Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
Department of Digestive, Fujian Provincial Hospital, Fuzhou, China.
Dig Dis Sci. 2024 Jun;69(6):2109-2122. doi: 10.1007/s10620-024-08395-9. Epub 2024 Apr 2.
Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations.
Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression.
Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity.
Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.
胆固醇酯贮积症（CESD；OMIM：278,000）以前被认为是一种常染色体隐性等位基因突变遗传疾病，由于 LIPA 基因突变导致溶酶体酸性脂肪酶（LAL）活性降低。CESD 的特征是肝功能和脂质代谢异常，在严重的情况下，可能会发生肝衰竭导致死亡。在本研究中，对一个具有显性遗传的中国非经典 CESD 家系进行表型分析，并对相应的基因改变进行分析。
招募了一个非经典 CESD 家系的 7 名男性和 8 名女性。记录了临床特征和 LAL 活性。使用全基因组下一代测序（NGS）筛选候选基因和突变，Sanger 测序确认预测的突变，qPCR 检测 LIPA mRNA 表达。
该家系的 8 人被推测患有 CESD。发现家系中 4 名在世成员的 LAL 活性降低，但另外 4 名已故成员（可能死于肝衰竭）的 LAL 活性无法检测到。4 名在世亲属中有 3 名存在脂质代谢异常，4 名均存在肝功能异常。通过肝活检，先证者表现为明显增大的肝细胞内弥漫性泡状脂肪变和枯否细胞增生。令人惊讶的是，仅在先证者中通过基因测序发现了一个新发现的杂合突变，c.1133T>C（p.Ile378Thr）在 LIPA 上。所有携带 p.I378T 变异的在世家族成员均显示 LAL 活性降低。
表型分析表明，这可能是一个具有 LIPA 基因突变的常染色体显性非经典 CESD 家系。
