Medium-chain acyl-CoA dehydrogenase deficiency: Two novel ACADM mutations identified in a retrospective screening (original) (raw)
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The Journal of international medical research, 2018
Objective The aim of this study was to determine whether an expanded newborn screening programme, which is not yet available in Slovenia, would have detected the first two patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the country. Two novel ACADM mutations are also described. Methods Both patients were diagnosed clinically; follow-up involved analysis of organic acids in urine, acylcarnitines in dried blood spots, and genetic analysis of ACADM. Cut-off values of acylcarnitines in newborns were established using analysis of 10,000 newborns in a pilot screening study. Results In both patients, analysis of the organic acids in urine showed a possible β-oxidation defect, while the specific elevation of acylcarnitines confirmed MCAD deficiency. Subsequent genetic analysis confirmed the diagnosis; both patients were compound heterozygotes, each with one novel mutation (c.861 + 2T > C and c.527_533del). The results from a retrospective analysis of newborn screen...
Journal of Inherited Metabolic Disease, 2000
Patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency are unable to metabolize medium-chain fatty acids. Affected patients display a characteristic acylcarnitine profile when blood spots are collected after birth and analysed by tandem mass spectrometry. To determine the potential risk of metabolic decompensation in newborns with elevations of diagnostic metabolites (octanoylcarnitine>0.3, but <1 mmol/L), we investigated the relationship between octanoylcarnitine (C 8 ) concentration in neonatal blood spots and the 985A>G MCAD genotype. Octanoylcarnitine values from 7140 newborns' blood spots were sorted. The highest C 8 was $0.7 mmol/L, which is below the range in classical MCAD deficiency. Samples with C 8 levels above 0.25 mmol/L (group C) represented 1.4% of the total. Values between 0.05 and 0.25 mmol/L (group B) made up 87.8% of the total; 10.8% of the samples had C 8 values less than 0.05 mmol/L (group A). One hundred samples from each group were selected at random and genomic DNA was amplified by PCR and analysed for the presence of the 985A>G mutation. The analysed samples from groups A and B were all homozygous normal. The 100 samples from group C contained 26 samples that were heterozygous for the 985A>G mutation. These findings indicated that the frequency distribution of heterozygotes is not random within this population. Group C was further divided into C1, the 26 heterozygotes, and C2, the remaining 74 newborns in group C. In group C1 only 2 (8%) were in the 'high-risk' group characterized by either low birth weight or requiring admission to the neonatal intensive care unit. In contrast, 28 (38%) from C2 had low birth weight or were in the neonatal intensive care unit. In our dataset, C 8 /C 2 and C 8 /C 12 ratios were
The American Journal of Human Genetics, 2001
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most frequently diagnosed mitochondrial boxidation defect, and it is potentially fatal. Eighty percent of patients are homozygous for a common mutation, 985ArG, and a further 18% have this mutation in only one disease allele. In addition, a large number of rare disease-causing mutations have been identified and characterized. There is no clear genotype-phenotype correlation. High 985ArG carrier frequencies in populations of European descent and the usual avoidance of recurrent disease episodes by patients diagnosed with MCAD deficiency who comply with a simple dietary treatment suggest that MCAD deficiency is a candidate in prospective screening of newborns. Therefore, several such screening programs employing analysis of acylcarnitines in blood spots by tandem mass spectrometry (MS/MS) are currently used worldwide. No validation of this method by mutation analysis has yet been reported. We investigated for MCAD mutations in newborns from US populations who had been identified by prospective MS/MS-based screening of 930,078 blood spots. An MCAD-deficiency frequency of 1/15,001 was observed. Our mutation analysis shows that the MS/MS-based method is excellent for detection of MCAD deficiency but that the frequency of the 985ArG mutant allele in newborns with a positive acylcarnitine profile is much lower than that observed in clinically affected patients. Our identification of a new mutation, 199TrC, which has never been observed in patients with clinically manifested disease but was present in a large proportion of the acylcarnitine-positive samples, may explain this skewed ratio. Overexpression experiments showed that this is a mild folding mutation that exhibits decreased levels of enzyme activity only under stringent conditions. A carrier frequency of 1/500 in the general population makes the 199TrC mutation one of the three most prevalent mutations in the enzymes of fatty-acid oxidation.
