Niemann-Pick disease (NP) disease is a rare autosomal recessive lysosomal disease; it involves the accumulation of sphingolipids in cells throughout the body. NP disease is divided into four types based on the genetic cause and the signs and symptoms: type A, type B, type C1, and type C2. Niemann-Pick disease type B is a mild subtype of Niemann-Pick disease, characterized clinically by onset in childhood with hepatosplenomegaly, growth retardation, and lung disorders such as infections and dyspnea. Progressive and/or clinically significant neurologic manifestations occur infrequently. The diagnosis of Niemann-Pick disease is based on detection of either biallelic pathogenic variants in SMPD1 gene or residual ASM enzyme activity that is less than 10% of peripheral blood lymphocytes or cultured skin fibroblasts. Survival to adulthood can occur.
Niemann-Pick disease type B disorder results from deficient activity of sphingomyelinase, a lysosomal enzyme encoded by the SMPD1 gene located on chromosome 11p15.4. Mutations in this gene have been identified in patients with Niemann-Pick disease types A and B. A common NPD type B mutation, p.Arg610del (R608del), has been found to be the predominant mutant allele (87%) in Maghreb region of North Africa.
[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 (NPD-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 8 months with hepatosplenomegaly and he died at 3 years age. The second child was diagnosed at the age of 6 months. He underwent a bone marrow transplant at the age of 1 year, but had severe graft-versus-host disease with continuous diarrhea and severe bleeding. At 6 years of age, he remained severely neurologically 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 failed to be diagnosed. 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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