Mcad Test

[Maitane Roderiques]

Mediumchain acyl-coenzyme A dehydrogenase (MCAD) deficiency is an inherited disorder that prevents your body from breaking down certain fats and turning them into energy. Your metabolism involves the processes your body uses to produce energy. MCAD deficiency can cause problems with your metabolism.

MCAD deficiency is present from birth and is a lifelong condition. In the United States, all states test for MCAD deficiency at birth as part of newborn screening. Many other countries also provide routine newborn screening for MCAD deficiency. If MCAD deficiency is diagnosed and treated early, the disorder can be well managed through diet and lifestyle.

In the United States and many other countries, newborn screening programs test for MCAD deficiency. After your first evaluation, you may be referred to a specialist in evaluating and treating MCAD deficiency. You may also be referred to other health care team members, such as a registered dietitian.

To have an autosomal recessive disorder, you inherit two changed genes, sometimes called mutations. You get one from each parent. Their health is rarely affected because they have only one changed gene. Two carriers have a 25% chance of having an unaffected child with two unaffected genes. They have a 50% chance of having an unaffected child who also is a carrier. They have a 25% chance of having an affected child with two changed genes.

When you don't have enough of the MCAD enzyme in your body, certain fats called medium-chain fatty acids can't be broken down and turned into energy. This leads to low energy and low blood sugar. Also, fatty acids can build up in body tissues and cause damage.

If you inherit only one changed gene, you won't develop MCAD deficiency. With one changed gene, you are a carrier and can pass the changed gene to your children. But they wouldn't develop the condition unless they also inherited a changed gene from their other parent.

If you have a disability or medical condition that you believe requires an adjustment to standard testing conditions, we encourage you to apply for accommodated testing. Take these helpful steps to get started.

Fatty acid oxidation disorders are a group of inherited metabolic conditions that lead to an accumulation of fatty acids, and a decrease in cell energy metabolism. Each fatty acid oxidation disorder is associated with a specific enzyme defect in the fatty acid metabolic pathway and affects utilization of dietary and stored fat.

Newborn screening in Illinois includes testing for a panel of acylcarnitines. In some cases, an elevated level of a particular acylcarnitine may indicate the possibility of one of several different fatty acid oxidation disorders; the specific disorder cannot be determined without diagnostic further testing. It has been demonstrated that the following fatty acid oxidation disorders may be detected in newborn dried blood spot samples using this testing panel.

Affected infants can be diagnosed in the neonatal period. Children with MCAD have a significant risk of death during the first, or subsequent clinical episode of hypoglycemia. In the past, these deaths were sometimes attributed to sudden infant death syndrome (SIDS). In most cases, the first episode arises following illness or fasting, and occurs in infancy or early childhood. Fatty acid oxidation disorders can cause recurrent episodes of hypoglycemia. Clinical findings may include lethargy, hypotonia, failure to thrive, persistent vomiting, hepatomegaly, rhabdomyolysis and Reye syndrome-like episodes.

In Illinois, newborn screening for fatty acid oxidation defects is performed using tandem mass spectrometry to detect elevated acylcarnitine levels. Early specimen collection (after first 24 hours of age) may enhance the detection of these disorders, as acylcarnitine levels may decrease with infant age. False positive and false negative results are possible with this screening. Infants with a presumptive positive screening test require prompt follow-up and, when notified of these results, the clinician should immediately check on the clinical status of the baby and refer the infant to a metabolic disease specialist. The attending physician should also advise the parents to avoid any significant time gap in feedings.

Early diagnosis and treatment is essential for an improved prognosis. If left untreated, these conditions may result in significant disability and, ultimately, death. Most of these conditions are chronic, with life-long episodes of hypoglycemia. In some of the more severe infantile forms, there is a very poor prognosis. For most fatty acid oxidation disorders, including MCAD, management involves avoidance of

fasting and aggressive medical management during illness, especially if the child is vomiting or is not receiving adequate nutritional intake. At the time of intercurrent illness, the infant/child should be

MCAD is the most common of the fatty acid oxidation disorders with an incidence of approximately one in 10,000 to 20,000 births. LCHAD and VLCAD are rare disorders with an estimated incidence of one in 100,000 births. There is a mild form of SCAD deficiency that appears to be quite common, but the clinical significance of this condition is unclear.

