wilson disease and molecular genetic diagnosis

wilson disease is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances, or a combination of these, in individuals ranging from age three years to over 50 years. the primary consequence for most of those with wd is liver disease, appearing in late childhood or early adolescence as acute hepatitis, liver failure, or progressive chronic liver disease in the form of chronic active hepatitis or cirrhosis of the liver. in others, the first symptoms occur later in adulthood even up to 70 years of age with neurologic or neuropsychiatric presentation. most patients who present with neuropsychiatric manifestations have cirrhosis. the most common presenting neurologic feature is asymmetric tremor, occurring in approximately half of individuals with wilson disease. the character of the tremor is variable and may be predominantly resting, postural, or kinetic. frequent early symptoms include difficulty speaking, excessive salivation, ataxia, masklike facies, clumsiness with the hands, and personality changes. late manifestations (now rare because of earlier diagnosis and treatment) include dystonia, spasticity, grand mal seizures, rigidity, and flexion contractures. one study describes 4 distinct diagnostic categories based on patients major neurologic findings. 1) the patients in the parkinsonian group (45%) were distinguished by paucity of expression and movement. 2) the patients in the pseudosclerotic group (24%) had tremor resembling multiple sclerosis. 3) the patients in the dystonic group (15%) were characterized by hypertonicity associated with abnormal limb movements. 4) the patients in the choreic group (11%) were predominantly characterized by choreoathetoid abnormal movements associated with dystonia. psychiatric features include emotional lability, impulsiveness, disinhibition, and self-injurious behavior. the reported percentage of patients with psychiatric symptoms as the presenting clinical feature is 10-20%. the range of psychiatric abnormalities associated with wilson disease has been divided into 4 basic categories, as: behavioral /affective /schizophreniclike and cognitive. diagnosis of wilson disease depends on the detection of low serum copper and ceruloplasmin concentrations, increased urinary copper excretion, the presence of kayser-fleisher rings in the cornea, and/or increased hepatic copper concentration. atp7b is the only gene currently known to be associated with wilson disease. molecular genetic testing of the atp7b gene is clinically available. the mutation detection rate varies depending on the test method and the individuals ethnicity. molecular genetic testing is playing an increasingly important role in diagnosis, as copper studies are frequently equivocal. mutation analysis for diagnosis is cumbersome because of the occurrence of many mutations, each of which is rare. furthermore, most patients are compound heterozygotes (i.e. carry two different mutations). direct mutation analysis for diagnosis is only helpful if a mutation occurs with a reasonable frequency in the population. in northern, central and eastern europe, the most common mutations are: h1069q mutation (allele frequency, 43.5%), mutations of exon 8 (6.8%), 3400delc (3%) and p969q (1.6%). in other parts of the world, the pattern of mutations is different (turkey, a1003t and p969q. sardinia, utr -441/-427del, 2463delc. far east, r778l). eventually, a multiplex polymerase chain reaction for the most frequent wilsons disease mutations in the region should make direct mutation analysis for diagnosis feasible and obtainable within a week complete gene sequencing detects mutations in about 98% of individuals with wilson disease. during the past two years we have checked 15 wilson patients (referred to our lab) by molecular genetic test for the h1069q mutation and they were all normal for this mutation. therefore we set up molecular diagnosis for the r778l mutation last month and we have decided to investigate this mutation in iranian patients.