See “Manifestations and Evolution of Wilson Disease in Pediatric Patients Carrying ATP7B Mutation L708P” by Peña-Quintana et al on page 48.
The Wilson Disease Mutation Database (1) records >300 mutations in the ATP7B gene. Although H1069Q and R778L are relatively common mutant alleles in European and Asian populations, respectively, studies of Wilson disease (WD) from most countries have shown a large number of mutations, many patients being compound heterozygotes. In 3 island populations, however, a more homogeneous situation has been found. In Sardinia, the −441/−427 deletion in the promoter region accounts for 62% of alleles (2). In the Greek island of Kalymnos, only 2 mutations were found, H1069Q and R969Q (2). In Gran Canaria, García-Villarreal et al (3) found a high prevalence of WD and a high prevalence of the Leu708Pro (c.2123T>C) mutation in exon 8 of ATP7B, affecting the 3rd transmembrane region of ATP7B. In the present issue of the journal, Peña-Quintana et al (4) report on 11 paediatric patients from Gran Canaria, 4 homozygous and 5 heterozygous for L708P. What can the study of such genetically isolated populations teach us about WD?
1. Genotype/phenotype correlation. WD is pleiomorphic in its clinical presentation; does this result from genotypic diversity? Or, inverting the question, are individuals homozygous for the same mutation phenotypically homogeneous? The answer from these 3 island populations is clearly no. This should not surprise us because even monozygotic twins with WD may be discordant for hepatic (5) or neurological (6) phenotype. Attempts to find a genotype/phenotype correlation have largely been confounded by the genotypic diversity of the study population, but 2 conclusions seem well supported by the evidence. First, patients with the common central European mutation H1069Q tend to present later, and with neurological rather than hepatic disease, than those with other mutations (7). Second, patients with truncating mutations tend to have an earlier onset of WD and a lower plasma ceruloplasmin (measured by the functional oxidase assay rather than an immunoassay) than those with missense mutations (8). Fulminant hepatic failure is a rare presentation of WD but is reportedly higher in patients with truncating mutations (9). So we may conclude that the “severity” of an ATP7B gene mutation, that is, its ability to impair the function of the copper-transport protein ATP7B, influences but is not wholly determinant of disease severity.
2. Disease modifiers in WD. Here is fertile soil for speculation and further work. Of the possible environmental factors, we recognise that hepatotrophic viruses may precipitate hepatic failure, and that dietary copper load certainly influences outcome in an animal model, the LEC rat, even if the effect of diet on human WD is unproven. Of the obvious putative genetic modifiers, changes have not been found in other copper-transport proteins Atox 1 (10) or Ctr1. A single patient with a COMMD1 polymorphism (11), a variant in the XIAP gene of uncertain significance (12), and more recently described proteins such as clusterin (13), which facilitates ATP7B degradation and is yet to be studied in WD patients, all show that there is much more work to be done in this area. We may argue that the best groups of patients with WD in which to study these and other possible genetic modifiers are those homozygous for a single WD mutation, as found in Gran Canaria.
3. Natural history of WD. Peña-Quintana et al (4) describe 11 patients. One presented with jaundice and the others with asymptomatic elevation of transaminases, of whom 2 were screened because of an affected family member. The authors should be doubly commended here that extended family screening was done and that the investigation of accidentally discovered abnormal liver function tests included exclusion of WD, even in young children. All of the children had a liver biopsy, and the degree of histological abnormality in these asymptomatic children is striking. All had micro- and macro-steatosis, 10 had fibrosis and 2 were cirrhotic. This is consistent with other evidence that liver injury in WD is early, usually cryptic, accompanied by only modest elevation of transaminases because hepatocyte death in WD is apoptotic rather than necrotic, and proceeds to cirrhosis. It emphasises the need for early diagnosis.
4. Screening and genotypic frequency. Neonatal screening for WD would fit the Wilson and Jungner criteria if it were not technically impossible, biochemically because the normal neonate has a low ceruloplasmin, and genetically because in most populations, a large number of mutations render genetic diagnosis impractical. In these island populations, however, a screening program for the common mutation merits serious consideration. The Sardinian group examined 5290 newborns (2), finding 122 −441/−427 heterozygotes, an allelic frequency of 1.15%, and an inferred total WD mutation allelic frequency of 1.92%. Using the Hardy-Weinberg equilibrium, they calculated a WD incidence of 1 in 2707 live births, which is approximately 5 times the observed WD incidence in Sardinia. Similar results came from Kalymnos, but with smaller numbers and so wide confidence intervals. There is an urgent need for such studies to be carried out in other populations; it could be done in Gran Canaria and it could be done in Poland where a large proportion of the patients are H1069Q homozygotes. If we take the Sardinian results at face value, they are of great importance. They show that only one-fifth of genotypically affected individuals will phenotypically manifest; perhaps, that should not surprise us as we compare other monogenic liver disorders such as genetic haemochromatosis or α1 antitrypsin deficiency. More practically, they show that the prognosis of the neonates found to have 2 WD mutations is very uncertain, making the decision as to whether and when to start treatment even more difficult.
5. Prognosis of early-treated WD. In the absence of clinical trials evidence, treatment decisions in WD are presently guided by “expert” opinion, and most experts would probably agree that the appropriate treatment for the child with asymptomatic elevation of transaminases found to have WD is zinc acetate either ab initio or after an initial period of treatment with a chelator. Peña-Quintana et al treated their cases with penicillamine until urinary copper fell <500 μg/day, then changed to zinc acetate, and report satisfactory outcomes from this regime. It is to be hoped that with more assiduous family screening and greater clinical awareness of WD as a cause of asymptomatic transaminitis in early childhood, and possibly screening programmes in suitable populations, the proportion of WD cases detected at an early stage will increase and the proportion presenting later with devastating liver or neurological abnormality will decrease. We believe that treatment of presymptomatic cases started early and taken faithfully will achieve freedom from symptoms and disease progression, but this remains to be proved in long-term follow-up studies. Again, the island populations may be most suitable for these studies.
Rare WD mutations are also of interest to the anthropologist. L708P is believed to have arisen from a single ancestral mutation in the northeast region of Gran Canaria >56 generations ago, before the Spanish conquest of the Canary Islands in the 15th century (3). The Gran Canarians seem to have taken it with them to South America in the 16th to 19th centuries because it now constitutes the second most common WD allele in Brazil, whereas the absence of H1069Q exonerates central Europeans from this particular act of colonialism (14).
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