Fatty Acid Oxidation Disorders Panel, Sequencing

Last Literature Review: June 2021 Last Update:

Preferred molecular test to confirm or rule out a diagnosis of a fatty acid oxidation disorder following clinical and/or biochemical presentation

For biochemical test options, refer to the Laboratory Test Directory.

Fatty acid oxidation disorders are a heterogeneous group of disorders, and clinical presentation varies in both severity and age of onset. Specific symptoms may differ depending on whether an individual experiences neonatal onset or a later onset but may include hypoketotic hypoglycemia, lethargy, episodic emesis, seizures, hepatomegaly, cardiomyopathy, Reye-like symptoms, skeletal myopathy, myalgia, exercise intolerance, coma, or sudden death.

Disease Overview

Symptoms

Common Symptoms Based on Age of Onset
Neonatal Onset Later Onset
  • Hypoketotic hypoglycemia
  • Lethargy
  • Episodic emesis
  • Seizures
  • Arrhythmia
  • Reye-like symptoms
  • Hypertrophic cardiomyopathy
  • Hepatomegaly, hepatic failure
  • Encephalopathy
  • Coma
  • Sudden death
  • Myopathy
  • Myalgia
  • Muscle weakness
  • Exercise intolerance or exercise-induced rhabdomyolysis
  • Acute metabolic episodes triggered by fasting, infection, surgery

Testing Strategy

When a disorder of fatty acid oxidation is suspected, the following tests should be ordered:

  • Plasma acylcarnitines
  • Carnitine panel
  • Urine organic acids

In addition, acylglycines may be helpful for some disorders.

Because biochemical studies may be completely normal if obtained while patient is metabolically stable, molecular testing or functional studies are often needed for definitive diagnosis. For biochemical test options, refer to the Laboratory Test Directory.

Incidence

Approximately 1 in 5,000 to 1 in 10,000 births

Genetics

Etiology

Pathogenic germline variants in genes associated with fatty acid oxidation disorders (refer to the Genes Tested table)

Inheritance

Mostly autosomal recessive (AR); rarely autosomal dominant (AD) or X-linked (XL)

Test Interpretation

Clinical Sensitivity

Dependent on clinical phenotype

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Results

Result Variant(s) Detected Clinical Significance

Positive

One or more pathogenic or likely pathogenic variants detected

Diagnosis of heritable fatty acid oxidation defect is confirmed

Specific diagnosis depends on the variant(s) detected

Inconclusive

One or more variants of uncertain significance detected

Diagnosis of fatty acid oxidation defect remains uncertain

Negative

No pathogenic variants detected

Diagnosis of heritable fatty acid oxidation defect is less likely, but not excluded

Limitations

  • A negative result does not exclude a diagnosis of a fatty acid oxidation disorder.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted genes
    • Regulatory region and deep intronic variants, including the common SLC22A5 c.-149G>A variant
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • LPIN1(NM_001349200) exon 13
      • LPIN1(NM_001349201) exon 12
    • Large deletions/duplications in any of the tested genes
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing  
    • Low-level somatic variants

Genes Tested

Gene MIM No. Disorders Inheritance

ACAD9

611103

Mitochondrial complex I nuclear type 20 deficiency (ACAD9 deficiency)

AR

ACADM

607008

Medium chain acyl-CoA dehydrogenase deficiency (MCAD deficiency)

AR

ACADS

606885

Short chain acyl-CoA dehydrogenase deficiency (SCAD deficiency)

AR

ACADVL

609575

Very long chain acyl-CoA dehydrogenase deficiency (VLCAD deficiency)

AR

ACAT1

607809

Beta-ketothiolase deficiency (Β-ketothiolase deficiency, alpha-methylacetoacetic aciduria, 2-methyl-3-hydroxybutyric acidemia, 2-methylacetoacetyl-coenzyme A thiolase deficiency, 3-alpha-oxothiolase deficiency, 3-ketothiolase deficiency, 3-oxothiolase deficiency, MAT deficiency, methylacetoacetyl-coenzyme A thiolase deficiency, mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency, mitochondrial acetoacetyl-CoA thiolase deficiency, or T2 deficiency)

AR

CPT1A

600528

Carnitine palmitoyltransferase 1A deficiency (CPT1A deficiency)

AR

CPT2

600650

Carnitine palmitoyltransferase II (CPT II deficiency), lethal neonatal, and severe infantile onset

AR

CPT II deficiency, myopathic form

AR, AD

ECHS1

602292

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1 Deficiency)

AR

ETFA

608053

Multiple acyl-CoA dehydrogenase deficiency (MADD types I and II, Glutaric acidemia II, Glutaric aciduria II)

AR

ETFB

130410

Multiple acyl-CoA dehydrogenase deficiency (MADD types I and II, glutaric acidemia II, glutaric aciduria II)

AR

ETFDH

231675

Multiple acyl-CoA dehydrogenase deficiency (MADD type III, glutaric acidemia II, glutaric aciduria II)

AR

FLAD1

610595

Lipid storage myopathy due to flavin adenine dinucleotide synthetase deficiency (MADD-like illness)

AR

HADH

601609

Familial hyperinsulinism (3-hydroxyacyl-CoA dehydrogenase deficiency, familial hyperinsulinemic hypoglycemia, congenital hyperinsulinism [CHI], persistent hyperinsulinemic hypoglycemia of infancy [PHHI])

AR

HADHA

600890

 Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD deficiency, acute fatty liver pregnancy [AFLP] and hypertension, elevated liver enzymes, and low platelet [HELLP] syndromes, mitochondrial trifunctional protein deficiency)

AR

HADHB

143450

Trifunctional protein deficiency

AR

HMGCL

613898

3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG-CoA lyase deficiency)

AR

HMGCS2

600234

3-hydroxy-3-methylglutaryl-CoA synthase 2 deficiency (HMG-CoA synthase-2 deficiency)

AR

HSD17B10

300256

Hydroxysteroid 17-Beta Dehydrogenase Type 10 deficiency (HSD10 mitochondrial disease, HSD17B10 deficiency)

XL

LPIN1

605518

Acute recurrent myoglobinuria (LPIN1 deficiency)

AR

MLYCD

606761

Malonyl-CoA decarboxylase deficiency

AR

SLC22A5

603377

Systemic primary carnitine deficiency (carnitine transport defect, carnitine uptake defect, CDSP)

AR

SLC25A20

613698

Carnitine-acylcarnitine translocase deficiency (CACT deficiency)

AR

SLC52A1

607883

Riboflavin transporter deficiency 1 (riboflavin deficiency)

AD

SLC52A2

607882

Riboflavin transporter deficiency 2 (Brown-Vialetto-Van Laere syndrome 2)

AR

SLC52A3

613350

Riboflavin transporter deficiency 3 (Brown-Vialetto-Van Laere syndrome 1, Fazio-Londe syndrome)

AR