Invitae Fatty Acid Oxidation Defects Panel

• fatty-acid oxidation disorders
  • 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2D) deficiency
  • carnitine-acylcarnitine translocase (CACT) deficiency
  • carnitine palmitoyltransferase type I (CPT I) deficiency
  • carnitine palmitoyltransferase type II (CPT II) deficiency
  • HMG-CoA Lyase deficiency also known as 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
  • long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
  • malonyl-CoA decarboxylase deficiency
  • medium chain acyl-CoA dehydrogenase (MCAD) deficiency
  • medium/short chain acyl-CoA dehydrogenase (M/SCHAD) deficiency
  • mitochondrial trifunctional protein (TFP) deficiency
  • multiple acyl-CoA dehydrogenase (MCAD) deficiency (MADD) – also known as glutaric acidemia type II
  • NAD kinase 2 (NADK2) deficiency
  • primary carnitine deficiency – also known as carnitine transporter deficiency
  • short chain acyl-CoA (SCAD) dehydrogenase deficiency
  • short-branched chain acyl-CoA dehydrogenase (SBCAD) deficiency – also known as 2-methylbutyryl-CoA dehydrogenase
  • systemic primary carnitine deficiency
  • very long chain acyl-CoA dehydrogenase (VLCAD) deficiency

Fatty acid oxidation disorders are a broad group of inherited metabolic conditions that result from the inability to adequately metabolize fats for energy. In individuals with an FAOD, fats cannot be broken down, so fatty acids accumulate in tissues, there is a decrease in available ATP, gluconeogenesis cannot occur, and sufficient ketones cannot be generated. This results in an overall lack of energy for tissues and the potential for an acute metabolic crisis.

Fatty acid oxidation disorders have wide clinical heterogeneity, with specific symptoms and laboratory findings corresponding to the location of the metabolic block. In general, symptoms are episodic and correlate with periods of fasting or physiologic stress. During these crises, many patients experience lethargy, fasting hypoketotic hypoglycemia that may progress to metabolic acidosis, liver dysfunction, hypoglycemic seizures, coma, and death. Muscle tissues (both cardiac and skeletal) consume large quantities of fats when glucose is not available;consequently, many individuals with FAOD experience muscular symptoms such as cardiomyopathy, exercise intolerance, and muscle damage due to significant muscle cramping or rhabdomyolysis during a metabolic crisis. Undiagnosed FAODs have also been hypothesized to be the cause of up to 5% of unexpected sudden infant death syndrome (SIDS) cases and other instances of unexplained sudden death. Laboratory findings can include hypoketotic hypoglycemia, elevated creatinine kinase, elevated dicarboxylic acids on urine organic acids, decreased free carnitine, and increased acylcarnitine species corresponding to the metabolic block.

FAODs can present at any time during an individual’s lifespan, and some conditions have infantile through adult presentations. FAODs are often unmasked during a period that combines fasting with physiologic stress, such as illness. These periods increase the metabolic rate and are often accompanied by a diminished appetite; consequently, the body turns to fats for energy. The long-term prognosis for FAOD is generally good once a diagnosis is obtained and interventions such as dietary modifications, medications, and illness protocols are implemented.

All conditions covered by this test are inherited in an autosomal recessive manner. Males and females are equally affected.

Fatty acid oxidation disorders are one of the most common groups of inherited metabolic disorders. Collectively, the overall incidence of all FAODs is 1 in 10,000–14,000 live births.

Incidence of individual FAOD is variable. The incidences of some of the more common conditions are listed below. Adult-onset forms are under-recognized and these numbers are likely low:

• MCAD: California 1 in 19,000; Northern Germany 1 in 4,900; Japan 1 in 51,000
• VLCAD: United States 1 in 30,000

This test may be appropriate for:

• patients who present with lethargy and hypoketotic hypoglycemia, with or without hyperammonemia
• patients with nonspecific, negative, or unavailable findings on plasma acylcarnitines or urine organic acid analysis in whom a fatty-acid oxidation defect is still suspected