title: Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State.
abstract: BACKGROUND
  Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome.
  
  
  METHODS
  All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms.
  
  
  RESULTS
  We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 micromol/L in the asymptomatic vs. 19.1 micromol/L in the symptomatic, p<0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p<0.012). Four infants had initial C8 level >30 micromol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians.
  
  
  CONCLUSIONS
  No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 777, Rochester, NY 14642, USA. Georgianne_Arnold@urmc.rochester.edu
authors.forename: Georgianne L
authors.initials: GL
authors.lastname: Arnold
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Saavedra-Matiz
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Galvin-Parton
authors.forename: Richard
authors.initials: R
authors.lastname: Erbe
authors.forename: Ellen
authors.initials: E
authors.lastname: Devincentis
authors.forename: David
authors.initials: D
authors.lastname: Kronn
authors.forename: Shideh
authors.initials: S
authors.lastname: Mofidi
authors.forename: Melissa
authors.initials: M
authors.lastname: Wasserstein
authors.forename: Joan E
authors.initials: JE
authors.lastname: Pellegrino
authors.forename: Paul A
authors.initials: PA
authors.lastname: Levy
authors.forename: Darius J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Matthew
authors.initials: M
authors.lastname: Nichols
authors.forename: Michele
authors.initials: M
authors.lastname: Caggana
mesh_terms: D044944:Acyl-CoA Dehydrogenases / Q000172:deficiency* / Q000235:genetics*; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation; D015997:Neonatal Screening / Q000379:methods*; D009518:New York; D010641:Phenotype; D011379:Prognosis
chemical_list: D005227:Fatty Acids; D044944:Acyl-CoA Dehydrogenases; C008698:octanoylcarnitine; D002331:Carnitine