新时代扩大新生儿筛查背景下线粒体脂肪酸氧化障碍的诊断、基因特征分析及临床随访：单中心经验
Diagnosis, genetic characterization and clinical follow up of mitochondrial fatty acid oxidation disorders in the new era of expanded newborn screening: A single centre experience.
作者信息
Maguolo A, Rodella G, Dianin A, Nurti R, Monge I, Rigotti E, Cantalupo G, Salviati L, Tucci S, Pellegrini F, Molinaro G, Lupi F, Tonin P, Pasini A, Campostrini N, Ion Popa F, Teofoli F, Vincenzi M, Camilot M, Piacentini G, Bordugo A
机构信息
Department of Mother and Child, Pediatric Clinic, University Hospital of Verona, Verona, Italy.
Inherited Metabolic Diseases Unit and Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
出版信息
Mol Genet Metab Rep. 2020 Aug 5;24:100632. doi: 10.1016/j.ymgmr.2020.100632. eCollection 2020 Sep.
INTRODUCTION
Mitochondrial fatty acid oxidation disorders (FAODs) are a heterogeneous group of hereditary autosomal recessive diseases included in newborn screening (NBS) program in Italy. The aim of this study was to analyse FAODs cases, identified either clinically or by NBS,for clinical and genetic characterization and to evaluate a five years' experience of NBS, in the attempt to figure out the complexity of genotype-phenotype correlation and to confirm the clinical impact of NBS in our centre experience.
MATERIALS AND METHODS
We analysed FAODs patients diagnosed either by NBS or clinically, followed since February 2014 to April 2019 at the Regional Screening Centre and Inherited Metabolic Diseases Unit of Verona. Diagnosis was confirmed by plasma acylcarnitines, urinary organic acids, enzymatic and genetic testing. For not clear genotypes due to the presence of variants of uncertain significance, in silico predictive tools have been used as well as enzymatic activity assays. Patients underwent clinical, nutritional and biochemical follow up.
RESULTS
We diagnosed 30 patients with FAODs. 20 by NBS: 3 CUD, 6 SCADD, 5 MCADD, 4 VLCADD, 2 MADD. Overall incidence of FAODs diagnosed by NBS was 1:4316 newborns. No one reported complications during the follow up period. 10 patients were diagnosed clinically: 2 CUD, 2 CPT2D, 1 VLCADD, 5 MADD. Mean age at diagnosis was 29.3 years. Within this group, complications or symptoms were reported at diagnosis, but not during follow-up. 12 mutations not previously reported in literature were found, all predicted as pathogenic or likely pathogenic.
DISCUSSION AND CONCLUSIONS
Our study highlighted the great phenotypic variability and molecular heterogeneity of FAODs and confirmed the importance of a tailored follow up and treatment. Despite the short duration of follow up, early identification by NBS prevented diseases related complications and resulted in normal growth and psycho-motor development as well.
引言
线粒体脂肪酸氧化障碍（FAODs）是一组遗传性常染色体隐性疾病，意大利的新生儿筛查（NBS）项目中包含此类疾病。本研究旨在分析通过临床诊断或新生儿筛查确诊的FAODs病例，进行临床和基因特征分析，并评估五年的新生儿筛查经验，以明确基因型-表型相关性的复杂性，并在我们中心的经验中确认新生儿筛查的临床影响。
材料与方法
我们分析了自2014年2月至2019年4月在维罗纳地区筛查中心和遗传性代谢疾病科通过新生儿筛查或临床诊断的FAODs患者。通过血浆酰基肉碱、尿有机酸、酶学和基因检测确诊。对于因存在意义不明确的变异而导致基因型不明确的情况，使用了计算机预测工具以及酶活性测定。患者接受了临床、营养和生化随访。
结果
我们诊断出30例FAODs患者。20例通过新生儿筛查确诊：3例肉碱摄取障碍（CUD），6例短链酰基辅酶A脱氢酶缺乏症（SCADD），5例中链酰基辅酶A脱氢酶缺乏症（MCADD），4例极长链酰基辅酶A脱氢酶缺乏症（VLCADD），2例多种酰基辅酶A脱氢酶缺乏症（MADD）。通过新生儿筛查确诊的FAODs总体发病率为1:4316新生儿。随访期间无人报告并发症。10例患者通过临床诊断：2例CUD，2例肉碱棕榈酰转移酶2缺乏症（CPT2D），1例VLCADD，5例MADD。诊断时的平均年龄为29.3岁。在该组中，诊断时报告了并发症或症状，但随访期间未报告。发现了12种先前文献中未报道的突变，均预测为致病或可能致病。
讨论与结论
我们的研究突出了FAODs巨大的表型变异性和分子异质性，并证实了个体化随访和治疗的重要性。尽管随访时间较短，但新生儿筛查的早期识别预防了与疾病相关的并发症，并导致了正常的生长和心理运动发育。
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