The Demographics and Distribution of Type B Niemann-Pick Disease: Novel Mutations Lead to New Genotype/Phenotype Correlations

Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 01/2003; 71(6):1413-9. DOI: 10.1086/345074
Source: PubMed

ABSTRACT 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.

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Available from: Calogera M Simonaro, Mar 14, 2014
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    • "The nonsynonymous variation rs141641266/c.1460C > T/p.A487V, previously assumed to be a missense mutation causing Niemann-Pick disease (NPD) type B (Simonaro et al., 2002), leads to normal L-ASM and only slightly lower S-ASM activity levels (Rhein et al., 2013). More than 100 clinically relevant missense mutations in the SMPD1 gene leading to enzymes with decreased catalytic activity, the cause of autosomal recessive NPD types A and B (Brady et al., 1966; Schuchman, 2010), have been deposited in the Human Gene Mutation Database (www. "
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    ABSTRACT: Acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, hydrolyzes sphingomyelin to ceramide and phosphorylcholine. In mammals, the expression of a single gene, SMPD1, results in two forms of the enzyme that differ in several characteristics. Lysosomal ASM (L-ASM) is located within the lysosome, requires no additional Zn2+ ions for activation and is glycosylated mainly with high-mannose oligosaccharides. By contrast, the secretory ASM (S-ASM) is located extracellularly, requires Zn2+ ions for activation, has a complex glycosylation pattern and has a longer in vivo half-life. In this review, we summarize current knowledge regarding the physiology and pathophysiology of S-ASM, including its sources and distribution, molecular and cellular mechanisms of generation and regulation and relevant in vitro and in vivo studies. Polymorphisms or mutations of SMPD1 lead to decreased S-ASM activity, as detected in patients with Niemann-Pick disease B. Thus, lower serum/plasma activities of S-ASM are trait markers. No genetic causes of increased S-ASM activity have been identified. Instead, elevated activity is the result of enhanced release (e.g., induced by lipopolysaccharide and cytokine stimulation) or increased enzyme activation (e.g., induced by oxidative stress). Increased S-ASM activity in serum or plasma is a state marker of a wide range of diseases. In particular, high S-ASM activity occurs in inflammation of the endothelium and liver. Several studies have demonstrated a correlation between S-ASM activity and mortality induced by severe inflammatory diseases. Serial measurements of S-ASM reveal prolonged activation and, therefore, the measurement of this enzyme may also provide information on past inflammatory processes. Thus, S-ASM may be both a promising clinical chemistry marker and a therapeutic target.
    Biological Chemistry 03/2015; 396(6-7). DOI:10.1515/hsz-2015-0109 · 2.69 Impact Factor
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    • "The primary sequence of RsASML shared positive homology and predicted secondary structure with human aSMase over the entire catalytic and C-terminal domains (Fig. 1b). This included a C-terminal cysteine pair known to form a disulfide in human aSMase [33], as well as 18 amino acids mutated in Niemann-Pick Type A or B patients [34]–[43]. A reverse BLAST search with the RsASML protein sequence identified RsASML as belonging to the Metallophosphatase (MPP)_aSMase protein superfamily with an E-value of 5.22e−48. "
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    ABSTRACT: Acid sphingomyelinase (aSMase) is a human enzyme that catalyzes the hydrolysis of sphingomyelin to generate the bioactive lipid ceramide and phosphocholine. ASMase deficiency is the underlying cause of the genetic diseases Niemann-Pick Type A and B and has been implicated in the onset and progression of a number of other human diseases including cancer, depression, liver, and cardiovascular disease. ASMase is the founding member of the aSMase protein superfamily, which is a subset of the metallophosphatase (MPP) superfamily. To date, MPPs that share sequence homology with aSMase, termed aSMase-like proteins, have been annotated and presumed to function as aSMases. However, none of these aSMase-like proteins have been biochemically characterized to verify this. Here we identify RsASML, previously annotated as RSp1609: acid sphingomyelinase-like phosphodiesterase, as the