Paeds · genetics-dysmorphology-and-metabolism
Disorders of metal metabolism: Wilson and Menkes disease
Also known as Wilson disease · Hepatolenticular degeneration · ATP7B deficiency · Menkes disease · Menkes kinky hair disease · ATP7A deficiency · Copper transport disorders
A fellowship approach to the two inherited copper-transporting ATPase disorders: Wilson disease, in which a defective ATP7B gene causes copper to accumulate and poison the liver and basal ganglia, and Menkes disease, in which a defective ATP7A gene prevents copper from ever leaving the gut and reaching the brain so that copper-dependent enzymes fail. Recognise Wilson by its hepatic and neuropsychiatric faces and the Kayser-Fleischer ring, confirm with low ceruloplasmin and high urinary copper, and treat with chelation or zinc, reserving transplant for acute failure. Recognise Menkes in the hypotonic, failing infant with kinky hair and seizures, confirm with low serum copper, and treat with subcutaneous copper histidinate as early as possible.
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Target exams
Red flags
- A child or young adult with unexplained chronic hepatitis, transaminitis or cryptogenic cirrhosis - think Wilson disease and check ceruloplasmin and 24-hour urinary copper before it decompensates to acute liver failure
- Acute liver failure with a Coombs-negative haemolytic anaemia and renal failure in a child or adolescent is a Wilsonian crisis - a transplant emergency
- A teenager with new tremor, dystonia, dysarthria, deteriorating school performance or a first psychiatric episode, with or without liver disease - examine the eyes for Kayser-Fleischer rings
- An infant who was normal for the first two months then develops profound hypotonia, failure to thrive, seizures and developmental regression, with sparse kinky hair and hypothermia - think Menkes disease
- A failing, hypotonic infant with pili torti, pallid skin, bladder diverticula or arterial tortuosity on imaging - measure serum copper and ceruloplasmin urgently
- A family history of unexplained liver disease, movement disorder, psychiatric illness or infant male deaths on the maternal side
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Board mappings
- Wilson disease as a cause of chronic liver disease in children
- Menkes disease as an X-linked cause of infantile neurodegeneration and kinky hair
- Basic copper biochemistry and the role of ATP7A and ATP7B
- Leipzig diagnostic scoring and the integrated work-up of Wilson disease
- Chelation therapy, zinc and the timing of liver transplantation in Wilson disease
- Molecular biology of ATP7A and ATP7B and the copper-dependent enzyme cascade in Menkes disease
- Recognising the Wilsonian acute liver failure with Coombs-negative haemolysis
- Interpreting ceruloplasmin, urinary copper and hepatic copper together
- Counselling a family with a new Menkes disease diagnosis
- Short case of a child with a movement disorder and Kayser-Fleischer rings
- Long case of a child surviving Wilson disease discussing treatment adherence and transplantation
- Inherited metabolic liver disease
- Neurodegeneration in infancy
- Genetics and counselling of inherited copper disorders
- Biochemistry of copper transport and the ATP7A/ATP7B pumps
- Diagnosis and management of Wilson disease
- Clinical features and prognosis of Menkes disease
- Examination of the child with a movement disorder and hepatic signs
- Communicating a life-limiting X-linked diagnosis to parents
- Wilson disease in the differential of paediatric liver disease
- Menkes disease as an infantile neurodegenerative disorder
- Copper metabolism and its inherited disorders
- Wilson disease
- Menkes disease and occipital horn syndrome
- Multidisciplinary management of inherited copper disorders
- Wilson disease and hepatolenticular degeneration
- Menkes kinky hair disease
- Genetic counselling in inherited copper transport defects
The fellowship mark goes to the candidate who holds the single unifying idea while answering each disease in depth. That idea is the copper-transporting ATPase: a membrane pump that moves copper across a barrier. Two sister genes encode two such pumps. ATP7B sits in the hepatocyte and loads copper into ceruloplasmin and into bile, so when it fails, copper stays in the body and accumulates. ATP7A sits in the gut enterocyte and the blood-brain barrier and ferries dietary copper into the circulation and the brain, so when it fails, copper is trapped in the enterocyte and the body is starved. The same ion, the same protein family, the opposite clinical problem - and this single contrast explains every clinical, biochemical and therapeutic fact a fellowship examiner will probe. [1] [5]
Overview & Definition
Wilson disease and Menkes disease are inherited disorders of copper transport caused by defects in two homologous copper-transporting ATPases. The first, Wilson disease (hepatolenticular degeneration), follows autosomal recessive loss of the ATP7B copper transporter on chromosome 13. Because ATP7B normally loads copper into the plasma protein ceruloplasmin and excretes excess copper into bile, its failure leaves copper trapped in the hepatocyte; copper then accumulates, poisons the liver, and eventually spills into the blood to deposit in the brain, cornea and other organs. It is a disorder of copper toxicity. [1] [3]
The second, Menkes disease (kinky hair disease), follows X-linked recessive loss of the ATP7A copper transporter. ATP7A normally shuttles dietary copper out of the gut enterocyte into the bloodstream and across the blood-brain barrier, so its failure traps copper in the enterocyte and denies it to the body and brain. The result is a functional systemic copper deficiency in which copper-dependent enzymes - lysyl oxidase, dopamine-beta-hydroxylase, tyrosinase and cytochrome c oxidase among them - fail to mature, producing the characteristic hair, vascular, pigmentation and neurodegenerative features. It is a disorder of copper deficiency. [5] [6]
These two conditions are paired deliberately because the contrast is the teaching. Both are diseases of copper, both are caused by a pump that cannot move copper, and both produce devastating brain injury - but the direction of the error is opposite, and so is the treatment. Remove the copper in Wilson, replace the copper in Menkes. The candidate who internalises this contrast will never confuse the biochemistry, the lab values, or the management. [1] [5]
References12ShowHide
- [1]Schilsky ML, Roberts EA, Bronstein JM, et al. A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology, 2023.PMID 36152019
- [2]Ferenci P, Caca K, Loudianos G, Mieli-Vergani G, Tanner S, Sternlieb I, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int, 2003.PMID 12955875
- [3]Schilsky ML. Wilson Disease: Diagnosis, Treatment, and Follow-up. Clin Liver Dis, 2017.PMID 28987261
- [4]Kaler SG, Holmes CS, Goldstein DS, Tang J, Godwin SC, Donsante A, et al. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med, 2008.PMID 18256395
- [5]Tümer Z, Møller LB. Menkes disease. Eur J Hum Genet, 2010.PMID 19888294
- [6]Horn N, Wittung-Stafshede P. ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle. Biomedicines, 2021.PMID 33917579
- [7]Litwin T, Dzieżyc K, Członkowska A. Wilson disease-treatment perspectives. Ann Transl Med, 2019.PMID 31179305
- [8]Brewer GJ, Yuzbasiyan-Gurkan V. Wilson disease. Medicine (Baltimore), 1992.PMID 1635439
- [9]Schilsky ML. Liver transplantation for Wilson's disease. Ann N Y Acad Sci, 2014.PMID 24820352
- [10]Nayagam JS, Jeyaraj R, Foskett P, et al. ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants. Clin Gastroenterol Hepatol, 2023.PMID 36096368
- [11]Mulligan C, Bronstein JM. Wilson Disease: An Overview and Approach to Management. Neurol Clin, 2020.PMID 32279718
- [12]Haddad MR, Choi EY, Zerfas PM, et al. Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model. Mol Ther Methods Clin Dev, 2018.PMID 30090842