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.

• MeSH
• Alanine Transaminase blood   MeSH
• Aspartate Aminotransferases blood   MeSH
• Cholesterol blood   MeSH
• Child MeSH
• Adult MeSH
• Liver Cirrhosis etiology   MeSH
• Liver * metabolism   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipase deficiency   MeSH
• Longitudinal Studies MeSH
• Adolescent MeSH
• Young Adult MeSH
• Cholesterol Ester Storage Disease * blood   pathology   MeSH
• Child, Preschool MeSH
• Prospective Studies MeSH
• Spleen pathology   MeSH
• Sterol Esterase deficiency   MeSH
• Liver Transplantation MeSH
• Wolman Disease * blood   pathology   MeSH
• Fatty Liver blood   etiology   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Alanine Transaminase MeSH
• Aspartate Aminotransferases MeSH
• Cholesterol MeSH
• Lipase MeSH
• Sterol Esterase MeSH

BACKGROUND & AIMS: Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. METHODS: Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. RESULTS: 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. CONCLUSIONS: Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

• Keywords
• Dyslipidemia, Enzyme replacement, Fatty liver, Hepatomegaly, Lysosomal storage,
• MeSH
• Alanine Transaminase blood   MeSH
• Aspartate Aminotransferases blood   MeSH
• Adult MeSH
• Liver pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipids blood   MeSH
• Young Adult MeSH
• Recombinant Proteins administration & dosage   adverse effects   MeSH
• Drug Administration Schedule MeSH
• Sterol Esterase administration & dosage   adverse effects   deficiency   MeSH
• Wolman Disease blood   drug therapy   pathology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Alanine Transaminase MeSH
• Aspartate Aminotransferases MeSH
• LIPA protein, human MeSH Browser
• Lipids MeSH
• Recombinant Proteins MeSH
• Sterol Esterase MeSH

Immunohistochemical studies of the presence of lactosylceramide (LacCer) in lysosomal storage disorders (LSDs) were done using anti-LacCer monoclonal antibody of the CDw 17 type (clone MG-2). No sign of an association between LacCer and the lysosomal system in normal cells was observed, except for histiocytes active in phagocytosis. A comparative study of a group of LSDs showed a general tendency for LacCer to increase in storage cells in Niemann-Pick disease type C (NPC), and types A and B, GM1 gangliosidosis, acid lipase deficiency, glycogen storage disease type II and mucopolysaccharidoses. LacCer accumulated in storage cells despite normal activity of relevant lysosomal degrading enzymes. The accumulation of LacCer displayed variability within storage cell populations, and was mostly expressed in neurons in NPC. An absence of the increase in LacCer in storage cells above control levels was seen in neuronal ceroid lipofuscinoses (neurons and cardiocytes) and in Fabry disease. Gaucher and Krabbe cells showed significantly lower levels, or even the absence, of LacCer compared with control macrophages. Results of immunohistochemistry were corroborated by semiquantitative lipid thin-layer chromatography (TLC). It is suggested that different associations of LacCer with the lysosomal storage process may reflect differences in glycosphingolipid turnover induced by the storage-compromised lysosomal/endosomal system.

• MeSH
• Biomarkers analysis   MeSH
• Antigens, CD analysis   metabolism   MeSH
• Chromatography, Thin Layer methods   MeSH
• Child MeSH
• Adult MeSH
• Histiocytes chemistry   metabolism   pathology   MeSH
• Immunohistochemistry methods   MeSH
• Liver chemistry   metabolism   pathology   MeSH
• Lactosylceramides analysis   metabolism   MeSH
• Humans MeSH
• Lysosomal Storage Diseases classification   metabolism   pathology   MeSH
• Macrophages chemistry   metabolism   pathology   MeSH
• Cerebral Cortex chemistry   metabolism   pathology   MeSH
• Neurons chemistry   metabolism   pathology   MeSH
• Spleen chemistry   metabolism   pathology   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Biomarkers MeSH
• Antigens, CD MeSH
• CDw17 antigen MeSH Browser
• Lactosylceramides MeSH