Diagnosis -- Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD)


Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD)


Based on clinical and laboratory presentation along with confirmatory biochemical genetic results, the diagnosis of medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) was made.

Prevalence of Medium-chain acyl-coenzyme a dehydrogenase deficiency (MCADD) is 5.3 per 100,000 births and is more prevalent in individuals of northern European descent [1,2].

It is a disorder of mitochondrial fatty acid ß-oxidation and is one of the most common inborn errors of metabolism, commonly diagnosed through newborn testing these days. Fatty acid ß oxidation is a major source of energy following depletion of hepatic glycogen stores. Medium-chain acyl-coenzyme A dehydrogenase (MCAD) catalyzes dehydrogenation of acyl-CoAs esterified with fatty acids chains of six to ten carbons. Terminal products of fatty acid oxidation are acetyl-CoA, FADH and NADH, all of which support energy production. Increased glycogen utilization by various tissues along with impaired ketogenesis results in hypoglycemia, metabolic acidosis, liver function derangements, lethargy, coma and subsequently death [1,3,4].

Clinical features
MCAD deficient individuals appear healthy at birth. The untreated individual may present in the initial days of life, but more often between 3 - 24 months. Prior to MS/MS, newborn screening, late adulthood presentation was also common in mild phenotype cases [5]. The clinical hallmark is hypoketotic hypoglycemia in the setting of vomiting, lethargy, or seizures; often precipitated by infectious disease (e.g., viral infection) or other stressors that reduce PO intake. Hepatomegaly, increased liver transaminase, metabolic acidosis, and hyperammonemia are also common features [6]. Diagnosis
MCAD should be suspected in an infant with positive newborn screening result, previously healthy individuals who become symptomatic, or in sudden unexpected death. Our patient was previously healthy and presented with lethargy and hypoketotic hypoglycemia on day 3 [5].

The diagnosis is established by confirmatory biochemical testing (plasma acylcarnitine) and pathogenic variants in the ACADM gene. Acylcarnitine analysis show increased concentrations of octanoylcarnitine (C8) along with lesser elevated concentrations of C6-, C10-, and C10:1-acylcarnitines [7] (https://clir.mayo.edu assessed on 8/18/21).

Urine organic acid and urine acyl glycine analysis can also provide supportive evidence of MCADD deficiency. Increased levels of hexanoylglycine (C6), octanoylglycine (C8), decanoylglycine (C10) along with low ketone are usual pattern on urine organic acid analysis [8]. Our case showed a significantly elevated level of hexanoylglycine only with a low ketone level. Blood carnitine level can be low, because excess acylcarnitine binds with free carnitine and gets excreted; however, it was normal in our case.

Genetics and Genotype-phenotype correlation
ACADM gene is located on chromosome 1p31.1; mature MCAD protein is a homo-tetramer and is active in mitochondria. In literature, nearly 175 disease-associated variants have been described so far.

Individuals homozygous for the common c.985A>G variant (most common variant) show the highest C8 concentrations and are more likely to have neonatal symptoms [9]. c.199T>C (p.Tyr67His) variant is associated with milder biochemical derangements and clinical manifestations [10]. With the inclusion of MCAD deficiency in the NBS panel, less common compound heterozygotes variants are now frequently identified. Our patient is a compound heterozygous for c199T>C (p.Tyr67His), a mild pathogenic variant along with a second classic pathogenic variant c.985A>G (p.Lys329Glu).

Differential diagnosis
Due to extensive newborn screening test these days, essentially all cases, including asymptomatic ones, are identified in a very early stage of life. Prior to the NBS era, MCAD deficient cases were suspected if there is Reye-like syndromic presentation and other differentials to consider were other disorders of fatty acid ß oxidation, urea cycle disorder, organic acidurias, respiratory chain defects, and inborn errors of carbohydrate metabolism [1].

Management and Prevention
MCAD deficiency can cause severe metabolic derangement along with hypoglycemia. During a decompensation event, IV administration of glucose (bolus followed by continuous infusion) should be initiated immediately, and a glucose level between 120-170 mg/dL is recommended to achieve and maintain. The mainstay of prevention is avoiding fasting with frequent feedings at specific intervals; for example infants feeding should be at every 2-3 hours. A majority of literature support L-carnitine supplementation when the blood carnitine level is low; and it has been found to improve exercise tolerance [1,3,11].

Genetic counseling
MCAD is an autosomal recessive disorder. The parents of an affected child are carriers of at least one ACADM pathogenic variant. Prior to the NBS era, the unaffected siblings used to get tested for MCAD deficiency because it could remain asymptomatic until late adulthood. However, with the broad application of newborn screening, this is no longer necessary. In North American / European populations, the carrier frequency for a pathogenic variant can be as high as 1/40 individuals. Biochemical screening testing is uninformative for carrier detection because of their autosomal recessive status [1, 12].


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  9. 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.
  10. 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 Jun;68(6):1408-18. doi: 10.1086/320602. Epub 2001 May 8. PMID: 11349232; PMCID: PMC1226127.
  11. 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 PMID: 15877203
  12. 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, K°lvraa 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 PMID: 7904584

Contributed by Azfar Neyaz, MD, and Steven F. Dobrowolski, PhD

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