The natural history of dihydrolipoamide dehydrogenase deficiency in Israel

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Inherited Metabolic Disease Pub Date : 2024-07-23 DOI:10.1002/jimd.12778
Ben Pode-Shakked, Yuval E. Landau, Nava Shaul Lotan, Joshua Manor, Nitsan Haham, Eyal Kristal, Eli Hershkovitz, Guy Hazan, Yarden Haham, Shlomo Almashanu, Yair Anikster, Orna Staretz-Chacham
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Abstract

Dihydrolipoamide dehydrogenase (DLD) deficiency is an ultra-rare autosomal-recessive inborn error of metabolism, affecting no less than five mitochondrial multienzyme complexes. With approximately 30 patients reported to date, DLD deficiency was associated with three major clinical presentations: an early-onset encephalopathic phenotype with metabolic acidosis, a predominantly hepatic presentation with liver failure, and a rare myopathic phenotype. To elucidate the demographic, phenotypic, and molecular characteristics of patients with DLD deficiency within the Israeli population, data were collected from metabolic disease specialists in four large tertiary medical centers in the center and south of Israel. Pediatric and adult patients with biallelic variants in DLD were included in the study. A total of 53 patients of 35 families were included in the cohort. Age at presentation ranged between birth and 10 years. Wide phenotypic variability was observed, from asymptomatic individuals in their sixth decade of life, to severe, neonatal-onset disease with devastating neurological sequelae. Six DLD variants were noted, the most common of which was the c.685G>T (p.G229C) variant in homozygous form (24/53 patients, 45.3%; 13/35 families), observed mostly among patients of Ashkenazi-Jewish descent, followed by the homozygous c.1436A>T (p.D479V) variant, found in 20 patients of Bedouin descent (37.7%; 16/35 families). Overall, patients did not necessarily present as one of the previously described distinct clinical phenotypes. DLD deficiency is a panethnic disorder, with significant phenotypic variability, and comprises a continuum, rather than three distinct clinical presentations.

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以色列二氢脂酰胺脱氢酶缺乏症的自然史。
二氢脂酰胺脱氢酶(DLD)缺乏症是一种超罕见的常染色体隐性先天性代谢异常,影响至少五个线粒体多酶复合物。迄今报道的约 30 例 DLD 缺乏症患者主要有三种临床表现:伴有代谢性酸中毒的早发性脑病表型、伴有肝功能衰竭的主要肝病表型和罕见的肌病表型。为了阐明以色列人口中 DLD 缺乏症患者的人口学、表型和分子特征,我们从以色列中部和南部四个大型三级医疗中心的代谢疾病专家那里收集了数据。研究对象包括患有 DLD 双倍拷贝变异的儿童和成人患者。共有 35 个家庭的 53 名患者被纳入队列。发病年龄从出生到 10 岁不等。观察到的表型差异很大,从六十岁时无症状的个体,到严重的、新生儿期发病并伴有破坏性神经系统后遗症的患者。研究发现了六种 DLD 变异,其中最常见的是同源的 c.685G>T (p.G229C) 变异(24/53,45.3%;13/35 个家庭),主要见于阿什肯纳齐-犹太后裔患者,其次是同源的 c.1436A>T (p.D479V) 变异,见于 20 名贝都因后裔患者(37.7%;16/35 个家庭)。总体而言,患者并不一定表现为先前描述的不同临床表型之一。DLD 缺乏症是一种泛种族疾病,具有显著的表型变异性,是一个连续体,而不是三种截然不同的临床表现。
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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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