Disorders of metal metabolism: Wilson and Menkes disease — formative SAQs

SAQ 1 (10 marks)

A 13-year-old boy presents with a six-month history of a progressive tremor, slurred speech and deteriorating school performance. His mother reports he has become irritable and withdrawn. Liver function tests show AST 110 and ALT 88. Slit-lamp examination reveals golden-brown deposits at the periphery of both corneae. [1] [3]

a) Name the likely diagnosis, the defective gene and its inheritance, and explain the single unifying concept that links this disease to Menkes disease. (2 marks) [1]

b) Describe the integrated copper panel you order to confirm the diagnosis, and explain how the Leipzig score (Ferenci 2003) integrates these results into a validated diagnostic instrument. Include the caveat that a normal ceruloplasmin does not exclude the diagnosis. (3 marks) [1] [2]

c) Outline the definitive medical management of this child, naming the three therapeutic pillars (chelation, zinc, transplant), the mechanism by which zinc acts, and the rationale for preferring trientine over penicillamine for initial therapy in a neurologically presenting patient. (3 marks) [1] [7]

d) Describe the family screening obligations at this diagnosis, and explain why pre-symptomatic treatment of an affected sibling is one of the most effective interventions in inherited metabolic medicine. (2 marks) [1]

SAQ 2 (10 marks)

A 3-month-old male infant who was normal at birth now has profound hypotonia, failure to thrive, intractable myoclonic seizures and sparse brittle lightly-pigmented hair twisted on microscopy (pili torti). Cerebral angiography shows marked arterial tortuosity. Serum copper and ceruloplasmin are low. [5] [4]

a) Name the diagnosis, the defective gene and its inheritance, and explain why this infant was normal for the first two months. (2 marks) [5]

b) Explain how a failure of copper egress from the gut enterocyte (rather than a failure of intake or absorption) produces the systemic copper deficiency, and relate each clinical feature to a specific copper-dependent enzyme failure: arterial tortuosity, hypothermia, hair depigmentation, and neurodegeneration. (4 marks) [5] [6]

c) Outline the treatment with subcutaneous copper histidinate, explain why the route must be subcutaneous and not oral, and discuss the evidence from the Kaler neonatal study regarding the treatment window and its limitations. (2 marks) [4]

d) Contrast the genetic counselling of this family with that of a Wilson disease family, explaining the recurrence risk for the carrier mother and the options for future pregnancies. (2 marks) [5]

Marking guide

SAQ 1. The diagnosis is Wilson disease (hepatolenticular degeneration), caused by autosomal recessive loss of ATP7B on chromosome 13q14.3. The unifying concept linking Wilson and Menkes disease is the copper-transporting ATPase: both are caused by a defective membrane pump that moves copper across a barrier. ATP7B (liver) failure causes copper to accumulate; ATP7A (gut) failure causes copper to be wasted. The integrated panel is serum ceruloplasmin (low, under 0.2 g/L, but an acute-phase reactant normal in 10 to 15 percent), 24-hour urinary copper (elevated above 0.6 to 1 micromole per 24 hours), slit-lamp examination for Kayser-Fleischer rings, and hepatic copper on biopsy (gold standard above 250 micrograms per gram dry weight), confirmed by ATP7B molecular testing. The Leipzig score assigns points for each of these and a high score confirms without biopsy in typical cases. The three pillars are chelation (penicillamine or trientine, which bind copper for urinary excretion), zinc (induces enterocyte metallothionein to block dietary copper absorption, used for maintenance and pre-symptomatic siblings), and liver transplantation (curative, for acute failure or decompensated cirrhosis). Trientine is preferred over penicillamine for initial therapy in a neurologically presenting patient because penicillamine can cause an initial neurological worsening by mobilising tissue copper. All first-degree relatives must be screened biochemically and molecularly; an affected pre-symptomatic sibling is started on zinc or chelation to prevent the disease from ever declaring itself. [1] [2]

SAQ 2. The diagnosis is Menkes disease, caused by X-linked recessive loss of ATP7A on Xq21.1. The infant was normal for the first two months because residual maternal and placental copper sustained enzyme function until the accumulating demand of growth exceeded the supply. The functional problem is copper egress: the enterocyte absorbs dietary copper normally but cannot release it into the blood without ATP7A, so copper is trapped and lost when the enterocyte sloughs, and the body and brain are functionally copper-deficient. Arterial tortuosity reflects lysyl oxidase failure (elastin and collagen cross-linking); hypothermia and autonomic instability reflect dopamine-beta-hydroxylase failure (catecholamine synthesis); hair depigmentation reflects tyrosinase failure (melanin); and neurodegeneration reflects cytochrome c oxidase failure (oxidative phosphorylation). The treatment is subcutaneous copper histidinate, which bypasses the enterocyte block and delivers bioavailable copper to the circulation. Oral copper is useless because it adds to the copper already trapped in the enterocyte. The Kaler neonatal study demonstrated that treatment started in the first month of life improves survival and neurological outcome, but benefit is limited in patients with null ATP7A variants and it does not reverse established neurodegeneration. The counselling differs from Wilson disease: Wilson is autosomal recessive and counsels siblings (one-in-four risk); Menkes is X-linked and counsels the carrier mother, whose recurrence risk in future male offspring is 50 percent, with prenatal or preimplantation genetic diagnosis available. [4] [5]