Newborn Screening For Medium-chain acyl-CoA Dehydrogenase Deficiency Research Articles

A nationwide retrospective observational study of population newborn screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the Netherlands.

To evaluate the Dutch newborn screening (NBS) for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency since 2007, a nationwide retrospective, observational study was performed of clinical, laboratory and epidemiological parameters of patients with MCAD deficiency born between 2007 and 2015. Severe MCAD deficiency was defined by ACADM genotypes associated with clinical ascertainment, or variant ACADM genotypes with a residual MCAD enzyme activity <10%. Mild MCAD deficiency was defined by variant ACADM genotypes with a residual MCAD enzyme activity ≥10%. The prevalence of MCAD deficiency was 1/8300 (95% CI: 1/7300-1/9600). Sensitivity of the Dutch NBS was 99% and specificity ~100%, with a positive predictive value of 86%. Thirteen newborns with MCAD deficiency suffered from neonatal symptoms, three of them died. Of the 189 identified neonates, 24% had mild MCAD deficiency. The acylcarnitine ratio octanoylcarnitine (C8)/decanoylcarnitine (C10) was superior to C8 in discriminating between mild and severe cases and more stable in the first days of life. NBS for MCAD deficiency has a high sensitivity, specificity, and positive predictive value. In the absence of a golden standard to confirm the diagnosis, the combination of acylcarnitine (ratios), molecular and enzymatic studies allows risk stratification. To improve evaluation of NBS protocols and clinical guidelines, additional use of acylcarnitine ratios and multivariate pattern-recognition software may be reappraised in the Dutch situation. Prospective recording of NBS and follow-up data is warranted covering the entire health care chain of preventive and curative medicine.

The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common fatty acid oxidation disorder. Typically, undiagnosed individuals are asymptomatic until an episode of increased energy demand and fasting occurs, resulting in metabolic derangement. Phenotypic heterogeneity has been increasingly realized, with reports of both neonates and adults manifesting with life-threatening symptoms including encephalopathy, rhabdomyolysis, and cardiac failure. If diagnosed presymptomatically, outcome is favorable basically by avoidance of fasting. Early detection by newborn screening (NBS) has significantly reduced the incidence of severe adverse events including deaths. In this manuscript we focus on the natural course of the disease in both children and adults. Although NBS for MCADD has been successfully established, continuing efforts need to be made to avoid acute crises and deterioration of outcome in screened patients entering adolescence and adulthood.

Newborn screening for medium chain acyl CoA dehydrogenase deficiency

Medium chain acyl CoA dehydrogenase deficiency (MCADD) is an uncommon inborn error of fatty acid oxidation that is a preventable cause of morbidity and mortality. Newborn screening for MCADD has...

Newborn screening for MCAD deficiency: experience of the first three years in British Columbia, Canada.

Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency is an autosomal recessive disorder of fatty acid oxidation, with potential fatal outcome. MCAD deficiency is diagnosed by acylcarnitine analysis on newborn screening blood spot cards by tandem mass spectrometry. Early diagnosis of MCAD and presymptomatic treatment can potentially reduce morbidity and mortality. To evaluate incidence, clinical outcome, biochemical and molecular phenotype of MCAD cases detected in the first three years of newborn screening in British Columbia (BC). Medium chain length acylcarnitines, octanoylcarnitine (C8) and decanoylcarnitine (C10), were measured on newborn screening blood spot cards. Out of 121,000 live births, 17 newborns had C8 values above the screening cut-off of 0.38 umol/L. Ten newborns had elevated C8 on repeat cards and were investigated further. Both C8 and C8/C10 ratios remained abnormal in all confirmed MCAD cases. Positive predictive value of screening was 58% with no false negative results. Seven patients were homozygous for the common c.985A > G MCAD mutation and three others were compound heterozygous for the c.985A > G and a second mutation. Two novel mutations were identified (c.260T > C and c.382T > A). The estimated incidence of MCAD was approximately 1:12,000 live births. Upon frequent feeding and carnitine supplementation, none of the patients had metabolic crises or adverse outcomes. Frequency of MCAD in BC is comparable to reports from other newborn screening programs. Persistence of elevated C8 levels and C8/C10 ratios in confirmed MCAD cases suggest that these are sensitive markers for newborn screening. Early detection and treatment have successfully prevented adverse health outcomes in patients with MCAD.

