Clinical characteristics.

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid β-oxidation. Fatty acid β-oxidation fuels hepatic ketogenesis, which provides a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. MCAD deficiency is the most common disorder of fatty acid β-oxidation and one of the most common inborn errors of metabolism. Most children are now diagnosed through newborn screening. Clinical symptoms in a previously apparently healthy child with MCAD deficiency include hypoketotic hypoglycemia and vomiting that may progress to lethargy, seizures, and coma triggered by a common illness. Hepatomegaly and liver disease are often present during an acute episode. Children appear normal at birth and – if not identified through newborn screening – typically present between age three and 24 months, although presentation even as late as adulthood is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged periods of fasting.

Diagnosis/testing.

The diagnosis of MCAD deficiency is established in a proband with confirmatory biochemical testing results and biallelic pathogenic variants in ACADM identified on molecular genetic testing. Diagnostic testing is typically initiated after either a positive newborn screening result or suggestive biochemical testing in a previously healthy individual who develops symptoms. Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without needing provocative tests. Assays to determine residual enzyme activity are possible but not routinely necessary and not clinically available in many regions.

Management.

Treatment of manifestations: The most important intervention is giving simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or IV if needed to reverse catabolism and sustain anabolism.

Prevention of primary manifestations: The mainstay is avoidance of fasting: infants require frequent feedings; toddlers could be placed on a relatively low-fat diet (e.g., <30% of total energy from fat) and could receive 2 g/kg of uncooked cornstarch at bedtime to ensure sufficient glucose overnight.

Agents/circumstances to avoid: Hypoglycemia (e.g., from excessive fasting); infant formulas that contain medium-chain triglycerides as the primary source of fat.

Evaluation of relatives at risk: If the ACADM pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs and offspring of the proband. If the ACADM pathogenic variants in the family are not known, plasma acylcarnitine and urine acylglycine analysis can be used to clarify the disease status.

Genetic counseling.

MCAD deficiency is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual are at a 25% risk of being affected, a 50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not carriers. Because of the high carrier frequency for the ACADM c.985A>G pathogenic variant in individuals of northern European origin, carrier testing should be discussed with reproductive partners of individuals with MCAD deficiency. Once both ACADM pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for MCAD deficiency are possible.

Suggestive Findings

MCAD deficiency should be suspected in:

• An infant with a positive newborn screening result;
• A previously healthy individual who becomes symptomatic and has supportive clinical and laboratory findings; or
• A case of sudden and unexpected death.

Establishing the Diagnosis

The diagnosis of MCAD deficiency is established in a proband with Suggestive Findings (see above) by confirmatory biochemical testing and biallelic pathogenic variants in ACADM identified by molecular genetic testing (see Table 1). Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without using provocative tests. Assays to determine residual enzyme activity are possible but not routinely necessary and not clinically available in many regions.

Note: Confirmatory postmortem testing is possible in the individual with sudden and unexpected death if MCAD deficiency is suspected.

Clinical Description

Fatty acid β-oxidation fuels hepatic ketogenesis, a major source of energy for peripheral tissues once glycogen stores become depleted during prolonged fasting and/or periods of higher energy demands (see Pathophysiology). The frequent feeding schedule of infants typically precludes the need for alternative energy sources, but as the interval between feeds increases, reliance on fatty acid catabolism commensurately increases. This may manifest in preprandial hypoglycemia symptoms such as lethargy, irritability, jitteriness, seizures, or hypoglycemic crisis. MCAD deficiency is a known cause of sudden infant death syndrome (SIDS) [Roe et al 1986].

Pathophysiology

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid β-oxidation. Fatty acid β-oxidation releases energy and provides acetyl-CoA for hepatic ketogenesis. Once glycogen stores are depleted during prolonged fasting and periods of higher energy demands, peripheral tissues switch to using energy from fatty acid oxidation to preserve glucose for utilization by the brain. The brain can also use ketone bodies derived from fatty acids.

Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to CoA esters in the mitochondrial matrix. Fatty acid β-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the β-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH⁺, and NADH₂.

MCAD deficiency impairs the energy supply to peripheral tissues through ketogenesis and increases glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine- and acylcarnitine-esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage [Derks et al 2014].

Genotype-Phenotype Correlations

Inclusion of MCAD deficiency in NBS programs has led to the identification of individuals with less pronounced abnormalities in their acylcarnitine profiles who are compound heterozygotes either for the common European ACADM pathogenic variant c.985A>G (p.Lys329Glu), previously known as p.Lys304Glu), and another pathogenic variant, or for two non-c.985A>G pathogenic variants [Albers et al 2001, Andresen et al 2001, Zschocke et al 2001, Maier et al 2005, Smith et al 2010].

• Most individuals are compound heterozygous for the c.985A>G pathogenic variant and another deletion or pathogenic variant, or homozygous for c.985A>G.
• Individuals homozygous for the common c.985A>G variant had the highest C8 newborn screen values and were most likely to have neonatal symptoms [Waddell et al 2006, Arnold et al 2010, Bentler et al 2016].
• Individuals with compound heterozygous pathogenic variants c.985A>G and c.600-18G>A have a mild phenotype and may not be detected by NBS due to residual MCAD enzyme activity [Grünert et al 2015].
• A collaborative retrospective analysis of a cohort of 221 affected individuals identified by NBS in the United States showed that C8 level and genotype were significant predictors of neonatal symptoms. Individuals with neonatal symptoms had significantly higher C8 values [Bentler et al 2016].

The c.199T>C pathogenic variant has an allele frequency of approximately 6% in MCAD-deficient newborns [Andresen et al 2001, Maier et al 2005, Waddell et al 2006, Nichols et al 2008] and is associated with some residual MCAD enzymatic activity [Andresen et al 2001]. Individuals who are heterozygous for the c.199T>C variant and another pathogenic variant may have lower acylcarnitine levels but still be at risk for metabolic crisis [Gramer et al 2015].

While it appears that residual enzyme activity levels better correlate with phenotype [Touw et al 2013], it is reasonable to assume that environmental factors (e.g., diet, stress, or intercurrent illnesses) are critical in determining the natural history of this disorder.

For several presumably mild pathogenic variants identified only presymptomatically through NBS, expression studies that may aid in risk assessment have also been conducted to evaluate the effect of the variant on protein folding, temperature sensitivity, and enzyme activity [Jank et al 2014, Koster et al 2014].

