A novel variant of uncertain significance in the LIPA gene was found in 2 pairs of siblings presenting with clinical and biochemical findings suggestive of lysosomal acid lipase deficiency (LAL-D). However, since the patients had residual levels of lysosomal acid lipase (LAL) activity, a definite diagnosis of LAL-D could not be established.

“When confronted with a challenge of confirming the diagnosis of a treatable inherited metabolic disorder, a clinician should consider a multitude of aspects: clinical manifestations, specific biomarkers, enzyme assay results, and molecular genetic findings,” the study’s authors said. “We hope that this report calls cases with considerable discrepancy between those aspects to attention.”

Sequencing analysis revealed that siblings from family 1 were compound heterozygous for a pathogenic c.419G>A (p.Trp140Ter) variant and a novel variant of uncertain significance, c.851C>T (p.Ser284Phe), of the LIPA gene. Siblings from family 2 were homozygous for the novel variant of uncertain significance, c.851C>T, and showed typical histopathological findings of LAL-D in the liver. The analysis of LAL activity in 3 patients revealed residual levels of enzyme activity.

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Clinical, biochemical, and genetic findings were consistent with the diagnosis of the cholesteryl ester storage disease type of LAL-D. However, given the uncertain nature of the novel variant and the evidence of enzyme activity, a final diagnosis could not be established for the siblings from family 2 and so enzyme replacement therapy could not be initiated.

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The 4 patients presented with hepatosplenomegaly in early childhood and their initial examination raised suspicion of LAL-D.

Patient 1 presented with hepatosplenomegaly at 3 years of age. Clinical examination revealed elevated serum transaminases with preserved synthetic liver function, mild leukopenia and thrombocytopenia, and altered plasma lipid profile. Moreover, he had high levels of chitotriosidase, angiotensin converting enzyme, and acid phosphatase.

His younger sibling, patient 2, presented with hepatosplenomegaly at the age of 1.5 years. He had elevated liver enzymes with preserved liver function, thrombocytopenia, and altered lipidogram.

Patient 3 presented with hepatosplenomegaly at 2 months of age. He had slightly elevated serum transaminases at initial examination, extremely high chitotriosidase, and altered lipidogram.

His older sister, patient 4, presented with hepatosplenomegaly at the age of 2.5 years. Clinical examination revealed elevated transaminases, dyslipidemia, and anemia.

The case report was published in Balkan Journal of Medical Genetics.


Sarajlija A, Armengol L, Maver A, et al. A novel variant in the gene associated with distinct phenotype. Balk J Med Genet. 2022;25(1):93-100. doi:10.2478/bjmg-2022-0010