Abstract：
OBJECTIVE: This study aimed to investigate the incidence rate, clinical phenotype, gene variation spectrum, and prognosis of neonatal hyperhomocysteinemia (HHcy) and explore its diagnosis, individualised treatment, and prevention strategies.
METHODS: We screened 84722 neonates for HHcy using liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with biochemical detection, urine gas chromatography-mass spectrometry (GC-MS), and next-generation sequencing (NGS) for gene analysis to comprehensively differentiate and diagnose diseases.
RESULTS: 18 children (P1-P18) were diagnosed with methylmalonic acidemia (MMA) and HHcy, and fourteen known and one new variant of the MMACHC gene were found. Five children showed poor mental reactions, brain dysplasia, lethargy, hyperbilirubinemia, and jaundice, whereas the other 13 children had no evident abnormalities. These children were all cobalamin- and folic acid-reactive types, and they were mainly supplemented with cobalamin, L-carnitine, betaine, and folic acid. The mother of P12 had a prenatal diagnosis at the next pregnancy; the results showed that MMACHC gene was not pathogenic and she gave birth to a healthy baby. One child (P19) was diagnosed with methylenetetrahydrofolate reductase (MTHFR) deficiency, and one new mutation was detected in the MTHFR gene. Patient P19 showed congenital brain dysplasia, neonatal anaemia, and hyperbilirubinemia, and treatment consisted mainly of betaine and cobalamin supplementation. One child (P20) was confirmed to have methionine adenosyltransferase I (MAT I) deficiency but had no clinical manifestations. After treatment, all the children had a good prognosis.
CONCLUSIONS: The incidence of neonatal HHcy in the Zibo area was 1/4236, and the common pathogenic variants were c.609G>A, c.80A>G, and c.482G>A in the MMACHC gene. Patients with HHcy can achieve a good prognosis if pathogenic factors and targeted treatment are identified. Gene analysis and prenatal diagnosis contribute to the early prevention of HHcy.
METHODS: We screened 84722 neonates for HHcy using liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with biochemical detection, urine gas chromatography-mass spectrometry (GC-MS), and next-generation sequencing (NGS) for gene analysis to comprehensively differentiate and diagnose diseases.
RESULTS: 18 children (P1-P18) were diagnosed with methylmalonic acidemia (MMA) and HHcy, and fourteen known and one new variant of the MMACHC gene were found. Five children showed poor mental reactions, brain dysplasia, lethargy, hyperbilirubinemia, and jaundice, whereas the other 13 children had no evident abnormalities. These children were all cobalamin- and folic acid-reactive types, and they were mainly supplemented with cobalamin, L-carnitine, betaine, and folic acid. The mother of P12 had a prenatal diagnosis at the next pregnancy; the results showed that MMACHC gene was not pathogenic and she gave birth to a healthy baby. One child (P19) was diagnosed with methylenetetrahydrofolate reductase (MTHFR) deficiency, and one new mutation was detected in the MTHFR gene. Patient P19 showed congenital brain dysplasia, neonatal anaemia, and hyperbilirubinemia, and treatment consisted mainly of betaine and cobalamin supplementation. One child (P20) was confirmed to have methionine adenosyltransferase I (MAT I) deficiency but had no clinical manifestations. After treatment, all the children had a good prognosis.
CONCLUSIONS: The incidence of neonatal HHcy in the Zibo area was 1/4236, and the common pathogenic variants were c.609G>A, c.80A>G, and c.482G>A in the MMACHC gene. Patients with HHcy can achieve a good prognosis if pathogenic factors and targeted treatment are identified. Gene analysis and prenatal diagnosis contribute to the early prevention of HHcy.
摘要：
目的：本研究旨在调查发病率，临床表型，基因变异谱,新生儿高同型半胱氨酸血症(HHcy)的诊断及预后,个性化治疗,和预防策略。
方法：我们使用液相色谱-串联质谱（LC-MS/MS）结合生化检测对84722例新生儿进行HHcy筛查，尿气相色谱-质谱(GC-MS),和下一代测序（NGS）进行基因分析，以全面区分和诊断疾病。
结果：18名儿童（P1-P18）被诊断为甲基丙二酸血症（MMA）和HHcy，发现了14个已知的MMACHC基因和一个新的变体。五个孩子表现出不良的心理反应，脑发育不良,嗜睡,高胆红素血症,和黄疸,而其他13名儿童无明显异常。这些孩子都是钴胺和叶酸反应型，它们主要补充了钴胺素，左旋肉碱,甜菜碱,和叶酸。P12的母亲在下一次怀孕时进行了产前诊断；结果表明MMACHC基因没有致病性，她生下了一个健康的婴儿。一名儿童（P19）被诊断为亚甲基四氢叶酸还原酶（MTHFR）缺乏症，在MTHFR基因中检测到一个新的突变。患者P19显示先天性脑发育不良，新生儿贫血,和高胆红素血症,治疗主要包括甜菜碱和钴胺素的补充。一名儿童（P20）被证实患有甲硫氨酸腺苷转移酶I（MATI）缺乏症，但没有临床表现。治疗后,所有患儿预后良好.
结论：淄博地区新生儿HHcy发病率为1/4236，常见致病变异为c.609G>A，c.80A>G，在MMACHC基因中c.482G>A。HHcy患者若明确致病因素并进行针对性治疗,可取得良好预后。基因分析和产前诊断有助于HHcy的早期预防。
方法：我们使用液相色谱-串联质谱（LC-MS/MS）结合生化检测对84722例新生儿进行HHcy筛查，尿气相色谱-质谱(GC-MS),和下一代测序（NGS）进行基因分析，以全面区分和诊断疾病。
结果：18名儿童（P1-P18）被诊断为甲基丙二酸血症（MMA）和HHcy，发现了14个已知的MMACHC基因和一个新的变体。五个孩子表现出不良的心理反应，脑发育不良,嗜睡,高胆红素血症,和黄疸,而其他13名儿童无明显异常。这些孩子都是钴胺和叶酸反应型，它们主要补充了钴胺素，左旋肉碱,甜菜碱,和叶酸。P12的母亲在下一次怀孕时进行了产前诊断；结果表明MMACHC基因没有致病性，她生下了一个健康的婴儿。一名儿童（P19）被诊断为亚甲基四氢叶酸还原酶（MTHFR）缺乏症，在MTHFR基因中检测到一个新的突变。患者P19显示先天性脑发育不良，新生儿贫血,和高胆红素血症,治疗主要包括甜菜碱和钴胺素的补充。一名儿童（P20）被证实患有甲硫氨酸腺苷转移酶I（MATI）缺乏症，但没有临床表现。治疗后,所有患儿预后良好.
结论：淄博地区新生儿HHcy发病率为1/4236，常见致病变异为c.609G>A，c.80A>G，在MMACHC基因中c.482G>A。HHcy患者若明确致病因素并进行针对性治疗,可取得良好预后。基因分析和产前诊断有助于HHcy的早期预防。
