Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation
Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation
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DOI：
10.1212/01.wnl.0000158475.12907.d6
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发表时间：
2005-04-26
期刊：
影响因子：
9.9
通讯作者：
Kure, S
中科院分区：
文献类型：
--
作者：
Flusser, H;Korman, SH;Kure, S
背景：典型的新生儿起病的甘氨酸脑病(GE)具有破坏性和生命危险。较温和、发病较晚的变异已有报道，但通常是零星的和不完全确定的。目的：研究以色列贝都因血缘关系中9例轻度类风湿关节炎的临床、生化表型和分子基础。方法：用基因组DNA筛查GLDC、AMT和GCSH基因突变。Northern印迹和逆转录聚合酶链式反应(RT-PCR)检测淋巴细胞GLDC的表达。结果：临床表现为低眼压、异常运动、惊厥、中度智力低下，粗大运动功能、日常生活能力和接受性语言能力相对较差。攻击性和易怒是突出的。脑脊液/血浆甘氨酸比率轻度至中度升高。所有9名患者都是纯合子，他们的父母是杂合子，新的翻译沉默的GLDC外显子22颠换约2607C>；A淋巴母细胞GLDC mRNA水平显著降低。鉴定出3种异常剪接的基因：外显子22和外显子22至23的跳跃，以及插入一个87碱基对的隐蔽外显子。C.2607C>；A纯合子也在一名无关但单倍型相同的患者中被鉴定出来，尽管有严重的新生儿GE，但结果异常良好。突变分析能够对三个未受影响的怀孕和一个受影响的怀孕进行产前诊断。结论：该家系突变导致错接和甘氨酸脱羧酶表达降低。与典型甘氨酸脑病患者相比，GLDC基因剪接正常的4%~6%可能是患者临床预后相对较好的原因。
Background: Classic neonatal-onset glycine encephalopathy (GE) is devastating and life threatening. Milder, later onset variants have been reported but were usually sporadic and incompletely defined. Objective: To determine the clinical and biochemical phenotype and molecular basis of mild GE in nine children from a consanguineous Israeli Bedouin kindred. Methods: Genomic DNA was screened for GLDC, AMT, and GCSH gene mutations. GLDC expression in lymphoblasts was studied by Northern blot and reverse transcriptase PCR analysis. Results: Clinical features included hypotonia, abnormal movements, convulsions, and moderate mental retardation with relative sparing of gross motor function, activities of daily living skills, and receptive language. Aggression and irritability were prominent. CSF-to-plasma glycine ratio was mildly to moderately elevated. All nine patients were homozygous and their parents heterozygous for a novel, translationally silent GLDC exon 22 transversion c. 2607C > A. Lymphoblast GLDC mRNA levels were considerably reduced. Three aberrantly spliced cDNA species were identified: exon 22 and exon 22 to 23 skipping, and insertion of an 87-base pair cryptic exon. Homozygosity for c. 2607C > A was also identified in an unrelated but haplotypically identical patient with an unusually favorable outcome despite severe neonatal-onset GE. Mutation analysis enabled prenatal diagnosis of three unaffected and one affected pregnancies. Conclusions: The mutation in this kindred led to missplicing and reduced GLDC (glycine decarboxylase) expression. The 4 to 6% of normally spliced GLDC mRNA in the patients may account for their relatively favorable clinical outcome compared with patients with classic glycine encephalopathy.