Division of Child Neurology, Nationwide Children's Hospital, Columbus, Ohio.
Duke Clinical and Translational Science Institute, Duke University School of Medicine, Durham, North Carolina.
Pediatrics. 2023 Aug 1;152(2). doi: 10.1542/peds.2023-062100.
Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene that lead to cerebral creatine deficiency and neurotoxic levels of guanidinoacetate. Untreated, GAMT deficiency is associated with hypotonia, significant intellectual disability, limited speech development, recurrent seizures, behavior problems, and involuntary movements. The birth prevalence of GAMT deficiency is likely between 0.5 and 2 per million live births. On the basis of small case series and sibling data, presymptomatic treatment with oral supplements of creatine, ornithine, and sodium benzoate, and a protein-restricted diet to reduce arginine intake, appear to substantially improve health and developmental outcomes. Without newborn screening, diagnosis typically happens after the development of significant impairment, when treatment has limited utility. GAMT deficiency newborn screening can be incorporated into the tandem-mass spectrometry screening that is already routinely used for newborn screening, with about 1 per 100 000 newborns screening positive. After a positive screen, diagnosis is established by finding an elevated guanidinoacetate concentration and low creatine concentration in the blood. Although GAMT deficiency is significantly more rare than other conditions included in newborn screening, the feasibility of screening, the low number of positive results, the relative ease of diagnosis, and the expected benefit of presymptomatic dietary therapy led to a recommendation from the Advisory Committee on Heritable Disorders in Newborns and Children to the Secretary of Health and Human Services that GAMT deficiency be added to the Recommended Uniform Screening Panel. This recommendation was accepted in January 2023.
胍基乙酸甲基转移酶（GAMT）缺乏症是一种由于 GAMT 基因的致病性变异导致的肌酸生物合成的常染色体隐性遗传病，可导致脑肌酸缺乏和胍基乙酸的神经毒性水平升高。未经治疗，GAMT 缺乏症与张力减退、严重智力残疾、语言发育受限、反复癫痫发作、行为问题和不自主运动有关。GAMT 缺乏症的出生患病率可能在每 100 万活产儿中有 0.5 至 2 例。基于小病例系列和兄弟姐妹数据，口服肌酸、精氨酸和苯甲酸钠补充剂以及限制蛋白质以减少精氨酸摄入的治疗方法，在出现明显损伤之前进行，可显著改善健康和发育结果。如果没有新生儿筛查，诊断通常发生在出现明显损伤之后，此时治疗的效果有限。GAMT 缺乏症的新生儿筛查可以纳入已经常规用于新生儿筛查的串联质谱筛查中，大约每 100000 名新生儿中就有 1 名筛查阳性。阳性筛查后，通过在血液中发现升高的胍基乙酸浓度和低肌酸浓度来确诊。尽管 GAMT 缺乏症明显比新生儿筛查中包含的其他疾病更为罕见，但筛查的可行性、阳性结果的数量较少、诊断相对容易以及预期的早期饮食治疗益处，导致遗传性新生儿和儿童疾病咨询委员会向卫生与公众服务部长建议将 GAMT 缺乏症添加到推荐的统一筛查面板中。这一建议于 2023 年 1 月被采纳。
