Larancuent Cesar E, Weiler Tracey, Kana Sajel L
Health Sciences, Florida International University, Herbert Wertheim College of Medicine, Miami, USA.
Genetics, Florida International University, Herbert Wertheim College of Medicine, Miami, USA.
Cureus. 2025 Jun 19;17(6):e86380. doi: 10.7759/cureus.86380. eCollection 2025 Jun.
Newborn screening (NBS) is performed to screen for conditions where early intervention can make a difference in a patient's prognosis. We present the case of a patient with glutaric aciduria type 1 (GA1) that was missed on NBS but was diagnosed through exome sequencing (ES) at eight years of age. We report the case of a patient who was born in Florida in 2011 and underwent routine NBS, which was negative for all tested conditions, including amino acidemias. At 11 months of age, the patient presented with seizures. Upon physical examination, she had hypotonia, ptosis, and macrocephaly. A urinary tract infection was found, and the seizures were attributed to fever from an infectious source. Laboratory testing revealed marginally elevated levels of pyruvate, acylcarnitine, and total carnitine. Magnetic resonance imaging and spectroscopy (MRI/MRS) showed signs of basal ganglia damage. At 12 months of age, she was tested for pathogenic variants in PDHA1, PTEN, and the mitochondrial genome, to look for an underlying molecular diagnosis for her symptoms. No pathogenic variants were found. At eight years of age, ES revealed that the patient was a compound heterozygote for pathogenic variants in GCDH, confirming a diagnosis of GA1. There is little correlation between biochemical markers and phenotype severity in GA1; therefore, biochemical markers can potentially be within normal limits in a symptomatic patient. Diagnosis is complicated by low excretor phenotypes: some patients excrete lower levels of organic acids in the urine. Furthermore, there are no pathognomonic clinical findings, and these patients do not always have MRI findings. ES of our patient led to the diagnosis of GA1, where biomarkers and imaging did not, highlighting the clinical utility of gene sequencing. As we will explore, this is not an isolated case of disease missed in biochemical testing. GA1 should be included in a differential if a patient has symptoms consistent with the condition and/or if biochemical markers are marginally normal. Lowering the threshold for positive biochemical results is not sufficient to address this issue, as it would create an excess of false positives. Since GA1 can also result in inconclusive biochemical tests, false-negative results will still occur. As NBS cannot unequivocally rule out GA1 in these patients, enzyme and/or genetic testing may yield a diagnostic result and inform appropriate management.
新生儿筛查（NBS）用于筛查早期干预可改善患者预后的疾病。我们报告一例1型戊二酸血症（GA1）患者，该患者在新生儿筛查中被漏诊，但8岁时通过外显子组测序（ES）确诊。我们报告的这名患者于2011年出生在佛罗里达州，接受了常规新生儿筛查，所有检测项目结果均为阴性，包括氨基酸血症。11个月大时，该患者出现癫痫发作。体格检查发现她肌张力低下、上睑下垂和巨头畸形。发现有尿路感染，癫痫发作归因于感染源引起的发热。实验室检测显示丙酮酸、酰基肉碱和总肉碱水平略有升高。磁共振成像和波谱分析（MRI/MRS）显示基底神经节受损迹象。12个月大时，对她进行了PDHA1、PTEN和线粒体基因组致病变异检测，以寻找其症状的潜在分子诊断依据。未发现致病变异。8岁时，外显子组测序显示该患者为GCDH致病变异的复合杂合子，确诊为GA1。在GA1中，生化标志物与表型严重程度之间几乎没有相关性；因此，有症状患者的生化标志物可能在正常范围内。低排泄型表型使诊断变得复杂：一些患者尿液中有机酸排泄水平较低。此外，没有特征性的临床发现，这些患者也并非总有MRI表现。我们患者的外显子组测序确诊了GA1，而生物标志物和影像学检查未能确诊，突出了基因测序的临床应用价值。正如我们将探讨的，这并非生化检测漏诊疾病的孤立案例。如果患者有与该病相符的症状和/或生化标志物略正常，鉴别诊断时应考虑GA1。降低生化检测阳性结果的阈值不足以解决此问题，因为这会产生过多假阳性。由于GA1也可能导致生化检测结果不确定，仍会出现假阴性结果。由于新生儿筛查不能明确排除这些患者患有GA1，酶和/或基因检测可能会得出诊断结果并指导适当的治疗。
