Published online November 15, 2004
PEDIATRICS Vol. 114 No. 6 December 2004, pp. e672-e677 (doi:10.1542/peds.2004-0887)
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ELECTRONIC ARTICLE

The Natural History of Type B Niemann-Pick Disease: Results From a 10-Year Longitudinal Study

Melissa P. Wasserstein, MD*, Robert J. Desnick, PhD, MD*, Edward H. Schuchman, PhD{ddagger}, Sabera Hossain, MS§, Sylvan Wallenstein, PhD§, Carin Lamm, MD|| and Margaret M. McGovern, PhD, MD*

* Departments of Human Genetics and Pediatrics
{ddagger} Department of Human Genetics and the Carl Icahn Institute for Molecular Medicine and Gene Therapy
§ Departments of Biomathematical Sciences
|| Pediatrics, Mount Sinai School of Medicine, New York, New York

Objectives. Type B Niemann-Pick disease (NPD-B) caused by acid sphingomyelinase deficiency is a rare, autosomal recessive, lysosomal storage disorder with a broad range of disease severity. The objectives of this study were to document the natural history of the disease in a large, clinically heterogeneous patient population that was followed for a period of 10 years and to determine how genotype influences phenotype.

Methods. Twenty-nine patients with NPD-B had serial evaluations at least 9 months apart. Organ volumes, hematologic indices, lipid concentrations, pulmonary function, and hepatic activity were studied, and individual phenotypic severity was compared with genotype.

Results. All patients with intact spleens had splenomegaly (mean value: 12.7 multiples of normal [MN]; range: 4.5–27.3 MN), and all but 1 had hepatomegaly (mean volume: 1.91 MN; range: 0.93–3.21 MN). At initial visit, 39% had thrombocytopenia and 3% had leukopenia. At final visit, the percentages increased to 54% and 34%, respectively. Mean annual decreases in platelet count and leukocyte count were 7 x 103 and 0.2 x 103 per mm3, respectively. The typical atherogenic lipid profile was worse in older patients. A total of 69% of patients had low diffusion capacity for carbon monoxide, and more than one third had low forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second/forced vital capacity at initial visit. All measurements of pulmonary function showed a gradual deterioration over time. Liver dysfunction was characterized by stable elevation of hepatic transaminases and bilirubin. Homozygotes for {Delta}R608, P323A, and P330R had milder disease than patients with all other genotypes.

Conclusions. The natural history of NPD-B is characterized by hepatosplenomegaly with progressive hypersplenism, worsening atherogenic lipid profile, gradual deterioration in pulmonary function, and stable liver dysfunction.

Key Words: Niemann-Pick • acid sphingomyelinase • lysosomal storage disease • natural history

Abbreviations: NPD, Niemann-Pick disease • ASM, acid sphingomyelinase • PFT, pulmonary function test • DLCO, diffusion capacity for carbon monoxide • HDL, high-density lipoprotein • MN, multiples of normal • LDL, low-density lipoprotein • FEV1, forced expiratory volume at 1 second • FVC, forced vital capacity • TLC, total lung capacity

Accepted Jul 13, 2004.


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