Wilson disease is a rare, inherited autosomal recessive disease of copper metabolism and may be more common where consanguinity is prevalent. Much has been known about the disease after it was first described by Kinnier Wilson as ‘progressive lenticular degeneration in 1912. Over 500 mutations of the ATP7B gene has been identified with no clear genotype to phenotype correlation. Loss of ATP7B function leads various grades of reduced biliary excretion of copper and reduced incorporation of copper into ceruloplasmin; accumulation and toxicity of copper in the liver, brain and other tissues results in liver toxicity and other myriad manifestations of the disease. The clinical features may vary from asymptomatic state to chronic liver disease, acute liver failure, neuropsychiatric manifestations and hemolytic anemia. Diagnosis is based on the combination of clinical sign's, biochemical features, histologic findings and mutation analysis of ATP7B gene. Subtle geographical differences exist with a disproportionate proportion of children presenting with acute liver failure. A high index of suspicion is needed for an early diagnosis. Ratios of biochemical indices for early diagnosis need validation across geographical regions and may not be particularly applicable in children. Better biomarkers or the need for tests for early detection of ALF persists. Drugs used in the treatment of Wilson disease include copper chelating agents such as d-Penicillamine, trientine and zinc salt. Untreated Wilson disease uniformly leads to death from liver disease or severe neurological disability. Early recognition and treatment has excellent prognosis. Liver transplantation is indicated in acute liver failure and end stage liver disease. Family screening in order to detect the disorder in the first-degree relatives is warranted. This review provides an overview of different aspects of Wilson disease including geographical differences in presentations and clinical management and the limitations of currently available tests.

A Review and Current Perspective on Wilson Disease

Wilson disease (WD) is an autosomal-recessive disorder of hepatocellular copper deposition caused by pathogenic variants in the copper-transporting gene, ATP7B. Early detection and treatment are critical to prevent lifelong neuropsychiatric, hepatic, and systemic disabilities. Due to the marked heterogeneity in age of onset and clinical presentation, the diagnosis of Wilson disease remains challenging to physicians today. Direct sequencing of the ATP7B gene is the most sensitive and widely used confirmatory testing method, and concurrent biochemical testing improves diagnostic accuracy. More than 600 pathogenic variants in ATP7B have been identified, with single-nucleotide missense and nonsense mutations being the most common, followed by insertions/deletions, and, rarely, splice site mutations. The prevalence of Wilson disease varies by geographic region, with higher frequency of certain mutations occurring in specific ethnic groups. Wilson disease has poor genotype-phenotype correlation, although a few possible modifiers have been proposed. Improving molecular genetic studies continue to advance our understanding of the pathogenesis, diagnosis, and screening for Wilson disease.

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The Genetics of Wilson Disease

Context: Geographic distribution of ATP7B mutations in different populations.Objective: To summarise common mutations in the ATP7B gene and graphically illustrate their prevalence in different populations.Methods: A literature search was done using PubMed and the Wilson Disease Mutation Database (http://www.wilsondisease.med.ualberta.ca/database).Results: p.His1069Gln is the most prevalent mutation seen in Europe. In the Mediterranean countries, the array of prevalent mutations is different from the rest of Europe. In Far East Asian countries, the mutation p.Arg778Leu is the most common. In India, no single mutation seems to be dominant, owing to the vast ethnic diversity of the country. The p.Cys271* mutation is dominant in the east, west and south, but not reported in the north. In the Middle East, data from Saudi Arabia shows the p.Gln1399Arg mutation as the most prevalent. In the US, the p.His1069Gln is dominant, whereas in Brazil the mutation c.3402delC dominates.Conclusion: Clinical features...

