Sajeev Mona, Chin Sharon, Ho Gladys, Bennetts Bruce, Sankaran Bindu Parayil, Gutierrez Bea, Devanapalli Beena, Tolun Adviye Ayper, Wiley Veronica, Fletcher Janice, Fuller Maria, Balasubramaniam Shanti
Genetic Metabolic Disorders Service, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, North Adelaide, SA 5006, Australia.
Int J Neonatal Screen. 2021 May 14;7(2):25. doi: 10.3390/ijns7020025.
Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in , , or genes result in enzyme deficiency. We report the case of a female infant who presented with mild gross motor delay at 4 months, and seizures with hypoglycaemia at 5 months. Newborn screening returned total leucine/isoleucine at the 99.5th centile of the population; however, as second-tier testing reported minimal alloisoleucine, the results were considered inconsistent with MSUD. Plasma amino acid and urine organic acid analyses at 5 months were, however, consistent with a diagnosis of MSUD. A brain MRI showed bilateral symmetrical T2 hyperintense signal abnormalities involving white matter, globus pallidus, thalamus, brainstem, and dentate nuclei with restricted diffusion. A repeat MRI 10 months post-dietary-intervention showed the resolution of these changes and progression in myelination. Her clinical phenotype, including protein tolerance, correlated with intermediate MSUD. Molecular analysis of all three genes identified two variants of uncertain significance, c.434-15_434-4del and c.365A>G (p. Tyr122Cys) in the gene. The rate of leucine decarboxylation in fibroblasts was reduced, but not to the extent observed in classical MSUD patients, supporting an intermediate form of MSUD. Previously reported mRNA splicing studies supported a deleterious effect of the c.434-15_434-4del variant. This functional evidence and confirmation that the variants were in trans, permitted their reclassification as pathogenic and likely pathogenic, respectively, facilitating subsequent prenatal testing. This report highlights the challenges in identifying intermediate MSUD by newborn screening, reinforcing the importance of functional studies to confirm variant pathogenicity in this era of molecular diagnostics.
枫糖尿症是由支链α-酮酸脱氢酶缺乏引起的，该酶负责亮氨酸、异亮氨酸和缬氨酸的降解。 、 或 基因中的双等位基因致病性变异导致酶缺乏。我们报告了一名女婴的病例，该女婴在4个月时出现轻度大运动发育迟缓，5个月时出现癫痫发作并伴有低血糖。新生儿筛查结果显示总亮氨酸/异亮氨酸处于人群第99.5百分位；然而，由于二线检测报告异亮氨酸含量极低，因此这些结果被认为与枫糖尿症不符。然而，5个月时的血浆氨基酸和尿有机酸分析结果与枫糖尿症的诊断一致。脑部MRI显示双侧对称的T2高信号异常，累及白质、苍白球、丘脑、脑干和齿状核，扩散受限。饮食干预10个月后的复查MRI显示这些变化消失，髓鞘形成进展。她的临床表型，包括蛋白质耐受性，与中间型枫糖尿症相关。对所有三个基因的分子分析鉴定出两个意义不明确的变异，即 基因中的c.434-15_434-4del和c.365A>G（p.Tyr122Cys）。成纤维细胞中亮氨酸脱羧率降低，但未降至经典枫糖尿症患者所观察到的程度，支持中间型枫糖尿症的诊断。先前报道的mRNA剪接研究支持c.434-15_434-4del变异具有有害作用。这种功能证据以及确认变异为反式排列，使得它们分别被重新分类为致病性和可能致病性，便于后续的产前检测。本报告强调了通过新生儿筛查识别中间型枫糖尿症的挑战，强化了功能研究在这个分子诊断时代确认变异致病性的重要性。