Newborn Screening for MCAD Deficiency

Abstract Background: Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency is an autosomal recessive disorder of fatty acid oxidation, with potential fatal outcome. MCAD deficiency is diagnosed by acylcarnitine analysis on newborn screening blood spot cards by tandem mass spectrometry. Early diagnosis of MCAD and presymptomatic treatment can potentially reduce morbidity and mortality. Objectives: To evaluate incidence, clinical outcome, biochemical and molecular phenotype of MCAD cases detected in the first three years of newborn screening in British Columbia (BC). Methods and Results: Medium chain length acylcarnitines, octanoylcarnitine (C8) and decanoylcarnitine (C10), were measured on newborn screening blood spot cards. Out of 121,000 live births, 17 newborns had C8 values above the screening cut-off of 0.38 umol/L. Ten newborns had elevated C8 on repeat cards and were investigated further. Both C8 and C8/C10 ratios remained abnormal in all confirmed MCAD cases. Positive predictive value of screening was 58% with no false negative results. Seven patients were homozygous for the common c.985A>G MCAD mutation and three others were compound heterozygous for the c.985A>G and a second mutation. Two novel mutations were identified (c.260T>C and c.382T>A). The estimated incidence of MCAD was ~1:12,000 live births. Upon frequent feeding and carnitine supplementation, none of the patients had metabolic crises or adverse outcomes. Conclusion: Frequency of MCAD in BC is comparable to reports from other newborn screening programs. Persistence of elevated C8 levels and C8/C10 ratios in confirmed MCAD cases suggest that these are sensitive markers for newborn screening. Early detection and treatment have successfully prevented adverse health outcomes in patients with MCAD. Key words: Neonatal screening; fatty acid oxidation complex; Acyl-CoA dehydrogenase; medium chain Acyl-CoA dehydrogenase; sudden infant death Resume Contexte : Le deficit en acyl-coenzyme A deshydrogenase (DACAD) des acides gras a chaine moyenne est un trouble autosomique recessif d’oxydation des acides gras qui peut etre mortel. Ce deficit est diagnostique par spectrometrie de masse en tandem des acylcarnitines dans le sang du nouveau-ne (une tache de sang est recueillie sur une fiche en papier). Il est possible que le diagnostic precoce et le traitement avant l’apparition des symptomes reduisent la morbidite et la mortalite liees au DACAD. Objectifs : Evaluer l’incidence, les resultats cliniques et les phenotypes biochimiques et moleculaires des cas de DACAD deceles au cours des trois premieres annees du programme de depistage des nouveau-nes en Colombie-Britannique (C. B.). Methode et resultats : Deux acylcarnitines a chaine moyenne, l’octanoylcarnitine (C8) et le decanoylcarnitine (C10), ont ete mesures sur les fiches de taches de sang des nouveau-nes. Sur 121 000 naissances vivantes, 17 nouveau-nes affichaient des valeurs superieures au seuil de de pistage de 0,38 umol/L pour le C8. Dix nouveau-nes avaient un C8 eleve sur plusieurs fiches de suite et ont fait l’objet d’examens plus pousses. Le niveau de C8 et le ratio C8/C10 demeuraient anormaux dans tous les cas confirmes de DACAD. La valeur predictive positive du depistage etait de 58 %, sans resultat faussement negatif. Sept patients etaient homozygotes pour la mutation commune c.985A>G du DACAD et trois autres etaient heterozygotes composites pour la mutation c.985A>G et pour une deuxieme mutation. Deux nouvelles mutations ont ete reperees (c.260T>C et c.382T>A). L’incidence estimative du DACAD etait de ~1:12 000 naissances vivantes. Avec une alimentation frequente et une supplementation en carnitine, aucun patient n’a subi de crise metabolique ni de resultat defavorable. Conclusion : La frequence du DACAD en C.-B. est comparable a celle d’autres programmes de depistage des nouveau-nes. La persistance d’un C8 et d’un ratio C8/C10 eleves dans les cas confirmes de DACAD donne a penser que ce sont des indicateurs sensibles pour le depistage des nouveau-nes. Le depistage et le traitement precoces ont reussi a prevenir des resultats cliniques defavorables chez les patients atteints de DACAD. Mots cles : depistage neonatal; trouble d’oxydation des acides gras; acyl-CoA deshydrogenase; acyl-CoA deshydrogenase a chaine moyenne; mort subite du nourrisson

