Mercimek-Mahmutoglu S, Pop A, Kanhai W, Fernandez Ojeda M, Holwerda U, Smith D, Loeber J G, Schielen P C J I, Salomons G S
Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Canada; Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada.
Metabolic Unit, Department of Clinical Chemistry, VU Medical Center, Neurosciences Campus, Amsterdam, The Netherlands.
Gene. 2016 Jan 1;575(1):127-31. doi: 10.1016/j.gene.2015.08.045. Epub 2015 Aug 28.
GAMT deficiency is an autosomal recessive disorder of creatine biosynthesis causing developmental delays or intellectual disability in untreated patients as a result of irreversible brain damage occurring prior to diagnosis. Normal neurodevelopmental outcome has been reported in patients treated from neonatal period highlighting the importance of early treatment.
Five hundred anonymized newborns from the National Newborn Screening Program of The Netherlands were included into this pilot study. Direct sequencing of the coding region of the GAMT gene was applied following DNA extraction. The disease causing nature of novel missense variants in the GAMT gene was studied by overexpression studies. GAA and creatine was measured in blood dot spots.
We detected two carriers, one with a known common (c.327G>A) and one with a novel mutation (c.297_309dup (p.Arg105Glyfs*) in the GAMT gene. The estimated incidence of GAMT deficiency was 1:250,000. We also detected five novel missense variants. Overexpression of these variants in GAMT deficient fibroblasts did restore GAMT activity and thus all were considered rare, but not disease causing variants including the c.131G>T (p.Arg44Leu) variant. Interestingly, this variant was predicted to be pathogenic by in silico analysis. The variants were included in the Leiden Open Variation Database (LOVD) database (www.LOVD.nl/GAMT). The average GAA level was 1.14μmol/L±0.45 standard deviations. The average creatine level was 408μmol/L±106. The average GAA/creatine ratio was 2.94±0.136.
The estimated incidence of GAMT deficiency is 1:250,000 newborns based on our pilot study. The newborn screening for GAMT deficiency should be implemented to identify patients at the asymptomatic stage to achieve normal neurodevelopmental outcome for this treatable neurometabolic disease. Biochemical investigations including GAA, creatine and GAMT enzyme activity measurements are essential to confirm the diagnosis of GAMT deficiency. According to availability, all missense variants can be assessed functionally, as in silico prediction analysis of missense variants is not sufficient to confirm the pathogenicity of missense variants.
胍氨酸甲基转移酶（GAMT）缺乏症是一种常染色体隐性遗传的肌酸生物合成障碍疾病，由于在诊断前就已发生不可逆的脑损伤，未经治疗的患者会出现发育迟缓或智力残疾。有报道称，从新生儿期开始治疗的患者神经发育结局正常，这凸显了早期治疗的重要性。
来自荷兰国家新生儿筛查项目的500名匿名新生儿被纳入这项初步研究。DNA提取后，对GAMT基因的编码区进行直接测序。通过过表达研究来探究GAMT基因中新型错义变异的致病性质。在血斑中检测GAA（葡萄糖醛酸酶）和肌酸。
我们检测到两名携带者，一名携带已知的常见突变（c.327G>A），另一名携带新型突变（GAMT基因中的c.297_309dup（p.Arg105Glyfs*））。GAMT缺乏症的估计发病率为1:250,000。我们还检测到五个新型错义变异。这些变异在GAMT缺乏的成纤维细胞中过表达确实恢复了GAMT活性，因此所有这些变异都被认为是罕见的，但不是致病变异，包括c.131G>T（p.Arg44Leu）变异。有趣的是，通过计算机分析预测该变异具有致病性。这些变异已被纳入莱顿开放变异数据库（LOVD）（www.LOVD.nl/GAMT）。GAA的平均水平为1.14μmol/L±0.45标准差。肌酸的平均水平为408μmol/L±106。GAA/肌酸的平均比值为2.94±0.136。
基于我们的初步研究，GAMT缺乏症在新生儿中的估计发病率为1:250,000。应开展GAMT缺乏症的新生儿筛查，以识别无症状阶段的患者，使这种可治疗的神经代谢疾病实现正常的神经发育结局。包括GAA、肌酸和GAMT酶活性测量在内的生化检查对于确诊GAMT缺乏症至关重要。根据实际情况，所有错义变异都可以进行功能评估，因为错义变异的计算机预测分析不足以确认其致病性。
