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336

Section 3

Organic syndromes of schizophrenia: genetic disorders related to SLP

27Wilson’sDisease

Edward C. Lauterbach and Leslie Lester-Burns

Facts box

r
ECT should only be administered with

r

extreme caution in WD, given the capacity

Wilson’s Disease (WD) is an autosomal

for prolonged seizures and the dearth of

recessive disorder involving multiple

studies reporting safety and efficacy.

mutations of the gene ATP7B on

r
The pathophysiology of psychosis in WD is

chromosome 13q14.3, a gene critical to

poorly understood.

hepatic copper excretion.

r
It leads to copper deposition primarily in the
liver and the basal ganglia lenticular nucleus
(putamen and globus pallidus), leading to the

Wilson’s Disease (WD) is an autosomal recessive dis-degeneration.

order involving multiple mutations of the gene ATP7B

r
Reported prevalence rates of psychosis are
on chromosome 13q14.3, a gene critical to hepatic cop-quite variable, from 2%–11%.

per excretion
[1].
WD therefore results in an accu-r
Beyond the typical positive symptoms of
mulation and deposition of copper throughout the
hallucinations, delusions, and thought

body, including the liver, brain, musculoskeletal sys-disorders, a wide diversity of psychiatric
tem, heart, kidneys, endocrine system, red blood cells,
features are observed, including silliness,

skin, and other tissues. Wilson
[2]
was the first to
euphoria, sexual preoccupation,

link liver cirrhosis with basal ganglia movement dis-hebephrenia, catatonia, occasional
orders in this illness. Copper deposition occurs pri-hallucinations, “hysterical” behavior, and
marily in the liver and the basal ganglia lenticular
“narrowing of mental horizons.”

nucleus (putamen and globus pallidus), leading to
r
Cognitive disorders occur in somewhat less
the alternative name for WD, hepatolenticular degen-than 25% of patients.

eration.Widespread copper deposition can produce a
r

variety of psychiatric and medical manifestions of WD

At times, psychotic features emerge within

[3]
but, with early detection, WD responds well to cur-several months after commencing anticopper
rently available decoppering agents.

therapy due to rapid copper mobilization,

In this chapter, we first consider WD in gen-

but persistent treatment usually leads to

eral, including its epidemiology, presentation, progno-remission.

r

sis, genetics, pathogenetic mechanisms, neuropathol-For treatment of psychosis, conventional
ogy, diagnosis, neuroradiology, clinical features, and
psychopharmacological approaches should

treatment. We then consider psychosis arising in the
be applied with special consideration of the

context of WD, other psychiatric features that are
effects of copper deposition on the brain,

associated with primary schizophrenia, and important
liver, kidney, heart, and bone marrow.

r

clinical issues that must be considered in treating the
The risk of extrapyramidal side effects,

psychosis of WD. Finally, we conclude with patho-including neuroleptic malignant syndrome,
physiological considerations and directions for future
is higher.

research in WD psychoses.

337

Organic Syndromes of Schizophrenia – Section 3

General considerations

chondrial electron transport chain, catecholamine
metabolism (tyrosine metabolism, dopamine beta-The prevalence of WD approximates 1 case per 30,000

hydroxylase, and monoamine oxidase), melanin for-

[4].
About one-third of patients with WD present with
mation, collagen and elastin cross-linkage, and free
each of the three primary disease presentations: hep-radical deactivation (superoxide dismutase). Exces-atic (hepatic WD), neurological (neurological WD),
sive copper accumulation can lead to cellular demise
and psychiatric (psychiatric WD). Severe mutations
through a number of potential mechanisms. These
result in childhood and adolescent onset of hepatic
include free radical-induced cellular oxidation, inhib-WD, whereas less severe mutations usually result in
ited protein synthesis, poisoning of enzymes (in mito-onset in the second through fourth decade of life with
chondria, cytosol, and cell membrane), intracellu-neurological or psychiatric presentations. The progno-lar failure (of mitochondria, peroxisomes, micro-sis depends upon the clinical manifestations present
tubules, plasma membranes, enzymes, and DNA

at the time treatment is begun. Without treatment,
cross-linking), and induction of cellular injury, inflam-patients may die within 6 months to 5 years of WD

mation, and cell death due to unbound ionic copper
onset. With treatment, however, patients can live fairly
[9, 10].
Mitochondrial copper accumulation can also
normal lives. Thus, early recognition and treatment are
produce premature oxidative aging and mitochon-critical in WD.

drial DNA mutations, further impairing cell function
The gene (ATP7B) is located on chromosome

[13].
A thorough review of normal copper metabolism
13q14 band 14.1–21.1
[5].
The gene product appears
can be found elsewhere
[9].
Copper overload in WD

to be a copper-containing P-type ATPase. Copper is
induces CD95 (APO-1/Fas)-mediated apoptosis
[14],

incorporated into apoceruloplasmin by this ATP7B

and both increased degradation and functional inac-P-type ATPase localized in the trans-Golgi network
tivity of the X-linked inhibitor of apoptosis, XIAP,
[6].
Normally, apoceruloplasmin binds copper to form
reducing its ability to inhibit caspase-3
[15].

holoceruloplasmin, which is then packaged in vesi-Brain pathology can include widespread copper
cles and excreted into the biliary system, but apoc-deposition, gliosis, and astrocytic proliferation, espe-eruloplasmin in WD fails to bind copper
[6].
Holo-cially in grey matter. Spongy necrosis, demyelina-ceruloplasmin is therefore lacking in the biliary sys-tion, and denervation may be evident in frontal,
tem
[7],
reflecting impaired copper transport from
parietal, and occipital cortical areas. Macroscopically,
the hepatocyte to the biliary system. ATP7B muta-ventricular dilatation, lenticular atrophy, yellowish or
tions produce an abnormal interaction between the
reddish brown discoloration, softening, and spongy
ATPase and copper chaperone proteins such as Atox1,
degeneration are seen. Cavitation is especially appar-preventing copper incorporation into apoceruloplas-ent in rapidly progressive juvenile dystonic forms
min to form holocerulosplasmin
[8],
impairing hepa-of WD, whereas atrophy is more common in more
tobiliary copper excretion. Biliary excretion normally
slowly progressive adult forms. The pathology of hep-accounts for 10% of copper loss each day
[9],
and
atic encephalopathy is similar to WD pathology and
impaired biliary excretion soon leads to copper accu-is occasionally superimposed
[16].
Liver failure can
mulation. More than 200 mutations of the WD gene
increase pallidal manganese concentrations.