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

Characterization of the molecular spectrum of Medium-Chain Acyl-CoA Dehydrogenase Deficiency in a Greek newborns cohort: Identification of a novel variant

ObjectivesThe purpose of the current study was to screen newborns in Greece and to identify the responsible mutations for Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD). Design and methods47.812 neonates were screened for the potential presence of MCADD in Greece, via a LC–MS/MS protocol. The “suspected” samples were subjected to genetic testing via PCR–RFLP and sequencing of the coding region of the ACADM gene. Urine samples were collected and then analyzed with a GC/MS method. ResultsThe MCADD prevalence is 1 in 15,937 births. The alleles c.985A>G and c.245insT were detected in the 29.2% and 20.8% of the “suspected” cohort, respectively. A novel variant with potential pathogenicity was identified. ConclusionsThe c.245insT allele seems to prevail in the Greek cohort of “suspected” specimens. Therefore, this variant along with the c.985A>G allele could constitute a panel for both prenatal and neonatal MCADD screening in the Greek population.

MCAD deficiency in Denmark

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common defect of fatty acid oxidation. Many countries have introduced newborn screening for MCADD, because characteristic acylcarnitines can easily be identified in filter paper blood spot samples by tandem mass spectrometry (MS/MS), because MCADD is a frequent disease, and because of the success of early treatment initiated before clinical symptoms have emerged. In Denmark we have screened 519,350 newborns for MCADD by MS/MS and identified 58 affected babies. The diagnosis of MCADD was confirmed in all 58 newborns by mutation analysis. This gives an incidence of MCADD detected by newborn screening in Denmark of 1/8954. In sharp contrast to this we found that the incidence of clinically presenting MCADD in Denmark in the 10year period preceding introduction of MS/MS-based screening was only 1 in 39,691. This means that four times more newborns with MCADD are detected by screening than what is expected based on the number of children presenting clinically in an unscreened population.The mutation spectrum in the newborns detected by screening is different from that observed in clinically presenting patients with a much lower proportion of newborns being homozygous for the prevalent disease-causing c.985A>G mutation. A significant number of the newborns have genotypes with mutations that have not been observed in patients detected clinically. Some of these mutations, like c.199T>C and c.127G>A, are always associated with a milder biochemical phenotype and may cause a milder form of MCADD with a relatively low risk of disease manifestation, thereby explaining part of the discrepancy between the frequency of clinically manifested MCADD and the frequency of MCADD determined by screening. In addition, our data suggest that some of this discrepancy can be explained by a reduced penetrance of the c.985A>G mutation, with perhaps only 50% of c.985A>G homozygotes presenting with disease manifestations.Interestingly, we also report that the observed number of newborns identified by screening who are homozygous for the c.985A>G mutation is twice that predicted from the estimated carrier frequency. We therefore redetermined the carrier frequency in a new sample of 1946 blood spots using a new assay, but this only confirmed that the c.985A>G carrier frequency in Denmark is approximately 1/105.We conclude that MCADD is much more frequent than expected, has a reduced penetrance and that rapid genotyping using the initial blood spot sample is important for correct diagnosis and counseling.

Incidence of medium-chain acyl-CoA dehydrogenase deficiency in Canada using the Canadian Paediatric Surveillance Program: Role of newborn screening.

The incidence of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) was estimated using the Canadian Paediatric Surveillance Program (CPSP) in Canada over a three-year period. Data regarding mutations associated with MCADD cases were collected wherever available. Data were collected over a 36-month period using a monthly mailed questionnaire distributed through the CPSP to more than 2500 Canadian paediatricians, medical geneticists and paediatric pathologists. During the three years of MCADD surveillance, 46 confirmed cases out of a total of 71 reported cases were found - an average of approximately 15 cases per year. This rate is lower than the initial estimate of approximately 30 cases per year of MCADD in Canada, based on the reported incidence of MCADD in the literature of approximately one in 10,000 to one in 20,000. All cases ascertained by newborn screening were asymptomatic. There were two deaths, both in jurisdictions without newborn screening for MCADD. The data support population-based newborn screening for MCADD.

Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England: Prevalence, predictive value and test validity based on 1.5 million screened babies

BackgroundMedium chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare, life-threatening condition. Early diagnosis by screening asymptomatic newborns may improve outcome, but the benefit to newborns identified with variants not encountered clinically is uncertain.ObjectiveTo estimate, overall and by ethnic group: screen-positive prevalence and predictive value (PPV); MCADD prevalence; proportion MCADD variants detected of predicted definite or uncertain clinical importance.SettingAll births in areas of high ethnic minority prevalence in England.MethodsProspective multicentre pilot screening service; testing at age five to eight days; standardized screening, diagnostic and management protocols; independent expert review of screen-positive cases to assign MCADD diagnosis and predicted clinical importance (definite or uncertain).ResultsApproximately 1.5 million babies (79% white; 10% Asian) were screened. MCADD was confirmed in 147 of 190 babies with a positive screening result (screen-positive prevalence: 1.20 per 10,000; MCADD prevalence: 0.94 per 10,000; PPV 77% [95% CI 71–83]), comprising 103 (70%) with MCADD variants of definite clinical importance (95 white [95%]; 2 Asian [2%]) and 44 (30%) with variants of uncertain clinical importance (29 white [67%]; 12 Asian [28%]).ConclusionOne baby in every 10,000 born in England is diagnosed with MCADD by newborn screening; around 60 babies each year. While the majority of MCADD variants detected are predicted to be of definite clinical importance, this varies according to ethnic group, with variants of uncertain importance most commonly found in Asian babies. These findings provide support for MCADD screening but highlight the need to take account of the ethnic diversity of the population tested at implementation.

The first three years of screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) by newborn screening ontario

BackgroundMedium chain acyl-CoA dehydrogenase deficiency (MCADD) is a disorder of mitochondrial fatty acid oxidation and is one of the most common inborn errors of metabolism. Identification of MCADD via newborn screening permits the introduction of interventions that can significantly reduce associated morbidity and mortality. This study reports on the first three years of newborn screening for MCADD in Ontario, Canada.MethodsNewborn Screening Ontario began screening for MCADD in April 2006, by quantification of acylcarnitines (primarily octanoylcarnitine, C8) in dried blood spots using tandem mass spectrometry. Babies with positive screening results were referred to physicians at one of five regional Newborn Screening Treatment Centres, who were responsible for diagnostic evaluation and follow-up care.ResultsFrom April 2006 through March 2009, approximately 439 000 infants were screened for MCADD in Ontario. Seventy-four infants screened positive, with a median C8 level of 0.68 uM (range 0.33-30.41 uM). Thirty-one of the screen positive infants have been confirmed to have MCADD, while 36 have been confirmed to be unaffected. Screening C8 levels were higher among infants with MCADD (median 8.93 uM) compared to those with false positive results (median 0.47 uM). Molecular testing was available for 29 confirmed cases of MCADD, 15 of whom were homozygous for the common c.985A > G mutation. Infants homozygous for the common mutation tended to have higher C8 levels (median 12.13 uM) relative to compound heterozygotes for c.985A > G and a second detectable mutation (median 2.01 uM). Eight confirmed mutation carriers were identified among infants in the false positive group. The positive predictive value of a screen positive for MCADD was 46%. The estimated birth prevalence of MCADD in Ontario is approximately 1 in 14 000.ConclusionsThe birth prevalence of MCADD and positive predictive value of the screening test were similar to those identified by other newborn screening programs internationally. We observed some evidence of correlation between genotype and biochemical phenotype (C8 levels), and between C8 screening levels and eventual diagnosis. Current research priorities include further examining the relationships among genotype, biochemical phenotype, and clinical phenotype, with the ultimate goal of improving clinical risk prediction in order to provide tailored disease management advice and genetic counselling to families.

