Brown Madalyn, Ashcraft Paula, Arning Erland, Bottiglieri Teodoro, McClintock William, Giancola Frank, Lieberman David, Hauser Natalie S, Miller Rebecca, Roullet Jean-Baptiste, Pearl Phillip, Gibson K Michael
Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington.
Baylor Scott & White Research Institute, Institute of Metabolic Disease, Dallas, Texas.
Mol Genet Genomic Med. 2019 May;7(5):e629. doi: 10.1002/mgg3.629. Epub 2019 Mar 4.
We present a patient with Rett syndrome (RTT; MECP2) and autosomal-recessive succinic semialdehyde dehydrogenase deficiency (SSADHD; ALDH5A1 (aldehyde dehydrogenase 5a1 = SSADH), in whom the current phenotype exhibits features of SSADHD (hypotonia, global developmental delay) and RTT (hand stereotypies, gait anomalies).
γ-Hydroxybutyric acid (GHB) was quantified by UPLC-tandem mass spectrometry, while mutation analysis followed standard methodology of whole-exome sequencing.
The biochemical hallmark of SSADHD, GHB was increased in the proband's dried bloodspot (DBS; 673 µM; previous SSADHD DBSs (n = 7), range 124-4851 µM); control range (n = 2,831), 0-78 µM. The proband was compound heterozygous for pathogenic ALDH5A1 mutations (p.(Asn418IlefsTer39); maternal; p.(Gly409Asp); paternal) and a de novo RTT nonsense mutation in MECP2 (p.Arg255*).
The major inhibitory neurotransmitter, γ-aminobutyric acid (GABA), is increased in SSADHD but normal in RTT, although there are likely regional changes in GABA receptor distribution. GABAergic anomalies occur in both disorders, each featuring an autism spectrum phenotype. What effect the SSADHD biochemical anomalies (elevated GABA, GHB) might play in the neurodevelopmental/epileptic phenotype of our patient is currently unknown.
我们报告了一名患有雷特综合征（RTT；MECP2）和常染色体隐性遗传性琥珀酸半醛脱氢酶缺乏症（SSADHD；ALDH5A1（醛脱氢酶5a1 = SSADH））的患者，其当前表型表现出SSADHD（肌张力减退、全面发育迟缓）和RTT（手部刻板动作、步态异常）的特征。
采用超高效液相色谱-串联质谱法定量测定γ-羟基丁酸（GHB），同时按照全外显子测序的标准方法进行突变分析。
SSADHD的生化标志物GHB在该先证者的干血斑中升高（673 μM；之前的SSADHD干血斑样本（n = 7），范围为124 - 4851 μM）；对照范围（n = 2,831）为0 - 78 μM。先证者为致病的ALDH5A1突变（p.(Asn418IlefsTer39)；来自母亲；p.(Gly409Asp)；来自父亲）的复合杂合子，以及MECP2基因的一个新发RTT无义突变（p.Arg255*）。
主要抑制性神经递质γ-氨基丁酸（GABA）在SSADHD中升高，但在RTT中正常，尽管GABA受体分布可能存在区域变化。两种疾病均出现GABA能异常，且均具有自闭症谱系表型。目前尚不清楚SSADHD的生化异常（GABA、GHB升高）可能对我们患者的神经发育/癫痫表型产生何种影响。
