title: Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency.
abstract: BACKGROUND
  Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited defect in the mitochondrial fatty acid oxidation pathway, resulting in significant morbidity and mortality in undiagnosed patients.Newborn screening (NBS) has considerably improved MCADD outcome, but the risk of complication remains in some patients. The aim of this study was to evaluate the relationship between genotype, biochemical parameters and clinical data at diagnosis and during follow-up, in order to optimize monitoring of these patients.
  
  
  METHODS
  We carried out a multicenter study in southwest Europe, of MCADD patients detected by NBS. Evaluated NBS data included free carnitine (C0) and the acylcarnitines C8, C10, C10:1 together with C8/C2 and C8/C10 ratios, clinical presentation parameters and genotype, in 45 patients. Follow-up data included C0 levels, duration of carnitine supplementation and occurrence of metabolic crises.
  
  
  RESULTS
  C8/C2 ratio and C8 were the most accurate biomarkers of MCADD in NBS. We found a high number of patients homozygous for the prevalent c.985A > G mutation (75%). Moreover, in these patients C8, C8/C10 and C8/C2 were higher than in patients with other genotypes, while median value of C0 was significantly lower (23 μmol/L vs 36 μmol/L).The average follow-up period was 43 months. To keep carnitine levels within the normal range, carnitine supplementation was required in 82% of patients, and for a longer period in patients homozygotes for the c.985A>G mutation than in patients with other genotypes (average 31 vs 18 months). Even with treatment, median C0 levels remained lower in homozygous patients than in those with other genotypes (14 μmol/L vs 22 μmol/L).Two patients died and another three suffered a metabolic crisis, all of whom were homozygous for the c.985 A>G mutation.
  
  
  CONCLUSIONS
  Our data show a direct association between homozygosity for c.985A>G and lower carnitine values at diagnosis, and a higher dose of carnitine supplementation for maintenance within the normal range. This study contributes to a better understanding of the relationship between genotype and phenotype in newborn patients with MCADD detected through screening which could be useful in improving follow-up strategies and clinical outcome.
authors.affiliation: Unidad de Diagnóstico y Tratamiento de Enfermedades Congénitas del Metabolismo, Departamento de Pediatría, Hospital Clínico Universitario, Universidad de Santiago, Santiago de Compostela, Spain. maria.luz.couce.pico@sergas.es
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Couce
authors.forename: Paula
authors.initials: P
authors.lastname: Sánchez-Pintos
authors.forename: Luisa
authors.initials: L
authors.lastname: Diogo
authors.forename: Elisa
authors.initials: E
authors.lastname: Leão-Teles
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Martins
authors.forename: Helena
authors.initials: H
authors.lastname: Santos
authors.forename: Maria Amor
authors.initials: MA
authors.lastname: Bueno
authors.forename: Carmen
authors.initials: C
authors.lastname: Delgado-Pecellín
authors.forename: Daisy E
authors.initials: DE
authors.lastname: Castiñeiras
authors.forename: José A
authors.initials: JA
authors.lastname: Cocho
authors.forename: Judit
authors.initials: J
authors.lastname: García-Villoria
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.forename: José M
authors.initials: JM
authors.lastname: Fraga
authors.forename: Hugo
authors.initials: H
authors.lastname: Rocha
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency*; D009202:Cardiomyopathies / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology*; D002331:Carnitine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood* / Q000172:deficiency*; D019587:Dietary Supplements; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006720:Homozygote; D006801:Humans; D022124:Hyperammonemia / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology*; D015994:Incidence; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000188:drug therapy / Q000453:epidemiology; D008297:Male; D009135:Muscular Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology*; D015997:Neonatal Screening / Q000379:methods*; D010641:Phenotype; D015995:Prevalence; D013030:Spain / Q000453:epidemiology; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000097:blood
chemical_list: C116917:acylcarnitine; D014803:Vitamin B Complex; D042964:Acyl-CoA Dehydrogenase; D002331:Carnitine