Clinical Research Institute, Kanagawa Children's Medical Center, Minami-ku, Yokohama, Japan.
J Inherit Metab Dis. 2010 Feb;33(1):85-90. doi: 10.1007/s10545-009-9022-9. Epub 2010 Jan 6.
Deficiency of 4-aminobutyrate aminotransferase (GABA-T) is a rare disorder of GABA catabolism, with only a single sibship reported. We report on a third case, a Japanese female infant with severe psychomotor retardation and recurrent episodic lethargy with intractable seizures, with the diagnosis facilitated by proton magnetic resonance (MR) spectroscopy ((1)H-MRS).
Neuroimaging was performed at the first episode of lethargy. For (1)H-MRS, locations were placed in the semioval center and the basal ganglia. Quantification of metabolite concentrations were derived using the LCModel. We confirmed the diagnosis subsequently by enzyme and molecular studies, which involved direct DNA sequence analysis and the development of a novel multiplex ligation-dependent probe amplification test.
(1)H-MRS analysis revealed an elevated GABA concentration in the basal ganglia (2.9 mmol/l). Based on the results of quantitative (1)H-MRS and clinical findings, GABA-T deficiency was suspected and confirmed in cultured lymphoblasts. Molecular studies of the GABA-T gene revealed compound heterozygosity for a deletion of one exon and a missense mutation, 275G>A, which was not detected in 210 control chromosomes.
Our results suggest that excessive prenatal GABA exposure in the central nervous system (CNS) was responsible for the clinical manifestations of GABA transaminase deficiency. Our findings suggest the dual nature of GABA as an excitatory molecule early in life, followed by a functional switch to an inhibitory species later in development. Furthermore, quantitative (1)H-MRS appears to be a useful, noninvasive tool for detecting inborn errors of GABA metabolism in the CNS.
4-氨基丁酸转氨酶（GABA-T）缺乏症是 GABA 分解代谢的一种罕见疾病，仅有一个同胞家族报道过。我们报告了第三个病例，一名日本女性婴儿，患有严重的精神运动发育迟缓，反复出现伴有难治性癫痫发作的发作性昏睡，质子磁共振（MR）光谱（1 H-MRS）有助于诊断。
在昏睡的首次发作时进行神经影像学检查。对于 1 H-MRS，将位置放置在半卵圆中心和基底节。使用 LCModel 定量代谢物浓度。随后通过酶和分子研究证实了诊断，其中包括直接 DNA 序列分析和开发新的多重连接依赖性探针扩增测试。
1 H-MRS 分析显示基底节中 GABA 浓度升高（2.9 mmol/L）。基于定量 1 H-MRS 和临床发现，怀疑并在培养的淋巴母细胞中证实了 GABA-T 缺乏症。GABA-T 基因的分子研究显示，一个外显子缺失和一个错义突变 275G>A 的复合杂合性，在 210 个对照染色体中未检测到。
我们的结果表明，中枢神经系统（CNS）中过多的产前 GABA 暴露导致了 GABA 转氨酶缺乏症的临床表现。我们的发现表明，GABA 在生命早期作为兴奋性分子具有双重性质，随后在发育后期功能转变为抑制性物质。此外，定量 1 H-MRS 似乎是一种有用的、非侵入性的工具，可用于检测 CNS 中 GABA 代谢的先天性错误。