Nomenclature

MCAD deficiency was first described in individuals presenting with a Reye-like phenotype and urine organic acid analysis that revealed overexcretion of medium-chain dicarboxylic acids and hexanoylglycine in the absence of significant ketosis [Kølvraa et al 1982, Roe et al 1986, Bzduch et al 2001]. Accordingly, it is likely that prior to MCAD deficiency having been better delineated, affected individuals were misdiagnosed as having Reye syndrome.

Note that historical nomenclature begins amino acid numbering at p.1 of the mature protein, whereas current nomenclature begins amino acid numbering at p.1 of the pro-protein. Therefore, the common pathogenic variant encoded by c.985A>G (p.Lys329Glu) was historically known as p.Lys304Glu.

Prevalence

The overall prevalence of MCAD deficiency is 5.3 (4.1-6.7, 99% CI) per 100,000 births across a variety of populations [Feuchtbaum et al 2012]. MCAD deficiency is prevalent in individuals of (especially northern) European descent. The carrier frequency for the c.985A>G pathogenic variant in ACADM is between 1:40 and 1:100 in northern Europeans, suggestive of a founder effect [Gregersen et al 1993, Tanaka et al 1997]. A similar prevalence has been observed among Portuguese with Roma ancestry [Rocha et al 2014] and Native Americans of California [Feuchtbaum et al 2012].

The number of newborns detected with MCAD deficiency through NBS programs exceeds that expected based on the population frequency of the common c.985A>G pathogenic variant [Andresen et al 2001, Maier et al 2005, Wilcken et al 2009, Vilarinho et al 2010, Andresen et al 2012, Touw et al 2012].

The c.449_452delCTGA deletion is more prevalent in Asian (i.e., Taiwanese, Japanese, and Korean) populations [Woo et al 2011, Chien et al 2013, Hara et al 2016, Tajima et al 2016].

Based on NBS programs or pilot studies worldwide, the incidence of MCAD deficiency has been determined as follows:

• Asia
  • Japan. 1:51,000 live births [Shigematsu et al 2002]. There has also been a significant increase in the diagnosis of MCAD deficiency in Japanese individuals, with most having at least one novel pathogenic variant [Hara et al 2016, Tajima et al 2016].
  • Saudi Arabia. 1:18,000 live births [Al-Hassnan et al 2010]
  • Taiwan. 1:263,500 live births [Chien et al 2013]
• Australia. New South Wales. 1:19,000 live births [Wilcken et al 2009]
• Europe. The prevalence in live births in Europe has ranged from a high of 1:4,900 in northern Germany [Sander et al 2001] to a low of 1:24,900 in Austria [Kasper et al 2010] or 1:23,000 in central Italy.
• North America. Prevalence has ranged from 1:23,400 live births in Canada [Prasad et al 2012] to ranges of 1:13,000 to 1:19,000 in various states aross the United States [Chace et al 2002, Frazier et al 2006, Hsu et al 2008, Nichols et al 2008, Anderson et al 2012, Feuchtbaum et al 2012].

Historically, MCAD deficiency was considered less common in the Hispanic, African American, and Native American populations in the USA. More recent analysis of data from California demonstrated that MCAD deficiency may be as prevalent in Native Americans (1:7,500 live births) as in northern Europeans. Prevalences are similar among newborns of Hispanic, black, and Middle Eastern origin (1:23,000 live births) [Feuchtbaum et al 2012].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an asymptomatic individual with a diagnosis of medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency or an abnormal newborn screen, the following evaluations are recommended:

• Plasma acylcarnitine analysis
• Plasma free and total carnitine levels
• Urine acylglycine analysis
• Urine organic acid analysis
• Consultation with a biochemical geneticist, clinical geneticist, and/or genetic counselor

In a symptomatic individual diagnosed with MCAD deficiency, the following additional laboratory studies should be considered when clinically appropriate:

• Blood glucose concentration
• Liver function tests (i.e., AST, ALT, alkaline phosphatase, prothrombin time, partial thromboplastin time, total bilirubin, albumin)
• Blood gas analysis
• Ammonia (collected in a sodium-heparin tube, placed on ice immediately, and sent STAT to the lab on ice)
• Lactic acid
• CBC with differential
• Electrolytes
• Blood cultures (in case of fever)

Treatment of Manifestations

The acute illness places the infant with MCAD deficiency at high risk for metabolic crisis. Metabolic crisis should be considered a medical emergency and implementation of treatment is essential. Consultation with a biochemical geneticist should be obtained as soon as possible.

• Early initiation of investigation of the underlying cause of the metabolic stress and initiation of appropriate treatment is necessary.
• Treatment recommendations are available but should be implemented in consultation with a biochemical geneticist [Aldubayan et al 2017]. See New England Consortium of Metabolic Programs and Genetic Metabolic Dietitians International.

The most important aspect of treating symptomatic individuals is reversal of catabolism and prevention of hypoglycemia by providing simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or intravenous fluids if the individual is unable to receive sufficient oral intake to maintain anabolism.

IV administration of glucose should be initiated immediately with a bolus of 2 mL/kg 25% dextrose, followed by 10% dextrose with appropriate electrolytes at a rate of 1.5 times maintenance rate or at 10-12 mg glucose/kg/minute to achieve and maintain a blood glucose level higher than 5 mmol/L, or between 120 and 170 mg/dL [Saudubray et al 1999].

Emergency letter. All affected individuals should have a frequently updated "emergency" letter that may be given, if needed, to health care providers who may not be familiar with MCAD deficiency. This letter should include a detailed explanation of the management of acute metabolic decompensation, emphasizing the importance of preventive measures (e.g., intravenous glucose regardless of "normal" laboratory results, overnight in-hospital observation), and the telephone numbers of the individual's metabolic specialist.

• A MedicAlert^® bracelet may be helpful.
• The New England Metabolic Consortium of Metabolic Programs website provides an example of a post-emergency management letter for MCAD (pdf); see Acute Illness Protocol (page 4).

Prevention of Primary Manifestations

Surveillance

A medical or clinical biochemical geneticist or similarly qualified metabolic specialist should be consulted immediately during concurrent illness, especially when it involves fever and/or poor caloric intake.

During the first months of life, monthly visits should be considered to ensure that families understand and are comfortable with treatment while the infant is otherwise well. A metabolic dietician (see gmdi.org) should be involved to ensure proper nutrition in terms of quality and quantity.

The frequency of routine follow-up visits is individualized based on comfort level of the affected persons, their families, and health care providers.

