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Medium Chain Acyl CoA Dehydrogenase Deficiency

Deficiency of Medium-Chain Acyl-CoA Dehydrogenase

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an uncommon medical condition characterized by a deficiency of medium chain acyl-CoA dehydrogenase. This enzyme is responsible for the catabolism of medium chain fatty acids and its deficiency can lead to a variety of potentially life-threatening complications.


Presentation

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a disorder that is inherited via the autosomal recessive inheritance pattern. The inborn inability to catabolize medium chain fatty acids usually causes an abnormal buildup of fat in the hepatic and cerebral regions, alongside a multitude of other sequelae.

The condition is primarily diagnosed during early childhood, although there have been some documented cases where diagnosis was delayed until adulthood [1] [2]. Patients may be asymptomatic, or experience various symptoms, ranging from vomiting to a comatose state and sudden death [3] [4]. The symptom mainly related to MCAD deficiency is that of hypoketotic hypoglycemia, which is responsible for an altered mental status, weakness, lethargy or coma in young children or infants. Jitteriness, irritability and epileptic activity may also be manifestations due to which parents seek medical help.

Cardiological abnormalities and related symptomatology have also been documented in cases of infants diagnosed with MCAD deficiency. Pulmonary hemorrhage, ventricular tachycardias and irregular sleep patterns are amongst the symptoms described [5] [6] [7] [8]. They are typically elicited during a fasting period within the day, or following a confirmed or suspected viral infection. Although no neurological findings are usually present, severe metabolic stress can lead to corresponding deficits [1] [9]. Furthermore, growth may be slightly hindered and the young patients affected by MCAD deficiency may present with tachypnea, somnolence and hepatomegaly; the latter is very frequently associated with the condition [10].

Patients who do not manifest symptoms in early life will usually present in adulthood with cephalalgia and vomiting.

