Novel Treatment & Screening Strategies in Gamma-Hydroxybutyric Aciduria

描述（由申请人提供）：人琥珀酸半醛脱氢酶（SSADH；醛脱氢酶5a1 (Aldh5a1)）缺乏症是一种影响GABA神经递质系统的罕见神经遗传性疾病。Aldh5a1-/-小鼠表现出早期失神性癫痫发作，并演变成致命的全身性惊厥癫痫，类似于在人类疾病中观察到的癫痫发作表型。研究人员的长期目标是为患者确定一种有效的治疗策略，并将其作为扩大新生儿SSADH缺乏症筛查的跳板。研究人员将通过以下假设和目的来实现这些目标：假设1是长期应用gs -742，一种口服活性GABABR受体（GABABR）拮抗剂，用于Aldh5a1-/-小鼠将防止早期死亡并使神经药理异常正常化。Specific Aim 1将描述sds -742治疗的Aldh5a1-/-小鼠的拟人、神经药理学、癫痫阈值和GABABR结构。假设2：成人ssadh缺陷患者的SGS-742干预将改善神经心理缺陷，恢复因长期暴露于超生理GABA水平而下调的GABABR功能。Specific Aim 2将是一项使用神经精神评估和经颅磁刺激（TMS；估计GABABR功能）作为结果测量的6名成年ssadh缺陷患者的SGS-742的试点试验。假设3：胍丁酸（GB）是一种GABA类似物，在SSADH缺乏的生理液体中升高，是识别新生儿血斑中SSADH缺乏的可靠生物标志物。具体目标3实施了新生儿SSADH缺乏筛查的试点评估，将建立规范范围和敏感性/特异性相关性。设计是队列对照，除了第二阶段，每个患者将作为自己的对照。虽然在这种疾病中使用非侵入性经颅磁刺激是新颖的，但在整个过程中都应用了公认的方法（神经药理学、串联质谱法、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.