Dyslipidemia and Sustained Transaminase Elevations from Early Childhood are Common in Lysosomal Acid Lipase Deficiency

s 307 Objective/Purpose: In order to better characterize the presentation and progression of LAL D, we have conducted a multinational observational study in children and adults with LAL Deficiency (n5 48). Methods: Data was compiled by performing a retrospective chart review of subjects with documented LAL Deficiency. Results: The median age (range) of first symptoms was 5.8 (0.0 to 42.0) years and the median age at diagnosis was 9.5 (1.2 to 46.1) years. The median age at which dyslipidemia or elevated transaminases was reported was 8.4 and 8.2 years, respectively. 44 of the 48 patients had an ALT above the upper limit of normal (median 80.5 U/L) at the first recorded assessment (on study), and almost all remained abnormal. (follow-up interval 3 to 24 months). The median highest reported total cholesterol, LDL and triglycerides were 316 mg/dL, 239 mg/dL, and 219 mg/dL respectively and the median lowest HDL was 26.5 mg/dL. 67% of patients had dietary interventions during the course of their disease and 65% had received lipid lowering therapy. Although improvements in serum lipids were observed in some patients, these interventions seemed to have a limited effect on controlling the liver disease. Six of the 48 patients underwent liver transplant: 4 patients were under the age of 18 at the time of transplant, while 2 were over the age of 40 and both developed end-stage liver disease rather precipitously. Conclusion: Disease appears to be progressive in some patients despite restriction of dietary fat or lipid lowering therapy. End-stage hepatic complications may develop rapidly and without apparent warning. In conclusion, this study confirms that dyslipidemia and hepatic dysfunction are common in LAL D children, although the diagnosis is often delayed because of non-specific presentation. Supplementary Figure Summary of results of patients sequenced* for pathogenic mutations and variants of unknown pathogenicity in LDLR, APOB, PCSK9, and LDRAP1. 115 Gene Sequencing in US Patients with Severe Clinical Familial Hypercholesterolemia* Marisa Schoen, BA, Emil deGoma, MD, Martianne Stef, PhD, Marina Cuchel, MD, PhD, Daniel Rader, MD, (Philadelphia, PA) Lead Author’s Financial Disclosures: None Study Funding: Yes Funding Sources: Genetic sequencing was performed at no cost by Progenika Biopharma SA. Background/Synopsis: Familial hypercholesterolemia (FH) is characterized by increased plasma levels of lowdensity lipoprotein (LDL) cholesterol, tendon xanthoma, and premature atherosclerotic cardiovascular disease. FH, also called autosomal dominant hypercholesterolemia, can result from mutations in the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB), or the proprotein convertase subtilisin/kexin type 9 gene (PCSK9). Gene sequencing for molecular diagnosis of FH is rarely performed clinically in the US. Objective/Purpose: To determine the specific mutations in patients with clinical and laboratory characteristics of severe clinical FH. Methods: DNA samples of research subjects with clinical and laboratory characteristics of FH were sent to PROGENIKA Inc for genetic sequencing. Next-generation sequencing was performed using SEQPRO LIPO v1, which is designed to detect mutations in the three known genes causing autosomal dominant hypercholesterolemia (i.e., LDLR, APOB, and PCSK9) and in the LDRAP1 gene causing autosomal recessive hypercholesterolemia. It also analyses copy number variations in the LDLR associated with FH. Results: Under an IRB-approved protocol, DNA samples from 25 patients meeting MEDPED (Make Early Diagnosis-Prevent Early Death) criteria for definite FH (mean LDL-C 406 mg/dL) were sequenced for LDLR, APOB, PCSK9, and LDLRAP1. 17 (68%) subjects were found to have a heterozygous pathogenic mutation in LDLR; 2 (8%) subjects were found to have a heterozygous variant of unknown pathogenicity in LDLR; and 6 (24%) subjects had no pathogenic mutations detected. Of the 6 without a detectable mutation, the mean LDL-C was 416 mg/dL (range 242 to 519 mg/dL) and 2 are on LDL apheresis. Conclusion: Our findings show that while pathogenic mutations or variants of unknown significance in LDLR were detected in 76% of patients selected for severe clinical FH phenotypes, no disease-causing mutations were found in 6 (24%) subjects. These findings suggest that other causes of severe FH phenotype may be present and highlight the need for further evaluation to improve diagnosis and management of these patients.