Sudden Infant Death Syndrome
  • Diagnosis may be difficult, since the disorder may present as hypoglycemia, sudden infant death syndrome or a Reye's syndrome-like illness.[ncbi.nlm.nih.gov]
  • Title Frequency of Medium-Chain Acyl-CoA Dehydrogenase Deficiency G-985 Mutation in Sudden Infant Death Syndrome Abstract A small percentage of apparent sudden infant death syndrome (SIDS) victims may have an unsuspected metabolic disorder.[corescholar.libraries.wright.edu]
Fatigue
  • On follow-up, a total of 44 patients reported fatigue (35%; 28/80), muscle pain (31%; 25/80), and/or reduced exercise tolerance (39%; 31/80).[ncbi.nlm.nih.gov]
  • It has been reported presenting after a first episode of alcohol intoxication. [ 4 ] It very occasionally presents in adulthood with muscle weakness and fatigue. Survivors of acute episodes may have severe hypoglycaemia-induced brain damage.[patient.info]
  • Survivors remain asymptomatic between episodes but may have delayed achievement of developmental milestones and are more likely to have reduced exercise tolerance, fatigue, myalgia, neuro-psychiatric symptoms, and weight gain 8.[ispub.com]
Epilepsy
  • A boy with delayed psychomotor development, attention deficit disorder, and therapy-resistant epilepsy was treated with valproate. The patient died of liver failure after 4 months of valproate treatment.[ncbi.nlm.nih.gov]
Turkish
  • In addition, we show that MCADD appears to occur as frequently in Turkish newborns as in the native German population.[ncbi.nlm.nih.gov]
Progressive Dementia
  • A female patient with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency developed normally until 13 months of age after which she showed a gradual developmental delay, followed by progressive dementia, and a decrease in head circumference growth culminating[ncbi.nlm.nih.gov]
Vomiting
  • Patients who do not manifest symptoms in early life will usually present in adulthood with cephalalgia and vomiting.[symptoma.com]
  • This case report describes a 30-year-old white man who, following a period of nausea and vomiting, was admitted to the hospital with sudden mental status deterioration followed rapidly by clinical deterioration and death.[ncbi.nlm.nih.gov]
Nausea
  • This case report describes a 30-year-old white man who, following a period of nausea and vomiting, was admitted to the hospital with sudden mental status deterioration followed rapidly by clinical deterioration and death.[ncbi.nlm.nih.gov]
  • Symptoms in the mother may only include nausea, vomiting, and abdominal pain, but the underlying issues can be severely problematic and sometimes life-threatening to the mother and fetus if the fetus is not delivered as soon as possible.[counsyl.com]
  • […] believe they said there were clear droplets viewed on biopsy, and somehow I had thought they were referring to glycogen that is non-stained when used with PAS). 7) Know that carnitine acyl-transferase-I is in the cytosol; CAS-II is in the mitochondria. 8) Nausea[forums.studentdoctor.net]
  • Postoperative nausea and vomiting can delay restarting of oral feeds and increase the risk of hypoglycemia.[ispub.com]
Failure to Thrive
  • Long-term outcomes include developmental and behavioral disability, chronic muscle weakness, failure to thrive, cerebral palsy, and attention deficit disorder (ADD).[ncbi.nlm.nih.gov]
  • MCADD is usually diagnosed in infancy or early childhood, when the affected individual presents with symptoms such as vomiting, low blood sugar, lack of energy, and failure to thrive.[nxgenmdx.com]
Recurrent Vomiting
  • Characteristic features of MCAD deficiency include: Reye-like syndrome (an acquired encephalopathy characterized by recurrent vomiting, agitation, and lethargy), fasting intolerance with vomiting, recurrent episodes of hypoglycemic coma, hypoketotic dicarboxylic[mayomedicallaboratories.com]
Tachycardia
  • Pulmonary hemorrhage, ventricular tachycardias and irregular sleep patterns are amongst the symptoms described. They are typically elicited during a fasting period within the day, or following a confirmed or suspected viral infection.[symptoma.com]
Cyanosis
  • Two male siblings with medium-chain acyl-CoA dehydrogenase deficiency were reported, in whom the enzyme activity was essentially undetectable and the symptoms and signs, including cyanosis, apnea, low body temperature, hypoglycemia and hyperammonemia,[ncbi.nlm.nih.gov]
Cardiomegaly
  • Muscle weakness and cardiomegaly in association with morphological abnormalities of mitochondria in skeletal and cardiac muscles, respectively, were found on electron microscopic examination in one of them.[ncbi.nlm.nih.gov]
Hepatomegaly
  • When, inadvertently he was given medium-chain triglycerides for 2 days, the excretion of abnormal metabolites of medium-chain fatty acids increased and hepatomegaly became more pronounced.[ncbi.nlm.nih.gov]
  • Hypoglycemia Lethargy or coma Metabolic acidosis Hypotonia Later symptoms include: hepatomegaly, Reye syndrome-like episodes (hepatic encephalopathy), seizures, and sudden death Family history of sudden death in siblings Referral: If signs are present[archildrens.org]
  • Furthermore, growth may be slightly hindered and the young patients affected by MCAD deficiency may present with tachypnea, somnolence and hepatomegaly; the latter is very frequently associated with the condition.[symptoma.com]
Altered Mental Status
  • The symptom mainly related to MCAD deficiency is that of hypoketotic hypoglycemia, which is responsible for an altered mental status, weakness, lethargy or coma in young children or infants.[symptoma.com]
  • At age 22 months altered mental status and variable hypo- and hyperglycemia were reported during hospital admission for hand/foot/mouth disease [ 24 ].[bmcmedgenet.biomedcentral.com]
Neonatal Hypotonia
  • hypotonia, respiratory acidosis Treatment: Not established *Gene has been identified, and molecular basis has been elucidated.[merckmanuals.com]

Workup

The workup involved in the diagnosis of medium chain acyl-CoA dehydrogenase deficiency includes serum and urine laboratory testing and a liver biopsy, if deemed necessary. The first step is the medical history, which, for most of the patients is negative for the condition; this is due to the inheritance pattern of MCAD, the autosomal recessive pattern, which usually leads to no concurrent generations with the same medical condition.

Serum laboratory testing includes electrolytes, blood gasses, glucose and ammonia levels. Typical findings are diminished bicarbonate, an anion gap, slightly or moderately elevated ammonia levels and low blood glucose. In some cases, hypoglycemia-related symptomatology occurs before a measurable hypoglycemia has been established. During pregnancy, prenatal genetic testing renders a diagnosis feasible. Urine testing is carried out in order to eliminate the possibility of ketonuria and to evaluate the acylcarnitine excretion pattern alongside an organic acid profile. Residual enzymatic activity can also be measured, for prognostic and therapeutic reasons [11].

