Sebelipase alfa enzyme replacement therapy in Wolman disease: a nationwide cohort with up to ten years of follow-up

Tanguy Demaret,Pascale De Lonlay,Marie-Thérèse Abi Warde,Jean-Baptiste Arnoux,Florence Lacaille,Juliette Bouchereau,Camille Wicker,Christine Broissand,Dominique Plantaz,Cyril Gitiaux,Claire Belloche,David Grevent,Soumeya Bekri,Anaïs Brassier,Dalila Adjaoud

doi:10.1186/s13023-021-02134-3

Abstract

BackgroundWolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, presents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure and death before 12 months of age. In clinical trials, enzyme replacement therapy (ERT) with sebelipase alfa led to improved survival, growth and biological parameters in WD patients followed up to 5 years. Long-term follow-up and health-related quality of life (HRQoL) evaluation are lacking.ResultsWe performed a nationwide, retrospective study of sebelipase alfa in WD patients. Five patients with abolished LAL activity and bi-allelic LIPA mutations were included with a median follow-up of 7 years (1–10). ERT was initiated at a median age of 1 month (0–4). Infusion tolerance was excellent on the long-term with only one patient requiring systematic pre-medication. Cholestyramine, fat-soluble vitamin supplements and a specific diet (high in medium-chain triglycerides and low in long-chain fatty acids) were prescribed. Liver function tests, plasma lipid profiles, fat-soluble vitamin levels and growth parameters improved. Three patients transiently exhibited a neuromyopathic phenotype (footdrop gait, waddling walk or muscle fatigue) but electromyography and muscle strength testing were normal. At last follow-up, all patients were alive with normal growth parameters and a satisfactory HRQoL, no patient had special education needs, and one patient required parenteral nutrition since an acute gastroenteritis.ConclusionsEarly ERT initiation allowed 100% survival with positive outcomes. Very long-term follow-up and hematopoietic stem cell transplantation while on ERT should be evaluated to strengthen the benefits of sebelipase alfa.

Highlights

Wolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, pre‐ sents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure and death before 12 months of age
LALD phenotypes form a continuous spectrum between Wolman disease (WD) [4, 5] and cholesterol ester storage disease (CESD)
We report here the longest follow-up to date, of 5 WD patients treated with sebelipase alfa for a median duration of 7 years (1–10)

Summary

Introduction

Wolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, pre‐ sents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure and death before 12 months of age. Lysosomal acid lipase (LAL, EC 3.1.1.13) deficiency (LALD, MIM 278000) is an ultrarare lysosomal storage disease (LSD) associated with bi-allelic LIPA pathogenic variants causing strongly decreased LAL activity [1]. LALD phenotypes form a continuous spectrum between Wolman disease (WD) [4, 5] and cholesterol ester storage disease (CESD). WD patients present in the first months of life with failure to thrive, malabsorption, hepatosplenomegaly, liver failure and bilateral adrenal calcifications [7]. CESD has a higher prevalence of 1 per 160,000 [9], and presents during childhood or adulthood with hepatomegaly, elevated liver enzymes and dyslipidemia [10]

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