Rapid diagnosis of MCAD deficiency: quantitative analysis of octanoylcarnitine and other acylcarnitines in newborn blood spots by tandem mass spectrometry

We report the application of tandem mass spectrometry to prospective newborn screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. MCAD deficiency is diagnosed from dried blood spots on filter paper cards from newborns on the basis of the increase of medium chain length acylcarnitines identified by isotope dilution mass spectrometry methods. A robust and accurate semiautomated method for the analysis of medium chain length acylcarnitines as their butyl esters was developed and validated. Quantitative data from the analyses of 113 randomly collected filter paper blood spots from healthy newborns showed low concentrations of medium chain length acylcarnitines such as octanoylcarnitine. The maximum concentration of octanoylcarnitine was 0.22 mumol/L, with the majority being at or below the detection limit. In all 16 blood spots from newborns with confirmed MCAD deficiency, octanoylcarnitine was highly increased [median 8.4 mumol/L (range 3.1-28.3 mumol/L)], allowing easy detection. The concentration of octanoylcarnitine was significantly higher in these 16 newborns (< 3 days of age) than in 16 older patients (ages 8 days to 7 years) with MCAD deficiency (median 1.57 mumol/L, range 0.33-4.4). The combined experience of prospective newborn screening in Pennsylvania and North Carolina has shown a disease frequency for MCAD deficiency of 1 in 17,706. No false-positive and no known false-negative results have been found. A validated method now exists for prospective newborn screening for MCAD deficiency.

DNA analysis for detection of medium-chain acyl-CoA dehydrogenase deficiency in a Manitoba newborn population

Introduction: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the most frequent disorder of fatty acid β-oxidation, can cause episodic hypoglycemia, Reye-like encephalopathy and sudden death. A single mutation in the MCAD gene, K329E, has been associated with most cases of this disease. Consequently, unlike most other genetic disorders which are associated with multiplicities of mutations, it is possible to consider newborn screening for MCAD deficiency using a molecular genetic approach. Moreover, recent reports have stressed the need for instituting newborn screening for this disease to prevent the complications through presymptomatic detection and treatment. As a preliminary to this consideration, we prospectively surveyed 2000 consecutive newborn infants anonymously to determine the frequency of the K329E mutation in the Manitoba population. Methods: A 3 mm diameter disc punched from each of 2000 consecutive filter paper samples submitted for routine neonatal screening was treated with methanol for protein fixation and then directly subjected to PCR for amplication of a 199 base-pair segment surrounding nucleotide 985 in the MCAD gene. Samples found to have a K329E allele were tested by fast atom bombardment tandem mass spectrometry (FAB-MS) for the acylcarnitine profile consistent with MCAD deficiency. Results: Among the 2000 consecutive samples tested, 13 infants were found to be heterozygous for the K329E mutation. All had a normal acylcarnitine profile, indicating that a second unidentified mutation in these infants was unlikely. No homozygous infants were found. Discussion: The homozygote frequency predicted from this heterozygote frequency is 1:95 000 (CI 95%, 1:40 000–1:450 000). These results indicate that the K329E mutation is not sufficiently frequent in the Manitoba population to warrant DNA-based neonatal screening for MCAD deficiency.