Long-term outcome studies revealed that persons treated for MCAD deficiency are prone to excessive weight gain [Derks et al 2006]. Prepubertal children may become overweight given the frequent feeding as part of treatment, especially with the increasing incidence of obesity in pediatric and general populations worldwide. Growth parameters should be monitored carefully at each clinic visit. Accordingly, follow up should include weight control measures such as regular education about proper nutrition and recommended physical exercise.

Although development is typically normal for individuals treated prospectively, those who experience metabolic decompensations requiring hospitalization often demonstrate developmental and neurologic disabilities. Neurodevelopmental assessments and intervention should be considered for such individuals [Derks et al 2006].

Agents/Circumstances to Avoid

Hypoglycemia must be avoided by frequent feedings to avoid catabolism – if necessary, by intravenous administration of glucose.

Infant formulas, coconut oil, and other manufactured foods containing medium-chain triglycerides as the primary source of fat are contraindicated in MCAD deficiency.

Popular high-fat/low-carbohydrate diets are not appropriate in MCAD deficiency.

Alcohol consumption, in particular acute alcohol intoxication (e.g., binge drinking), often elicits metabolic decompensation in individuals with MCAD deficiency [Lang 2009].

Aspirin has been demonstrated to exacerbate MCAD deficiency by increasing mitochondrial fatty acid oxidation and long-chain fatty acid flux, and inhibiting peroxisomal fatty acid oxidation, which normally serves as a lipitoxic buffer [Uppala et al 2017].

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger sibs and offspring of a proband in order to identify as early as possible those who would benefit from treatment and preventive measures.

• If the ACADM pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs and offspring of a proband.
• If the ACADM pathogenic variants in the family are not known, plasma acylcarnitine and urine acylglycine analysis can be used to clarify the disease status of at-risk sibs and offspring of a proband.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women who have MCAD deficiency must avoid catabolism. This is supported by several case reports describing carnitine deficiency, acute liver failure, and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) in pregnant women with MCAD deficiency [Nelson et al 2000, Santos et al 2007, Leydiker et al 2011].

Therapies Under Investigation

A Phase I clinical trial examining the use of glycerol phenylbutyrate (Ravicti^®) at 2, 4, and 6 g/m²/day in four adults with MCAD deficiency who had at least one copy of the c.985A>G pathogenic variant was completed in 2017. The primary outcome was changes in the assessment of metabolic stress pre- and post-dosing with Ravicti^®. There were no serious adverse events. Previous molecular modeling has suggested that the MCAD enzyme may be able to utilize phenylbutyryl-CoA as a substrate [Kormanik et al 2012].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of a child affected with MCAD deficiency are obligate heterozygotes (i.e., presumed to be carriers of at least one ACADM pathogenic variant based on the presence of biallelic ACADM pathogenic variants in their affected child).
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• If both parents are carriers of an ACADM pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Given that a clear genotype-phenotype correlation does not exist for MCAD deficiency and that individuals may remain asymptomatic until late adulthood, apparently unaffected sibs should be tested for MCAD deficiency. See Management, Evaluation of Relatives at Risk.

Offspring of a proband

• The offspring of an individual with MCAD deficiency inherit an ACADM pathogenic variant from their affected parent.
• The carrier (heterozygote) frequency in the North American/European population for a pathogenic variant in ACADM may be as high as 1/40 individuals. Therefore, the risk to the offspring of an affected individual and a reproductive partner of northern European origin of having MCAD deficiency is ~1/80.
• Given the high carrier frequency in the general population, it is appropriate to test the offspring of an individual with MCAD deficiency for the disorder. See Management, Evaluation of Relatives at Risk.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ACADM pathogenic variant.

Carrier Detection

Molecular genetic testing to determine genetic status is possible if both ACADM pathogenic variants have been identified in an affected family member.

Note: Biochemical screening tests such as acylcarnitine, organic acid, or acylglycine analyses are not useful in determining carrier status.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Note: States store leftover dried blood spot samples for variable lengths of time following newborn screening testing. These samples may be retrievable with parent/patient consent for retrospective biochemical or molecular genetic testing.

Prenatal Testing and Preimplantation Genetic Testing

Once both ACADM pathogenic variants have been identified in an affected family member, prenatal molecular genetic testing for a pregnancy at increased risk and preimplantation genetic testing for MCAD deficiency are possible.

Prompt postnatal testing by NBS, plasma acylcarnitines, and urine acylglycines and consultation with a biochemical geneticist are indicated.

Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Author History

Irene J Chang, MD (2019-present)
Dietrich Matern, MD, PhD; Mayo Clinic College of Medicine (1999-2019)
J Lawrence Merritt 2nd, MD (2019-present)
Piero Rinaldo, MD, PhD; Mayo Clinic College of Medicine (1999-2019)

Revision History

• 27 June 2019 (ha) Comprehensive update posted live
• 5 March 2015 (me) Comprehensive update posted live
• 19 January 2012 (me) Comprehensive update posted live
• 3 February 2005 (me) Comprehensive update posted live
• 27 January 2003 (me) Comprehensive update posted live
• 20 April 2000 (me) Review posted live
• 16 December 1999 (dm) Original submission