first bacterial aSMase-like protein from the deadly plant pathogen Ralstonia solanacearum based on sequence homology with the catalytic and C-terminal domains of human aSMase. A biochemical characterization of RsASML does not support a role in sphingomyelin hydrolysis but rather finds RsASML capable of acting as an ATP diphosphohydrolase, catalyzing the hydrolysis of ATP and ADP to AMP. In addition, RsASML displays a neutral, not acidic, pH optimum and prefers Ni2+ or Mn2+, not Zn2+, for catalysis. This alters the expectation that all aSMase-like proteins function as acid SMases and expands the substrate possibilities of this protein superfamily to include nucleotides. Overall, we conclude that sequence homology with human aSMase is not sufficient to predict substrate specificity, pH optimum for catalysis, or metal dependence. This may have implications to the biochemically uncharacterized human aSMase paralogs, aSMase-like 3a (aSML3a) and aSML3b, which have been implicated in cancer and kidney disease, respectively, and assumed to function as aSMases.
    PLoS ONE 08/2014; 9(8):e105830. DOI:10.1371/journal.pone.0105830 · 3.23 Impact Factor
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    • "It is very interesting that with the exception of five exon point mutations, c.688C>T (p.Arg230Cys) [7], c.748A>T(p.Ser250Arg) [13], c.759C>A (p.Asp253Glu) [14], c.1565A>G (p.Asn522Ser) [10], c.1492C>T (p.Arg498Cys) [15], and a small insertion, c.1095_1096insG [7], the majority of mutations, including c.4delC, c.147_150del4, c.1307-1312dup6, c.842-849dup8, p.Glu248X, p.Gly336Ser, p.Trp342Cys, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser, p.Trp437Arg, p.Thr451Pro, p.His461Pro, p.Ala484Val, p.Ser486Arg, p.Pro533Leu, p.Val559Leu and p.Tyr500His, were novel according the SMPD1 gene mutation database ( These newly detected mutations have been deposited in the public databases dbSNP, with the batch accession number 1057561. "
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    ABSTRACT: Background Clinical observations and molecular analysis of the SMPD1 gene in Chinese patients with acid sphingomyelinase deficiency Niemann-Pick disease (NPD) are scarce. Methods A cohort of 27 Chinese patients diagnosed with acid sphingomyelinase deficiency, within the past five years, were collected and investigated for genotype, phenotype, and their correlations. Results The majority of our patients (25/27) were under 18 years of age. From the cohort group, eight (30%) fulfilled characters of type A. Four other patients experienced neurologic involvement after two years of age, these were classified as intermediate type. The remaining fifteen presented without clear neurologic involvement and were regarded as type B. One patient, from the type B group, presented with the unusual symptom of a secondary amenorrhea. Three patients, one from the type B group and two from the intermediate group, presented with pronounced proteinuria, in the late stages of the disease, indicating possible kidney involvement in NPD. Twenty-four SMPD1 gene mutations had been identified; eighteen of these are novel ones. These included four exonic small deletions/duplications (c.4delC, c.147_150del4, c.842-849dup8, c.1307-1312dup6), one termination mutation (p.Glu248X), and thirteen exonic point mutations (p.Gly336Ser, p.Trp342Cys, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser, p.Trp437Arg, p.Thr451Pro, p.His461Pro, p.Ala484Val, p.Ser486Arg, p.Tyr500His, p.Pro533Leu, p.Val559Leu). Notably, eight mutations had more than one occurrence with c.4delC and p.Glu248X accounting for ~30% of all alleles. Correlation analysis of genotype and phenotype indicated eight mutations, c.842-849dup8, p.Glu248X, p.Arg230Cys, p.Trp437Arg, p.His461Pro, p.Ala484Val p.Ser486Arg, and p.Pro533Leu,to be severe mutations. Five mutations, c.4delC, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser and p.Val559Leu were projected to be mild mutations. Interestingly, three intermediate individuals carried combinations of a mild mutation, c.4delC, on one allele and a severe mutation on the other allele. Conclusions The Chinese population may have a comparably high incidence of sphingomyelinase-deficient Niemann-Pick disease type A. This study has identified some novel genotype and phenotype correlations in this rare and devastating disorder.
    Orphanet Journal of Rare Diseases 01/2013; 8(1):15. DOI:10.1186/1750-1172-8-15 · 3.96 Impact Factor
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