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.

• Asymptomatic

  We measured the concentrations of these three acylglycines in 54 urine samples from 21 patients with confirmed MCAD deficiency during the acute and asymptomatic phases of the illness and compared the results with the concentrations in 98 samples from [ncbi.nlm.nih.gov]

• Sudden Infant Death Syndrome

  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]

  It is characterized by hypoketotic hypoglycemia, hyperammonemia, seizure, coma, and sudden infant death syndrome-like illness. [ncbi.nlm.nih.gov]

• Weakness

  A previously asymptomatic 30 year old man presented with rhabdomyolysis, muscle weakness, and acute encephalopathy after strenuous exertion in the cold without adequate food intake. Serum and muscle carnitine concentrations were decreased. [ncbi.nlm.nih.gov]

  CONSUMERS: Click here for the Consumer Version Topic Resources In these processes, there are numerous inherited defects, which typically manifest during fasting with hypoglycemia and metabolic acidosis ; some cause cardiomyopathy and muscle weakness. [merckmanuals.com]

  These can include lasting muscle weakness and pain, as well as reduced tolerance to exercise. [rarediseases.org]

• 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]

• Feeding Difficulties

  As breastfeeding rates increase, close management of feeding difficulties is essential for all neonates awaiting NBS results.Genet Med 18 12, 1315-1319. [ncbi.nlm.nih.gov]

• Tachypnea

  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]

  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]

• Vomiting

  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]

  Patients have vomiting and lethargy that may progress rapidly to seizures, coma, and sometimes death (which can also appear as SIDS). During attacks, patients have hypoglycemia, hyperammonemia, and unexpectedly low urinary and serum ketones. [merckmanuals.com]

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

  The effect of increased lipid mobilization is the production of toxic intermediates which can lead to vomiting, lethargy, coma, and even death. [themedicalbiochemistrypage.org]

• 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]

  […] 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]

  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]

  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]

• 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]

  […] acylcarnitine esters, elevated urinary C6–C14 dicarboxylic acids Clinical features: In the VLCAD-C type, arrhythmia, hypertrophic cardiomyopathy, sudden death In the VLCAD-H type, recurrent hypoketotic hypoglycemia, encephalopathy, mild acidosis, mild hepatomegaly [merckmanuals.com]

  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]

• Lethargy

  During a crisis, a patient may manifest with lethargy, emesis, respiratory arrest, seizures, hepatomegaly and rapid progression to cardiac arrest unless emergency treatment is implemented. [orpha.net]

  We describe an unusually severe case of medium chain acyl-CoA dehydrogenase (MCAD) deficiency in a term female neonate, who presented at 12 h of age with lethargy, poor feeding, hypoglycemia and ventricular tachyarrhythmias. [ncbi.nlm.nih.gov]

  As a result, these fats are not converted to energy, which can lead to the characteristic signs and symptoms of this disorder such as lethargy and hypoglycemia. [ghr.nlm.nih.gov]

• Irritability

  The gap between feeds is then long enough for acute hypoglycaemia to occur, producing symptoms of preprandial irritability, drowsiness, jitteriness, sweating, coma and seizures. It can present as sudden death in adults. [patient.info]

  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. [symptoma.com]

  Symptoms of a MCADD metabolic crisis include: poor feeding vomiting excessive sleepiness irritability muscle spasms enlarged liver If a metabolic crisis is not treated, breathing problems, seizures, coma, brain damage and sometimes death can occur. [newbornscreening.on.ca]

  You might see signs such as: Sleeping longer or more often Tiredness Behavior changes Irritable mood Poor appetite Fever Diarrhea Low blood sugar (referred to as hypoglycemia) Vomiting Many of these signs may occur when your baby eats foods that his or [babysfirsttest.org]

  Some of the first symptoms of a metabolic crisis are: extreme sleepiness behavior changes irritable mood poor appetite Some of these other symptoms may also follow: fever diarrhea vomiting hypoglycemia If a metabolic crisis is not treated, a child with [newbornscreening.info]

• Somnolence

  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]

  Despite this catabolic state her vigilance had always been normal with no signs of somnolence or lethargy and clinical symptoms of hypoglycemia were not observed. [bmcmedgenet.biomedcentral.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]

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.

• Ketonuria

  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. [symptoma.com]

  […] oxidoreductase (ETF:QO) ETFDH (4q32-qter)* Short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency (601609) SCHAD HADHSC (4q22-q26) Biochemical profile: Ketotic C8–C14 3-hydroxydicarboxylic aciduria Clinical features: Recurrent myoglobinuria, ketonuria [merckmanuals.com]

  ～99% 4. medium chain β-ketothiolase deficiency，中鎖β‐ケトチオラーゼ欠損症 70～99% 5. short chain acyl-CoA dehydrogenase deficiency，短鎖アシル‐CoA脱水素酵素欠損症 70～99% 6. medium- / short- chain 3-hydroxyacyl-CoA dehydrogenase deficiency，中鎖／短鎖3‐ヒドロキシアシル‐CoA脱水素酵素欠損症 70～99% 7. ketonuria [jc-metabolomics.com]

  Ketonuria and medium-chain acyl-CoA dehydrogenase deficiency. [ncbi.nlm.nih.gov]

• Hypoketotic Hypoglycemia

  Clinical manifestations thus include fasting hypoglycemia, severe metabolic acidosis, and hyperammonemia. [merckmanuals.com]

  It is characterized by hypoketotic hypoglycemia, hyperammonemia, seizure, coma, and sudden infant death syndrome-like illness. [ncbi.nlm.nih.gov]

  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 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]

  The metabolic consequences are severe and include hypoketotic hypoglycemia leading to a Reye-like hepatic encephalopathy syndrome and sudden death. [dovepress.com]

• 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]

• Hyperuricemia

  They may have elevated liver enzymes, acidosis with increased anion gap, hyperuricemia, and hyperammonemia. In undiagnosed patients, the first metabolic crisis is often fatal and patients are at risk of sudden death. [invitae.com]

• Liver Biopsy

  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]

  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]

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]

Treatment during acute exacerbations includes hydration, high-dose glucose, bed rest, urine alkalinization, and carnitine supplementation. [merckmanuals.com]

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]

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 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]

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]

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]

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]

Scope and epidemiology of pediatric sepsis. Pediatr Crit Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc. 2005;6(3 Suppl):S3-5. British Inherited Metabolic Diseases Group. [journals.sbmu.ac.ir]

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]

Epidemiology The incidence is up to 1 in every 12,000 births. [ 2 ] Presentation Typically this presents clinically with failure of fatty acid oxidation after fasting and an inability to generate energy during periods of increased energy demand. [patient.info]

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]

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]

Pathophysiology Fatty acids are unable to be metabolised beyond the medium-chain size (8-12 carbon stage), and gluconeogenesis is effectively inhibited. [patient.info]

[email protected]. 25 School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, ON, K1H 8 M5, Canada. b[email protected]. 26 School of Epidemiology, Public Health and Preventive Medicine [ncbi.nlm.nih.gov]

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]

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