Literature Cited

• Abulí A, Boada M, Rodríguez-Santiago B, Coroleu B, Veiga A, Armengol L, Barri PN, Pérez-Jurado LA, Estivill X. NGS-based assay for the identification of individuals carrying recessive genetic mutations in reproductive medicine. Hum Mutat. 2016;37:516-23. [PubMed: 26990548]
• Ahrens-Nicklas RC, Pyle LC, Ficicioglu C. Morbidity and mortality among exclusively breastfed neonates with medium-chain acyl-CoA dehydrogenase deficiency. Genet Med. 2016;18:1315-9. [PMC free article: PMC5538896] [PubMed: 27148938]
• Aksglaede L, Christensen M, Olesen JH, Duno M, Olsen RK, Andresen BS, Hougaard DM, Lund AM. Abnormal newborn screening in a healthy infant of a mother with undiagnosed medium-chain Acyl-CoA dehydrogenase deficiency. JIMD Rep. 2015;23:67-70. [PMC free article: PMC4484903] [PubMed: 25763512]
• Albers S, Levy HL, Irons M, Strauss AW, Marsden D. Compound heterozygosity in four asymptomatic siblings with medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2001;24:417-8. [PubMed: 11486912]
• Aldubayan SH, Rodan LH, Berry GT, Levy HL. Acute illness protocol for fatty acid oxidation and carnitine disorders. Pediatr Emerg Care. 2017;33:296-301. [PubMed: 28353532]
• Alfardan J, Mohsen AW, Copeland S, Ellison J, Keppen-Davis L, Rohrbach M, Powell BR, Gillis J, Matern D, Kant J, Vockley J. Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening. Mol Genet Metab. 2010;100:333-8. [PMC free article: PMC2906669] [PubMed: 20547083]
• Al-Hassnan ZN, Imtiaz F, Al-Amoudi M, Rahbeeni Z, Al-Sayed M, Al-Owain M, Al-Zaidan H, Al-Odaib A, Rashed MS. Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications. J Inherit Metab Dis. 2010;33 Suppl 3:S263-7.
• Anderson S, Botti C, Li B, Millonig JH, Lyon E, Millson A, Karabin SS, Brooks SS. Medium chain acyl-CoA dehydrogenase deficiency detected among Hispanics by New Jersey newborn screening. Am J Med Genet A. 2012;158A:2100-5. [PubMed: 22848008]
• Andresen BS, Dobrowolski SF, O'Reilly L, Muenzer J, McCandless SE, Frazier DM, Udvari S, Bross P, Knudsen I, Banas R, Chace DH, Engel P, Naylor EW, Gregersen N. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001;68:1408-18. [PMC free article: PMC1226127] [PubMed: 11349232]
• Andresen BS, Lund AM, Hougaard DM, Christensen E, Gahrn B, Christensen M, Bross P, Vested A, Simonsen H, Skogstrand K, Olpin S, Brandt NJ, Skovby F, Nørgaard-Pedersen B, Gregersen N. MCAD deficiency in Denmark. Mol Genet Metab. 2012;106:175-88. [PubMed: 22542437]
• Arnold GL, Saavedra-Matiz CA, Galvin-Parton PA, Erbe R, Devincentis E, Kronn D, Mofidi S, Wasserstein M, Pellegrino JE, Levy PA, Adams DJ, Nichols M, Caggana M. Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. Mol Genet Metab. 2010;99:263-8. [PubMed: 20036593]
• Bennett MJ, Rinaldo P, Millington DS, Tanaka K, Yokota I, Coates PM. Medium-chain acyl-CoA dehydrogenase deficiency: postmortem diagnosis in a case of sudden infant death and neonatal diagnosis of an affected sibling. Pediatr Pathol. 1991;11:889-95. [PubMed: 1775402]
• Bentler K, Zhai S, Elsbecker SA, Arnold GL, Burton BK, Vockley J, Cameron CA, Hiner SJ, Edick MJ, Berry SA, et al. 221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: findings from the Inborn Errors of Metabolism Collaborative. Mol Genet Metab. 2016;119:75-82. [PMC free article: PMC5031545] [PubMed: 27477829]
• Boles RG, Buck EA, Blitzer MG, Platt MS, Cowan TM, Martin SK, Yoon H, Madsen JA, Reyes-Mugica M, Rinaldo P. Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life. J Pediatr. 1998;132:924-33. [PubMed: 9627580]
• Bouvier D, Vianey-Saban C, Ruet S, Acquaviva C. Development of a tandem mass spectrometry method for rapid measurement of medium- and very-long-chain acyl-CoA dehydrogenase activity in fibroblasts. JIMD Rep. 2017;35:71-8. [PMC free article: PMC5585096] [PubMed: 27943070]
• Bzduch V, Behulova D, Lehnert W, Fabriciova K, Kozak L, Salingova A, Hrabincova E, Benedekova M. Metabolic cause of Reye-like syndrome. Bratisl Lek Listy. 2001;102:427-9. [PubMed: 11763681]
• Catarzi S, Caciotti A, Thusberg J, Tonin R, Malvagia S, la Marca G, Pasquini E, Cavicchi C, Ferri L, Donati MA, Baronio F, Guerrini R, Mooney SD, Morrone A. Medium-chain acyl-CoA deficiency: outlines from newborn screening, in silico predictions, and molecular studies. ScientificWorldJournal. 2013;2013:625824. [PMC free article: PMC3833120] [PubMed: 24294134]
• Chace DH, Diperna JC, Mitchell BL, Sgroi B, Hofman LF, Naylor EW. Electrospray tandem mass spectrometry for analysis of acylcarnitines in dried postmortem blood specimens collected at autopsy from infants with unexplained cause of death. Clin Chem. 2001;47:1166-82. [PubMed: 11427446]
• Chace DH, Hillman SL, Vanhove JLK, Naylor EW. Rapid diagnosis of MCAD deficiency - Quantitative analysis of octanoylcarnitine and other acylcarnitines in newborn blood spots by tandem mass spectrometry. Clin Chem. 1997;43:2106-13. [PubMed: 9365395]
• Chace DH, Kalas TA, Naylor EW. The application of tandem mass spectrometry to neonatal screening for inherited disorders of intermediary metabolism. Annu Rev Genomics Hum Genet. 2002;3:17-45. [PubMed: 12142359]
• Chien YH, Lee NC, Chao MC, Chen LC, Chen LH, Chien CC, Ho HC, Suen JH, Hwu WL. Fatty acid oxidation disorders in a chinese population in taiwan. JIMD Rep. 2013;11:165-72. [PMC free article: PMC3755561] [PubMed: 23700290]
• Clayton PT, Doig M, Ghafari S, Meaney C, Taylor C, Leonard JV, Morris M, Johnson AW. Screening For Medium chain acyl-coa dehydrogenase deficiency using electrospray ionisation tandem mass spectrometry. Arch Dis Child. 1998;79:109-15. [PMC free article: PMC1717662] [PubMed: 9797589]