Finally, a liver biopsy may illustrate wide mitochondrial membranes, large-droplet steatosis and electron-dense mitochondrial matrices, which are indicative of a mitochondrial oxidative disorder but are not pathognomonic of MCAD deficiency.

Hypoketotic Hypoglycemia
  • It is characterized by hypoketotic hypoglycemia, hyperammonemia, seizure, coma, and sudden infant death syndrome-like illness.[ncbi.nlm.nih.gov]
  • The symptom mainly related to MCAD deficiency is that of hypoketotic hypoglycemia, which is responsible for an altered mental status, weakness, lethargy or coma in young children or infants.[symptoma.com]
  • Typically hypoketotic hypoglycemia, lethargy and vomiting are triggered by an infection, fasting or surgery. Some patients, however, can present with a progressive metabolic crisis despite ketosis and normal blood glucose.[orpha.net]
  • The metabolic consequences are severe and include hypoketotic hypoglycemia leading to a Reye-like hepatic encephalopathy syndrome and sudden death.[dovepress.com]
  • Clinical considerations: May be asymptomatic Poor feeding, lethargy, tachypnea Hypoketotic hypoglycemia Metabolic acidosis Hyperammonemia Hepatomegaly Hypotonia History of sudden death in siblings Make sure baby is fed every 3 hours – while diagnostic[archildrens.org]
Fasting Hypoglycemia
  • BACKGROUND: Impairments in gluconeogenesis have been implicated in the pathophysiology of fasting hypoglycemia in medium-chain acyl-CoA dehydrogenase deficiency. However, whole body glucose and fat metabolism have never been studied in vivo.[ncbi.nlm.nih.gov]
  • Clinical manifestations thus include fasting hypoglycemia, severe metabolic acidosis, and hyperammonemia.[merckmanuals.com]
Liver Biopsy
  • The workup involved in the diagnosis of medium chain acyl-CoA dehydrogenase deficiency includes serum and urine laboratory testing and a liver biopsy, if deemed necessary.[symptoma.com]
  • This case report of a patient with medium-chain acyl CoA dehydrogenase (MCAD) deficiency illustrates that electron microscopy may help to differentiate this disorder from Reye syndrome even if a liver biopsy is performed in a patient who recovered from[ncbi.nlm.nih.gov]

Treatment

  • The patient died of liver failure after 4 months of valproate treatment.[ncbi.nlm.nih.gov]
  • The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment.[orpha.net]
  • TREATMENT Treatment for Medium Chain Acyl-CoA Dehydrogenase Deficiency involves avoidance of fasting. Individuals with the disorder require frequent food intake and often need high carbohydrate, low fat diets.[evolvegene.com]
  • Screening and treatment aim to prevent metabolic crises and allow children with MCADD to lead healthy lives. Treatment Open Treatment is started as early as possible and is usually life long.[newbornscreening.on.ca]

Prognosis

  • Prognosis The prognosis is excellent in diagnosed patients who avoid fasting and who are managed appropriately during an intercurrent illness/ metabolic crisis. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • Prognosis - Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) * Prognosis is difficult, because of the broad clinical spectrum. * The majority of children do well, if appropriately treated.[checkorphan.org]
  • Neonatal screening for the disorder is now possible but it is not known whether this would alter the prognosis. OBJECTIVE: To investigate the outcome of MCAD deficiency after the diagnosis has been established.[ncbi.nlm.nih.gov]
  • What Is the Prognosis for an Individual with Medium-Chain Acyl-CoA Dehydrogenase Deficiency? Early diagnosis and dietary management are crucial for the best outcome.[counsyl.com]

Etiology

  • Similar studies on the urine of two patients reported with Reye-like syndromes of unidentified etiology have suggested the retrospective diagnosis of medium-chain acyl-coA dehydrogenase deficiency.[ncbi.nlm.nih.gov]
  • Etiology MCADD is caused by mutations in the ACADM gene (1p31) which encodes the mitochondrial MCAD protein. The most prevalent mutation, c.985A G, (K329E), p.[orpha.net]
  • We conclude that the specific MCAD deficiency mutation G-985 is not strongly associated with SIDS and that MCAD deficiency probably does not make a significant contribution to the etiology of SIDS. Repository Citation Miller, M. E., Brooks, J.[corescholar.libraries.wright.edu]

