Further testing was prompted by a report suggesting that codon 129 mutations of the human prion gene (HPG) influence Wilson disease.2 Compared with patients who are heterozygous (M129V) or homozygous (V129V) for valine, those who are homozygous for methionine (M129M) have delayed symptom onset.2 Our patient was heterozygous (M129V). It is interesting to speculate that HPG heterozygosity, combined with a mutation causing a stop codon, predisposed our patient to more rapid accumulation of copper and earlier age of onset.
DISCUSSION
Wilson disease is an inherited disorder of copper metabolism.3 An inherent difficulty in its recognition, diagnosis, and management is its rarity: global prevalence is estimated as 1/30,000, although this varies by geographic location.1 In contrast, ADHD has a prevalence of 7.2%,4 making it 2400 times more prevalent than Wilson disease. Furthermore, abnormal liver function tests are common in children; the differential diagnosis includes etiologies such as infection (both viral and nonviral), immune-mediated inflammatory disease, drug toxicity (iatrogenic or medication-induced), anatomic abnormalities, and nonalcoholic fatty liver disease.5
Wilson disease is remarkable, however, for being easily treatable if detected and devastating if not. Although liver abnormalities often improve with treatment, delayed diagnosis and management significantly impact neurologic recovery: An 18-month delay results in 38% of patients continuing to have major neurologic disabilities.6 Untreated, Wilson disease may be fatal within 5 years of development of neurologic symptoms.7 Thus, it has been suggested that evaluation for Wilson disease be considered in any child older than 1 year who presents with unexplained liver disease, including asymptomatic elevations of serum transaminases.8
Mutations in ATP7B on chromosome 13 are responsible for the pathology of Wilson disease9; more than 250 mutations have been identified, including substitutions, deletions, and missense mutations.10 Affected patients may be compound heterozygotes11 and/or may possess new mutations, as seen in our patient.
Although copper absorption is normal, impaired excretion causes toxic accumulation in affected organs. ATP7B’s product, ATPase 2, regulates copper excretion, as well as copper binding to apoceruloplasmin to form the carrier protein ceruloplasmin. An ATP7B abnormality would prevent the latter—making ceruloplasmin a useful screening biomarker and a reliable marker for Wilson disease by age 1 year.8
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