X-linked adrenoleukodystrophy: phenotype-genotype correlation in hemizygous males and heterozygous females with ABCD1 mutations.

IF 0.6 4区医学 Q4 ENDOCRINOLOGY & METABOLISM

Neuro endocrinology letters Pub Date : 2021-09-10

Marketa Zemanova, Petr Chrastina, Lenka Dvorakova, Martin Reboun, Hana Vlaskova, Helena Jahnova, Nabil El-Lababidi, Jana Cepova, Tomas Honzik, Jiri Zeman

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引用次数: 0

Abstract

Objectives: X-linked adrenoleukodystrophy (X-ALD) causes cerebral adrenoleukodystrophy (cALD), myelopathy and/or adrenal insufficiency in males, and myelopathy/peripheral neuropathy in females. These distinct phenotypes are scarcely linked to a specific mutations. The objective herein was to find a link between the phenotype with the genotype mutation, serum very long-chain fatty acids (VLCFA), and the diet with Lorenzo´s and GTO oils in hemizygous males and heterozygous females.

Methods: A retrospective study design with follow-up of 45 hemizygous males and 50 heterozygous females carrying mutations in ABCD1 from 35 unrelated families with X-ALD. Mutation analysis was performed by Sanger sequencing of PCR and/or RT-PCR and the severity of missense mutations was evaluated using GERP++ score and CADD score.

Results: Twenty-five described and eight novel ABCD1 mutations were identified. Fifteen males and 23 females had severe mutations while 30 males and 27 females had less detrimental ones. cALD developed in 25 males (56%) including nine boys with severe mutations, 10 boys with less detrimental mutations and 6 adults with adrenomyelopathy. Myelopathy and/or adrenal insufficiency developed in 14 males (31%), six were asymptomatic. Adrenal insufficiency developed in two of five boys treated with hematopoietic stem cell transplantation (HSCT). Myelopathy/peripheral neuropathy developed in 26% of females. No correlation was found between the disease severity and the genotype, GERP++ and CADD scores, presence/absence of aberrant ALDP protein or X-inactivation. VLCFA were higher in males than heterozygous females and decreased during Lorenzo´s and GTO oils diet without a clear clinical impact on the disease.

Conclusion: The prognosis was unfavourable in most males and significant part of females. Therapy with early HSCT is effective. Thus, the need for early diagnosis with the neonatal screening is crucial.

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X连锁肾上腺白质营养不良症：ABCD1基因突变的半合子男性和杂合子女性的表型-基因型相关性。

研究目的X-连锁肾上腺白质营养不良症（X-ALD）会导致男性脑肾上腺白质营养不良症（cALD）、脊髓病和/或肾上腺功能不全，女性则会导致脊髓病/周围神经病变。这些不同的表型几乎都与特定的突变无关。本文的目的是寻找半合子男性和杂合子女性的表型与基因型突变、血清超长链脂肪酸（VLCFA）以及含洛伦佐油和 GTO 油的饮食之间的联系：采用回顾性研究设计，对来自 35 个无血缘关系的 X-ALD 家族中携带 ABCD1 基因突变的 45 名半合子男性和 50 名杂合子女性进行随访。突变分析通过 PCR 和/或 RT-PCR 的 Sanger 测序进行，并使用 GERP++ 评分和 CADD 评分评估错义突变的严重程度：结果：共发现25个已描述的ABCD1突变和8个新型ABCD1突变。25名男性（56%）患上了cALD，其中9名男孩突变严重，10名男孩突变不严重，6名成人患肾上腺肌病。14名男性（31%）出现脊髓病和/或肾上腺功能不全，其中6人无症状。在接受造血干细胞移植（HSCT）治疗的5名男孩中，有2人出现肾上腺功能不全。26%的女性出现脊髓病/周围神经病变。在疾病严重程度与基因型、GERP++和CADD评分、是否存在异常ALDP蛋白或X-失活之间未发现相关性。男性的 VLCFA 高于杂合子女性，在食用洛伦佐油和 GTO 油时，VLCFA 有所下降，但对疾病没有明显的临床影响：结论：大多数男性和大部分女性的预后不良。早期造血干细胞移植治疗是有效的。因此，通过新生儿筛查进行早期诊断至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuro endocrinology letters 医学-内分泌学与代谢

CiteScore

1.00

自引率

14.30%

发文量

审稿时长

6 months

期刊介绍： Neuroendocrinology Letters is an international, peer-reviewed interdisciplinary journal covering the fields of Neuroendocrinology, Neuroscience, Neurophysiology, Neuropsychopharmacology, Psychoneuroimmunology, Reproductive Medicine, Chronobiology, Human Ethology and related fields for RAPID publication of Original Papers, Review Articles, State-of-the-art, Clinical Reports and other contributions from all the fields covered by Neuroendocrinology Letters. Papers from both basic research (methodology, molecular and cellular biology, anatomy, histology, biology, embryology, teratology, normal and pathological physiology, biophysics, pharmacology, pathology and experimental pathology, biochemistry, neurochemistry, enzymology, chronobiology, receptor studies, endocrinology, immunology and neuroimmunology, animal physiology, animal breeding and ethology, human ethology, psychology and others) and from clinical research (neurology, psychiatry and child psychiatry, obstetrics and gynecology, pediatrics, endocrinology, immunology, cardiovascular studies, internal medicine, oncology and others) will be considered. The Journal publishes Original papers and Review Articles. Brief reports, Special Communications, proved they are based on adequate experimental evidence, Clinical Studies, Case Reports, Commentaries, Discussions, Letters to the Editor (correspondence column), Book Reviews, Congress Reports and other categories of articles (philosophy, art, social issues, medical and health policies, biomedical history, etc.) will be taken under consideration.