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.,Molecular Genetics and Metabolism Reports

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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.
Molecular Genetics and Metabolism Reports ( IF 1.9 ) Pub Date : 2020-08-05 , DOI: 10.1016/j.ymgmr.2020.100632
A Maguolo ₁ , G Rodella _{1,

2} , A Dianin _{1,

2} , R Nurti _{1,

2} , I Monge _{1,

2} , E Rigotti ₁ , G Cantalupo ₃ , L Salviati _{4,

5} , S Tucci ₆ , F Pellegrini ₇ , G Molinaro ₇ , F Lupi ₇ , P Tonin ₈ , A Pasini ₉ , N Campostrini ₉ , F Ion Popa ₉ , F Teofoli ₉ , M Vincenzi ₉ , M Camilot ₉ , G Piacentini ₁ , A Bordugo _{1,

2}

Affiliation

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.
Department of Surgical Sciences, Dentistry, Gynaecology and Paediatrics, Division of Child Neuropsychiatry, University of Verona, Verona, Italy.
Clinical Genetics Unit, Department of Women and Children's Health, University of Padova, Padua, Italy.
IRP Città della Speranza, Padua, Italy.
Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics and Adolescent Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Neonatal Intensive Care unit, Azienda Sanitaria Alto Adige, Bolzano, Italy.
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, Verona, Italy.
Department of Pediatrics, Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, AOUI, Verona, Italy.

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.

中文翻译：

扩大新生儿筛查新时代线粒体脂肪酸氧化障碍的诊断、遗传特征和临床随访：单中心经验。

介绍

线粒体脂肪酸氧化障碍 (FAODs) 是一组异质的遗传性常染色体隐性遗传疾病，包括在意大利新生儿筛查 (NBS) 计划中。本研究的目的是分析临床或 NBS 确定的FAODs 病例的临床和遗传特征，并评估 NBS 五年的经验，以试图找出基因型-表型相关性的复杂性并确认NBS 在我们中心经验中的临床影响。

材料和方法

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代谢疾病部门诊断出的由 NBS 或临床诊断出的FAODs 患者。通过血浆酰基肉碱、尿有机酸、酶学和基因检测证实了诊断。对于由于存在意义不确定的变体而导致的不明确基因型，已使用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 名FAOD 患者。20 个国家统计局：3 CUD、6 SCAD、5 MCADD、4 VLCADD、2 MADD。NBS 诊断的FAODs 总发病率为1:4316 新生儿。在随访期间没有人报告并发症。10 名患者被临床诊断：2 名 CUD、2 名 CPT2D、1 名 VCADD、5 名 MADD。诊断时的平均年龄为 29.3 岁。在该组中，并发症或症状在诊断时报告，但在随访期间未报告。发现了 12 种先前未在文献中报道的突变，均被预测为致病性或可能致病性。