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5a 1（Aldh 5a 1））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。 Aldh 5a 1-/-小鼠表现出早期失神癫痫发作，其演变成致死性全身性惊厥性癫痫，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，并将这种治疗扩展到SSADH缺乏症的新生儿筛查中。 研究人员将通过以下假设和目标来实现这些目标：假设1是长期应用SGS-742（一种口服活性GABAB受体（GABABR）拮抗剂）于Aldh 5a 1-/-小鼠将防止早期致死并使神经药理学异常正常化。 具体目标1将表征SGS-742处理的Aldh 5a 1-/-小鼠的人体形态学、神经药理学、癫痫发作阈值和GABABR结构。 假设2是SGS-742干预成年SSADH缺陷患者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。 Specific Aim 2将是一项SGS-742在6名SSADH缺乏的成年患者中进行的试点试验，使用神经精神评估和经颅磁刺激（TMS;估计GABABR功能）作为结局指标。 假设3是胍基丁酸盐（GB），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缺乏的可靠生物标志物。 具体目标3对新生儿筛查SSADH缺乏症进行试点评估，建立标准范围和敏感性/特异性相关性。 除目标2外，设计为队列对照，其中每例患者将作为其自身对照。 公认的方法学应用于整个（神经药理学，串联质谱，神经心理电池），虽然使用非侵入性TMS在这种疾病是新颖的。

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.