A Novel Variant in the LIPA Gene Associated with Distinct Phenotype

Area of Science:

• Genetics
• Biochemistry
• Pediatrics

Background:

• Lysosomal acid lipase deficiency (LAL-D) is a rare inherited metabolic disorder caused by LIPA gene variants.
• LAL-D presents a spectrum from severe Wolman disease to chronic cholesteryl ester storage disease (CESD).
• Diagnosis relies on clinical, biochemical, histopathological, and genetic data, but challenges arise with atypical presentations.

Purpose of the Study:

• To report on two sibling pairs with LAL-D-like phenotypes and novel LIPA gene variants.
• To investigate discrepancies between clinical presentation, LAL enzyme activity, and genetic findings in these patients.
• To discuss the diagnostic challenges posed by variants of unknown significance (VUS) in LAL-D.

Main Methods:

• Clinical evaluation of patients presenting with hepatosplenomegaly.
• Genetic analysis of the LIPA gene to identify pathogenic variants and VUS.
• Assessment of lysosomal acid lipase (LAL) enzyme activity.
• Liver histopathology examination.

Main Results:

• Two families presented with hepatosplenomegaly and LAL-D-like features.
• Family 1 had compound heterozygosity for a known pathogenic LIPA variant and a novel VUS (c.851C>T).
• Family 2 was homozygous for the novel LIPA VUS (c.851C>T) and showed LAL-D histopathology, yet had preserved LAL enzyme activity.

Conclusions:

• Discrepancies between preserved LAL enzyme activity, clinical phenotype, and LIPA gene variants complicate LAL-D diagnosis.
• Variants of unknown significance in the LIPA gene require careful interpretation in the context of clinical and biochemical data.
• These cases underscore the complexity of diagnosing inherited metabolic disorders when multiple diagnostic parameters are discordant.