Deep sequencing of SMPD1 gene revealed a heterozygous frameshift mutation (p.Ser192Alafs) in a Palestinian infant with Niemann–Pick disease type A: a case report

Abstract

BackgroundNiemann–Pick disease is caused by reduced level of the lysosomal enzyme acid sphingomyelinase. Children can survive between 2 and 12 years based on the disease type. Two main types are well known: type A and B. Niemann–Pick disease type A is characterized by severe central nervous system deterioration and hepatosplenomegaly while type B is a progressive hypersplenism accompanied with gradual deterioration of pulmonary function.Case presentationWe describe an 11-month-old Palestinian baby boy with hepatosplenomegaly, hypotonia, delayed motor development, laryngomalacia, bilateral cherry-red spots, and failure to thrive. Metabolic screening, blood count, differential tests, immunology screen, infectious disease screen, urine, biochemical tests as well as molecular diagnosis were performed. The molecular diagnosis was done by amplifying the whole sphingomyelin phosphodiesterase 1 (SMPD1) gene, followed by deep sequencing. The obtained sequences were aligned, de novo assembled and compared to human reference gene (GenBank GeneID: NG_011780.1, Ensembl version ENSG00000166311 and protein identified as UniProtKB – P17405).Two known mutations were identified in our patient: the pathogenic frameshift mutation NM_000543.4(SMPD1):c.573delT (p.Ser192Alafs) and the benign polymorphism NM_000543.4(SMPD1):c.107T>C (p.Val36Ala). The enzyme study showed a very low level of enzymatic activity of acidic sphingomyelinase (0.1 nmol/ml per hour). Correlations between clinical findings, laboratory data, and sequence analysis are presented.ConclusionsIn conclusion, this is the first report about a heterozygote frameshift p.Ser192AlafsX65 in a Palestinian patient with Niemann–Pick disease type A, emphasizing the importance of deep sequencing in genetic diagnosis of this rare inherited disease.

SMPD1 Expression Profile and Mutation Landscape Help Decipher Genotype–Phenotype Association and Precision Diagnosis for Niemann–Pick Disease Types A and B

“…Patients with NPA often die before age three years from diagnosis (early onset) (6). Symptoms of NPA include central nervous system (CNS) deterioration, cherry-red macula, and massive hepatosplenomegaly, leading to death at an early age, whereas patients with NPB have a better prognosis (7), which symptoms are non-neuropathic. Most of them could survive into adulthood and even until the 70s.…”

SMPD1 Expression Profile and Mutation Landscape Help Decipher Genotype–Phenotype Association and Precision Diagnosis for Acid Sphingomyelinase Deficiency

“…Patients with NPA often die before diagnosis (early onset) (8). Symptoms of NPA include central nervous system (CNS) deterioration, cherry-red macula, and massive hepatosplenomegaly, leading to death at an early age, whereas patients with NPB have a better prognosis (9), which symptoms are non-neuropathic. Most of them could survive into adulthood and even until the 70s.…”

“…Since the pathogenic factor for the two NPD types are mutations in the SMPD1 gene, systematically exploring the underlying mechanism that causes these two subtypes is necessary. Because the pathogenic mutations of the SMPD1 gene are primarily found in compound heterozygotes and clinical case reports, investigating the phenotype-genotype association is the key to distinguishing the two subtypes (8)(9)(10)(11). Genotype-phenotype relationships for pathogenicity could be associated with the molecular basis, such as gene mutation and expression (12).…”