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We have collected demographic and/or mutation information on a worldwide sample of 394 patients with type B Niemann-Pick disease (NPD). The disorder is panethnic, with the highest incidence occurring in individuals of Turkish, Arabic, and North African descent. Only five of the 394 patients were Ashkenazi Jewish, revealing that, unlike the type A form of NPD, type B NPD does not occur frequently within this population. Mutation analysis of the acid sphingomyelinase (ASM) gene (designated "SMPD1") was performed on 228 patients (324 unique alleles), and several novel, "common" mutations were found. Among these were the L137P, fsP189, and L549P mutations, which accounted for approximately 75% of the alleles in Turkish patients, the H421Y and K576N mutations, which accounted for approximately 85% of the alleles in Saudi Arabian patients, the S379P, R441X, R474W, and F480L mutations, which accounted for approximately 55% of the alleles in Portuguese/Brazilian patients, and the A196P mutation, which accounted for approximately 42% of the alleles in Scottish/English patients. The previously reported DeltaR608 mutation occurred on approximately 12% of the alleles studied. Overall, a total of 45 novel mutations were found, and several new genotype/phenotype correlations were identified. In particular, the L137P, A196P, and R474W mutations were consistent with a less severe form of type B NPD, whereas the H421Y and K576N mutations led to an early-onset, more severe form that was specific to Saudi Arabia. These data provide the first extensive demographic assessment of this disorder and describe several new mutations that can be used to predict phenotypic outcome and to gain new insights into the structure and function of ASM.

Niemann-Pick type C (NPC) disease is an autosomal recessive lipid-storage disorder usually characterized by hepatosplenomegaly and severe progressive neurological dysfunction, resulting from mutations affecting either the NPC1 gene (in 95% of the patients) or the yet-to-be-identified NPC2 gene. Our initial study of 25 patients with NPC1 identified a T3182-->C transition that leads to an I1061T substitution in three patients. The mutation, located in exon 21, affects a putative transmembrane domain of the protein. PCR-based tests with genomic DNA were used to survey 115 unrelated patients from around the world with all known clinical and biochemical phenotypes of the disease. The I1061T allele constituted 33 (14.3%) of the 230 disease-causing alleles and was never found in controls (>200 alleles). The mutation was particularly frequent in patients with NPC from Western Europe, especially France (11/62 alleles) and the United Kingdom (9/32 alleles), and in Hispanic patients whose roots were in the Upper Rio Grande valley of the United States. The I1061T mutation originated in Europe and the high frequency in northern Rio Grande Hispanics results from a founder effect. All seven unrelated patients who were homozygous for the mutation and their seven affected siblings had a juvenile-onset neurological disease and severe alterations of intracellular LDL-cholesterol processing. The mutation was not found (0/40 alleles) in patients with the severe infantile neurological form of the disease. Testing for this mutation therefore has important implications for genetic counseling of families affected by NPC.