Minerals and Trace Elements 215large amounts of copper salts. Symptoms include
vomiting, diarrhea, hemolytic anemia, renal and liver
damage, sometimes (at about 100 g or more) followed
by coma and death. Clinical symptoms of chronic
copper toxicity appear when the capacity for protec-
tive copper binding in the liver is exceeded. These
symptoms include hepatitis, liver cirrhosis, and
jaundice.
Consumption of formula milks, heavily contami-
nated with copper after boiling or storage in brass
vessels, is usually a feature of Indian childhood cir-
rhosis, which occurs in early-weaned infants between
the ages of 6 months and 5 years. Symptoms include
abdominal distension, irregular fever, excessive crying,
and altered appetite, followed by jaundice and often
death. Some believe that a genetic disorder enhances
susceptibility to this toxicity syndrome, associated
with excessive dietary exposure to copper and massive
accumulation of liver copper.
Genetic diseases
There are several disorders that result in defi ciency or
toxicity from exposure to copper intakes that are
adequate or tolerated by the general population. The
most important of these are Menkes’ syndrome, an
X-linked copper defi ciency that is usually fatal in early
childhood; Wilson’s disease, an autosomal recessive
disorder resulting in copper overload; and acerulo-
plasminemia, an autosomal recessive disorder of iron
metabolism. All three disorders are characterized by
low serum copper and ceruloplasmin.
Menkes’ syndrome, which affects 1 in 300 000 in
most populations, is caused by mutations in the gene
that encodes a novel member of the family of cation-
transporting p-type ATPases. The gene is expressed
in extrahepatic tissues, and symptoms result from
an inability to export copper from cells, particularly
from intestinal cells and across the placenta. The syn-
drome has three forms, classic, mild, and occipital
horn. Among the symptoms of the classic (most
severe) Menkes’ syndrome are abnormal myelination
with cerebellar neurodegeneration (giving progres-
sive mental retardation), abnormal (steely, kinky)
hair, hypothermia, hypopigmentation, seizures, con-
vulsions, failure to thrive, and connective tissue
abnormalities resulting in deformities in the skull,
long bones and ribs, and twisted, tortuous arteries.
Death usually occurs in the severe forms before 3
years of age.
Wilson’s disease, which affects 1 in 30 000 in
most populations, is caused by numerous (over 100
recognized) mutations in the gene for a copper-
transporting ATPase. The defect results in impaired
biliary excretion of copper and accumulation of
copper in the liver and brain of homozygous indi-
viduals or compound heterozygotes. Abnormalities in
copper homeostatis, however, may also occur in het-
erozygous carriers, who may make up 1–2% of the
population. The age of onset is from childhood
onwards and patients may present in three different
ways: with hepatic symptoms (liver cirrhosis and fatty
infi ltration in the latter stages), with neurological
symptoms (degeneration of the basal ganglia result-
ing in defective movement, slurred speech, diffi culty
swallowing, face and muscle spasms, dystonia, and
poor motor control), or with psychiatric and behav-
ioral problems (including depression and schizophre-
nia, loss of emotional control, temper tantrums, and
insomnia). Kayser–Fleischer rings (corneal copper
deposits) in the eyes are generally present in neuro-
logical or psychiatric presentations. The phenotypic
differences between Wilson’s disease and Menkes’
syndrome are probably owing to the tissue-specifi c
expression of the ATPase genes.
If Wilson’s disease is diagnosed early, copper chela-
tion therapy, usually with d-penicillamine, can be
benefi cial, although neurological symptoms are often
irreversible and liver disease may be advanced at the
time of diagnosis. Zinc supplements limit copper
absorption and subsequent accumulation, and this is
the treatment of choice for maintenance therapy.
Aceruloplasminemia, which affects about 1 in 2
million individuals, is caused by mutations in the
ceruloplasmin gene. Ceruloplasmin is involved in
iron metabolism and, in the disease, there is an accu-
mulation of ferrous iron within the recticuloendothe-
lial system with pathogenesis mainly linked to the
slow accumulation of iron in the brain, rather than
other tissues. Symptoms include dementia, speech
problems, retinal degeneration, poor muscle tone,
and diabetes. Early therapy with the high-affi nity iron
chelator desferoxamine can relieve some of the
symptoms.
Disruption of copper metabolism may be involved
in other neurodegenerative diseases such as the accu-
mulation of amyloid β-protein in Alzheimer’s disease
and the accumulation of modifi ed prion protein in
human prion disease.