通过对常见的 c.-32-13T>G“迟发型”GAA 变异的新生儿筛查，深入了解庞贝病患儿的表型。
Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T>G "late-onset" GAA variant.
机构信息
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Department of Orthopedics, Duke University School of Medicine, Durham, NC, USA.
出版信息
Mol Genet Metab. 2017 Nov;122(3):99-107. doi: 10.1016/j.ymgme.2017.09.008. Epub 2017 Sep 19.
OBJECTIVE
Newborn screening (NBS) has led to early diagnosis and early initiation of treatment for infantile onset Pompe Disease (IOPD). However, guidelines for management of late onset Pompe disease (LOPD) via NBS, especially with the IVS c.-32-13T>G are not clear. This IVS variant is noted in 68-90% cases with LOPD and has been presumed to result in "adult" disease in compound heterozygosity, with a few cases with earlier onset and a mild to no phenotype in homozygosity. Our study evaluates newborns with LOPD having IVS variant with a diligent multidisciplinary approach to determine if they have an early presentation.
METHODS
Seven children with LOPD identified by NBS with IVS variant (3 compound heterozygous, and 4 homozygous) were evaluated with clinical, biochemical (CK, AST, ALT, and urinary Glc), cardiac evaluation, physical therapy (PT), occupational, and speech/language therapy.
RESULTS
All seven patients demonstrated motor involvement by age 6months; the three patients with c.-32-13 T>G variant in compound heterozygosity had symptoms as neonates. Patients with c.-32-13 T>G variant in compound heterozygosity had more involvement with persistent hyperCKemia, elevated AST and ALT, swallowing difficulties, limb-girdle weakness, delayed motor milestones, and were initiated on ERT. The patients with c.-32-13T>G variant in homozygosity had normal laboratory parameters, and presented with very subtle yet LOPD specific signs, identified only by meticulous assessments.
CONCLUSION
This patient cohort represents the first carefully phenotyped cohort of infants with LOPD with the "late-onset" GAA variant c.-32-13T>G detected by NBS in the USA. It emphasizes not only the opportunity for early detection of skeletal and other muscle involvement in infants with c.-32-13T>G variant but also a high probability of overlooking or underestimating the significance of clinically present and detectable features. It can thus serve as a valuable contribution in the development of evaluation and treatment algorithms for infants with LOPD.
目的
新生儿筛查（NBS）已能实现婴儿早发型庞贝病（IOPD）的早期诊断和早期治疗。然而，通过 NBS 对晚发型庞贝病（LOPD）进行管理的指南尚不清楚，尤其是针对 IVS c.-32-13T>G 这种变体的情况。这种 IVS 变体在 68-90%的 LOPD 病例中都有发现，且据推测在复合杂合子中会导致“成人”疾病，在纯合子中也有少数病例表现为发病更早且表型更轻或无。我们的研究通过一种严谨的多学科方法评估了患有 IVS 变体的 LOPD 新生儿，以确定他们是否有早期表现。
方法
通过 NBS 识别出 7 例携带 IVS 变体的 LOPD 新生儿（3 例为复合杂合子，4 例为纯合子），并对其进行临床、生化（CK、AST、ALT 和尿 Glc）、心脏评估、物理治疗（PT）、职业治疗和言语/语言治疗。
结果
所有 7 例患者在 6 月龄时均出现运动障碍；3 例复合杂合子患者的症状为新生儿期。在复合杂合子中，c.-32-13T>G 变体的 3 例患者有持续性高 CK 血症、AST 和 ALT 升高、吞咽困难、肢体带肌无力、运动发育迟缓等表现，并开始接受 ERT 治疗。c.-32-13T>G 变体的纯合子患者实验室参数正常，仅通过细致的评估发现存在非常轻微但具有 LOPD 特异性的体征。
结论
本患者队列代表了美国通过 NBS 首次检测到“晚发型”GAA 变体 c.-32-13T>G 的 LOPD 婴儿的首次经过精心表型分析的队列。它不仅强调了在 c.-32-13T>G 变体婴儿中早期发现骨骼和其他肌肉受累的机会，而且还强调了临床上存在和可检测的特征很容易被忽视或低估。因此，它可以为 LOPD 婴儿的评估和治疗算法的制定提供有价值的参考。
Zotero 插件