Laboratory Diagnosis in Neurology, 1 Ed.

Disorders of Copper Metabolism

Epidemiology

The prevalence of Wilson's disease is 1 per 30 000 population, while that of Menkes’ disease (kinky hair syndrome) is 1 per 100 000 live male births.

Pathophysiology

As a cofactor of numerous enzymes, copper is an essential heavy metal. However, at too high concentrations it is toxic. The defects underlying the two inherited disorders of copper metabolism, Wilson's disease and Menkes’ disease, are in the copper-transporting ATPases (ATP7B and ATP7A, respectively):

• In Wilson's disease, the autosomal (13q14.3) recessive defect leads to copper overload of the body.

• In Menkes’ disease, the X-linked (Xq13.3) recessive defect causes copper deficiency.

Clinical Features

Wilson's disease. This disease is characterized by the deposition of copper in various tissues. Hepatopathy is often present; it is always the guiding symptom when the disease manifests in childhood. Neurological symptoms predominate in adolescents and adults; they typically include ataxia, tremor, and extrapyramidal symptoms. Primary psychiatric symptoms with behavioral abnormalities, personality changes, and cognitive and affective disorders may occur at the beginning. The pathognomonic Kayser-Fleischer rings in the cornea are not always present (Schmidt, 2003).

Menkes’ disease. The disease presents at or shortly after birth and is characterized by severe delay in psychomotor development and by convulsive seizures. Connective tissue abnormalities often manifest as severely twisted cerebral arteries. The characteristic hair (pili torti, twisted hairs), from which the synonym “kinky hair syndrome” derives, is pathognomonic. Patients usually die before the age of 3. Evaluation of the therapeutic effect of daily parenteral supplementation with copper has not yet been conclusive. An allelic variant of the disease is the occipital horn syndrome characterized only by connective tissue abnormalities (Kaler, 1998).

Diagnosis

Laboratory analysis involves determination of copper in serum and in 24-hour urine (mostly by flame atomic absorption spectrophotometry) and of ceruloplasmin in the serum (by immunonephelometry or immunoturbidimetry).

Wilson's disease. Copper and ceruloplasmin levels in the serum are usually reduced, while copper excretion in the urine is increased. Excretion can be intensified by administering D-penicillamine which chelates copper.

Menkes’ disease. Copper and ceruloplasmin levels in the serum are severely reduced. Excretion of copper in the urine is not indicative. In the first 6 weeks of life, these values may be low in healthy children as well, making it difficult to interpret test results. Since copper is a co-factor of dopamine β-hydroxylase, plasma and CSF catecholamine levels are reduced in Menkes’ disease (as determined by HPLC). A definitive biochemical diagnosis of Menkes’ disease can be made by a few specialized laboratories; this involves examining the copper efflux in cultured fibroblasts. A molecular genetic test is also available to confirm the diagnosis.

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