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

A Maguolo; G Rodella; A Dianin; R Nurti; I Monge; E Rigotti; G Cantalupo; L Salviati; S Tucci; F Pellegrini; G Molinaro; F Lupi; P Tonin; A Pasini; N Campostrini; F Ion Popa; F Teofoli; M Vincenzi; M Camilot; G Piacentini; A Bordugo

doi:10.1016/j.ymgmr.2020.100632

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

Mol Genet Metab Rep. 2020 Aug 5:24:100632. doi: 10.1016/j.ymgmr.2020.100632. eCollection 2020 Sep.

Authors

A Maguolo¹, G Rodella^{1

2}, A Dianin^{1

2}, R Nurti^{1

2}, I Monge^{1

2}, E Rigotti¹, G Cantalupo³, L Salviati^{4

5}, S Tucci⁶, F Pellegrini⁷, G Molinaro⁷, F Lupi⁷, P Tonin⁸, A Pasini⁹, N Campostrini⁹, F Ion Popa⁹, F Teofoli⁹, M Vincenzi⁹, M Camilot⁹, G Piacentini¹, A Bordugo^{1

2}

Affiliations

¹ Department of Mother and Child, Pediatric Clinic, University Hospital of Verona, Verona, Italy.
² 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.
³ Department of Surgical Sciences, Dentistry, Gynaecology and Paediatrics, Division of Child Neuropsychiatry, University of Verona, Verona, Italy.
⁴ Clinical Genetics Unit, Department of Women and Children's Health, University of Padova, Padua, Italy.
⁵ IRP Città della Speranza, Padua, Italy.
⁶ 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.
⁷ Neonatal Intensive Care unit, Azienda Sanitaria Alto Adige, Bolzano, Italy.
⁸ Department of Neurosciences, Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, Verona, Italy.
⁹ Department of Pediatrics, Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, AOUI, Verona, Italy.

Abstract

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.

Keywords: ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; CACTD, carnitine-acylcarnitine translocase deficiency; CK, creatine kinase; CPT1/2 D, carnitine palmitoyl-CoA transferase 1/2 deficiency; CUD, carnitine uptake defect; DBS, dried blood spots; DNA, Deoxyribonucleic acid; Enzymatic activity; Expanded newborn screening; FAODs, fatty acid oxidation disorders; Fatty acid oxidation defects; Hypoglycaemia; LCHADD, Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency; MADD, multiple acyl-CoA dehydrogenase deficiency; MCADD, medium-chain acyl-CoA dehydrogenase deficiency; Myopathy; NBS, newborn screening; NGS, next generation sequencing; PCR, polymerase chain reaction; SCADD, short chain acyl-CoA dehydrogenase deficiency; Synergistic heterozygosity; TFPD, trifunctional protein deficiency; TMS, tandem mass spectrometry; VLCADD, very-long-chain acyl-CoA dehydrogenase deficiency.