Novel mutations causing medium chain acyl‐CoA dehydrogenase deficiency: Under‐representation of the common c.985 A > G mutation in the New York state population

Abstract

Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is one of the most common fatty acid oxidation disorders. A subpopulation of children with MCADD present with metabolic crisis induced by fasting or illness, become lethargic, and can experience seizures or coma, culminating in a 20% mortality rate during the first episode. The frequency of these metabolic crises can be reduced with early diagnosis and treatment. The prevalence of MCADD in the United States is estimated to be 1 per 15,000 with p.K304E (c.985A > G) accounting for 90% of mutant alleles. In an 18-month period after initiating screening, the New York State Newborn Screening Mass Spectrometry Laboratory screened 385,893 newborns and referred 511 samples with elevated (>or=0.3 micromol/L) octanoylcarnitine (C8) levels for molecular testing. Of these referrals, six p.K304E homozygotes and 154 heterozygotes were identified. Twenty infants were biochemically confirmed with MCADD, per report from the child's pediatrician and/or treatment center. In these 20 cases, p.K304E accounted for only 47.5% of the mutant alleles. Further testing showed a second variant, p.Y42H, accounted for 7.5% of mutant alleles while the remaining 45% were unknown. Samples from all diagnosed non-p.K304E homozygous infants, and samples with C8 levels >or=1.0 micromol/L were sequenced (n = 16). Six novel and seven previously reported mutations were detected. These results suggest that p.K304E has a far lower representation in New York newborns with MCADD than current literature estimates and its full mutational spectrum is still unknown.

Relevance of Expanded Neonatal Screening of Medium-Chain Acyl Co-A Dehydrogenase Deficiency: Outcome of a Decade in Galicia (Spain)

“…Similar to other studies, the prevalent mutation in our population is c.985A>G (p.K329E), which was found in 75% of the alleles with MCADD, but was not as high as previously anticipated (Yokota et al 1991;Giroux et al 2007;Waddell et al 2006;Blois et al 2005), although it is rather high if we consider other neonatal screening studies (Andresen et al 2001;Maier et al 2005;Nichols et al 2008;Smith et al 2010) as in the screened individuals it is usual to find milder mutations, while the common mutation c.985A> G is most frequently found in the clinically presenting patients.…”

Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency

“…Patient 39 presented a biochemical profile similar to MCAD carrier, as also described Hsu et al [42], and never showed clinical signs. The percentage of cases homozygous for the common mutation (76%) detected in our cohort was higher than previously reported, ranging from 30% to 71% (47.4% [3]; 43% [4]; 53% [19]; 61% [21]; 37% [27]; 71% [30]; 40% [31]; 63% [32]; 36.4% [33]; 52% [34]; 30% [35]). Our results could have a bias due to the high proportion of patients of Gypsy ethnicity (31/45, 69%), in whom the common allele shows a high population frequency [43]; 22/26 (84.6%) of our patients from Portugal were homozygous for the common mutation, while the remaining 12 homozygous patients were from Spain.…”

“…Approximately 80% of patients diagnosed clinically are homozygous for the common c.985A>G mutation [25,29]. Patients diagnosed as a result of screening show a different mutational spectrum, with a lower proportion (30-71%) of homozygotes for the common mutation [3,20,21,23,25,27,30-35]. This diagnosis-dependent difference in frequency of the homozygous c.985A>G mutation could be due to the increased detection of milder biochemical phenotypes by newborn screening, with a relatively low risk of developing clinical disease, and associated to mutations found only in screened populations [4,31,36].…”

Functional Effects of Different Medium-Chain Acyl-CoA Dehydrogenase Genotypes and Identification of Asymptomatic Variants

“…With the advent of newborn screening, where many newborns are identified in the absence of a clinical presentation, a second prevalent mutation was identified c.199T>C (allele frequency approximately 6%). This mutation however, has never been conclusively linked to clinical symptoms [7], [9], [10], [14], [15]. Instead, most children with the c.199T>C allele are placed on preventative measures, which potentially masks the natural clinical course of the disease.…”