Comprehensive genetic testing of an asymptomatic woman revealed that she had lysosomal acid lipase deficiency (LAL-D), as published in the Journal of Clinical Lipidology. The authors noted that the diagnosis was confirmed by enzymatic activity assay and she was started on sebelipase alfa enzyme replacement therapy.

“This case represents a successful early identification of the rare ‘needle’ in the hyperlipidemia ‘haystack’ by performance of one-step rather than the recommended two-step genetic-testing method,” the authors wrote.

“Automated 2nd-step testing for comprehensive lipidemia genetics would improve the ability to detect less common and rare causes of inherited dyslipidemia rather than reliance on clinic-based algorithms.”

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The patient in this case had a routine lipid profile performed as part of routine testing prior to college matriculation. She was determined to have severe combined hyperlipidemia, leading to the initiation of high-intensity statin treatment and a referral for dyslipidemia testing, which revealed mutations in the lysosomal acid lipase (LIPA) gene.

The statin therapy was effective in lowering her lipid levels, but she still had elevated alanine transaminase and hepatic stenosis, prompting the enzymatic activity assay that confirmed the diagnosis of LAL-D.

To date, the diagnosis of LAL-D is severely hampered because it requires broad population testing of individuals with a specific combined phenotype of fatty liver and hyperlipidemia, which is a very rare phenomenon. In the present case, a comprehensive (#36 genes) lipidemia panel was employed at the same time as a Familial Hypercholesterolemia Panel (#4 genes), detecting LAL-D in 1 step.

In this way, potentially years of delay in diagnosis and treatment were avoided, and enzyme replacement therapy could be initiated immediately. Automated second-step testing in lipidemia genetics to improve the detection of rare cases of inherited dyslipidemia would be an important advance from current practices based on clinical algorithms.


Sakers A, Soffer D. Cholesteryl ester storage disease uncovered during unusually broad genetic screening for hypercholesterolemia. J Clin Lipidol. 2022;16(1). doi:10.1016/j.jacl.2021.09.023