• Couce ML, Sánchez-Pintos P, Diogo L, Leão-Teles E, Martins E, Santos H, Bueno MA, Delgado-Pecellín C, Castiñeiras DE, Cocho JA, García-Villoria J, Ribes A, Fraga JM, Rocha H. Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: regional experience and high incidence of carnitine deficiency. Orphanet J Rare Dis. 2013;8:102. [PMC free article: PMC3718718] [PubMed: 23842438]
• Derks TG, Reijngoud DJ, Waterham HR, Gerver WJ, Van Den Berg MP, Sauer PJ, Smit GP. The natural history of medium-chain acyl CoA dehydrogenase deficiency in the Netherlands: clinical presentation and outcome. J Pediatr. 2006;148:665-70. [PubMed: 16737882]
• Derks TG, Touw CM, Ribas GS, Biancini GB, Vanzin CS, Negretto G, Mescka CP, Reijngoud DJ, Smit GP, Wajner M, Vargas CR. Experimental evidence for protein oxidative damage and altered antioxidant defense in patients with medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2014;37:783-9. [PubMed: 24623196]
• Derks TG, Van Spronsen FJ, Rake JP, Van Der Hilst CS, Span MM, Smit GP. Safe and unsafe duration of fasting for children with MCAD deficiency. Eur J Pediatr. 2007;166:5-11. [PubMed: 16788829]
• Dessein AF, Fontaine M, Andresen BS, Gregersen N, Brivet M, Rabier D, Napuri-Gouel S, Dobbelaere D, Mention-Mulliez K, Martin-Ponthieu A, Briand G, Millington DS, Vianey-Saban C, Wanders RJ, Vamecq J. A novel mutation of the ACADM gene (c.145C>G) associated with the common c.985A>G mutation on the other ACADM allele causes mild MCAD deficiency: a case report. Orphanet J Rare Dis. 2010;5:26. [PMC free article: PMC2967532] [PubMed: 20923556]
• Douillard C, Mention K, Dobbelaere D, Wemeau JL, Saudubray JM, Vantyghem MC. Hypoglycaemia related to inherited metabolic diseases in adults. Orphanet J Rare Dis. 2012;7:26. [PMC free article: PMC3458880] [PubMed: 22587661]
• Duran M, Hofkamp M, Rhead WJ, Saudubray JM, Wadman SK. Sudden child death and 'healthy' affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency. Pediatrics. 1986;78:1052-7. [PubMed: 3786030]
• Ensenauer R, Winters JL, Parton PA, Kronn DF, Kim JW, Matern D, Rinaldo P, Hahn SH. Genotypic differences of MCAD deficiency in the Asian population: novel genotype and clinical symptoms preceding newborn screening notification. Genet Med. 2005;7:339-43. [PubMed: 15915086]
• Feillet F, Steinmann G, Vianey-Saban C, de Chillou C, Sadoul N, Lefebvre E, Vidailhet M, Bollaert PE. Adult presentation of MCAD deficiency revealed by coma and severe arrythmias. Intensive Care Med. 2003;29:1594-7. [PubMed: 12897989]
• Feuchtbaum L, Carter J, Dowray S, Currier RJ, Lorey F. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet Med. 2012;14:937-45. [PubMed: 22766612]
• Feuchtbaum L, Yang J, Currier R. Follow-up status during the first 5 years of life for metabolic disorders on the federal Recommended Uniform Screening Panel. Genet Med. 2018;20:831-9. [PubMed: 29215646]
• Frazier DM, Millington DS, McCandless SE, Koeberl DD, Weavil SD, Chaing SH, Muenzer J. The tandem mass spectrometry newborn screening experience in North Carolina: 1997-2005. J Inherit Metab Dis. 2006;29:76-85. [PubMed: 16601872]
• Frazier DM. Medium chain acyl CoA dehydrogenase deficiency (MCADD). Genetic Metabolic Dietitians International: Nutrition Guidelines. 2008. Available online. Accessed 9-7-22.
• Gregersen N, Winter V, Curtis D, Deufel T, Mack M, Hendrickx J, Willems PJ, Ponzone A, Parrella T, Ponzone R, Ding J-H, Zhang W, Chen YT, Kahler S, Roe CR, Kølvraa S, Schneiderman K, Andresen BS, Bross P, Bolund L. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe. Hum Hered. 1993;43:342-50. [PubMed: 7904584]
• Grosse SD, Khoury MJ, Greene CL, Crider KS, Pollitt RJ. The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: an update. Genet Med. 2006;8:205-12. [PubMed: 16617240]
• Grünert SC, Wehrle A, Villavicencio-Lorini P, Lausch E, Vetter B, Schwab KO, Tucci S, Spiekerkoetter U. Medium-chain acyl-CoA dehydrogenase deficiency associated with a novel splice mutation in the ACADM gene missed by newborn screening. BMC Med Genet. 2015;16:56. [PMC free article: PMC4557819] [PubMed: 26223887]
• Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, Uziel G, Lamantea E, Invernizzi F, Poulton J, Rolinski B, Iuso A, Biskup S, Schmidt T, Mewes HW, Wittig I, Meitinger T, Zeviani M, Prokisch H. Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet. 2010;42:1131-4. [PubMed: 21057504]
• Hale DE, Stanley CA, Coates PM. Genetic defects of acyl-CoA dehydrogenases: studies using an electron transfer flavoprotein reduction assay. Prog Clin Biol Res. 1990;321:333-48. [PubMed: 2326298]
• Hara K, Tajima G, Okada S, Tsumura M, Kagawa R, Shirao K, Ohno Y, Yasunaga S, Ohtsubo M, Hata I, Sakura N, Shigematsu Y, Takihara Y, Kobayashi M. Significance of ACADM mutations identified through newborn screening of MCAD deficiency in Japan. Mol Genet Metab. 2016;118:9-14. [PubMed: 26947917]
• Hsu HW, Zytkovicz TH, Comeau AM, Strauss AW, Marsden D, Shih VE, Grady GF, Eaton RB. Spectrum of medium-chain acyl-CoA dehydrogenase deficiency detected by newborn screening. Pediatrics. 2008;121:e1108-14. [PubMed: 18450854]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Huidekoper HH, Schneider J, Westphal T, Vaz FM, Duran M, Wijburg FA. Prolonged moderate-intensity exercise without and with L-carnitine supplementation in patients with MCAD deficiency. J Inherit Metab Dis. 2006;29:631–6. [PubMed: 16972171]