All of these disorders are inherited in an autosomal recessive pattern. As an autosomal recessive disorder, the parents of a child with one of these conditions are unaffected, healthy carriers of the condition, and have one normal gene and one abnormal gene. With each pregnancy, carrier parents have a 25 percent chance of having a child with two copies of the abnormal gene and the resulting fatty acid oxidation defect. Carrier parents have a 50 percent chance of having a child who is an unaffected carrier, and a 25 percent chance of having an unaffected, non-carrier child. These risks would hold true for each pregnancy. All siblings of infants diagnosed with a fatty acid oxidation disorder should be tested and genetic counseling services should be offered to the family.

Fatty acid oxidation is essential for energy production. This metabolic pathway is complex and comprises as many as 20 individual steps including uptake and activation of fatty acids by cells, the carnitine cycle and the beta-oxidation spiral, with various enzymes required for the oxidation of unsaturated fatty acids. Inherited enzymatic defects in the pathway lead to accumulation of fatty acids or a decrease in cell energy metabolism and result in the clinical manifestations of the disorder.

The diagnosis of MCAD deficiency is established in a proband with confirmatory biochemical testing results and biallelic pathogenic variants in ACADM identified on molecular genetic testing. Diagnostic testing is typically initiated after either a positive newborn screening result or suggestive biochemical testing in a previously healthy individual who develops symptoms. Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without needing provocative tests. Assays to determine residual enzyme activity are possible but not routinely necessary and not clinically available in many regions.

Treatment of manifestations: The most important intervention is giving simple carbohydrates by mouth (e.g., glucose tablets or sweetened, non-diet beverages) or IV if needed to reverse catabolism and sustain anabolism.

Evaluation of relatives at risk: If the ACADM pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs and offspring of the proband. If the ACADM pathogenic variants in the family are not known, plasma acylcarnitine and urine acylglycine analysis can be used to clarify the disease status.

MCAD deficiency is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual are at a 25% risk of being affected, a 50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not carriers. Because of the high carrier frequency for the ACADM c.985A>G pathogenic variant in individuals of northern European origin, carrier testing should be discussed with reproductive partners of individuals with MCAD deficiency. Once both ACADM pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for MCAD deficiency are possible.

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is the most common fatty acid β-oxidation disorder. Fatty acid β-oxidation fuels hepatic ketogenesis, a major source of energy for peripheral tissues after glycogen stores are depleted during prolonged fasting and periods of higher energy demands.

Elevations of C8-acylcarnitine with lesser elevations of C6-, and C10-acylcarnitine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing. The cut-off values for C8 differ by NBS program and may be combined with elevated secondary markers including C0, C2, and C10:1, and the ratios of C8/C2 and C8/C10 in presumptive positive cases to aid in NBS sensitivity (Mayo Clinic CLIR, accessed 7-26-23).

Follow-up testing includes: plasma acylcarnitine analysis, urine organic acid analysis, and urine acylglycine analysis. If the test results support the likelihood of MCAD deficiency, additional testing is required to establish the diagnosis (see Establishing the Diagnosis).

The positive predictive value for elevations of C8-acylcarnitines is currently considered to be very high with the use of tandem mass spectrometry (MS/MS). False positives for elevations of C8-acylcarnitines are not common but can be seen in term infants who are appropriate for gestational age and heterozygous for the common c.985A>G pathogenic variant (see Table 1), and premature infants [McCandless et al 2013]. False negatives have been reported in newborns with low free carnitine levels, such as infants born to a mother with low free carnitine levels, including previously undiagnosed mothers with MCAD deficiency, maternal carnitine transporter deficiency, or nutritional carnitine deficiency [Leydiker et al 2011, Aksglaede et al 2015].

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