ClinVar Genomic variation as it relates to human health

In an Ashkenazi Jewish patient with Niemann-Pick disease type B (607616), Levran et al. (1991) identified a 3-base deletion at nucleotides 1821-1823 which predicted the removal of an arginine residue from position 608 of the acid sphingomyelinase polypeptide. The other cDNA clone from this patient had the R496L mutation previously identified in type A Niemann-Pick disease patients (607608.0001). The delta-R608 mutation was not found in 15 unrelated non-Jewish type B patients, with the notable exception of 1 mildly affected patient of Arab descent who was homoallelic for the delta-R608 mutation. These results indicated that the delta-R608 mutation predicts the type B Niemann-Pick disease phenotype, even in the presence of the R496L type A allele, thereby providing the first genotype/phenotype correlation for this lysosomal storage disease. Although only 2 patients had been studied, it appeared that the delta-R608 mutation was a frequent cause of type B Niemann-Pick disease in Ashkenazi Jews. The terms homoallelic and heteroallelic (for genetic compound) seem to have been used particularly by Desnick and his colleagues, e.g., Levran et al. (1991); they are useful terms for the situations repeatedly encountered as more and more intragenic lesions are identified in mendelian disorders. Niemann-Pick disease type B has a high frequency in the Maghreb region of North Africa, which includes Morocco, Algeria, and Tunisia. In a study of 15 unrelated, non-Jewish North African type B patients, Vanier et al. (1993) found that 12 were homozygous and 2 compound heterozygous for the arg608-to-del mutation. They found the mutation in only 1 of 16 alleles from type B patients from other geographic areas (France, U.K., Italy, Czechoslovakia). A varying severity of the clinical and enzymatic expression was observed in homozygotes for this mutation. The R608 deletion mutation was found in a 55-year-old Belgian woman of Caucasian origin who had had progressive Parkinson disease for the previous 4 years and presented for acute onset of severe back pain, pain in the rib cage due to multiple vertebral fractures, as well as dyspnea due to interstitial lung disease (Volders et al., 2002). The patient was short statured as a child and the parents were first cousins. The vertebral fractures were thought to be due to increased physical activity after treatment of Parkinson disease, a genetic predisposition, and worsening disease due to interfering medication. She was treated with cholesterol-lowering drugs such as statins to decrease sphingomyelin synthesis, avoidance of drugs that inhibit sphingomyelinase, and bisphosphonates. No new fractures occurred, but the interstitial lung disease progressed. Fernandez-Burriel et al. (2003) reported that the R608 deletion was the most prevalent among patients in Gran Canaria Island in patients with Niemann-Pick disease. They estimated the prevalence of the disease as 0.8-1:100,000 in their community; all patients carried the arg608-to-del mutation. Because of the heterogeneity of the clinical phenotype and the high prevalence of the arg608-to-del mutation in their community, they suggested that the mutation be routinely tested for in adults with hepatosplenomegaly of unknown origin before trying more invasive tests such as liver or bone marrow biopsy. Rodriguez-Pascau et al. (2009) identified the R608del mutation in 38% of alleles from 21 patients of Spanish origin with Niemann-Pick disease. All patients with the R608del mutation had type B disease. In vitro functional expression studies in COS-7 cells showed that the mutant protein had 21.46% residual activity. Haplotype analysis suggested a founder effect. (less)