Geographic distribution of ATP7B mutations in Wilson disease

Clinical practice guidelines for Wilson's disease (WD) have been published by the American Association for the Study of Liver Diseases and European Association for the Study of the Liver in 2008 and 2012, respectively Their focus was on the hepatic aspects of the disease Recently, a position paper on pediatric WD was published by the European Society of Pediatric Gastroenterology Hepatology and Nutrition A need was felt to harmonize guidelines for the hepatic, pediatric, and neurological aspects of the disease and contextualize them to the resource-constrained settings Therefore, experts from national societies from India representing 3 disciplines, hepatology (Indian National Association for Study of the Liver), pediatric hepatology (Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition), and neurology (Movement Disorders Society of India) got together to evolve fresh guidelines A literature search on retrospective and prospective studies of WD using MEDLINE (PubMed) was performed Members voted on each recommendation, using the nominal voting technique The Grades of Recommendation, Assessment, Development and Evaluation system was used to determine the quality of evidence Questions related to diagnostic tests, scoring system, and its modification to a version suitable for resource-constrained settings were posed While ceruloplasmin and 24-h urine copper continue to be important, there is little role of serum copper and penicillamine challenge test in the diagnostic algorithm A new scoring system – Modified Leipzig score has been suggested with extra points being added for family history and serum ceruloplasmin lower than 5 mg/dl Liver dry copper estimation and penicillamine challenge test have been removed from the scoring system Differences in pharmacological approach to neurological and hepatic disease and global monitoring scales have been included Rising bilirubin and worsening encephalopathy are suggested as indicators predicting need for liver transplant but need to be validated The clinical practice guidelines provide recommendations for a comprehensive management of WD which will be of value to all specialties

Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India.

Wilson's disease (WD) is an autosomal recessive disease involving a defect of copper transport by the hepatic lysosomes. It leads to excess copper deposition in the liver, the brain, the kidneys and the skeletal system, affecting most commonly children or young adults and running an invariably fatal course if not adequately treated by de-coppering therapy. The last century has witnessed several changes, notable among these are: Increased awareness, improved diagnostic facilities leading to earlier recognition even in the pre-symptomatic phase, clear distinction from its mimics, aggressive therapeutic approaches owing to availability of effective treatment and an overall reduction in the morbidity and mortality. It is widely acknowledged that the disease is not as rare as once believed. Sir SAK Wilson published his landmark article in 1912, but it was only in 1968 that the first patient of WD was reported from our country. Publications from India on WD have focused on phenotypic characterization, documentations of lesser recognized aspects of the disease e.g. seizures, behavior abnormality, speech and cognitive impairment, sub-clinical affection of visual pathway, heart and autonomic function and pre-symptomatic detection. Attempts have been made to understand the clinical heterogeneity of the disease through identification of biochemical and immunological markers, magnetic resonance imaging, neuropathological study and genetic analysis for novel and/or known mutations. Assessment of impairment and severity and effect of various therapeutic interventions namely zinc sulphate on the long-term outcome and quality of life have also been studied. Nevertheless, clinicians often face difficulties in long-term care of these patients. Diagnostic errors leading to delay in diagnosis and initiation of treatment are common, even in patients with positive family history. There is no consensus regarding therapeutic protocols since the use of penicillamine, once a 'gold standard' for treatment, has been debated by experts. Mortality and morbidity of this potentially treatable disease and nonavailability of medications to the poor patients remain a major area of concern.

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Wilson's disease: An Indian perspective.

Objective: To analyze ATP7B mutations in Wilson’s disease (WD) patients from the Indian subcontinent and to correlate these with WD phenotype. Meth­ ods: We studied 27 WD patients from 25 unrelated families. Twenty-two families were from three south­ ern Indian states – Tamil Nadu, Andhra Pradesh and Kerala. We applied conformation- sensitive gel elec­ trophoresis (CSGE) to screen for the mutations in patients and their families. PCR products exhibiting aberrant patterns in CSGE were subjected to direct DNA sequencing. As siblings affected by WD within a family share identical ATP7B genotype, we com­ pared WD phenotype among affected siblings within families. Results: ATP7B mutations were detected in 22 of the 25 probands –13 were homozygotes and 9 were compound heterozygotes. Eleven novel muta­ tions were detected. Only two common mutations were found: G3182A in 4 (16%) and C813A in 3 (12%) probands. ‘Hot spots’ for ATP7B mutations were exons 18 and 13. Lack of common dominant mutations prevented correlation of individual ATP7B mutations with WD phenotype. Symptomatic WD in a live sibling was not found in any family. In 8 fami­ lies, a sibling died of presumed WD – in 6 of these, WD phenotype was identical to that in the proband. Conclusions: We describe the spectrum of ATP7B mutations including 11 novel mutations in Indian WD patients and document lack of a single dominant mutation. Identical WD phenotype among siblings in only 6 of 8 families with >1 child affected by WD suggests that factors other than ATP7B mutations influence WD phenotype. [Indian J Gastroenterol 2006;25:277-282]

