OBJECTIVE: The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults. METHODS: Investigators reviewed medical records of LAL D patients ages ≥5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset. RESULTS: A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9.0 years (range 0-42); mean age at diagnosis was 15.2 years (range 1-46). Twenty-nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low-density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid-lowering therapies, and 44% had high-density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ∼1.15 multiples of normal (MN) and median spleen volume was ∼2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9-43.5 years). CONCLUSION: This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.

*Division of Genetics Birth Defects and Metabolism Ann and Robert H Lurie Children's Hospital of Chicago Chicago IL †Department of Medicine Addenbrooke's Hospital NHS Trust Cambridge UK ‡Medical Genetics Division Stanford University Stanford CA §Department of Pediatrics Regina Margherita Hospital Turin Italy ||Seattle Children's Hospital Seattle WA ¶Department of Vascular Medicine Internal Medicine Academic Medical Center Amsterdam The Netherlands New York Presbyterian Columbia University Medical Center New York NY **Department of Pediatrics 1st Faculty of Medicine Charles University Prague Czech Republic ††Departement de l'Enfant et de l'Adolescent Hopitaux Universitaires de Geneve Geneva Switzerland ‡‡Division of Clinical and Metabolic Genetics Hospital for Sick Children Toronto Ontario Canada §§Department of Pediatrics Unit of Rare Diseases Gaslini Institute Genoa Genova Italy ||||Department of Inherited Metabolic Disorders Birmingham Children's Hospital Birmingham UK ¶¶Department of Adult Inherited Metabolic Diseases Salford Royal NHS Foundation Salford UK Screening Department Institute of Mother and Child Warsaw Poland ***University of Minnesota Minneapolis MN †††Synageva BioPharma Corp Lexington MA ‡‡‡Hopital Necker Enfants Malades Paris France

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