Kalvakuntla Sanjana, Lee MinJae, Chung Wendy K, Demarest Scott, Freed Amber, Horning Kyle J, Bichell Terry Jo, Iannaccone Susan T, Goodspeed Kimberly
Medical School, University of Texas Southwestern Medical Center, Dallas, TX, United States.
Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, United States.
Front Neurosci. 2023 Feb 21;17:1024388. doi: 10.3389/fnins.2023.1024388. eCollection 2023.
SLC6A1-related disorder is a genetic neurodevelopmental disorder that is caused by loss of function variants in the gene. Solute Carrier Family 6 Member 1 () gene encodes for gamma-aminobutyric acid (GABA) transporter type 1 (GAT1), which is responsible for reuptake of GABA from the synaptic cleft. Tight regulation of GABA levels plays an important role in brain development by balancing inhibitory and excitatory neuronal signaling. Consequently, individuals with SLC6A1-related disorder can have manifestations such as developmental delay, epilepsy, autism spectrum disorder, and a subset have developmental regression.
In this study, we identified patterns of developmental regression among a cohort of 24 patients with SLC6A1-related disorder and assessed for clinical characteristics associated with regression. We reviewed medical records of patients with SLC6A1-related disorder and divided subjects into two groups: 1) regression group and 2) control group. We described the patterns of developmental regression including whether there was a trigger prior to the regression, multiple episodes of regression, and whether or not skills were recovered. We assessed the relationship of clinical characteristics among the regression and control groups including demographic factors, seizures, developmental milestone acquisition, gastrointestinal problems, sleep problems, autism spectrum disorder, and behavioral problems.
Individuals with developmental regression had a loss of skills that were previously mastered in developmental domains including speech and language, motor, social, and adaptive skills. The mean age at regression was 2.7 years and most subjects had regression of language or motor skills triggered by seizures, infection, or spontaneously. Although there was no significant difference in clinical characteristics between the two groups, there was a higher prevalence of autism and severe language impairment in the regression group.
Future studies of a larger cohort of patients are required to make definitive conclusions. Developmental regression is often a sign of severe neurodevelopmental disability in genetic syndromes, but it is poorly understood in SLC6A1-related disorder. Understanding the patterns of developmental regression and the associated clinical characteristics in this rare disorder will be important to medical management, prognostication, and could impact the design of future clinical trials.
SLC6A1相关障碍是一种遗传性神经发育障碍，由该基因的功能缺失变异引起。溶质载体家族6成员1（SLC6A1）基因编码γ-氨基丁酸（GABA）转运体1型（GAT1），其负责从突触间隙重新摄取GABA。通过平衡抑制性和兴奋性神经元信号，GABA水平的严格调节在大脑发育中起重要作用。因此，患有SLC6A1相关障碍的个体可能有发育迟缓、癫痫、自闭症谱系障碍等表现，并且一部分患者会出现发育倒退。
在本研究中，我们确定了24例SLC6A1相关障碍患者队列中的发育倒退模式，并评估了与倒退相关的临床特征。我们回顾了SLC6A1相关障碍患者的病历，并将受试者分为两组：1）倒退组和2）对照组。我们描述了发育倒退的模式，包括倒退前是否有触发因素、多次倒退发作以及技能是否恢复。我们评估了倒退组和对照组之间临床特征的关系，包括人口统计学因素、癫痫发作、发育里程碑获得情况、胃肠道问题、睡眠问题、自闭症谱系障碍和行为问题。
有发育倒退的个体在包括言语和语言、运动、社交和适应技能等发育领域中失去了先前掌握的技能。倒退的平均年龄为2.7岁，大多数受试者的语言或运动技能倒退由癫痫发作、感染或自发触发。虽然两组之间的临床特征没有显著差异，但倒退组中自闭症和严重语言障碍的患病率更高。
需要对更大队列的患者进行进一步研究才能得出明确结论。发育倒退通常是遗传综合征中严重神经发育障碍的一个迹象，但在SLC6A1相关障碍中对此了解甚少。了解这种罕见疾病中发育倒退的模式和相关临床特征对于医疗管理、预后评估很重要，并且可能会影响未来临床试验的设计。
