Journal of Child Neurology ( IF 1.9 ) Pub Date : 2021-01-04 , DOI: 10.1177/0883073820981262 Phillip L Pearl 1 , Melissa L DiBacco 1 , Christos Papadelis 2, 3, 4 , Thomas Opladen 5 , Ellen Hanson 6 , Jean-Baptiste Roullet 7 , K Michael Gibson 7
Objective:
The SSADHD Natural History Study was initiated in 2019 to define the natural course and identify biomarkers correlating with severity.
Methods:
The study is conducted by 4 institutions: BCH (US clinical), WSU (bioanalytical core), USF (biostatistical core), and Heidelberg (iNTD), with support from the family advocacy group (SSADH Association). Recruitment goals were to study 20 patients on-site at BCH, 10 with iNTD, and 25 as a standard-of care cohort.
Results:
At this half-way point of this longitudinal study, 28 subjects have been recruited (57% female, mean 9 years, range 18 months–40 years). Epilepsy is present in half and increases in incidence and severity, as do psychiatric symptoms, in adolescence and adulthood. The average Full Scale IQ (FSIQ) was 53 (Verbal score of 56, Non Verbal score of 49), and half scored as having ASD. Although there was no correlation between gene variant and phenotypic severity, there were extreme cases of lowest functioning in one individual and highest in another that may have genotype-phenotype correlation. The most common EEG finding was mild background slowing with rare epileptiform activity, whereas high-density EEG and magnetoencephalography showed reduction in the gamma frequency band consistent with GABAergic dysfunction. MR spectroscopy showed elevations in the GABA/NAA ratio in all regions studied with no crossover between subjects and controls.
Conclusions:
The SSADH Natural History Study is providing a unique opportunity to study the complex pathophysiology longitudinally and derive electrophysiologic, neuroimaging, and laboratory data for correlation and to serve as biomarkers for clinical trials and prognostic assessments in this ultra-rare inherited disorder of GABA metabolism.
中文翻译:
琥珀酸半醛脱氢酶缺乏症:自然史研究回顾
客观的:
SSADHD 自然史研究于 2019 年启动,旨在定义自然病程并确定与严重程度相关的生物标志物。
方法:
该研究由 4 个机构进行:BCH(美国临床)、WSU(生物分析核心)、USF(生物统计核心)和海德堡(iNTD),并得到了家庭倡导组织(SSADH 协会)的支持。招募目标是在 BCH 现场研究 20 名患者、10 名 iNTD 患者和 25 名作为标准护理队列的患者。
结果:
在这项纵向研究的中途,招募了 28 名受试者(57% 为女性,平均 9 岁,范围 18 个月至 40 岁)。癫痫在青春期和成年期的发病率和严重程度增加了一半,精神症状也是如此。平均全量表智商 (FSIQ) 为 53(语言得分 56,非语言得分 49),一半得分为患有 ASD。尽管基因变异与表型严重程度之间没有相关性,但在一个个体中功能最低而在另一个个体中功能最高的极端案例可能具有基因型 - 表型相关性。最常见的脑电图发现是轻度背景减慢伴罕见的癫痫样活动,而高密度脑电图和脑磁图显示伽马频带减少与 GABA 能功能障碍一致。
结论:
SSADH 自然历史研究提供了一个独特的机会,可以纵向研究复杂的病理生理学,并获得相关的电生理学、神经影像学和实验室数据,并作为这种超罕见遗传性 GABA 代谢疾病的临床试验和预后评估的生物标志物。