The SMPD1 gene, located on chromosome 11p15.4, gives instructions for making a lysosomal enzyme called acid sphingomyelinase. This enzyme converts sphingomyelin to ceramide, and has phospholipase C activities toward 1,2-diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol. Defects in this enzyme are the cause of Niemann-Pick (NP) disease types A and B. The enzymatic defect results in pathologic accumulation of sphingomyelin and other lipids in the monocyte-macrophage system, which is the primary site of pathology in patients with NP disease.
The SMPD1 gene comprises six coding exons, spanning approximately 4.7 kb within genomic DNA. Studies showed that SMPD1 gene is paternally imprinted and that clinical variability results from differential expression of the mutant alleles in patients with NPD. Several lines of evidence demonstrate the involvement of Sphingomyelinase in cell death. Stress-mediated activation of sphingomyelinase leads to the production of ceramide, which serves as a second messenger in initiating apoptosis, therefore lymphoblasts from Niemann-Pick patients did not resposnd to ionizing radiation with ceramide generation and apoptosis. In the same vein, inactivation of endogenous hepatocellular sphingomyelinase activity protected hepatocytes from TNF-alpha-induced apoptosis.
To date, over 160 mutations distributed along the SMPD1 gene have been detected in patients with Niemann-Pick disease types A and B. The majority of mutations are missense; however, nonsense, splicing, small insertions or deletions have been reported. Four common mutations have been identified; three of these mutations (Leu304Pro, Arg498Leu and Phe333Serfs) account for about 95% of patients with NPD-A, and one recurrent mutation, Arg608del, is responsible for most cases of NPD-B of Ashkenazi Jewish origin.
[See: Saudi Arabia> Simonaro et al., (2002)]
Simonaro et al., (2002) conducted a study worldwide for patients with type B Niemann-Pick disease (NPD). Dimorphic and/or mutation information were collected for 394 NPD type B patients. The highest incidence was in individuals of Turkish, Arabic, and North African descent. Of these patients, there were two Jordanians, 20 Tunisians, and 18 Saudis. A total of 45 novel mutations were found, of these several common mutations within ethnic groups were identified. The H421Y and K576N mutations were found to be the common mutations among Saudi patients accounting for more than 85% of the alleles. These mutations led to an early-onset and more severe form of type B NPD. The previously reported delR608 mutation was found in about 12% of the alleles studied.
Hellani et al., (2004) performed mutation screening in a consanguineous family with severe Niemann-Pick disease type B for the SMPD1 gene followed by preimplantaion genetic diagnosis (PGD) using nested PCR and sequencing. The family had three children with NPD-B. The first child presented at the age of months with hepatosplenomegaly and he died at 3 years old age. The second child was diagnosed at the age of 6 months. He underwent BMT at the age of 1 year, but had severe Graft-versus-host with continues diarrhea and severe bleeding. At 6 years of age, he remained severely neurological crippled and his development level was 6 months only. The third child was a 4.5-year-old boy who was diagnosed with the disease at 2 months of age. He developed liver failure with jaundice and low platelet count. A novel homozygous c.1597T>C in exon 6 of the SMPD1 gene was identified in the three affected patients. This mutation resulted in a W533R amino acid substitution. The parents were carriers for this mutation. The PGD for eight embryos revealed that three embryos were heterozygous for the W533R mutation, three were normal, one embryo was mutant, and one was failed to diagnose. A singleton pregnancy was obtained after one heterozygous embryo and one normal embryo were transferred. Postnatal DNA testing revealed a normal homozygous genotype for the newborn.
Monies et al. (2017) outlined the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One patient, a 3-year-old female, suffered from severe neonatal cholestasis and fluctuating GGT. Using a multigene panel for gastrointestinal disorders, a homozygous mutation (c.1267C>T, p.H423Y) was identified in exon 4 of the patient’s SMPD1 gene. As SMPD1 is associated with Niemann-Pick disease, the atypical presentation of the patient helped expand the phenotype of this disorder.
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