, and, in all likelihood, the cerebral damage—as discussed below.
The onset of neurologic symptoms is usually in the second, and less often in the third, decade, but rarely beyond that time. Half of patients are symptomatic by age 15 years, but exceptional cases, including two under our care, had their first clinical manifestations as late as their midfifties. In all instances the initial event is a deposition of copper in the liver, leading to an acute or chronic hepatopathy and eventually to multilobular cirrhosis and splenomegaly (Scheinberg and Sternlieb). In childhood, the liver disorder often takes the form of attacks of jaundice, unexplained hepatosplenomegaly, or hypersplenism with thrombocytopenia and bleeding. Rarely is there clear evidence of cirrhosis alone. The hepatic abnormalities may be asymptomatic (except for elevated serum transaminases), in which case the initial clinical presentation is neurologic. In some instances, a hemolytic anemia or, less often, renal tubular acidosis may first draw attention to the disease.
The first neurologic manifestations are most often extrapyramidal with a proclivity to affect the oropharyngeal musculature. The typical presentations are tremor of a limb or of the head and generalized slowness of movement (i.e., a parkinsonian syndrome); or slowness of movement of the tongue, lips, pharynx, larynx, and jaws, resulting in dysarthria, dysphagia, and hoarseness; or there may be slowness of finger movement and occasionally choreic movements or dystonic postures of the limbs. Often the mouth is held slightly open in the early stage of the disease. Exceptionally, an abnormality of behavior (argumentativeness, impulsiveness, excessive emotionality, depression, delusions) or a gradual impairment of intellectual faculties precedes other neurologic signs by a year or more (see Starosta-Rubinstein et al).