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

Abstract

Background: 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.

Results: 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_CO), 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_CO 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.

Conclusions: 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.

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

Fig. 1

Disposition of study participants

Fig. 2

Kaplan–Meier overall survival probability in children and adults with ASMD. The analysis included one patient death unrelated to ASMD (see Table 2)

Fig. 3

Lung diffusion capacity during the study observation period. Percent predicted diffusion capacity of carbon monoxide (DL_CO) adjusted for hemoglobin in the pediatric (a) and adult (b) cohorts at baseline (BL), year 1, and final assessment. Diffusion capacity stratified by presence or absence of dyspnea at baseline for pediatric and adult groups combined is shown in C. Solid horizontal line indicates threshold for abnormal values (< 80% of the predicted normal values)

Fig. 4

Splenomegaly during the observation period. Spleen volumes in Multiples of Normal (MN) for the pediatric (a) and adult (b) cohorts at baseline (BL), year 1, and final assessment. Severity of splenomegaly cutoffs are indicated by solid lines where mild is < 5 MN, moderate is ≥ 5 and ≤ 15 MN, and severe is > 15 MN [15]

Fig. 5

Hepatomegaly during the observation period. Liver volumes in multiples of normal (MN) in the pediatric (a) and adult (b) cohorts at baseline (BL), year 1, and final assessment. Severity of hepatomegaly cutoffs are indicated by solid lines where mild is < 1.25 MN, moderate is ≥ 1.25 and ≤ 2.5 MN, and severe is > 2.5 MN [15]

Fig. 6

Compromised growth during the observation period. Individual height (cm) by age for males (a) and females (b) in the pediatric cohort overlaid on CDC growth chart percentiles indicated by different colors with 95–97, 50–75 and 3–5 percentiles marked. CDC normative growth charts stop at age 18. Since growth in some patients continued to be below normative curves after reaching adulthood, data through age 20 are included. Individual patient data are indicated by circles connected by blue dashed lines