Multiple Acyl-CoA Dehydrogenase Deficiency

Clinical characteristics: Multiple acyl-CoA dehydrogenase deficiency (MADD) represents a clinical spectrum in which presentations can be divided into type I (neonatal onset with congenital anomalies), type II (neonatal onset without congenital anomalies), and type III (late onset).

Individuals with type I or II MADD typically become symptomatic in the neonatal period with severe metabolic acidosis, which may be accompanied by profound hypoglycemia and hyperammonemia. Many affected individuals die in the newborn period despite metabolic treatment. In those who survive the neonatal period, recurrent metabolic decompensation resembling Reye syndrome and the development of hypertrophic cardiomyopathy can occur. Congenital anomalies may include dysmorphic facial features, large cystic kidneys, hypospadias and chordee in males, and neuronal migration defects (heterotopias) on brain MRI.

Individuals with type III MADD, the most common presentation, can present from infancy to adulthood. The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain, although metabolic decompensation with episodes of rhabdomyolysis can also be seen. Rarely, individuals with late-onset MADD (type III) may develop severe sensory neuropathy in addition to proximal myopathy.

Diagnosis/testing: The diagnosis of MADD is established in a proband with elevation of several acylcarnitine species in blood in combination with increased excretion of multiple organic acids in urine and/or by identification of biallelic pathogenic variants in ETFA, ETFB, or ETFDH.

Management: Treatment of manifestations: Routine daily treatment includes limitation of protein and fat in the diet, avoidance of prolonged fasting, high-dose riboflavin (100-300 mg daily), carnitine supplementation (50-100 mg/kg daily in 3 divided doses) in those with carnitine deficiency, and coenzyme Q₁₀ supplements (60-240 mg daily in 2 divided doses). Further treatments include feeding therapy with consideration of gastrostomy tube for those with failure to thrive, as well as standard treatment for developmental delay, cardiac dysfunction, and sensory neuropathy. Emergency outpatient treatment for mild decompensation includes decreasing the fasting interval, administration of antipyretics for fever, and antiemetics for vomiting. Acute treatment includes hospitalization with intravenous fluid containing at least 10% dextrose, and bicarbonate therapy depending on the metabolic status.

Prevention of primary manifestations: Avoidance of fasting and supplementation with riboflavin, L-carnitine, and coenzyme Q₁₀; a diet restricted in fat and protein is prescribed for some affected individuals based on the severity of the disorder.

Prevention of secondary complications: Education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors. Prompt initiation of dextrose containing intravenous fluids is essential to avoid complications such as liver failure, rhabdomyolysis, encephalopathy, and coma. Written protocols for emergency treatment should be provided to parents and primary care providers/pediatricians, and to teachers and school staff.

Surveillance: Measurement of plasma free and total carnitine, acylcarnitine profile, serum creatine kinase (CK), urine organic acids, head circumference (in infants and children), and growth and developmental milestones at each visit; neuropsychological testing and standardized quality-of-life assessment tools for affected individuals and parents/caregivers as needed; EKG and echocardiogram annually for individuals with severe forms of MADD and less frequently for individuals with milder presentations.

Agents/circumstances to avoid: Inadequate caloric provision during stressors (including following vaccination); prolonged fasting; dehydration; high-fat, high-protein diet; volatile anesthetics and those that contain high doses of long-chain fatty acids; administration of intravenous intralipids during an acute metabolic crisis.

Evaluation of relatives at risk: Testing of all at-risk sibs of any age is warranted (targeted molecular genetic testing if the familial pathogenic variants are known in parallel with plasma acylcarnitine profile, plasma free and total carnitine, and urine organic acid assay) to allow for early diagnosis and treatment of MADD.

Pregnancy management: Successful pregnancy with low-fat, high-carbohydrate diet in late-onset MADD has been published. There is no evidence to suggest that taking supplemental carnitine during pregnancy leads to adverse fetal effects. Riboflavin is a B vitamin and is considered an essential nutrient that is likely eliminated through feces and urine and does not result in excessive tissue absorption.

Genetic counseling: MADD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% change of being affected, a 50% chance of being unaffected and a carrier, and a 25% change of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.