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

Orphanet J Rare Dis 2021 May 10;16(1):212. doi: 10.1186/s13023-021-01842-0.

PMID: 33971920

Margaret M McGovern, Melissa P Wasserstein, Bruno Bembi

Highlights: 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.

Abstract

Background: Acid sphingomyelinase deficiency (ASMD) (also known as Niemann-Pick disease types A and B) is a rare and severe lysosomal storage disorder. The goal of this prospective, multi-center, international longitudinal study in children and adults was to define the clinical characteristics of chronic forms of ASMD as well as disease burden over time.

Results: Fifty-nine individuals (31 males/28 females) with chronic ASMD types A/B and B with at least two disease symptoms from five countries took part in the study. At the beginning, after a year, and at the final visit (ranging from 4.5 to 11 years), disease features were assessed. Thirty patients (51%) were under the age of 18 at the start of the study (median age 12), and 29 were adults (median age 32 years). Overall, 32/59 patients completed the last visit, with 9 patients dead, 9 discontinued, and 9 patients were lost to follow up. Splenomegaly, hepatomegaly, interstitial lung disease, lung diffusion capacity (DLCO), and dyslipidemia were all common clinical features that tended to deteriorate with time. At baseline, spleen volumes varied from 4 to 29 times normal, and splenomegaly was moderate or severe in 86%, 83%, and 90% of patients at baseline, year 1, and final visits, respectively. The prevalence of interstitial lung disease was 66% (39/59) at baseline and 78% (25/32) at the last visit, with the median % predicted DLCO decreasing by more than 10% from baseline to the final visit. Nine patients (15%) died, eight of them died of ASMD-related reasons (most often pneumonia); five of these eight patients (63%) exhibited symptoms at or before the age of two. Six of the nine deaths happened before the age of 50, and three occurred before the age of 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). The majority of children experienced development problems that lasted into adulthood.

Conclusion: This study adds to our understanding of chronic ASMD's natural history by providing a longitudinal perspective of the disease's symptoms and main morbidities in children and adults, as well as assisting in the selection of clinically relevant endpoints in therapeutic trials.

Keywords: ASMD, Lysosomal storage disease, Natural history, Niemann-Pick disease type A/B, Niemann-Pick disease type B