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Impaired Glucose Metabolism

MCAD is a particular threat in infants

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Most infants are born with the innate ability to maintain blood glucose and serum ketone levels through the pathways of oxidative metabolism and gluconeogenesis. On rare occasions, a newborn has an inborn error of metabolism and cannot maintain adequate blood sugar levels for development. These infants are often quiet and viewed as "well behaved" by the parents. However, the docile behavior is a result of impaired glucose metabolism. If this condition is not recognized and treated, severe retardation and growth development can result.

The most common inborn error of metabolism affecting glucose metabolism is medium-chain acyl-coA dehydrogenase deficiency (MCAD).1 The incidence of MCAD in the United States is approximately 1 in 15,000 live births.1

MCAD is inherited as an autosomal recessive disease, thus both biologic parents are carriers but do not exhibit the clinical phenotype. MCAD may contribute to approximately 1% of sudden infant death syndrome cases per year.2 Undiagnosed, MCAD has a mortality rate of greater than 20%.2,3 Thus, NPs and PAs need to consider MCAD in the differential diagnosis list in children with mental retardation, as well as babies who sleep all night but are behind the growth curve.

Pathophysiology

Beta-oxidation is the primary pathway for the metabolism of medium-chain fatty acids.1 These substrates enter the citric acid cycle, resulting in the formation of Acyl-CoA. In MCAD, mitochondrial metabolism cannot perform the initial tasks or steps in the pathway, especially in times of stress or fasting, and beta-oxidation is impaired.4 This results in profound hypoglycemia and metabolic acidosis. The accumulation of fatty acids and low glucose levels leads to the clinical presentation of lethargy, coma and occasionally, cardiac death.4

The mutation resulting in MCAD is on chromosome 1, where the Acyl-CoA dehydrogenase C-4 to C-12 straight chain gene (ACADM) is located.3 More than 80 genotypes of ACADM are recognized, and they have varying phenotypic expression.2 The most common mutation results from a substitution of glutamic acid for lysine in position 304.2 Due to the glutamic acid/lysine replacement, enzyme structure is abnormal, and beta-oxidation is impaired. Other mutations result in smaller or less stable enzymes, affecting beta oxidation in various ways.

Clinical Presentation

Symptoms of MCAD generally present between ages 2 months and 2 years.3-5 They become more prominent as feeding intervals are lengthened, due to falling blood sugars during fasting intervals of more than 3 to 5 hours.2-6 Stressful events, such as otitis media or recent viral illness, can also cause the symptoms of MCAD to surface due to increased needs for energy metabolism.

The clinical presentation of this disorder may include lethargy, vomiting, seizure, coma or even cardiac arrest.5,6 The infant is often tachypnic, and severe liver dysfunction is common. Clinical symptoms result from profound hypoglycemia in the brain.1,2,3,6,7 The differential diagnoses include Reye syndrome, especially with a history of aspirin use.

Over time, significant encephalopathy occurs secondary to accumulation of the medium chain Acyl-CoA intermediates in the brain. Other long-term complications include growth retardation, learning and speech disabilities and attention deficit disorders.7

Although rare, adult presentation of MCAD has been described. Cases have been diagnosed between the ages of 16 and 45.7 Symptoms are often related to fasting or alcohol abuse. In older patients, the symptoms of hypoglycemia often manifest as headache.2

Ventricular tachycardia has been described in adults with MCAD, as well as encephalopathy resulting from brain deposition of octanate acid.5,7 In undiagnosed cases of MCAD, adults present similarly to chronic alcoholics, with cirrhosis and steatosis.7 Diagnosis may follow pregnancy, postsurgical events, or exercising when basal metabolism is increased.

Diagnosis

The diagnosis of MCAD in infants and adults is triggered by clinical suspicion and is supported by laboratory analysis and genetic testing (Table 1).4 Symptoms must be correlated with a history of fasting or stress. Rapid deterioration out of proportion to the patient's clinical state is common.7

Treatment and Management

MCAD can be managed with frequent feeding and by limiting the types of fats in the diet. Affected patients should not be allowed to fast for more than a few hours at a time. The length of time a patient can go without eating increases with age (Table 2). Acute treatment of the lethargic infant who may have MCAD should be with intravenous glucose solution.

