Disorders of metal metabolism and transport
Autosomal recessive (1/30,000 births); due to mutation in the ATP7B gene that encodes for a cell membrane ATP-sensitive copper pump. The con-dition results in a build-up of intracellular hepatic copper with subsequent hepatic dysfunction, neurological abnormalities, and haemolytic anaemia.
Usually develop from the age of 10yrs onwards (rare <5yrs). Half of patients first present with chronic active hepatitis (which may lead to cir-rhosis), and half with neurological symptoms including mood disorder, psychosis, and features consistent with Parkinson’s disease. Haemolysis is usually present only in severe cases. Other features seen include renal tubular acidosis, renal stones, and cardiomyopathy.
• Low plasma concentrations of caeruloplasmin (in 80% of patients). Elevated 24hr urinary copper excretion.
• Ophthalmoscopy to detect Kayser–Fleischer rings (although their absence does not rule out Wilson disease).
• Lifelong chelating agents (e.g. D-penicillamine).
• Liver transplantation may be needed in severe disease.
X-linked recessive. Caused by mutation in the gene encoding Cu2+-transporting ATPase, alpha polypeptide. The disease is characterized by:
• early onset growth retardation;
• peculiar hair development (sparse, steely, or kinky hair);
• focal cerebral and cerebellar degeneration.
The phenotype also includes hypotonia, seizures, microcephaly, and oste-oporosis. Predisposition to intracranial haemorrhage is also recognized.
Biochemical analysis reveals low plasma levels of caeruloplasmin and copper.
At least 4 inherited iron-overload disorders have been identified:
• Classic haemochromatosis (HFE 1): autosomal recessive affecting 1 in 200 to 1 in 400 of population. Caused by mutation in either HFE gene (on 6p21.3) or haemojuvelin gene (HJV) (1q21).
• Juvenile haemochromatosis (HFE 2): AR.
• Haemochromatosis type 3 (HFE 3): AR.
• Haemochromatosis type 4 (HFE4): AD.
The clinical features of haemochromatosis are wide ranging and include:
• Cirrhosis of the liver.
• Hypermelanotic pigmentation of the skin.
• Heart failure (cardiomyopathy).
• Joint stiffness and arthritis.
• Involvement of the endocrine glands: can lead to diabetes mellitus, adrenal insufficiency, gonadal failure, and hypopituitarism.
• Increased susceptibility to certain infections is recognized (e.g. Salmonella, Klebsiella).
Primary hepatocellular carcinoma complicating cirrhosis is responsible for about one-third of deaths in affected homozygotes.
Increased serum iron and ferritin levels. Liver biopsy.
Repeated therapeutic phlebotomy.