Acyl-CoA dehydrogenase, medium chain (MCAD) deficiency is a congenital metabolic disorder of the mitochondrial fatty acid oxidation. Fatty acid oxidation, which fuels hepatic ketogenesis, is an essential process of converting certain fats into energy, particularly when carbohydrates are so scarce. In hepatic cells, ketogenesis is the major source of energy after the depletion of hepatic glycogen, during prolonged fasting, and periods of high energy demands. Several enzymes work in a step-wise fashion during fatty acid oxidation. In MCAD deficiency, patients have inadequate levels of an enzyme required for the step that metabolizes a group of fats called medium-chain fatty acids.
The disorder begins during infancy or early childhood. MCAD deficiency is characterized by the following clinical signs and symptoms: hypoketotic hypoglycemia, vomiting, and lethargy that are triggered by fasting or certain viral infections. In addition, serious complications can also be associated with MCAD deficiency such as seizures, breathing difficulties, liver problems, brain damage, coma, and sudden unexpected death.
The global incidence of MCAD deficiency is estimated to be 1:12,000 live births. Urinalysis of the organic acids, plasma medium chain fatty acids and plasma acylcarnitines is the major diagnostic tool for this disorder. Management can be made by huge glucose infusion and eventually L-carnitine supplementation.
MCAD deficiency is an inherited disorder which is transmitted in an autosomal recessive pattern. To date, more than 40 mutations in the ACADM gene have been identified to cause MCAD deficiency. Alterations in the gene lead to an inadequate level of MCAD. Thus, medium-chain fatty acids cannot be metabolized properly and the body will not be able to produce energy. As a result, medium-chain fatty acids may accumulate in tissues and can damage the liver and brain, causing serious complications.
Al Arrayed et al. (1999) applied newborn screening to 1000 Bahraini newborns taken at random during two years. Preliminary results showed 10 abnormal cases out of 1000 newborns (incidence 1%); although it was expected to find 100 affected births with metabolic diseases in every 1000 newborns annually. Deficiency of acyl-CoA dehydrogenase medium-chain was commonly found among Bahraini infants.
[Al Arrayed SS, Al Jishi E, Abbasi A, Rashed MS, Ozand PT. Newborn screening by using mass spectrometry. Bahrain Med Bull. 1999; 21(4)]
Ramadan et al. (2005) reported the first case of MCAD deficiency from Kuwait. The patient was a previously healthy 2-year old Non-Kuwaiti Arab girl, born to consanguineous parents, who was found unarousable one morning. At the hospital she was given a Glasgow Coma Scale of six. She developed a brief tonic-clonic seizure. Blood sugar was found to be 1.1 mmol/L. The child had taken a small meal the previous night, and had ~13.5 hours of fasting. Her liver was found to be enlarged and she was hypotonic. Urine was found to be negative for ketones, suggesting an inborn error of fatty acid oxidation. She was put on an IV bolus of 10% dextrose, followed by a continuous infusion. Following this, blood sugar went up to 14.5 mmol/L, although the child remained in a semi-conscious state for almost 7-hours. She slowly regained consciousness, and by the next morning was back in her usual state. Acylcarnitine results confirmed the diagnosis of MCAD deficiency. She was put on a low-fat, high-carb diet, with an instruction to the parents not to let her fast longer than 8-10 hours. She was discharged on a daily dose of L-carnitine. Upon follow-up, the girl was found to be doing well at the age of 3.5 years, with normal growth, no hepatomegaly, and normal neurodevelopment. Her three siblings were checked for MCAD deficiency and were found to be normal.
[Ramadan DG, Al-Sharkawy I, Al-Ruqum FA. Hypoglycemic coma in a young girl: First case of medium chain acyl coA dehydrogenase (MCAD) deficiency identified in Kuwait. Kuwait Med J. 2005; 37(1):50-3.]
In 2003, the Hamad Medical Corporation, in partnership with the University Children's Hospital of Heidelberg built a comprehensive newborn screening program. Between December 2003 and July 2006, Lindner et al. (2007) investigated 25,214 neonates born in Qatar for inborn errors of metabolism and endocrine disorders. Six neonates were diagnosed with MCAD deficiency. The high frequency of this disorder in Qatar was a completely unexpected finding.
Al Hassnan et al. (2010) presented the incidence, biochemical phenotype and molecular findings of MCADD in the Saudi population. The study included 13 neonates with the condition that were diagnosed by the national neonatal screening program between 2006 and 2008 that encompassed 237,812 newborns. This gave an incidence of 1:18,293 for MCADD in the country. In addition, another 17 cases of MCADD had earlier been diagnosed using MS/MS. All 30 patients were included in the study. Biochemical data was available for 24 of these patients. The median C8 carnitine level was well above the cut-off limit at 3.31 Um (range: 0.81-16.33uM). These levels were higher among the newborns than the older patients. The C8 carnitine/C2-carnitine was clearly discriminatory. However, the secondary markers were not as consistently useful. Three patients, all of them non-neonates, had C6 carnitine and C10:1-carnitine levels that were below the cut-off. Molecular analysis revealed two novel mutations in the ACADM gene in the patients and indicated the presence of a founder mutation.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Fatty acid oxidation disorders were diagnosed in 18/248 patients (7%) through uncovering the deficiency of relevant enzymes. Among them, two cases from a single family were found to have MCAD deficiency. The estimated incidence of this condition is 1 in 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
Al-Shamsi et al. (2014) undertook a study to calculate the birth prevalence of IEMs among Emiratis in the UAE by taking into consideration all neonates born with an inherited metabolic condition at Tawam Hospital between 1995 and 2012. A total of 37 distinct IEMs were found in Emirati neonates in this study, providing an estimated IEM birth prevalence of 75.24 per 100,000 live births. Medium Chain Acyl CoA Dehydrogenase Deficiency was found to have a birth prevalence of less than 0.98 per 100,000. A single mutation in the ACADM gene was identified in the affected patient(s).