Balkan Journal of Medical Genetics

A NOVEL VARIANT IN THE LIPA GENE ASSOCIATED WITH DISTINCT PHENOTYPE
Sarajlija A.1,6, Armengol L.2, Maver A.3, Kitic I.4,6, Prokic D.4,6, Cehic M.1, Djuricic M.S.5,7, Peterlin B.3
*Corresponding Author: Adrijan Sarajlija, MD, PhD, Mother and Child Health Care Institute of Serbia “Dr. Vukan Cupic”, School of Medicine, University of Belgrade, Radoja Dakica 6-8, Belgrade, 11070, Serbia, Tel: +381113108287, E-mail: adrijans2004@yahoo.com
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INTRODUCTION

Lysosomal acid lipase (LAL) is a 399-amino acid protein encoded by the LIPA gene (1). Pathogenic variants in LIPA cause a rare autosomal-recessive disease belonging to the family of lysosomal storage disorders (LSDs) (2). Two types of lysosomal acid lipase deficiency (LAL-D) were recognized: early onset form (Wolman’s disease) and late-onset type (cholesteryl ester storage disease - CESD) (3). This classification is mostly replaced by the understanding that LAL-D includes a spectrum ranging from severe manifestations in infancy to more chronic course and later onset (4). The severity of clinical features of LAL-D is not entirely dependent on the level of enzyme activity and specific causative genetic variants (5,6). Severe infantile phenotype includes hepatosplenomegaly, malabsorption, adrenal calcifications and psychomotor regression, while patients with residual enzyme activity are usually recognized due to chronic hepatosplenomegaly with associated laboratory abnormalities: elevated serum low density lipoprotein (LDL) cholesterol and triglycerides (TG), low serum high density lipoprotein (HDL) cholesterol and moderately elevated serum transaminases (5-9). Liver histopathology typically reveals microvesicular steatosis (cytoplasmic lipid vesicles stained by Oilred, Sudan black, Sudan IV), lysosomal accumulation of cholesteryl esters, and TG, along with Maltese cross-type birefringent needle-shaped cholesteryl ester crystals in frozen sections. Immunohistochemical use of lysosomal markers in fixed paraffin-embedded samples facilitates the diagnosis of CESD (10,11). Additional biomarker findings that are useful for the diagnosis of LAL-D are high plasma concentration of chitotriosidase as well as elevated oxysterols (12,13). Current treatment options include enzyme replacement therapy (sebelipase-alpha), statins, liver transplantation and stem cell transplantation (14,15). Approximately 120 disease-causing variants in LIPA have been reported to date, mostly located in exon 8 (16). The most frequently encountered pathogenic variant is NM_000235.4:c.894G>A, responsible for the skipping of exon 8 and the CESD phenotype (5). To date, clinical implications for heterozygous carriers of LIPA variants have been scarcely studied (16). There have been reports of reevaluation of variants detected in the LIPA gene by next generation sequencing in the context of the clinical phenotype (17). We present four Serbian patients from two families with clinical manifestations which are highly suggestive of LAL-D, harboring a novel LIPA variant with preserved enzyme activity. Our study was approved by the Institutional Ethics Committee and informed consent was obtained by the involved patients.

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