• Iafolla AK, Thompson RJ Jr, Roe CR. Medium-chain acyl-coenzyme A dehydrogenase deficiency: clinical course in 120 affected children. J Pediatr. 1994;124:409–15. [PubMed: 8120710]
• Jager EA, Kuijpers MM, Bosch AM, Mulder MF, Rubio-Gozalbo ME, Visser G, de Vries M, Williams M, Waterham HR, van Spronsen FJ, Schielen PCJI, Derks TGJ. A nationwide retrospective observational study of population newborn screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency In the Netherlands. J Inherit Metab Dis. 2019;42:890-7. [PubMed: 31012112]
• Jank JM, Maier EM, Reiß DD, Haslbeck M, Kemter KF, Truger MS, Sommerhoff CP, Ferdinandusse S, Wanders RJ, Gersting SW, Muntau AC. The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase. PLoS One. 2014;9:e93852. [PMC free article: PMC3981736] [PubMed: 24718418]
• Janzen N, Hofmann AD, Schmidt G, Das AM, Illsinger S. Non-invasive test using palmitate in patients with suspected fatty acid oxidation defects: disease-specific acylcarnitine patterns can help to establish the diagnosis. Orphanet J Rare Dis. 2017;12:187. [PMC free article: PMC5740567] [PubMed: 29268767]
• Gramer G, Haege G, Fang-Hoffmann J, Hoffmann GF, Bartram CR, Hinderhofer K, Burgard P, Lindner M. Medium-chain acyl-CoA dehydrogenase deficiency: evaluation of genotype-phenotype correlation in patients detected by newborn screening. JIMD Rep. 2015;23:101-12. [PMC free article: PMC4484909] [PubMed: 25940036]
• Kaku N, Ihara K, Hirata Y, Yamada K, Lee S, Kanemasa H, Motomura Y, Baba H, Tanaka T, Sakai Y, Maehara Y, Ohga S. Diagnostic potential of stored dried blood spots for inborn errors of metabolism: a metabolic autopsy of medium-chain acyl-CoA dehydrogenase deficiency Journal of Clinical Pathology 2018;71:885-9. [PubMed: 29720407]
• Kang HM, Ahn SH, Choi P, Ko YA, Han SH, Chinga F, Park AS, Tao J, Sharma K, Pullman J, Bottinger EP, Goldberg IJ, Susztak K. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med. 2015;21:37–46. [PMC free article: PMC4444078] [PubMed: 25419705]
• Kasper DC, Ratschmann R, Metz TF, Mechtler TP, Möslinger D, Konstantopoulou V, Item CB, Pollak A, Herkner KR. The national Austrian newborn screening program - eight years experience with mass spectrometry. past, present, and future goals. Wien Klin Wochenschr. 2010;122:607-13. [PubMed: 20938748]
• Kølvraa S, Gregersen N, Christensen E, Hobolth N. In vitro fibroblast studies in a patient with C6-C10-dicarboxylic aciduria: evidence for a defect in general acyl-CoA dehydrogenase. Clin Chim Acta. 1982;126:53-67. [PubMed: 7172449]
• Kormanik K, Kang H, Cuebas D, Vockley J, Mohsen AW. Evidence for involvement of medium chain acyl-CoA dehydrogenase in the metabolism of phenylbutyrate. Mol Genet Metab. 2012;107:684-9. [PMC free article: PMC3504130] [PubMed: 23141465]
• Koster KL, Sturm M, Herebian D, Smits SH, Spiekerkoetter U. Functional studies of 18 heterologously expressed medium-chain acyl-CoA dehydrogenase (MCAD) variants. J Inherit Metab Dis. 2014;37:917-28. [PubMed: 24966162]
• Lang TF. Adult presentations of medium-chain acyl-CoA dehydrogenase deficiency (MCADD). J Inherit Metab Dis. 2009;32:675-83. [PubMed: 19821147]
• Lee PJ, Harrison EL, Jones MG, Jones S, Leonard JV, Chalmers RA. L-carnitine and exercise tolerance in medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency: a pilot study. J Inherit Metab Dis. 2005;28:141-52. [PubMed: 15877203]
• Leydiker KB, Neidich JA, Lorey F, Barr EM, Puckett RL, Lobo RM, Abdenur JE. Maternal medium-chain acyl-CoA dehydrogenase deficiency identified by newborn screening. Mol Genet Metab. 2011;103:92-5. [PubMed: 21354840]
• Lindner M, Gramer G, Haege G, Fang-Hoffmann J, Schwab KO, Tacke U, Trefz FK, Mengel E, Wendel U, Leichsenring M, Burgard P, Hoffmann GF. Efficacy and outcome of expanded newborn screening for metabolic diseases--report of 10 years from south-west Germany. Orphanet J Rare Dis. 2011;6:44. [PMC free article: PMC3141366] [PubMed: 21689452]
• Lovera C, Porta F, Caciotti A, Catarzi S, Cassanello M, Caruso U, Gallina MR, Morrone A, Spada M. Sudden unexpected infant death (SUDI) in a newborn due to medium chain acyl CoA dehydrogenase (MCAD) deficiency with an unusual severe genotype. Ital J Pediatr. 2012;38:59. [PMC free article: PMC3502270] [PubMed: 23095120]
• Madsen KL, Preisler N, Orngreen MC, Andersen SP, Olesen JH, Lund AM, Vissing J. Patients with medium-chain acyl-coenzyme a dehydrogenase deficiency have impaired oxidation of fat during exercise but no effect of L-carnitine supplementation. J Clin Endocrinol Metab. 2013;98:1667-75. [PubMed: 23426616]
• Maier EM, Liebl B, Roschinger W, Nennstiel-Ratzel U, Fingerhut R, Olgemoller B, Busch U, Krone N, Kries RV, Roscher AA. Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat. 2005;25:443-52. [PubMed: 15832312]
• Maier EM, Pongratz J, Muntau AC, Liebl B, Nennstiel-Ratzel U, Busch U, Fingerhut R, Olgemoller B, Roscher AA, Roschinger W. Validation of MCADD newborn screening. Clin Genet. 2009;76:179-87. [PubMed: 19780764]
• Matern D. Acylcarnitines. In: Blau N, Duran M, Gibson KM, Dionisi-Vici C eds. Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Heidelberg, Gemany: Springer Verlag; 2014:775-84
• Mayell SJ, Edwards L, Reynolds FE, Chakrapani AB. Late presentation of medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2007;30:104.
• McCandless SE, Chandrasekar R, Linard S, Kikano S, Rice L. Sequencing from dried blood spots in infants with "false positive" newborn screen for MCAD deficiency. Mol Genet Metab. 2013;108:51-5. [PMC free article: PMC3676896] [PubMed: 23151387]