Medium‐chain acyl‐CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), caused by mutated ACADM gene, is a potentially fatal fatty acid oxidation defect. Detection of MCADD is now part of tandem mass spectrometry (MS-MS)-based newborn screening programs worldwide. To date, more than 67 mutations have been reported to cause MCADD with a single allele, c.985A>G, being the most common in patients of northwestern European descent. In Saudi Arabia, the Newborn Screening Program, officially launched in 2005, screens for 16 disorders including MCADD. Over a period of 3 years, 237,812 newborns were screened; 13 were identified to have MCADD giving an incidence of 1:18,293. Since the introduction of MS-MS to our institution, however, a total of 30 patients were detected to have MCADD. These cases were either newborns, at high-risk family members, or clinically suspected. The C8-carnitine levels (median 3.31, range 0.81-16.33 µM) were clearly diagnostic in all analyzed samples. Sequencing ACADM in 20 DBS revealed two novel mutations: c.362C>T (p.T121I) and c.347G>A (p.C116Y) substitutions, neither of which were detected in 300 chromosomes from controls. Eighteen (90%) patients were homozygous for the T121I mutation and two (10%) were compound heterozygous (T121I/C116Y). Our molecular data lend further support to MS-MS biochemical screening for MCADD and provide evidence for the relatively high incidence of MCADD in the Arab population. The identification of a founder mutation for MCADD has important implications for the preventive screening programs not only in Saudi Arabia but potentially also in other countries in the region.

Relationship of Octanoylcarnitine Concentrations to Age at Sampling in Unaffected Newborns Screened for Medium-Chain Acyl-CoA Dehydrogenase Deficiency

Although octanoylcarnitine (C8) concentrations measured from newborn screening dried blood spots are used to identify those at high risk of medium-chain acyl-CoA dehydrogenase deficiency (MCADD), age-related reference values are currently not available for unaffected newborn populations. Because age at sampling may vary within and between screening programs, variations in C8 concentrations by age may affect screening program performance. We determined whether C8 concentrations vary by age at sampling, sex, birth weight, or gestational age in unaffected newborns. We analyzed C8 concentrations from 227,098 unaffected newborns, including 179,729 from 6 English laboratories participating in a multicenter study and 47,369 from the single laboratory serving the New South Wales (NSW) Newborn Screening Program in Australia. In England, the majority of samples were collected at age 5-8 days and analyzed underivatized by use of tandem mass spectrometry (MS/MS); in NSW, samples were obtained at a median age of 3 days and analyzed derivatized by MS/MS. Information on infants' sex, birth weight, gestation, hospitalization, and transfusion status was recorded at time of sampling. C8 concentrations did not vary significantly by age at sampling, sex, birth weight, or gestational age and remained relatively constant during the first 2 weeks of life in unaffected babies being screened for MCADD. Newborn MCADD screening programs using this biomarker for screening samples collected after the first day and during the first 14 days of life do not need to adjust cutoff values to account for postnatal age, prematurity, or size at birth.

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.

Feature Construction Can Improve Diagnostic Criteria for High-Dimensional Metabolic Data in Newborn Screening for Medium-Chain Acyl-CoA Dehydrogenase Deficiency

In newborn screening with tandem mass spectrometry, multiple intermediary metabolites are quantified in a single analytical run for the diagnosis of fatty-acid oxidation disorders, organic acidurias, and aminoacidurias. Published diagnostic criteria for these disorders normally incorporate a primary metabolic marker combined with secondary markers, often analyte ratios, for which the markers have been chosen to reflect metabolic pathway deviations. We applied a procedure to extract new markers and diagnostic criteria for newborn screening to the data of newborns with confirmed medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and a control group from the newborn screening program, Heidelberg, Germany. We validated the results with external data of the screening center in Hamburg, Germany. We extracted new markers by performing a systematic search for analyte combinations (features) with high discriminatory performance for MCADD. To select feature thresholds, we applied automated procedures to separate controls and cases on the basis of the feature values. Finally, we built classifiers from these new markers to serve as diagnostic criteria in screening for MCADD. On the basis of chi(2) scores, we identified approximately 800 of >628,000 new analyte combinations with superior discriminatory performance compared with the best published combinations. Classifiers built with the new features achieved diagnostic sensitivities and specificities approaching 100%. Feature construction methods provide ways to disclose information hidden in the set of measured analytes. Other diagnostic tasks based on high-dimensional metabolic data might also profit from this approach.

Newborn screening for medium chain acyl-CoA dehydrogenase deficiency: evaluating the effects on outcome.

