Consensus recommendation for a diagnostic guideline for acid sphingomyelinase deficiency.

Disclaimer:This diagnostic guideline is intended as an educational resource and represents the opinions of the authors, and is not representative of recommendations or policy of the American College of Medical Genetics and Genomics (ACMG). The information should be considered a consensus based on expert opinion, as more comprehensive levels of evidence were not available in the literature in all cases. BACKGROUND: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and often fatal lysosomal storage disease. The underlying metabolic defect is deficiency of the enzyme acid sphingomyelinase that results in progressive accumulation of sphingomyelin in target tissues. ASMD manifests as a spectrum of severity ranging from rapidly progressive severe neurovisceral disease that is uniformly fatal to more slowly progressive chronic neurovisceral and chronic visceral forms. Disease management is aimed at symptom control and regular assessments for multisystem involvement. PURPOSE AND METHODS: An international panel of experts in the clinical and laboratory evaluation, diagnosis, treatment/management, and genetic aspects of ASMD convened to review the evidence base and share personal experience in order to develop a guideline for diagnosis of the various ASMD phenotypes. CONCLUSIONS: Although care of ASMD patients is typically provided by metabolic disease specialists, the guideline is directed at a wide range of providers because it is important for primary care providers (e.g., pediatricians and internists) and specialists (e.g., pulmonologists, hepatologists, and hematologists) to be able to identify ASMD.Genet Med advance online publication 13 April 2017.

A novel missense SMPD1 gene mutation, T460P, and clinical findings in a patient with Niemann-Pick disease type B presenting to a lipid disorders clinic.

Niemann-Pick disease, type B (NPD-B; OMIM 607616) is an inborn error of metabolism where reduced concentrations of the enzyme acid sphingomyelinase (ASM; EC 3.1.4.12) lead to multisystem disease though with survival into adulthood. The natural history of NPD-B is one of progressive hypersplenism and gradual deterioration of pulmonary function. We describe a 46-year-old South African man of French Huguenot descent who presented to a lipid disorders clinic with mixed hyperlipidaemia. Clinical examination and imaging findings revealed the presence of massive hepatosplenomegaly, interstitial lung disease and subclinical atherosclerosis; there were no neurological or cognitive abnormalities. Laboratory testing showed thrombocytopaenia, increased liver transaminases and mild hyperbilirubinaemia. Lysosomal enzyme analysis showed markedly reduced ASM activity, suggestive of NPD. DNA sequence analysis of the SMPD1 gene revealed that he was a compound heterozygote for the previously reported c.1829_1831delGCC (ΔR608) mutation and a novel missense mutation c.1378A > C (p.T460P). In conclusion, we describe the clinical findings of a case of NPD-B with mixed hyperlipidaemia, compound heterozygous for the SMPD1 ΔR608 mutation and a novel mutation, T460P.