SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants

Zampieri, Stefania; Filocamo, Mirella; Pianta, Annalisa; Lualdi, Susanna; Gort, Laura; Coll, Mauricio; Sinnott, Richard O.; Geberhiwot, Tarekegn; Bembi, Bruno; Dardis, Andrea

doi:10.1002/humu.22923

Cited by 83 publications

(83 citation statements)

References 73 publications

(81 reference statements)

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“…To date, more than 180 mutations have been found within the SMPD1 gene causing types A and B NPD [e.g.,55,56]. These include point mutations (missense and nonsense), small deletions, and splicing abnormalities.…”

Section: Molecular Geneticsmentioning

confidence: 99%

Types A and B Niemann-Pick disease

Schuchman

Desnick

2017

Molecular Genetics and Metabolism

222

186

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The eponym Niemann-Pick disease (NPD) refers to a group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. Due to the pioneering work of Roscoe Brady and co-workers, we now know that there are two distinct metabolic abnormalities that account for NPD. The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM; “types A & B” NPD), and the second is due to defective function in cholesterol transport (“type C” NPD). Herein only types A and B NPD will be discussed. Type A NPD patients exhibit hepatosplenomegaly in infancy and profound CNS involvement. They rarely survive beyond 2–3 years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Intermediate patients also have been reported with mild to moderate neurological findings. All patients with types A and B NPD have mutations in the gene encoding ASM (SMPD1), and thus the disease is more accurately referred to as ASM deficiency (ASMD). Herein we will review the clinical, pathological, biochemical, and genetic findings in types A and B NPD, and emphasize the seminal contributions of Dr. Brady to this disease. We will also discuss the current status of therapy for this disorder.

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Section: Molecular Geneticsmentioning

confidence: 99%

Types A and B Niemann-Pick disease

Schuchman

Desnick

2017

Molecular Genetics and Metabolism

222

186

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“…Thus, the genotype cannot be easily correlated with the phenotype. However, some assumptions can be made based on functional analysis of single mutants and for recurrent mutations found in homozygosity [5]. NPD type A was previously described in two studies in the Palestinian community.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, loss of normal protein function due to protein truncation is expected. Unfortunately, the frameshift mutation p.Ser192AlafsX65 has not been expressed in vitro but its occurrence in homozygosity in patients with NPD type A strongly suggests its severity [5, 6]. …”

Section: Resultsmentioning

confidence: 99%

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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

Nasereddin

Ereqat

2018

J Med Case Reports

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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.

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“…El déficit de EMA es un desorden autosómico recesivo causado por actividad enzimática de la EMA menor al 10% o por la presencia de mutaciones patogénicas bialélicas en el gen SMPD1 (también llamado gen ASM) (31,32).…”

Section: Déficit De Esfingomielinasa áCida (Ema) (Enfermedad De Niemaunclassified

Guía colombiana para el diagnóstico de la deficiencia de lipasa ácida

Escobar

Montoya

Bermejo

et al. 2017

Rev. Colomb. Gastroenterol.

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ResumenIntroducción: la deficiencia de lipasa ácida lisosomal (LAL-D) es una entidad de herencia autosómica recesiva que lleva a la acumulación de esteres de colesterol y triglicéridos en el hígado, bazo y otros órganos. La edad de inicio y la tasa de progresión son muy variables, lo que posiblemente sea explicado por las mutaciones presentes en el gen LIPA. Las manifestaciones clínicas son las mismas que para otras patologías hepáticas, cardiovasculares y metabólicas, lo que hace difícil reconocerla en la práctica clínica. Objetivo: proveer una guía que permita a los clínicos reconocer los principales grupos de riesgo en los cuales se debe sospechar de LAL-D y mejorar su diagnóstico. Metodología: este documento se diseñó como un consenso de expertos en el cual participaron médicos especialistas en gastroenterología, hepatología, endocrinología, genética, patología y pediatría. Se realizó una revisión de la literatura acerca de las manifestaciones clínicas y de las herramientas para el diagnóstico de LAL-D y se siguió la metodología de técnica de grupo nominal. Resultados: se generaron algoritmos diagnósticos por consenso para cada uno de los grupos de riesgo, que facilitaran la sospecha y el diagnóstico de LAL-D. Conclusiones: esta guía propone algoritmos para el diagnóstico de LAL-D con base en el consenso clínico, que buscan optimizar la ruta diagnóstica en los pacientes con dicha patología. Palabras claveDeficiencia de lipasa ácida, enfermedad por depósito de esteres de colesterol, enfermedad de Wolman, dislipidemia, hepatomegalia. AbstractIntroduction: Lysosomal acid lipase deficiency (LAL-D) is an inherited autosomal recessive entity that leads to the accumulation of cholesterol and triglyceride esters in the liver, spleen and other organs. The age of onset and rate of progression vary greatly, possibly explained by mutations of the LIPA gene. Clinical manifestations are the same as those of other hepatic, cardiovascular and metabolic pathologies which makes it difficult to recognize in clinical practice. Objective: The objectives of these guidelines is to help clinicians recognize the major groups at risk for LAL-D and to improve its diagnosis. Methodology: This document was designed as a consensus of experts in gastroenterology, hepatology, endocrinology, genetics, pathology and pediatrics. A review of the literature regarding clinical manifestations and tools for diagnosis of LAL-D was conducted and the nominal group technique was followed. Results: Diagnostic algorithms which facilitate suspicion and diagnosis of LAL-D were generated by consensus for each of the risk groups. Conclusions: This guide proposes algorithms for the diagnosis of LAL-D based on clinical consensus. The algorithms seek to optimize diagnosis for patients with this pathology.

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SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants

Cited by 83 publications

References 73 publications

Types A and B Niemann-Pick disease

Types A and B Niemann-Pick disease

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

Guía colombiana para el diagnóstico de la deficiencia de lipasa ácida

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