Clinical, biochemical and molecular identification and characterization of Argentinean patients with Niemann- Pick Disease

Abstract

Niemann-Pick disease (NPD) is a group of rare autosomal recessive lysosomal storage diseases; it comprises two different entities: 1) acid sphingomyelinase deficiency (ASMD) (including NPD types A and B), activity coded by SMPD1 gene, and 2) transport proteins deficiency coded by NPC1 and NPC2 genes (Types C and D). Type A NPD is a fatal neurodegenerative disorder of infancy. Type B NPD is characterized by being phenotypically variable withhepatosplenomegaly and pulmonary infiltrates. Type C NPD presents a heterogeneous clinical spectrum leading to progressive neurological deterioration.

The aim of this study was to report the clinical, biochemical and molecular studies for the characterization of patients, in the context of a systematic research protocol of this pathology in Argentina.

Research protocol: 1- compatible patient selection, 2- histological and biochemical studies, 3- enzymatic determinations, 4- filipin test in fibroblast culture, 5- molecular analysis.

Out of twenty three studied patients with phenotype compatibility, we diagnosed three patients with NPD: two type B NPD and one type C NPD. Hepatosplenomegaly was observed in Type B NPD patients; they did not present any neurological symptoms. Foam cells were seen in bone marrow biopsy. The liver biopsy transmission electron microscopy (TEM) indicated the presence of electron-lucent vacuoles and electron-dense membranes in hepatocytes. The plasma chitotriosidase enzyme was slightly increased. Sphingomyelinase enzyme level was lower. The SMPD1 gene sequencing revealed that patient 1 is homozygote for the mutation p.R608del. Patient 2 is compound heterozygous, allele 1 p-Ser147leufsTer19 and allele 2 a novel mutation (p.Lys578Thr). The NPD-C patient presented ataxia, mental and motor retardation and language impairment with seizures and hepatosplenomegaly. The skin TEM indicated the presence of electron-lucent vacuoles and multivesicular bodies in fibroblasts. The plasma chitotriosidase was slightly increased. Functional studies in fibroblasts with Filipin were positive. The NPC1 gene sequencing indicated that the patient is homozygote for the missense mutation p.R1186H.

This study indicates that the relevant clinical evaluations combined with histopathological, biochemical and genetic analyses have contributed to an effective diagnostic process for NPD.