• Millington DS, Kodo N, Norwood DL, Roe CR. Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism. J Inherit Metab Dis. 1990;13:321-4. [PubMed: 2122093]
• Morris AA, Taylor RW, Lightowlers RN, Aynsley-Green A, Bartlett K, Turnbull DM. Medium chain acyl-CoA dehydrogenase deficiency caused by a deletion of exons 11 and 12. Hum Mol Genet. 1995;4:747-9. [PubMed: 7633427]
• Nennstiel-Ratzel U, Arenz S, Maier EM, Knerr I, Baumkötter J, Röschinger W, Liebl B, Hadorn HB, Roscher AA, von Kries R. Reduced incidence of severe metabolic crisis or death in children with medium chain acyl-CoA dehydrogenase deficiency homozygous for c.985A>G identified by neonatal screening. Mol Genet Metab. 2005;85:157-9. [PubMed: 15896661]
• Nelson J, Lewis B, Walters B. The HELLP syndrome associated wiht fetal medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2000;23:518-9. [PubMed: 10947209]
• Nichols MJ, Saavedra-Matiz CA, Pass KA, Caggana M. 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. Am J Med Genet A. 2008;146A:610-9. [PubMed: 18241067]
• Niwa T. Mass spectrometry in disorders of organic acid metabolism. Clin Chim Acta. 1995;241-242:293-384. [PubMed: 8612342]
• Pedersen CB, Bischoff C, Christensen E, Simonsen H, Lund AM, Young SP, Koeberl DD, Millington DS, Roe CR, Roe DS, Wanders RJ, Ruiter JP, Keppen LD, Stein Q, Knudsen I, Gregersen N, Andresen BS. Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening. Pediatr Res. 2006;60:315–20. [PubMed: 16857760]
• Potter BK, Little J, Chakraborty P, Kronick JB, Evans J, Frei J, Sutherland SC, Wilson K, Wilson BJ. Variability in the clinical management of fatty acid oxidation disorders: results of a survey of Canadian metabolic physicians. J Inherit Metab Dis. 2012;35:115–23. [PubMed: 21630065]
• Prasad C, Speechley KN, Dyack S, Rupar CA, Chakraborty P, Kronick JB. Incidence of medium-chain acyl-CoA dehydrogenase deficiency in Canada using the Canadian Paediatric Surveillance Program: role of newborn screening. Paediatr Child Health. 2012;17:185-9. [PMC free article: PMC3381659] [PubMed: 23543005]
• Rashed MS, Ozand PT, Bennett MJ, Barnard JJ, Govindaraju DR, Rinaldo P. Inborn errors of metabolism diagnosed in sudden death cases by acylcarnitine analysis of postmortem bile. Clin Chem. 1995;41:1109–14. [PubMed: 7628085]
• Raymond K, Bale AE, Barnes CA, Rinaldo P. Medium-chain acyl-CoA dehydrogenase deficiency: sudden and unexpected death of a 45 year old woman. Genet Med. 1999;1:293–4. [PubMed: 11258631]
• Rhead WJ. Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: a global perspective. J Inherit Metab Dis. 2006;29:370-7. [PubMed: 16763904]
• Rinaldo P, Matern D, Bennett MJ. Fatty Acid oxidation disorders. Annu Rev Physiol. 2002;64:477–502. [PubMed: 11826276]
• Rinaldo P, O'Shea JJ, Coates PM, Hale DE, Stanley CA, Tanaka K. Medium-chain acyl-CoA dehydrogenase deficiency. Diagnosis by stable-isotope dilution measurement of urinary n-hexanoylglycine and 3-phenylpropionylglycine. N Engl J Med. 1988;319:1308–13. [PubMed: 3054550]
• Rinaldo P, Raymond K, al-Odaib A, Bennett MJ. Clinical and biochemical features of fatty acid oxidation disorders. Curr Opin Pediatr. 1998;10:615-21 [PubMed: 9848022]
• Rinaldo P, Schmidt-Sommerfeld E, Posca AP, Heales SJ, Woolf DA, Leonard JV. Effect of treatment with glycine and L-carnitine in medium-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr. 1993;122:580–4. [PubMed: 8463904]
• Rinaldo P, Studinski AL, Matern D. Prenatal diagnosis of disorders of fatty acid transport and mitochondrial oxidation. Prenat Diagn. 2001;21:52–4. [PubMed: 11180241]
• Rinaldo P, Yoon HR, Yu C, Raymond K, Tiozzo C, Giordano G. Sudden and unexpected neonatal death: a protocol for the postmortem diagnosis of fatty acid oxidation disorders. Semin Perinatol. 1999;23:204-10. [PubMed: 10331471]
• Rocha H, Castiñeiras D, Delgado C, Egea J, Yahyaoui R, González Y, Conde M, González I, Rueda I, Rello L, Vilarinho L, Cocho J. Birth prevalence of fatty acid β-oxidation disorders in Iberia. JIMD Rep. 2014;16:89-94. [PMC free article: PMC4221301] [PubMed: 25012579]
• Roe CR, Ding J. Mitochondrial fatty acid oxidation disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. Chap 101. 8 ed. New York, NY: McGraw-Hill; 2001:2297-326.
• Roe CR, Millington DS, Maltby DA, Kinnebrew P. Recognition of medium-chain acyl-CoA dehydrogenase deficiency in asymptomatic siblings of children dying of sudden infant death or Reye-like syndromes. J Pediatr. 1986;108:13–8. [PubMed: 3944676]
• Sander S, Janzen N, Janetzky B, Scholl S, Steuerwald U, Schafer J, Sander J. Neonatal screening for medium chain acyl-CoA deficiency: high incidence in Lower Saxony (northern Germany). Eur J Pediatr. 2001;160:318–9. [PubMed: 11388605]
• Santos L, Patterson A, Moreea SM, Lippiatt CM, Walter J, Henderson M. Acute liver failure in pregnancy associated with maternal MCAD deficiency. J Inherit Metab Dis. 2007;30:103. [PubMed: 17186412]
• Saudubray JM, Martin D, de Lonlay P, Touati G, Poggi-Travert F, Bonnet D, Jouvet P, Boutron M, Slama A, Vianey-Saban C, Bonnefont JP, Rabier D, Kamoun P, Brivet M. Recognition and management of fatty acid oxidation defects: A series of 107 patients. J Inherit Metab Dis. 1999;22:488–502. [PubMed: 10407781]
• Schatz UA, Ensenauer R. The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population. J Inherit Metab Dis. 2010;33:513–20. [PubMed: 20532824]