Epidemiology

  • This article updates a human genome epidemiology review of MCADD published in 1999. The focus of this update is on epidemiologic parameters rather than mutations associated with MCADD.[ncbi.nlm.nih.gov]
  • Summary Epidemiology The estimated birth prevalence of MCADD is thought to range from 1/4,900 to 1/27,000 in Caucasian populations and is highest in individuals of Northern European descent. The worldwide birth prevalence is 1/14,600.[orpha.net]
  • The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: an update. Genet Med. 2006 Apr;8(4):205-12. Review. Hsu HW, Zytkovicz TH, Comeau AM, Strauss AW, Marsden D, Shih VE, Grady GF, Eaton RB.[ghr.nlm.nih.gov]
Sex distribution
Age distribution

Pathophysiology

  • Results suggest involvement of free radicals in the pathophysiology of MCAD deficiency. The underlying mechanisms behind the increased SOD activity upon carnitine supplementation need to be determined.[ncbi.nlm.nih.gov]
  • The pathophysiology of MCAD deficiency results from the inability to carry out the first step of beta-oxidation.[emedicine.com]
  • Propofol infusion syndrome: update of clinical manifestation and pathophysiology. Minerva Anestesiol. 2009;75(5):339-344. Farag E, Deboer G, Cohen BH, Niezgoda J. Metabolic acidosis due to propofol infusion. Anesthesiology. 2005;102(3):697-698-699.[journals.sbmu.ac.ir]

Prevention

  • Rebecca.Sparkes@albertahealthservices.ca. 25 School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, ON, K1H 8 M5, Canada. bwilson@uottawa.ca. 26 School of Epidemiology, Public Health and Preventive Medicine[ncbi.nlm.nih.gov]
  • Managing and preventing illness events explored parental experiences of managing illness events and their approach to preventing these events.[shura.shu.ac.uk]
  • Treatment involves: Frequent feeding, especially when ill To prevent a metabolic crisis, babies with MCADD must not go a long time without eating.[newbornscreening.on.ca]

References

Article

  1. Wilcken B, Haas M, Joy P, et al. Outcome of neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency in Australia: a cohort study. Lancet. 2007;369:37–42.
  2. Schatz UA, Ensenauer R. The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population. J Inherit Metab Dis. 2010;33:513–520.
  3. Hoflack M, Caruba C, Pitelet G, et al. Infant coma in the emergency department: 2 cases of MCAD deficiency. Arch Pediatr. 2010;17:1074–1077.
  4. Yusupov R, Finegold DN, Naylor EW, Sahai I, Wainsbren S, Levy HL. Sudden death in medium chain acyl-coenzyme a dehydrogenase deficiency (MCADD) despite newborn screening. Mol Genet Metab. 2010;101:33–39.
  5. Maclean K, Rasiah VS, Kirk EPE, et al. Pulmonary haemorrhage and cardiac dysfunction in a neonate with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Acta Paediatr. 2005;94:114–6.
  6. Rice G, Brazelton T, Maginot K, Srinivasan S, Hollman G, Wolff JA. Medium chain acyl-coenzyme A dehydrogenase deficiency in a neonate. N Engl J Med. 2007;357:1781.
  7. Baruteau J, Sachs P, Broue P, et al. Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects:. J Inherit Metab Dis. September 2013; 36:795-803.
  8. Leydiker KB, Neidich JA, Lorey F, et al. Maternal medium-chain acyl-CoA dehydrogenase deficiency identified by newborn screening. Mol Genet Metab. 2011;103:92–95.
  9. Grosse SD, Khoury MJ, Greene CL, Crider KS, Pollit RJ. The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: an update. Genet Med. 2006;8:205–212.
  10. Yusuf K, Jirapradittha J, Amin HJ, Yu W, Hasan SU. Neonatal ventricular tachyarrhythmias in medium chain acyl-CoA dehydrogenase deficiency. Neonatology. 2010;98:260–264.
  11. Touw CM, Smit GP, de Vries M, et al. 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 May; 25. 7:30.

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Last updated: 2019-07-11 19:55