Novel Treatment & Screening Strategies in Gamma-Hydroxybutyric Aciduria

描述(申请人提供)：人类琥珀酸半醛脱氢酶(SSADH；乙醛脱氢酶5a1(Aldh5a1))缺乏症是一种罕见的影响GABA神经递质系统的神经遗传学疾病。Aldh5a1-/-小鼠表现出早期失神发作，演变为致命性全身性惊厥性癫痫，类似于在人类疾病中观察到的癫痫表型。研究人员的长期目标是为患者定义一种有效的治疗策略，并以该治疗为跳板，扩大对SSADH缺乏症新生儿的筛查。研究人员将通过以下假设和目标努力实现这些目标：假设1是对Aldh5a1/-小鼠长期应用口服活性GABAB受体(GABR)拮抗剂SGS-742将防止早期死亡并使神经药理异常正常化。具体目标1将描述SGS-742处理的Aldh5a1/-小鼠的人体形态、神经药理学、癫痫阈值和GABABR结构。假设2 SGS-742对成年SSADH缺陷患者的干预将改善神经心理缺陷，并恢复因长期暴露于超生理GABA水平而下调的GABABR功能。特定目标2将是SGS-742在6名成年SSADH缺陷患者中的试点试验，使用神经精神评估和经颅磁刺激(TMS；估计GABR功能)作为结果衡量标准。假设3：Gb是一种GABA类似物，在SSADH缺乏的生理液体中升高，是鉴定新生儿血斑中SSADH缺陷的可靠生物标志物。具体目标3实施新生儿SSADH缺乏症筛查的试点评估，将建立标准范围和敏感性/特异性相关性。设计为队列对照，但目标2除外，每个患者都将作为自己的对照。虽然非侵入性TMS在这种疾病中的应用是新的，但公认的方法学在整个过程中都得到了应用(神经药理学、串联质谱仪、神经心理学电池)。

DESCRIPTION (provided by applicant): Human succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1 (Aldh5a1)) deficiency is a rare neurogenetic disorder affecting the GABA neurotransmitter system. Aldh5a1-/- mice manifest early absence seizures which evolve into lethal generalized convulsive epilepsy, similar to seizure phenotypes observed in the human disease. The investigators' long-term goals are to define an effective treatment strategy for patients and springboard that treatment into expanded newborn screening for SSADH deficiency. The investigators will work toward these goals via the following hypotheses and aims: Hypothesis 1 is that chronic application of SGS-742, an orally active GABAB receptor (GABABR) antagonist, to Aldh5a1-/- mice will prevent early lethality and normalize neuropharmacological abnormalities. Specific Aim 1 will characterize anthropormorphics, neuropharmacology, seizure threshold, and GABABR structure in Aldh5a1-/- mice treated with SGS-742. Hypothesis 2 is that SGS-742 intervention in adult SSADH-deficient patients will improve neuropsychological deficits and restore GABABR function downregulated by chronic exposure to supraphysiological GABA levels. Specific Aim 2 will be a pilot trial of SGS-742 in six adult SSADH-deficient patients using neuropsychiatric evaluations and transcranial magnetic stimulation (TMS; estimating GABABR function) as outcome measures. Hypothesis 3 is that guanidinobutyrate (GB), a GABA analogue elevated in SSADH-deficient physiological fluids, represents a reliable biomarker to identify SSADH deficiency in newborn bloodspots. Specific Aim 3 implements a pilot evaluation of newborn screening for SSADH deficiency that will establish normative ranges and sensitivity/specificity correlations. The design is cohort-control except for Aim 2, where each patient will serve as their own control. Accepted methodology is applied throughout (neuropharmacology, tandem mass spectrometry, neuropsychological batteries), although the use of noninvasive TMS in this disorder is novel.