• Schmidt-Sommerfeld E, Bobrowski PJ, Penn D, Rhead WJ, Wanders RJ, Bennett MJ. Analysis of carnitine esters by radio-high performance liquid chromatography in cultured skin fibroblasts from patients with mitochondrial fatty acid oxidation disorders. Pediatr Res. 1998;44:210–4. [PubMed: 9702916]
• Searle C, Andresen BS, Wraith E, Higgs J, Gray D, Mills A, Allen KE, Hobson E. A Large Intragenic Deletion in the ACADM Gene Can Cause MCAD Deficiency but is not Detected on Routine Sequencing. JIMD Rep. 2013;11:13-6. [PMC free article: PMC3755559] [PubMed: 23546811]
• Shigematsu Y, Hirano S, Hata I, Tanaka Y, Sudo M, Sakura N, Tajima T, Yamaguchi S. Newborn mass screening and selective screening using electrospray tandem mass spectrometry in Japan. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;776:39–48.
• Smith EH, Thomas C, McHugh D, Gavrilov D, Raymond K, Rinaldo P, Tortorelli S, Matern D, Highsmith WE, Oglesbee D. Allelic diversity in MCAD deficiency: The biochemical classification of 54 variants identified during 5 years of ACADM sequencing. Mol Genet Metab. 2010;100:241–50. [PubMed: 20434380]
• Sturm M, Herebian D, Mueller M, Laryea MD, Spiekerkoetter U. Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants. PLoS One. 2012;7:e45110. [PMC free article: PMC3444485] [PubMed: 23028790]
• Swigonová Z, Mohsen AW, Vockley J. Acyl-CoA dehydrogenases: Dynamic history of protein family evolution. J Mol Evol. 2009;69:176–93. [PMC free article: PMC4136416] [PubMed: 19639238]
• Tajima G, Hara K, Tsumura M, Kagawa R, Okada S, Sakura N, Hata I, Shigematsu Y, Kobayashi M. Screening of MCAD deficiency in Japan: 16 years' experience of enzymatic and genetic evaluation. Mol Genet Metab. 2016;119:322-8. [PubMed: 27856190]
• Tal G, Pitt J, Morrisy S, Tzanakos N, Boneh A. An audit of newborn screening procedure: impact on infants presenting clinically before results are available. Mol Genet Metab. 2015;114:403-8. [PubMed: 25604974]
• Tanaka K, Gregersen N, Ribes A, Kim J, Kølvraa S, Winter V, Eiberg H, Martinez G, Deufel T, Leifert B, Santer R, Francois B, Pronicka E, Laszlo A, Kmoch S, Kremensky I, Kalaydjicva L, Ozalp I, Ito M. A survey of the newborn populations in Belgium, Germany, Poland, Czech Republic, Hungary, Bulgaria, Spain, Turkey, and Japan for the G985 variant allele with haplotype analysis at the medium chain Acyl-CoA dehydrogenase gene locus: clinical and evolutionary consideration. Pediatr Res. 1997;41:201–9. [PubMed: 9029639]
• Touw CM, Smit GP, de Vries M, de Klerk JB, Bosch AM, Visser G, Mulder MF, Rubio-Gozalbo ME, Elvers B, Niezen-Koning KE, Wanders RJ, Waterham HR, Reijngoud DJ, Derks TG. Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehyrogenase deficiency: data from a cohort study. Orphanet J Rare Dis. 2012;7:30. [PMC free article: PMC3543239] [PubMed: 22630369]
• Touw CM, Smit GP, Niezen-Koning KE, Bosgraaf-de Boer C, Gerding A, Reijngoud DJ, Derks TG. In vitro and in vivo consequences of variant medium-chain acyl-CoA dehydrogenase genotypes. Orphanet J Rare Dis. 2013;8:43. [PMC free article: PMC3610156] [PubMed: 23509891]
• Treem WR, Stanley CA, Goodman SI. Medium-chain acyl-CoA dehydrogenase deficiency: metabolic effects and therapeutic efficacy of long-term L-carnitine supplementation. J Inherit Metab Dis. 1989;12:112–9. [PubMed: 2502671]
• Uppala R, Dudiak B, Beck ME, Bharathi SS, Zhang Y, Stolz DB, Goetzman ES. Aspirin increases mitochondrial fatty acid oxidation. Biochem Biophys Res Commun. 2017;482:346–51. [PMC free article: PMC5195905] [PubMed: 27856258]
• Vilarinho L, Rocha H, Sousa C, Marcão A, Fonseca H, Bogas M, Osório RV. Four years of expanded newborn screening in Portugal with tandem mass spectrometry. J Inherit Metab Dis. 2010;33 Suppl 3:S133-8. [PubMed: 20177789]
• Waddell L, Wiley V, Carpenter K, Bennetts B, Angel L, Andresen BS, Wilcken B. Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations. Mol Genet Metab. 2006;87:32–9. [PubMed: 16291504]
• Wanders RJ, Ruiter JP, Ijlst L, Waterham HR, Houten SM. The enzymology of mitochondrial fatty acid beta-oxidation and its application to follow-up analysis of positive neonatal screening results. J Inherit Metab Dis. 2010;33:479–94. [PMC free article: PMC2946543] [PubMed: 20490924]
• Wilcken B, Haas M, Joy P, Wiley V, Bowling F, Carpenter K, Christodoulou J, Cowley D, Ellaway C, Fletcher J, Kirk EP, Lewis B, McGill J, Peters H, Pitt J, Ranieri E, Yaplito-Lee J, Boneh A. Expanded newborn screening: outcome in screened and unscreened patients at age 6 years. Pediatrics. 2009;124:e241–8. [PubMed: 19620191]
• Wilcken B, Haas M, Joy P, Wiley V, Chaplin M, Black C, Fletcher J, McGill J, Boneh A. Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study. Lancet. 2007;369:37-42. [PubMed: 17208640]
• Wiles JR, Leslie N, Knilans TK, Akinbi H. Prolonged QTc interval in association with medium-chain acyl-coenzyme A dehydrogenase deficiency. Pediatrics. 2014;133:e1781-6. [PMC free article: PMC4035587] [PubMed: 24799540]
• Woo HI, Park HD, Lee YW, Lee DH, Ki CS, Lee SY, Kim JW. Clinical, biochemical and genetic analyses in two Korean patients with medium-chain acyl-CoA dehydrogenase deficiency. Korean J Lab Med. 2011;31:54-60. [PMC free article: PMC3111034] [PubMed: 21239873]
• Zschocke J, Schulze A, Lindner M, Fiesel S, Olgemoller K, Hoffmann GF, Penzien J, Ruiter JP, Wanders RJ, Mayatepek E. Molecular and functional characterisation of mild MCAD deficiency. Hum Genet. 2001;108:404–8. [PubMed: 11409868]