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Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants.

ABSTRACT: The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.Investigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients.Records for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months).These data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452-458.

SUBMITTER: Jones SA

PROVIDER: S-EPMC4857209 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants.

Jones Simon A SA Valayannopoulos Vassili V Schneider Eugene E Eckert Stephen S Banikazemi Maryam M Bialer Martin M Cederbaum Stephen S Chan Alicia A Dhawan Anil A Di Rocco Maja M Domm Jennifer J Enns Gregory M GM Finegold David D Gargus J Jay JJ Guardamagna Ornella O Hendriksz Christian C Mahmoud Iman G IG Raiman Julian J Selim Laila A LA Whitley Chester B CB Zaki Osama O Quinn Anthony G AG

Genetics in medicine : official journal of the American College of Medical Genetics 20150827 5

<h4>Purpose</h4>The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.<h4>Methods</h4>Investigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients.<h4>Results</h4>Records for 35 patients, 26 with early GF, were analyzed. Promi ...[more]

PMID: 26312827

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Project description:BACKGROUND:Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age. RESULTS:Nine patients were enrolled; median age at baseline was 3.0 months (range 1.1-5.8 months). Sixty-seven percent (exact 95% CI 30%-93%) of sebelipase alfa-treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%-16%) for a historical control group (n?=?21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ?24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious. CONCLUSION:Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency TRIAL REGISTRATION: Clinicaltrials.gov NCT01371825 . Registered 9 June 2011.

Dataset Information

Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants.

Publications

Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants.

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