Genetic Testing

The discovery of the underlying genetic defect in Wilson disease raised the hope of overcoming the obstacles in diagnosing the disease. Genetic testing in Wilson disease, however, is complicated by the fact that most patients are compound heterozygous with different mutations on each allele. More than 300 ATP7B mutations spread over the entire coding sequence have been described and are listed in a database that can be downloaded at http://www. uofa-medical-genetics.org. The most frequent ATP7B mutation found in Caucasians is a histidine by glutamine exchange at codon 1069 (H1069Q) in exon 14, which is found in 10% to 70% of Wilson's disease chromosomes.1-16-1 It is proposed that the H1069Q mutation results in an increased degradation of mutated protein within the endoplasmic reticulum.[17] Another frequent mutation in Caucasians represent 3402delC, whereas the most frequent mutation in Asia is R778L.[18]

The large number of mutations and the high prevalence of compound heterozygotes hamper geno-type-phenotype correlation analysis. In a homogeneous population from Saxonia, Germany, H1069Q was found in 87% of patients. Homozygosity for H1069Q was shown to be associated with later onset of disease, predominance of neurological symptoms, and milder hepatic disease compared to compound heterozygotes or carriers of other mutations.[16] This correlation has also been established in several other populations.1-19,20-1 However, conflicting results have been obtained by others.[21] Genotype-phenotype correlation of other mutations is rendered difficult by their low frequency and the different ethnic backgrounds of the populations studied. The phenotypic appearance of a certain genotype is most probably influenced by a variety of genetic, epigenetic, and environmental factors that remain to be elucidated.

Genetic testing in Wilson disease is possible in affected index patients and indicated in patients in which the clinical presentation and the laboratory tests do not allow a definite diagnosis. Genetic testing is also indicated to identify asymptomatic relatives. It has to be pointed out that a negative genetic test result does not exclude Wilson disease in a suspected case.

Several methods have been described for mutation detection in Wilson disease. In areas where a specific mutation is common, such as H1069Q in Central Europe, genotyping using restriction fragment length polymorphism (RFLP) analysis or melting curve analysis with fluorescence resonance energy transfer (FRET) probes is feasible.[22]

For screening further mutations, single-strand conformation polymorphism (SSCP) analysis represents an alternative approach. However, sensitivity of SSCP is low with a detection rate of only 50-60%, and homozy-gous individuals may be missed by this method because of absent heteroduplex generation. Moreover, ATP7B contains numerous harmless polymorphisms that cannot be discriminated from disease-causing mutations by an altered SSCP mobility pattern.

Direct DNA sequencing with a sensitivity of 65-85% is available in specialized laboratories, but is time-consuming and cost-intensive.

Predictive genetic testing of family members is possible and can be generally recommended. Screening of sibs is especially mandatory, as each sib possesses a one in four chance of being affected. If the underlying mutations are unknown, haplotype analysis using microsatellite markers (D13S314, D13S301, D13S316) or intragenic SNPs is alternatively feasible to detect asymptomatic sibs. The risk for offspring of an affected patient is approximately 1 per 180, assuming a carrier frequency of 1 per 90. This risk, however, is markedly higher in consanguineous families.

Although prenatal testing is principally feasible, Wilson disease is in our opinion no indication for prenatal diagnosis and induced abortion because treatment started in asymptomatic individuals after birth allows a normal life span.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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