Gauchers Disease in the UK: Screening Non-Jewish Patients for the Two Common Mutations

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This is the title of a research paper, published recently in the Journal of Medical Genetics (volume 30, pages 280-283), written by Andrew J Walley, M Luiza Barth, Ian Ellis, Anthony H Fenson and Ann Harris. The researchers are based either at the Institute of Molecular Medicine, John Radcliffe Hospital, Oxford or at the Division of Medical and Molecular Genetics, UMDS-Guy's Campus, London. Andrew Walley summarises the paper here:

We reported an investigation into the genetic mutations that cause Gauchers disease among non-Jewish patients in the UK. Other workers have reported that only four mutations account for 97% of all Ashkenazi Jewish patients, so screening and counselling is generally possible in this patient group.

The current study looked at whether most cases of Gauchers disease in non-Jewish patients could be accounted for by the same four mutations. The frequency of Gauchers disease is much lower in the general population and there is less data available on non-Jewish patients. We also wished to investigate further a correlation reported previously in the United States between particular mutations and clinical severity.

Twenty six patients and two carriers were screened for the four common mutations. These are known by many names but, in line with common notation in other genetic diseases, we have named them in a way that is simple for a scientist to understand. Their names are N370S (previously known as 370 or 1226), L444P (previously known as 1448 or NciI), Ins84G (previously known as 84GG) and 1066+1G->A (previously known as IVS+2).

To understand the results it should be noted that every patient has two mutations, one inherited from their mother and one from their father. Each copy of the gene is known as an allele and so each patient has two mutant alleles. A carrier has one mutant allele and one unaffected allele.

In the population examined in this study, 54 mutant alleles were screened. Out of these 54 alleles, 26% were N370S, 35% were L444P and of the remaining 39%, three previously described rare mutations were detected and the rest remained undefined. These findings were similar to data previously reported by Dr E. Beutler on non-jewish patients in the US.

The large percentage of undefined mutations showed that general screening would be impractical but prenatal screening might be possible for a couple who had previously had an affected child.

Gauchers disease may present with different severities, ranging from severe disease occuring early in life to mild disease with late onset. Interestingly the study showed that if a patient had at least one allele with the N370S mutation, the course of the disease was likely to be relatively mild and that if a patient had at least one L444P allele, and no N370S allele, the course of the disease was likely to be more severe. Of the four patients studied with very severe disease, three out of the four each had two copies of the L444P allele.

On behalf of our research group, I would like to thank all the Gauchers patients, their families and GPs who organised the blood samples that made our research possible.

In the future we are looking: (i) to define those alleles carrying mutations that were not defined by this screening study, and (ii) to examine the effects of these mutations on glucocerebrosidase enzyme activity, to understand more about how mutations cause disease. The possibility exists that the remaining 39% ofalleles may be accounted for by just a few mutations but the search for those mutations may take quite some time yet.

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