Massively Parallel Sequencing
See Related Tests.
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
Neonatal Onset | Later Onset |
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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.
See Related Tests.
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 (see Genes Tested table)
Inheritance
Mostly autosomal recessive (AR); rarely autosomal dominant (AD) or X-linked (XL)
Test Interpretation
Clinical Sensitivity
Approximately 96%
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
- 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 |
26474213
Houten SM, Violante S, Ventura FV, et al. The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders. Annu Rev Physiol. 2016;78:23-44.
29926323
Knottnerus SJG, Bleeker JC, Wüst RCI, et al. Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Rev Endocr Metab Disord. 2018;19(1):93-106.
18708005
Kompare M, Rizzo WB. Mitochondrial fatty-acid oxidation disorders. Semin Pediatr Neurol. 2008;15(3):140-149.
32654032
Merritt JL 2nd, MacLeod E, Jurecka A, et al. Clinical manifestations and management of fatty acid oxidation disorders. Rev Endocr Metab Disord. 2020;21(4):479-493.
30740404
Merritt JL 2nd, Norris M, Kanungo S. Fatty acid oxidation disorders. Ann Transl Med. 2018;6(24):473.
20049534
Wilcken B. Fatty acid oxidation disorders: outcome and long-term prognosis. J Inherit Metab Dis. 2010;33(5):501-506.
Preferred molecular test to confirm or rule out a diagnosis of a fatty acid oxidation disorder following clinical and/or biochemical presentation
Also refer to Acylcarnitine Quantitative Profile, Plasma (0040033), Carnitine Panel (0081110), and Organic Acids, Urine (0098389)