Although individually rare, inborn errors of metabolism represent a potentially preventable cause of death and disability. Tandem mass spectrometry allows a number of these disorders to be detected in a single step. Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most important of these disorders. However, public health decisions on whether or not to implement new screening programmes rely on evidence regarding benefits and harms. This article reviews existing published evidence for newborn screening for MCADD and highlights where further information is required for public health decision making. This review reveals that important uncertainties remain about performance and outcome, including criteria and thresholds for defining a positive screening result, diagnostic criteria, test performance and longer-term outcome. Notably, despite a combined experience of screening well over one million infants, there has been no report of a systematic follow-up of longer-term outcome in affected infants detected by screening. Prospective data on mortality, neurological outcome, and cognitive function are required to assess the effectiveness of screening. Additionally, the impact of screening and treatment on the families of infants with true, borderline, and false positive diagnoses needs to be taken into account.

Newborn screening by tandem mass spectrometry for medium-chain Acyl-CoA dehydrogenase deficiency: a cost-effectiveness analysis.

To determine whether newborn screening by tandem mass spectrometry (MS/MS) for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is cost-effective versus not screening and to define the contributions of disease, test, and population parameters on the decision. A decision-analytic Markov model was designed to perform cost-effectiveness and cost-utility analyses measuring the discounted, incremental cost per life-year saved and per quality-adjusted life-year saved of newborn screening for MCADD compared with not screening. A hypothetical cohort of neonates made transitions among a set of health states that reflected clinical status, morbidity, and cost. Outcomes were estimated for time horizons of 20 and 70 years. Probabilities and costs were derived from a retrospective chart review of a 32-patient cohort treated over the past 30 years at the Children's Hospital of Philadelphia, clinical experience with MCADD patient management, patient-family interviews, cost surveys, state sources, and published studies. In addition to older patients who came to medical attention by symptomatic presentation, our patient group included 6 individuals whose MCADD had been diagnosed by supplemental newborn screening. Estimates of the expected net changes in costs and life expectancy for MCADD screening were used to compute the incremental cost-effectiveness ratios. Sensitivity analyses were performed on key input variables, and 95% confidence intervals (CIs) were computed through second-order Monte Carlo simulations. In our base-case analysis over the first 20 years of life, the cost of newborn screening for MCADD was approximately 11,000 dollars(2001 US dollars; 95% CI: <0-33,800 dollars) per life-year saved, or 5600 dollars (95% CI: <0-17,100 dollars) per quality-adjusted life-year saved compared with not screening. Over a 70-year horizon, the respective ratios were approximately 300 dollars (95% CI: <0-13,000 dollars) and 100 dollars (95% CI: <0-6900 dollars). The results were robust when tested over plausible ranges for diagnostic test sensitivity and specificity, MCADD prevalence, asymptomatic rate, and screening cost. Simulation modeling indicates that newborn screening for MCADD reduces morbidity and mortality at an incremental cost below the range for accepted health care interventions. At the 70-year horizon, the model predicts that almost all of the additional costs of screening would be offset by avoided sequelae.

Newborn screening with tandem mass spectrometry: Examining its cost-effectiveness in the Wisconsin Newborn Screening Panel

Objective: To examine the cost-effectiveness of tandem mass spectrometry (MS/MS) in a neonatal screening panel for 14 fatty acid oxidation and organic acidemia disorders in the Wisconsin Newborn Screening Program. Study design: An incremental cost-effectiveness analysis with a hypothetical cohort of 100,000 infants was performed. A threshold of $50,000/QALY (quality-adjusted life-year) was used to determine whether screening for medium-chain acyl-CoA dehydrogenase deficiency (MCAD) alone is costeffective or whether additional disorders would need to be incorporated into the analysis to arrive at a conclusion regarding the overall cost-effectiveness of MS/MS. Results: Under conservative assumptions, screening for MCAD alone yields an incremental cost-effectiveness ratio of $41,862/QALY. With the use of more realistic assumptions, screening becomes more cost-effective ($6008/QALY) and remains cost-effective so long as the incremental cost of screening remains under $13.05 per test. Adding the incremental costs of detecting the 13 other disorders on the screening panel still yields a result well within accepted norms for cost-effectiveness ($15,252/QALY). Conclusions: In Wisconsin, MS/MS screening for MCAD alone appears to be cost-effective. Future analyses should examine the cost-effectiveness of alternative follow-up and treatment regimens for MCAD and other panel disorders. (J Pediatr 2002;141:524-31)