ATP7B mutations in families in a predominantly Southern Indian cohort of Wilson's disease patients

Genotype phenotype correlation in Wilson’s disease within families-a report on four south Indian families

Copper and copper-containing proteins (cuproproteins) are essential for a variety of metabolic processes in human metabolism. An average adult diet contains approximately 5 mg of copper, 40% of which is absorbed in the upper gastrointestinal tract. Almost all of the absorbed copper is excreted in the bile as a complex that has no enterohepatic circulation. Wilson’s disease results from impaired biliary excretion of copper with the accumulation of copper in the liver and other organs. The gene responsible for Wilson’s disease ( ATP7b ) was cloned independently in three different laboratories in 1993. Thus far, more than 200 distinct mutations have been described. More than half of these are missense mutations within the conserved domains of the protein or in predicted transmembrane domains, while the remainder consist of small insertions and deletions, splice site abnormalities and nonsense mutations. Although some affected individuals are homozygous for specific alleles, the majority are compound heterozygotes. This degree of complexity indicates that mutation analysis will be impractical as a screening test for the disease, except for screening within families. ATP7b is a large polytopic membrane protein that uses the energy of ATP hydrolysis to transport copper from the cytosol into the secretory compartment of the hepatocyte. Mutations in the ATP7b gene have been associated with a variety of effects including abnormalities of copper transport, subcellular localization and interactions with other hepatic proteins such as atox1. It is likely that different mutations affect the protein in different ways but at least one common mutation (H1069Q) appears to affect protein folding with subsequent impairment of binding to catalytic sites. One feature of Wilson’s disease is the low serum level of ceruloplasmin. This protein is synthesized in hepatocytes and incorporates 6 atoms of copper prior to secretion into blood. Lack of functional ATP7b results in the secretion of apoceruloplasmin that is rapidly removed from the circulation. Caeruloplasmin does not appear to have a significant effect on copper metabolism as humans and mice with caeruloplasminemia have normal copper homeostasis (aceruloplasminemia). Unfortunately, there is no clear relationship between genotype and phenotype. For example, patients who are homozygous for specific alleles often fail to show similarities in relation to age of onset, clinical features or laboratory findings. This might have been predicted by previous studies showing variation in the clinical features of Wilson’s disease within families. Presumably, this reflects the influence of additional genetic or environmental factors on the manifestations of the disease. One minor genetic factor is that of apolipoprotein E genotypes that appear to influence the age of onset of symptoms in patients who are homozygous for H1069Q. Current challenges include a more detailed understanding of how mutations in the ATP7b gene affect the biliary excretion of copper and why specific mutations are poorly correlated with clinical features. This seems likely to involve the proteomics of Wilson’s disease that include cellular and other environmental influences on protein expression and function. See Table 1 for a summary of the key points presented.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1440-1746.2003.03389.x

ATP7b gene and Wilson's disease

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S Santhosh

Papers

ATP7B mutations in families in a predominantly Southern Indian cohort of Wilson's disease patients

Genotype phenotype correlation in Wilson’s disease within families-a report on four south Indian families

ATP7b gene and Wilson's disease

Prevalence of histone family E1 (HFE) mutant alleles in a Tamilian cohort from Vellore, South India.