目的:腺苷琥珀酸裂解酶(ADSL)缺乏是一种罕见的遗传性代谢紊乱,具有广泛的表型表现,经典地分为三种类型(新生儿,I型和II型)。我们的目标是更好地描绘病理谱,重点研究ADSL缺乏症患者的临床电特征和表型差异。
方法:7名患者,来自四个不同的家庭,做了连续脑电图检查,临床评估,和神经成像。我们还对文献中发表的病例进行了系统回顾,总结了现有的临床病例,神经生理学,和遗传数据。
结果:我们报告了7例以前未报告的ADSL缺乏症患者的长期随访(10-34年)。从文献综述来看,我们收集了81例以前报告的病例.在纳入的患者群体中,58%(51/88)被归类为ADSL缺乏症I型,28%(25/88)为II型,14%(12/88)为新生儿。最常报道的致病变异是p.R426H纯合子(19例),p.Y114H中复合杂合性(13例)和p.D430N纯合性(6例)。在大多数(89.2%)中,发病在生命的第一年。81.8%的患者出现癫痫,多形性癫痫发作,通常是难治性癫痫发作。EEG特征似乎显示出共同的模式和发育轨迹:i)具有theta-delta活动的一般背景组织不良ii)痉挛的心律失常,通常是ACTH敏感的,iii)额叶或额叶颞叶占优势的全身性癫痫放电,iv)睡眠结构改变的睡眠中的癫痫放电激活。影像学特征表现出额叶占优势的脑萎缩的一致发现,小脑萎缩,三种类型的白质异常。
结论:ADSL缺乏症呈现可变的表型表达,其严重程度部分归因于突变蛋白的残留活性,尽管精确的表型-基因型相关性尚不可行,我们描绘了一种常见的临床模式,神经放射学和神经生理学特征。
OBJECTIVE: Adenylosuccinate lyase (ADSL) deficiency is a rare inherited metabolic disorder with a wide phenotypic presentation, classically grouped into three types (neonatal, type I, and type II). We aim to better delineate the pathological spectrum, focusing on the electroclinical characteristics and phenotypic differences of patients with ADSL deficiency.
METHODS: Seven patients, from four different families, underwent serial electroencephalogram (EEG), clinical assessment, and neuroimaging. We also performed a systematic review of the cases published in the literature, summarizing the available clinical, neurophysiological, and genetic data.
RESULTS: We report seven previously unreported ADSL deficiency patients with long-term follow-up (10-34 years). From the literature review, we collected 81 previously reported cases. Of the included patient population, 58 % (51/88) were classified as having ADSL deficiency type I, 28% (25/88) as having type II, and 14% (12/88) as having neonatal. The most frequently reported pathogenic variants are p.R426H homozygous (19 patients), p.Y114H in compound heterozygosity (13 patients), and p.D430N homozygous (6 patients). In the majority (89.2%), disease onset was within the first year of life. Epilepsy is present in 81.8% of the patients, with polymorphic and often intractable seizures. EEG features seem to display common patterns and developmental trajectories: (i) poor general background organization with theta-delta activity; (ii) hypsarrhythmia with spasms, usually adrenocorticotropic hormone-responsive; (iii) generalized epileptic discharges with frontal or frontal temporal predominance; and (iv) epileptic discharge activation in sleep with an altered sleep structure. Imaging features present consistent findings of cerebral atrophy with frontal predominance, cerebellar atrophy, and white matter abnormalities among the three types.
CONCLUSIONS: ADSL deficiency presents variable phenotypic expression, whose severity could be partially attributed to residual activity of the mutant protein. Although a precise phenotype-genotype correlation was not yet feasible, we delineated a common pattern of clinical, neuroradiological, and neurophysiological features.