Invitae Multiple Acyl-CoA Dehydrogenase (MAD) Deficiency Panel

• multiple acyl-CoA dehydrogenase (MAD) deficiency (MADD) – also known as glutaric acidemia type 2 (GA2)
  • neonatal multiple acyl-CoA dehydrogenase deficiency with congenital anomalies
  • neonatal multiple acyl-CoA dehydrogenase deficiency without congenital anomalies
  • late-onset multiple acyl-CoA dehydrogenase deficiency
• ethylmalonic-adipic aciduria

MAD deficiency is an in inborn error of metabolism that interferes with the body’s ability to break down proteins and fats to produce energy. Incomplete breakdown of proteins and fats can cause blood and tissues to become acidotic, producing metabolic acidosis.

MAD deficiency is a fully penetrant disorder. Patients with MAD deficiency show a wide range of symptoms and severity. Patients with little or no enzyme activity typically have the severe neonatal presentation while patients with higher residual enzyme activity have the mild, late-onset form. Type I, the most severe form, can present in the neonatal period with life-threatening acidosis, vomiting, and seizures. Patients with the severe form may have physical abnormalities including facial dysmorphism, brain malformations, hypoglycemia, hypotonia, hepatomegaly, kidney cysts, and genital abnormalities. There may also be hepatomegaly, dilated cardiomyopathy, and sweaty-feet odor. Type I is typically fatal. Type II presents with similar symptoms but no physical abnormalities, and type III presents later, with intermittent episodes of hypoglycemia, metabolic acidosis, muscle weakness, and exercise-induced muscle pain. Some patients with the late-onset form remain asymptomatic despite the presence of biochemical abnormalities. Riboflavin has been shown to be an effective treatment for patients with late-onset MAD deficiency.

Patients with MAD deficiency typically show elevations of C4 and C5 in newborn screening. Upon plasma acylcarnitine analysis, patients can have elevations of C4, C5, and many other acylcarnitine species, which can lead to secondary carnitine deficiency. Severely affected patients can have elevations of 2-hydroxyglutaric acid, glutaric acid, ethylmalonic acid, and dicarboxylic aciduria during urine organic acids testing; patients with a milder form may only have elevations of ethylmalonic acid, adipic acid, ketones, and dicarboxylic acids. Isobutyrylglycine, isovalerylglycine, hexanoylglycine, and suberylglycine elevations may also be detected in urine. The organic aciduria can be normal in mildly affected patients, only manifest during times of metabolic stress.

For patients with a biochemical diagnosis of MAD deficiency (characteristic plasma acylcarnitines and urine organic acids, with or without enzyme analysis), >99% are expected to have pathogenic variants in ETFA, ETFB, or ETFDH. 93% of patients with late-onset disease carry pathogenic variants in ETFDH, 5% carry variants in ETFA, and 2% have variants in ETFB.

MAD deficiency is inherited in an autosomal recessive manner.

MAD deficiency is a very rare disorder with prevalence estimated at 1 in 200,000. There is great variation between countries and ethnicities. Incidence among the southern Chinese is approximately 1 in 22,500.

Testing for MAD deficiency should be considered in newborns and infants with:

• metabolic acidosis and non-ketotic hypoglycemia
• elevated blood acylcarnitines (increased C4-C18 species in patients with severely low carnitine)
• an abnormal urine organic acid profile (various combinations of increased dicarboxylic acids, glutaric acid, ethylmalonic acid, 2-hydroxyglutarate, and glycine conjugates)
• abnormal fibroblast fatty acid oxidation studies
• congenital anomalies (facial dysmorphism, rocker bottom feet, abnormal external genitalia)
• cardiomyopathy
• hepatomegaly
• dysplastic kidneys with cysts
  in children with:
• vomiting
• lethargy
• hepatomegaly
• seizures
  and in older children and adults with:
• muscle weakness
• exercise-induced muscle pain
• lipid storage myopathy