MON-271 - Cascade Screening Uncovers Lysosomal Acid Lipase Deficiency in Two Adult Sisters: Early Diagnosis Improves Outcomes

Background
Lysosomal Acid Lipase Deficiency (LAL-D) is a rare autosomal recessive condition caused by pathogenic variants in lipase A (LIPA), leading to deficiency of the lysosomal acid lipase enzyme, hepatic lipid accumulation, and progressive liver disease. Adult-onset cases present with hypercholesterolemia, elevated liver enzymes, and hepatomegaly. Timely recognition is critical since enzyme replacement therapy can dramatically improve outcomes.
Objectives/Purpose. To demonstrate the clinical impact of cascade screening and early initiation of enzyme replacement therapy through two related cases.

Case reports

The proband was a 30-year-old female with hyperlipidemia since adolescence (baseline LDL-C 234 mg/dL), elevated liver enzymes (ALT 88 U/L, AST 58 U/L), and hepatosplenomegaly. Initially diagnosed with Familial Hypercholesterolemia, she was treated with atorvastatin 40 mg. Her LDL-C decreased to 87 mg/dL while liver enzymes remained elevated. Family history revealed hyperlipidemia in multiple relatives and parental consanguinity. Physical examination showed BMI 26 kg/m2 wihtout arcus or xanthomas. Genetic testing (GenInCode LipidInCode) identified a homozygous LIPA gene variant, c.894G>A, p.(Gln298=), the most common variant in adult-onset LAL-D. She began sebelipase alfa 2 enzyme therapy and after 12 months of therapy, liver enzymes normalized (ALT 22 U/L, ALT 20 U/L). Her LDL-C also decreased an additional 29% to 62 mg/dL. Cascade screening identified her 32-year-old sister as homozygous for the same variant. The sister was diagnosed with hyperlipidemia (LDL-C of 229 mg/dL at age 25), elevated ALT (77 U/L), hepatomegaly, and stage 1 portal fibrosis on liver biopsy. She started on rosuvastatin 10 mg with improvement in LDL-C to 106 mg/dL. After genetic testing confirmed the LAL-D diagnosis, she also started sebelipase alfa 2 therapy. Her ALT normalized (42 U/L) after several months of therapy. LDL-C decreased an additional 17% to 88 mg/dl.



Conclusion:
These cases highlight the importance of considering LAL-D in adults with hypercholesterolemia and unexplained liver enzyme elevations, particularly when hepatomegaly is present. Cascade screening can identify affected relatives, enabling timely diagnosis. Early initiation of enzyme replacement therapy offers significant hepatic and metabolic benefits, as demonstrated by normalization of liver enzymes and further LDL-C reduction in both patients.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*