Early Discovery of Children With Lysosomal Acid Lipase Deficiency With the Universal Familial Hypercholesterolemia Screening Program

Abstract

Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive lysosomal storage disorder, caused by homozygous or compound heterozygous pathogenic variants in the LIPA gene. Clinically, LAL-D is under- and misdiagnosed, due to similar clinical and laboratory findings with other cholesterol or liver misfunctions. As a part of the Slovenian universal familial hypercholesterolemia (FH) screening, LAL-D is screened as a secondary condition among other rare dyslipidemias manifesting with hypercholesterolemia. Out of 669 children included, three were positive for a homozygous disease-causing splicing variant NM_000235.4: c.894G > A (NP_000226.2:p. Gln298Gln) in the LIPA gene (NG_008194.1). The mean age by the diagnosis of LAL-D was 9.8 ± 0.9 years. Moreover, all three LAL-D-positive children had an important elevation of transaminases and decreased activity of the lysosomal acid lipase enzyme. Abdominal MRI in all children detected an enlarged liver but a normal-sized spleen. In conclusion, universal FH screening algorithms with the confirmatory genetic analysis in the pediatric population enable also rare dyslipidemia detection at an early age. An important clinical criterion for differentiation between FH and the LAL-D-positive children has elevated transaminase levels (AST and ALT). In all three LAL-D positive children, an improvement in cholesterol and transaminase levels and steatosis of the liver has been seen after early treatment initiation.

A homozygous variant in the GPIHBP1 gene in a child with severe hypertriglyceridemia and a systematic literature review

“…European Atherosclerosis Society provided practical clinical guidelines for rare dyslipidaemia management for patients with extreme LDL-C, TG and HDL-C levels ( Hegele et al, 2020 ). Early detection of rare dyslipidemias in a pre-clinical stage is possible with an effective FH screening program capable of detecting other dyslipidemia than FH ( Groselj et al, 2018 , 2022 ; Marusic et al, 2020 ; Sustar et al, 2022 ) or with a gene panel applied as a part of a newborn screening program ( Remec et al, 2021 ). It is important to implement a worldwide registry for rare dyslipidemias, comparable to what already exists for FH/homozygous FH ( Tromp et al, 2022 ; Vallejo-Vaz et al, 2018 , 2021 ).…”

“…All genetic analyses were performed at the University Children’s Hospital Ljubljana in Slovenia in the same way as Slovenian national genetic testing for the universal familial hypercholesterolemia (FH) screening program in preschool children ( Groselj et al, 2018 , 2022 ; Sustar et al, 2022 ). Genomic DNA was isolated from the patient’s and his family members (mother, father and sister) peripheral blood using a Flexigene kit (Qiagen).…”

Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

“…The LIPA gene encodes for the lysosomal acid lipase, the enzyme essential for the degradation of cholesteryl esters that in absence of a functional enzyme accumulate within lysosomes giving rise to a severe disease characterized by high cholesterol levels that can be misdiagnosed as FH (Lysosomal Acid Lipase Deficiency—LALD) [ 64 ]. In Slovenia, during the universal screening for FH, 3 children suffering from LALD were identified among hypercholesterolemic children [ 65 ].…”

Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease

“…Another study screening 810 children in Turkey with either elevated transaminases for 3 months, hepatomegaly, or liver steatosis, fibrosis, or cirrhosis not explained by obesity or other causes by DBS found two LALD patients ( Kuloglu et al, 2019 ). A recent study published in this series of Frontiers in Genetics screened 669 Slovenian children with familial hypercholesterolemia and detected 3 cases of LALD homozygous for c.894G>A ( Sustar et al, 2022 ). Despite the rarity of LALD, with many cases undiagnosed until later in life, and the availability of effective treatment, screening especially in children with hypercholesterolemia or liver disease after eliminating common causes may be beneficial ( Vinje et al, 2018 ; Carter et al, 2019 ).…”