For infants, formulas that contain medium-chain fatty acids should be avoided.7 To maintain a sufficient blood glucose level overnight, 2g/kg of uncooked cornstarch can be given at bedtime.5 Adolescents and adults should consume diets rich in carbohydrates.3 Referral to a nutritionist for dietary counseling is recommended.

Dietary supplementation with carnitine has been suggested to improve the symptoms of MCAD.4 Carnitine helps conjugate toxic metabolites that accumulate in MCAD and also helps with their excretion in the liver. Carnitine can assist in maintaining blood glucose levels, preventing the severe hypoglycemia seen in MCAD.3,4 The recommended dose of carnitine is 100 mg/kg/day.3,4

Patient and Family Education

MCAD is manageable with strict dietary control, and this requires thorough education. The ingestion of frequent meals that are high in carbohydrate content and low in medium-chain fatty acids is critical.6,7 Adolescents and young adults with MCAD are at high risk of complications because of lifestyle choices common in this demographic.citation5 As a result of society's fixation on external appearance, young female patients with MCAD are particularly susceptible to fasting and hypoglycemia.7 Education for these patients is paramount.

Special attention should be given to activities that may not be recognized as being associated with hypoglycemia, such as surgical procedures and pregnancy.6,7 Regular check-ups with enforcement of dietary recommendations are recommended every 6 months.4,6

For patients in adolescence or adulthood, it is important to have a frank discussion about alcohol. The intake of alcohol can lead to reduced caloric intake, which promotes hypoglycemia and the symptoms of MCAD. Excessive intake of spirits can lead to vomiting, hypovolemia and stress, further taxing the demands of impaired glucose metabolism.

Exercise is another important issue. Because exercise is associated with increased metabolic demands and protein catabolism, excessive exercise should be avoided. The ingestion of nutritional supplements to ensure caloric support during exercise is recommended.

The patient with MCAD should always carry emergency contact information in case of acute complications. This reduces the risk of mortality and gives the emergency personal an advantage for treatment.6,7

Avoiding Poor Outcomes

Inborn errors in fatty acid oxidation leading to hypoglycemia can cause lethargy, seizures, coma and death. The most common genetic abnormality leading to these conditions is MCAD. Although rare, MCAD can have devastating consequences in infants, including death.

Diagnosis requires a high index of clinical suspicion and is supported by the findings of hypoglycemia, low serum ketones, lactic acidosis and abnormal liver function tests. Genetic testing is available, and diagnosis is possible in utero.

Not all states require screening, so NPs and PAs may see patients previously undiagnosed with MCAD.

Treatment consists of education for the parents, frequent feeding to avoid hypoglycemia, and avoidance of medium chain fatty acids. Adolescents and young adults are at high risk for complications and require special attention regarding lifestyle choices and exercise.

If undiagnosed, patients with MCAD have significant morbidity and mortality. Clinicians must recognize MCAD and maintain a high index of suspicion in order to treat patients with this disease.

Stefanie Herrmann is a physician assistant at Great Lakes Surgical Specialties/Shock Trauma, located at the University of Pittsburgh Medical Center-Hamut in Erie, Pa. She has completed a disclosure statement and reports no relationships related to this article.  

                                                                       

References

1. Schatz UA, Ensenauer R. The clinical manifestations of MCAD deficiency: challenges towards adulthood in the screened population. J Inher Metab Dis. 2010;33(5):515-520.

2. Genetics Home Reference. Medium-chain acyl-coA dehydrogenase deficiency. http://www.hgen.pitt.edu/counseling/public_health/mcad.htm

3. Carpenter K, et al. Evaluation of newborn screening for medium chain acyl-CoA dehydrogenase deficiency in 275000 babies. Arch Dis Child Fetal Neonatal Ed. 2001;85)2):F105 -F109.

4. Genetics Home Reference. ACDM. http://ghr.nlm.nih.gov/gene/ACADM.

5. Matern D, Rinaldo P. Medium-chain Acyl-Coenzyme A dehydrogenase deficiency. In: Pagon RA, et al, eds. GeneReviews. Seattle: University of Washington: 1993. Updated 2012. http://www.ncbi.nlm.nih.gov/books/NBK1424/

6. National Library of Medicine/National Institutes of Health. Newborn screening tests. http://www.nlm.nih.gov/medlineplus/ency/article/007257.htm

7. Eisenhauer R. Schatz UA. The clinical manifestations of MCAD deficiency: challenges towards adulthood in the screened population. J Inherit Metab Dis. 2010;33:515-520.




     

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