Cholesterol ester storage disease with a novel LIPA mutation (L264P) that presented massive hepatomegaly: A case report

Abstract

Cholesterol ester storage disease (CESD) is an autosomal recessive disorder caused by deficient lysosomal acid lipase (LAL) activity, resulting in cholesteryl ester (CE) accumulation. CESD patients have liver disease associated with mixed dyslipidemia leading to liver failure. We here report the case of an 11-year-old male CESD patient with a novel mutation who had the chief complaint of massive hepatomegaly. The patient's liver reached to his pelvis, and his spleen was 2 cm below the costal margin. The patient had elevated serum liver enzymes and mixed dyslipidemia. The liver biopsy tissue showed characteristic CESD pathology, which included microvesicular steatosis, mild fibrosis and foamy macrophages. Electron microscopy showed a remnant cleft of CE crystals, and dried blood spot testing showed reduced LAL activity. We identified compound heterozygous mutations in the LIPA gene in this patient, namely, c.607G>C and c.791T>C. The former mutation was previously reported only in a Japanese patient, whereas the latter mutation is novel. The findings of this study suggest that LIPA gene mutations in Japanese CESD patients are different from those in Western patients. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed, and thus the possibility of CESD should be considered in patients with hepatosplenomegaly and dyslipidemia.

Large‐scale functionalLIPAvariant characterization to improve birth prevalence estimates of lysosomal acid lipase deficiency

“…Due to the difference in the chemical structure of these substrates, it is possible that some variants may retain substrate specificity against the 4‐MU oleate substrate yet lose the ability to cleave natural substrates or vice versa. In this regard, it is interesting to note that there were three LAL variants mentioned above (c.607G>C/p.Val203Leu, c.791T>C/p.Leu264Pro, and c.811A>C/p.Asn271His), which have been reported to be pathogenic (Kojima et al, ; Kuranobu et al, ; Reiner et al, ), that showed relatively high levels of intracellular lipase activity in our assay. This could be due to any of the reasons discussed, or through a yet to be defined mechanism.…”

“…c.607G > C/p.Val203Leu and c.791T > C/p.Leu264Pro. These two novel variants appeared in compound heterozygous form in a patient reported in Kuranobu et al ()…”

“…Examples of these include splicing mutations such as the aforementioned E8SJM/c.894G>A pathogenic mutation found in the majority of patients with CA-LALD (Bernstein et al, 2013;Scott et al, 2013) as well as mutations that inhibit trafficking beyond the endoplasmic reticulum and trans-Golgi network as has been observed in other lysosomal storage diseases (Parenti et al, 2007;Ron & Horowitz, 2005;Spratley et al, 2016;Zhang et al, 2000). Another potential limitation of our analysis is the which have been reported to be pathogenic (Kojima et al, 2013;Kuranobu et al, 2016;Reiner et al, 2014), that showed relatively high levels of intracellular lipase activity in our assay. This could be | 2017 due to any of the reasons discussed, or through a yet to be defined mechanism.…”

“…Wild‐type LIPA complementary DNA (cDNA), along with 149 variants, were selected for in vitro functional assessment as follows. All missense, nonsense, and 1/2 base pair frameshift variants from the patients with LAL deficiency are reported in references (Himes et al, ; Hooper, Tran, Formby, & Burnett, ; Kuranobu et al, ; Pisciotta et al, ; Reiner et al, ; Ries et al,; Santillán‐Hernández et al, ; Scott et al, ; Valayannopoulos et al, ). This resulted in 47 known pathogenic variants from the literature being chosen.…”

A Novel Homozygous LIPA Mutation in a Korean Child with Lysosomal Acid Lipase Deficiency

“…The most common LIPA gene mutation in Caucasians is an exon 8 splice-junction mutation (E8SJM -1G>A ), which results in altered mRNA splicing and exon 8 skipping [ 3 ]. However, the LIPA gene mutations reported in Japanese patients include Tyr22X, Val203 Leu and Leu264Pro [ 8 9 ]. Additionally, sequencing of the LIPA gene in this Korean patient revealed a novel homozygous mutation in exon 5 (p.Thr177Ile).…”