Department of Pediatrics, Shimane University Faculty of Medicine, Izumo, Shimane, Japan.
Mol Genet Metab. 2011 Mar;102(3):343-8. doi: 10.1016/j.ymgme.2010.11.159. Epub 2010 Nov 25.
Glutaric acidemia type 1 (GA1) is a metabolic disease caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Untreated patients mostly develop severe striatal degeneration. More than 200 mutations have been reported in the GCDH gene, and common R402W and IVS10-2A>C were found in Caucasian and Chinese/Taiwanese, respectively. However, in Japan, genetic mutations have only been reported in a few cases. Herein, we report the clinical and molecular basis of GA1 in 19 Japanese patients, including six previously reported patients. All cases showed high urinary glutaric acid excretion. Eleven patients were severely impaired (three patients died), three had mild impairment, and five showed normal development. Four of 5 patients that developed normally were detected in the presymptomatic stage by neonatal or sibling screening. Nineteen mutations in 26 alleles were identified, and eight of them (89 or 90delC, Y155C, IVS4+2T＞C, G244S, Q352X, G354A, K361E, and 1144-1145delGC) were novel. S305L (12.1%, 4/34 alleles) was found in several cases, suggesting that this mutation is a common mutation. In contrast, R402W was not identified and IVS10-2A>C was only found in one allele, suggesting that Japanese patients with GA1 show allelic heterogeneity and have a different genetic background to patients from other countries. One of a pair of sisters with the same mutations (M339V/S305L) lacking residual activity was severely retarded, whereas the older girl remains asymptomatic at 22 years of age, indicating that genotype does not necessarily predict GA1 phenotype. We consistently found that there was no association between genotype and phenotype. However, children with mild impairment were diagnosed and treated earlier than severely impaired cases {4.7±2.5 months (range: 2-8 months) vs. 11.6±12.7 months (range: 4-51 months)}. Our results suggest that early detection and treatment but not genotype are associated with better patient outcome, reinforcing the importance of neonatal screening.
1 型戊二酸血症（GA1）是一种由戊二酰辅酶 A 脱氢酶（GCDH）缺乏引起的代谢性疾病。未经治疗的患者大多会出现严重的纹状体变性。在 GCDH 基因中已经报道了超过 200 种突变，常见的 R402W 和 IVS10-2A>C 分别在白种人和中国/台湾人中发现。然而，在日本，仅报道了少数病例的基因突变。在此，我们报告了 19 例日本患者的 GA1 临床和分子基础，其中包括 6 例先前报道的患者。所有病例均表现为高尿戊二酸排泄。11 例患者严重受损（3 例死亡），3 例轻度受损，5 例发育正常。5 例正常发育的患者中有 4 例通过新生儿或同胞筛查在症状前阶段被检测到。在 26 个等位基因中鉴定出 19 种突变，其中 8 种（89 或 90delC、Y155C、IVS4+2T＞C、G244S、Q352X、G354A、K361E 和 1144-1145delGC）为新突变。在几个病例中发现 S305L（12.1%，4/34 个等位基因），表明该突变是一种常见突变。相反，未发现 R402W，并且仅在一个等位基因中发现 IVS10-2A>C，表明日本 GA1 患者表现出等位基因异质性，并且具有与其他国家患者不同的遗传背景。一对具有相同突变（M339V/S305L）且残留活性缺失的姐妹中，病情较重的患者发育迟缓，而年龄较大的女孩在 22 岁时仍无症状，表明基因型不一定预测 GA1 表型。我们一致发现基因型与表型之间没有关联。然而，轻度受损的患儿比严重受损的患儿更早被诊断和治疗[4.7±2.5 个月（范围：2-8 个月）vs. 11.6±12.7 个月（范围：4-51 个月）]。我们的结果表明，早期发现和治疗而不是基因型与更好的患者预后相关，这再次强调了新生儿筛查的重要性。
