Second edition

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362 Neurodegenerative and movement disorders
scans, increased signal intensity may be seen in the caudate
and the putamen.
Given the large number of possible mutations, genetic
testing is not practical.
Course
Although there may be partial, temporary remissions, the
overall course is one of progression, with death within
5–10 years.
Etiology
Wilson’s disease is essentially a disease of copper metabolism.
Normally, after copper is absorbed from the intestine,
it is bound to hepatic ceruloplasmin and then for the most
part undergoes biliary excretion. In Wilson’s disease biliary
excretion is deficient and copper accumulates, first in the
liver, where it causes hepatitis, and then, once it spills over
into the systemic circulation, in the brain, where copper
deposition occurs primarily in a pericapillary distribution.
Macroscopically (Howard and Royce 1919), there is atrophy
and a brownish discoloration of the striatum, with, in
advanced cases, cavitation (Wilson 1912) and a mild degree
of cortical atrophy. Microscopically, there is neuronal loss
and astrocytosis in the striatum (more so the putamen than
the caudate) and to a lesser degree in the globus pallidus;
other affected structures include the cerebral cortex (especially
the frontal lobes [Barnes and Hurst 1926]), thalamus,
red nucleus, substantia nigra, dentate nucleus, and cerebellar
cortex. Copper deposition in Descemet’s membrane
gives rise to the classic Kayser–Fleischer ring.
As noted earlier, Wilson’s disease is an autosomal recessive
disease, and it results from mutations in the ATP7B
gene on chromosome 13 that codes for the copper-binding
ATPase (Bull et al. 1993; Chelly and Monaco 1993); multiple
different mutations have been identified (Thomas et al.
1995).
Differential diagnosis
Given the pleomorphic symptomatology of Wilson’s disease,
the differential diagnosis is large. In practice, given
the availability of treatment, and the consequent importance
of not missing the diagnosis, it is appropriate to test
for Wilson’s disease in any young person with a clinical
presentation consistent with Wilson’s disease that cannot
be readily and fully accounted for by another disease
process. One disorder in particular deserves mention as it
may mimic Wilson’s disease not only clinically but also
with respect to laboratory values. Hereditary ceruloplasmin
deficiency, like Wilson’s disease, is characterized by low
ceruloplasmin and total serum copper levels, but, unlike
Wilson’s disease, it is characterized by a low 24-hour urinary
copper level (Kawanami et al. 1996).
Treatment
Treatment is aimed at reducing the total copper burden.
Several methods are available, including chelation with
penicillamine, trientine, or tetrathiomolybdate; treatment
with zinc; and limiting copper intake.
Chelation has traditionally been accomplished with
penicillamine; however, this agent has multiple, severe
side-effects and also, in a significant minority of patients,
will either exacerbate pre-existing symptoms (Starosta-
Rubinstein et al. 1987) or, in pre-symptomatic patients,
cause them (Brewer et al. 1994; Glass et al. 1990).
Consequently, attention has shifted to two other chelating
agents, namely trientine and tetrathiomolybdate; of these,
tetrathiomolybdate is more effective than trientine
(Brewer et al. 2006), and is generally well-tolerated (Brewer
et al. 1996).
Zinc induces intestinal metallothionein, which in turn
binds copper and prevents its absorption; it is less effective
than chelating agents. Zinc is given in a dose of 50 mg three
times daily, before meals (Hoogenraad et al. 1987).
Dietary restriction of copper is the least effective of the
treatment measures and requires an avoidance of shellfish,
legumes, nuts, grains, coffee, chocolate, and organ meats.
On balance, symptomatic patients should probably be
treated with tetrathiomolybdate and zinc. Asymptomatic
patients, with no evidence of liver or brain involvement,
might be treated with zinc, with careful monitoring. With
chelation treatment of symptomatic patients, recovery is
slow, and up to a year or more may be required to see full
improvement. The degree of recovery varies with the severity
of symptoms before treatment; in mild cases there may
be complete recovery, whereas in severe cases, some degree
of residual symptomatology is to be expected.
A final alternative is liver transplantation, which, as it
restores the body’s ability to handle copper, is curative.
This should be considered in either treatment-resistant or
fulminant cases (Bax et al. 1998; Stracciari et al. 2000).
Symptomatic treatment of dementia is discussed in
Section 5.1, of personality change in Section 7.2, and of
psychosis in Section 7.1. Given that almost all patients with
Wilson’s disease will have some degree of hepatic failure,
doses of hepatically metabolized medications must be
adjusted accordingly.
All of the patient’s siblings should be offered testing for
copper and ceruloplasmin levels and, in doubtful cases,
consideration should be given to liver biopsy.
8.17 SPINOCEREBELLAR ATAXIA
Spinocerebellar ataxia (SCA), also known as autosomal
dominant cerebellar ataxia, is an uncommon, dominantly
inherited disorder characterized, in most cases, by a slowly
progressive ataxia, joined, over time, by various other features,
which may include dementia, personality change, or
delusions or hallucinations.