Prospective study of the natural history of chronic acid sphingomyelinase deficiency in children and adults: eleven years of observation

Acid sphingomyelinase deficiency (ASMD) (also known as Niemann-Pick disease types A and B) is a rare and debilitating lysosomal storage disorder. This prospective, multi-center, multinational longitudinal study aimed to characterize the clinical features of chronic forms of ASMD and disease burden o...

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Published in:	Orphanet journal of rare diseases Vol. 16; no. 1; p. 212
Main Authors:	McGovern, Margaret M, Wasserstein, Melissa P, Bembi, Bruno, Giugliani, Roberto, Mengel, K Eugen, Vanier, Marie T, Zhang, Qi, Peterschmitt, M Judith
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 10-05-2021 BioMed Central BMC
Subjects:	Adolescent Adult Adults Age Age groups ASMD Biomarkers Child Child, Preschool Children Clinical trials Complications and side effects Confidence intervals Development and progression Diseases Dyslipidemia Female Genotype & phenotype Humans Laboratories Liver Longitudinal Studies Lung diseases Lung Diseases, Interstitial Lysosomal storage disease Male Medical research Metabolism, Inborn errors of Middle Aged Mortality Natural history Niemann-Pick disease Niemann-Pick disease type A/B Niemann-Pick disease type B Niemann-Pick Disease, Type A Niemann-Pick Diseases Patient outcomes Patients Pediatric research Pediatrics Prospective Studies Rare diseases Sphingomyelin Phosphodiesterase Spleen Splenectomy Splenomegaly Survival analysis Thrombocytopenia Young Adult United States Niemann-Pick disease type A/B Lysosomal storage disease Niemann-Pick disease type B Natural history ASMD
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Summary:	Acid sphingomyelinase deficiency (ASMD) (also known as Niemann-Pick disease types A and B) is a rare and debilitating lysosomal storage disorder. This prospective, multi-center, multinational longitudinal study aimed to characterize the clinical features of chronic forms of ASMD and disease burden over time in children and adults. Fifty-nine patients (31 males/28 females) ranging in age from 7 to 64 years with chronic ASMD types A/B and B and at least two disease symptoms participated from 5 countries. Disease characteristics were assessed at baseline, after 1 year, and at the final visit (ranging from 4.5 to 11 years). Thirty patients (51%) were < 18 years at baseline (median age 12 years), and 29 were adults (median age 32 years). Overall, 32/59 patients completed the final visit, 9 died, 9 discontinued, and 9 were lost to follow up. Common clinical characteristics that tended to worsen gradually with time were splenomegaly, hepatomegaly, interstitial lung disease, lung diffusion capacity (DL ), and dyslipidemia. Spleen volumes ranged from 4 to 29 multiples of normal at baseline, and splenomegaly was moderate or severe in 86%, 83%, and 90% of individuals at baseline, year 1, and final visits, respectively. The proportion of all individuals with interstitial lung disease was 66% (39/59) at baseline and 78% (25/32) at the final visit, while median % predicted DL decreased by > 10% from baseline to the final visit. Nine patients died (15%), eight of causes related to ASMD (most commonly pneumonia); of these eight patients, five (63%) had symptom onset at or before age 2. Overall, six of the nine deaths occurred before age 50 with three occurring before age 20. Individuals with either severe splenomegaly or prior splenectomy were ten times more likely to have died during the follow-up period than those with smaller or intact spleens (odds ratio 10.29, 95% CI 1.7, 62.7). Most children had growth deficits that persisted into adulthood. This study provides important information about the natural history of chronic ASMD and provides a longitudinal view of the spectrum of disease manifestations and major morbidities in children and adults and supports the selection of clinically meaningful endpoints in therapeutic trials.
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ISSN:	1750-1172 1750-1172
DOI:	10.1186/s13023-021-01842-0