Introduction

Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited metabolic disorder that impairs the synthesis of creatine (CRE). Lack of CRE in the brain can cause intellectual disability, autistic-like behavior, seizures, and movement disorders. Identification at birth and immediate therapy can prevent intellectual disability and seizures. Here we report the first two cases of GAMT deficiency identified at birth by newborn screening (NBS) in Utah and New York.

Methods

NBS dried blood spots were analyzed by tandem mass spectrometry (MS/MS) using either derivatized or non-derivatized assays to detect guanidinoacetate (GUAC) and CRE. For any positive samples, a second-tier test using a more selective method, ultra-performance liquid chromatography (UPLC) combined with MS/MS, was performed to separate GUAC from potential isobaric interferences.

Results

NBS for GAMT deficiency began in Utah on June 1, 2015 using a derivatized method for the detection of GUAC and CRE. In May 2019, the laboratory and method transitioned to a non-derivatized method. GAMT screening was added to the New York State NBS panel on October 1, 2018 using a derivatized method. In New York, a total of 537,408 babies were screened, 23 infants were referred and one newborn was identified with GAMT deficiency. In Utah, a total of 273,902 infants were screened (195,425 with the derivatized method, 78,477 with the non-derivatized method), three infants referred and one was identified with GAMT deficiency. Mean levels of GUAC and CRE were similar between methods (Utah derivatized: GUAC = 1.20 ± 0.43 μmol/L, CRE = 238 ± 96 μmol/L; Utah non-derivatized: GUAC = 1.23 ± 0.61 μmol/L, CRE = 344 ± 150 μmol/L, New York derivatized: GUAC = 1.34 ± 0.57 μmol/L, CRE = 569 ± 155 μmol/L). With either Utah method, similar concentrations of GUAC are observed in first (collected around 1 day of age) and the second NBS specimens (routinely collected at 7–16 days of age), while CRE concentrations decreased in the second NBS specimens. Both infants identified with GAMT deficiency started therapy by 2 weeks of age and are growing and developing normally at 7 (Utah) and 4 (New York) months of age.

Conclusions

Newborn screening allows for the prospective identification of GAMT deficiency utilizing elevated GUAC concentration as a marker. First-tier screening may be incorporated into existing methods for amino acids and acylcarnitines without the need for new equipment or staff. Newborn screening performed by either derivatized or non-derivatized methods and coupled with second-tier testing, has a very low false positive rate and can prospectively identify affected children.

SummaryCerebral creatine deficiency syndromes caused by defects in creatine synthesis can result in intellectual disability, and are preventable if therapy is initiated early in life. This manuscript reports the identification of two infants with GAMT deficiency (one of the cerebral creatine deficiency syndromes) by newborn screening and demonstrates NBS feasibility using a variety of methods.

中文翻译：

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通过新生儿筛查对胍基乙酸甲基转移酶缺乏症患者进行前瞻性鉴定

介绍

胍基乙酸甲基转移酶 (GAMT) 缺乏症是一种遗传性代谢疾病，会损害肌酸 (CRE) 的合成。大脑中缺乏 CRE 会导致智力残疾、类似自闭症的行为、癫痫发作和运动障碍。出生时识别和立即治疗可以预防智力残疾和癫痫发作。在这里，我们报告了犹他州和纽约州通过新生儿筛查 (NBS) 发现的前两例 GAMT 缺乏症。

方法

NBS 干血斑通过串联质谱 (MS/MS) 分析，使用衍生化或非衍生化测定法检测胍基乙酸 (GUAC) 和 CRE。对于任何阳性样品，使用选择性更高的方法，即超高效液相色谱 (UPLC) 结合 MS/MS 进行第二层测试，以将 GUAC 与潜在的同量异位素干扰物分开。

结果

GAMT 缺陷的 NBS 于 2015 年 6 月 1 日在犹他州开始使用衍生方法检测 GUAC 和 CRE。2019 年 5 月，实验室和方法过渡到非衍生方法。GAMT 筛选于 2018 年 10 月 1 日使用衍生方法添加到纽约州 NBS 小组。在纽约，共有 537,408 名婴儿接受了筛查，23 名婴儿被转诊，一名新生儿被确定为 GAMT 缺乏症。在犹他州，共有 273,902 名婴儿接受了筛查（衍生方法 195,425 名，非衍生方法 78,477 名），转诊婴儿 3 名，确定 1 名患有 GAMT 缺乏症。方法之间的 GUAC 和 CRE 平均水平相似（Utah 衍生化：GUAC = 1.20 ± 0.43 μmol/L，CRE = 238 ± 96 μmol/L；Utah 非衍生化：GUAC = 1.23 ± 0.61 μmol/L，CRE = 344 ± 150 μmol/L，纽约衍生：GUAC = 1。34 ± 0.57 μmol/L，CRE = 569 ± 155 μmol/L)。在犹他州的任何一种方法中，在第一个（大约 1 日龄收集）和第二个 NBS 标本（通常在 7-16 日龄收集）中观察到相似浓度的 GUAC，而在第二个 NBS 标本中 CRE 浓度降低。两名被鉴定为 GAMT 缺乏症的婴儿在 2 周大时开始接受治疗，并在 7（犹他州）和 4（纽约）月龄时正常生长和发育。

结论

新生儿筛查允许利用升高的 GUAC 浓度作为标志物来前瞻性识别 GAMT 缺乏症。一级筛选可纳入现有的氨基酸和酰基肉碱方法，无需新设备或人员。通过衍生或非衍生方法进行新生儿筛查并结合二级检测，假阳性率非常低，并且可以前瞻性地识别受影响的儿童。

总结由肌酸合成缺陷引起的脑肌酸缺乏综合征可导致智力障碍，如果在生命早期开始治疗，则可以预防。这份手稿报告了通过新生儿筛查鉴定出两名患有 GAMT 缺乏症（一种脑肌酸缺乏症综合征）的婴儿，并使用多种方法证明了 NBS 的可行性。