Lack of genotype–phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State

Arnold, Georgianne L.; Saavedra-Matiz, Carlos A.; Galvin-Parton, Patricia; Erbe, Richard W.; DeVincentis, Ellen; Kronn, David; Mofidi, Shideh; Wasserstein, Melissa P.; Pellegrino, Joan E.; Levy, Paul A.; Adams, Darius; Nichols, Matthew; Casini, Michèle

doi:10.1016/j.ymgme.2009.10.188

Cited by 49 publications

(49 citation statements)

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“…The correlation between genotype and clinical phenotype in MCADD is not clear (Andresen et al 1997;Arnold et al 2010). Several asymptomatic patients being homozygous for the c.985A>G mutation have been reported (Andresen et al 2012;Duran et al 1986;Leydiker et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Abnormal Newborn Screening in a Healthy Infant of a Mother with Undiagnosed Medium-Chain Acyl-CoA Dehydrogenase Deficiency

et al. 2015

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A neonate with low blood free carnitine level on newborn tandem mass spectrometry screening was evaluated for possible carnitine transporter defect (CTD). The plasma concentration of free carnitine was marginally reduced, and the concentrations of acylcarnitines (including C6, C8, and C10:1) were normal on confirmatory tests. Organic acids in urine were normal. In addition, none of the frequent Faroese SLC22A5 mutations (p.N32S, c.825-52G>A) which are common in the Danish population were identified. Evaluation of the mother showed low-normal free carnitine, but highly elevated medium-chain acylcarnitines (C6, C8, and C10:1) consistent with medium-chain acyl-CoA dehydrogenase deficiency (MCADD). The diagnosis was confirmed by the finding of homozygous presence of the c.985A>G mutation in ACADM.

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Section: Discussionmentioning

confidence: 99%

Abnormal Newborn Screening in a Healthy Infant of a Mother with Undiagnosed Medium-Chain Acyl-CoA Dehydrogenase Deficiency

et al. 2015

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“…It seems that there is no clear relationship between genotype and phenotype (Andresen et al 1997;Lehotay et al 2004;Waddell et al 2006;Hsu et al 2008), but patients homozygous for the common mutation have higher levels of C8 (Andresen et al 2001;Waddell et al 2006;Smith et al 2010), and it is associated with a greater predisposition to suffer decompensation in situations of metabolic stress (Arnold et al 2010). Thus, compound heterozygous for the prevalent c.985A>G mutation and a milder mutation in the other allele may have a risk reduction due to their greater residual enzyme activity (Lehotay et al 2004).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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Neonatal screening of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is of major importance due to the significant morbidity and mortality in undiagnosed patients. MCADD screening has been performed routinely in Galicia since July 2000, and until now 199,943 newborns have been screened. We identified 11 cases of MCADD, which gives an incidence of 1/18,134. During this period, no false negative screens have been detected. At diagnosis, all identified newborns were asymptomatic. Our data showed that octanoylcarnitine (C8) and C8/C10 ratio are the best markers for screening of MCADD. C8 was increased in all patients and C8/C10 was increased in all but one patient.The common mutation, c.985A>G, was found in homozygosity in seven newborns and in compound heterozygosity in three, while one patient did not carry the common mutation at all. In addition, two novel mutations c.245G>C (p.W82S) and c.542A>G (p.D181G) were identified. Ten of the 11 identified newborns did not experience any episodes of decompensation. The patient with the highest level of medium chain acylcarnitines at diagnosis, who was homozygous for the c.985A>G mutation, died at the age of 2 years due to a severe infection. This is the first report of the results from neonatal screening for MCADD in Spain. Our data provide further evidence of the benefits of MCADD screening and contribute to better understanding of this disease.

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“…Neonatal triggers were defined as neonatal complications and interventions suggestive of underlying health complications determined by clinician authors as most likely to result in potential MCADD symptoms. Neonatal symptoms were defined by clinician authors as symptoms consistent with MCADD, many based on reports of symptoms manifested in individuals affected with MCADD (9) (14) (15) (16) (17) (18) (19) (20). Neonatal abnormal labs were defined by clinician authors as laboratory test abnormalities of potential concern in the context of MCADD (excluding newborn screening and MCADD diagnostic biochemical and molecular test results).…”

Section: Methodsmentioning

confidence: 99%

“…Higher C8 values in blood spot newborn screening have been reported in association with homozygosity for the common c.985A>G pathogenic gene variant (8), or the presence of other severe pathogenic variants such as deletion, nonsense, or splice site mutations in the ACADM gene (9). Higher blood spot C8 values have also been reported in MCADD affected neonates, particularly those homozygous for the c.985A>G mutation, whose blood spots were collected sooner after birth (10).…”

Section: Introductionmentioning

confidence: 99%

221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative

Berry

Thomas²,

Dodge³

et al. 2016

Molecular Genetics and Metabolism

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INTRODUCTION There is limited understanding of relationships between genotype, phenotype and other conditions contributing to health in neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) identified through newborn screening. METHODS Retrospective analysis of comprehensive data from a cohort of 221 newborn-screened subjects identified as affected with MCADD in the Inborn Errors of Metabolism – Information System (IBEM-IS), a long term follow-up database of the Inborn Errors of Metabolism Collaborative, was performed. RESULTS The average age at notification of first newborn screen results to primary care or metabolic providers was 7.45 days. The average octanoylcarnitine (C8) value on first newborn screen was 11.2 umol/L (median 8.6, range 0.36–43.91). A higher C8 level correlated with an earlier first subspecialty visit. Subjects with low birth weight had significantly lower C8 values. Significantly higher C8 values were found in symptomatic newborns, in newborns with abnormal lab testing in addition to newborn screening and/or diagnostic tests, and in subjects homozygous for the c.985A>G ACADM gene mutation or compound heterozygous for the c.985A>G mutation and deletions or other known highly deleterious mutations. Subjects with neonatal symptoms, or neonatal abnormal labs, or neonatal triggers were more likely to have at least one copy of the severe c.985A>G ACADM gene mutation. C8 and genotype category were significant predictors of the likelihood of having neonatal symptoms. Neonates with select triggers were more likely to have symptoms and laboratory abnormalities. CONCLUSIONS This collaborative study is the first in the United States to describe health associations of a large cohort of newborn-screened neonates identified as affected with MCADD. The IBEM-IS has utility as a platform to better understand the characteristics of individuals with newborn-screened conditions and their follow-up interactions with the health system.

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Lack of genotype–phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State

Cited by 49 publications

References 9 publications

Abnormal Newborn Screening in a Healthy Infant of a Mother with Undiagnosed Medium-Chain Acyl-CoA Dehydrogenase Deficiency

Abnormal Newborn Screening in a Healthy Infant of a Mother with Undiagnosed Medium-Chain Acyl-CoA Dehydrogenase Deficiency

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

221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative

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