Maternal medium-chain acyl-CoA dehydrogenase deficiency identified by newborn screening
Molecular Genetics and Metabolism, 2011
Medium-chain acyl-CoA dehydrogenase deficiency Expanded newborn screening Maternal Tandem mass spectrometry MCADD Maternal inborn error of metabolism Prior to the advent of expanded newborn screening, sudden and unexplained death was often the first and only symptom of medium-chain acyl-CoA dehydrogenase deficiency (MCADD). With the use of tandem mass spectrometry, infants can now be identified and treated before a life threatening metabolic decompensation occurs. Newborn screening has also been shown to detect previously undiagnosed maternal inborn errors of metabolism. We have now diagnosed two women with MCADD following the identification of low free carnitine in their newborns. While one of the women reported prior symptoms of fasting intolerance, neither had a history of metabolic decompensation or other symptoms consistent with a fatty acid oxidation disorder. These cases illustrate the importance of including urine organic acid analysis and an acylcarnitine profile as part of the confirmatory testing algorithm for mothers when low free carnitine is identified in their infants.
The Journal of Pediatrics, 2006
Neonatal screening programs for very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) have recently been implemented. We report 2 newborns with elevated C14:1-carnitine levels on day 3 of life and normal levels on days 5 to 7. Enzyme and molecular analyses confirmed VLCADD in the first patient and heterozygosity in the second patient. We conclude that the diagnosis of VLCADD can be missed by acylcarnitine analysis during anabolic conditions. An increased C14:1-carnitine level can also occur in heterozygous individuals. Elevated C14:1-carnitine level on neonatal screening warrants further diagnostic workup even if a repeat sample demonstrates normal acylcarnitine levels.
JIMD reports, 2017
Identification of very long-chain acyl-CoA dehydrogenase deficiency is possible in the expanded newborn screening (NBS) due to the increase in tetradecenoylcarnitine (C14:1) and in the C14:1/C2, C14:1/C16, C14:1/C12:1 ratios detected in dried blood spots. Nevertheless, different confirmatory tests must be performed to confirm the final diagnosis. We have revised the NBS results and the results of the confirmatory tests (plasma acylcarnitine profiles, molecular findings, and lymphocytes VLCAD activity) for 36 cases detected in three Spanish NBS centers during 4 years, correlating these with the clinical outcome and treatment. Our aim was to distinguish unambiguously true cases from disease carriers in order to obtain useful diagnostic information for clinicians that can be applied in the follow-up of neonates identified by NBS.Increases in C14:1 and of the different ratios, the presence of two pathogenic mutations, and deficient enzyme activity in lymphocytes (<12% of the intra-as...
Genetics in Medicine, 2007
Purpose: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenasedeficient patients through newborn screening due to an elevation of C 4 -acylcarnitine in dried blood spots. Because C 4 -acylcarnitine represents both isobutyryl-and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C 4 -acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions. Methods: Fibroblast cultures were established from infants with C 4 -acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydrogenase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase-and short-chain acyl-CoA dehydrogenase-deficient patients. Results: Quantification of C 4 -acylcarnitine in plasma and urine as well as ethylmalonic acid in urine allows the differentiation of isobutyryl-CoA dehydrogenase-deficient from short-chain acyl-CoA dehydrogenase-deficient cases. In nine unrelated patients with isobutyryl-CoA dehydrogenase deficiency, 10 missense mutations were identified in ACAD8. To date, 10 of the 13 isobutyryl-CoA dehydrogenase-deficient patients remain asymptomatic, two were lost to follow-up, and one patient required frequent hospitalizations due to emesis and dehydration but is developing normally at 5 years of age. Conclusion: Although the natural history of isobutyryl-CoA dehydrogenase deficiency must be further defined, we have developed an algorithm for rapid laboratory evaluation of neonates with an isolated elevation of C 4 -acylcarnitine identified through newborn screening. Genet Med 2007:9(2):108-116.