PDF(Pubmed)
Abstract：
Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal-recessive disorder of gamma-aminobutyric acid (GABA) metabolism, resulting in accumulation of GABA and gamma-hydroxybutyric acid (GHB) in physiological fluids. Approximately 450 patients have been diagnosed worldwide with this inherited neurotransmitter disorder. We report on a five-year-old male patient, homozygous for the pathogenic variant (NM_170740:c.1265G>A) in ALDH5A1 presenting with an unexpected association of typical SSADH deficiency manifestations with bilateral sensorineural hearing loss (SNHL). Brainstem evoked response audiometry (BERA) testing showed mid-frequency sensorineural hearing damage that suggested a hereditary component to SNHL. Whole exome sequencing (WES) failed to discern other genetic causes of deafness. Several variants of uncertain significance (VUS) detected in genes known for their role in hearing physiology could not be verified as the cause for the SNHL. It is known that central auditory processing depends on a delicate balance between excitatory and inhibitory neurotransmission, and GABA is known to play a significant role in this process. Additionally, excessive concentrations of accumulated GABA and GBH are known to cause a down-regulation of GABA receptors, which could have an adverse influence on hearing function. However, these mechanisms are very speculative in context of SNHL in a patient with inherited disorder of GABA metabolism. Injury of the globi pallidi, one of hallmarks of SSADH deficiency, could also be a contributory factor to SNHL, as was suspected in some other inborn errors in metabolism. We hope that this case will contribute to the understanding of phenotypic complexity of SSADH deficiency.
摘要：
琥珀酸半醛脱氢酶（SSADH）缺乏症是一种罕见的常染色体隐性遗传疾病，导致GABA和γ-羟基丁酸（GHB）在生理液中的积累。全世界大约有450名患者被诊断患有这种遗传性神经递质疾病。我们报道了一个5岁的男性病人,ALDH5A1中致病性变体（NM_170740：c.126G>A）的纯合子，表现出典型的SSADH缺乏症表现与双侧感音神经性听力损失（SNHL）的意外关联。脑干诱发反应测听法（BERA）测试显示中频感音神经性听力损伤，表明SNHL具有遗传性成分。全外显子组测序（WES）未能辨别耳聋的其他遗传原因。在已知其在听力生理学中的作用的基因中检测到的几种不确定意义的变体（VUS）无法被证实为SNHL的原因。众所周知，中枢听觉处理取决于兴奋性和抑制性神经传递之间的微妙平衡，已知GABA在此过程中发挥重要作用。此外,已知过量积累的GABA和GBH会导致GABA受体下调，这可能会对听力功能产生不利影响。然而,这些机制在患有GABA代谢遗传性疾病的患者的SNHL背景下是非常推测的。球的伤害，SSADH缺乏症的标志之一,也可能是SNHL的一个促成因素，正如在其他一些先天的新陈代谢错误中所怀疑的那样。我们希望这种情况将有助于理解SSADH缺乏症的表型复杂性。
