LCHAD deficiency results from the inability to metabolize long-chain fatty acids. Thus, the clinical features may result from either toxicity due to long-chain acyl-CoA esters that cause cardiomyopathy and cardiac arrhythmias or from a block in long-chain fatty acid oxidation that leads to an inability to synthesize ketone bodies and/or adenosine triphosphate from long-chain fatty acids. The fatty acid oxidation defect results in adverse effects on a number of organ systems, including the CNS, secondary to the hypoketotic hypoglycemia. Hypotonia and cardiomyopathy reflect the underlying energy deficiency. LCHAD deficiency is caused by mutation in the HADHA gene (2p23) which encodes the alpha subunit of the mitochondrial trifunctional protein. The trifunctional protein complex is an octamer that metabolizes long-chain fatty acids, and the LCHAD activity is specific for compounds of C12-C16 chain length.
Sequencing of the HADHA gene is recommended after a biochemical analysis consistent with LCHAD deficiency, and provides a complementary method to confirm the presence of mutations in a proband, identify carriers among the proband's relatives, and provide prenatal diagnosis in families with known mutations.
For patients with mutations not identified by full gene sequencing, a separate deletion/duplication assay is available using a targeted CGH array (GN).
- Confirmation of a clinical/biochemical diagnosis of LCHAD deficiency.
- Carrier testing in adults with a family history of LCHAD deficiency.
Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns, and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.
Analytical Sensitivity: ~99%
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
- Acylcarnitine Profile (AR)
- Urine Organic Acids (OA) Analysis
- Trifunctional Protein Deficiency Gene Sequencing (FZ)
- Custom Diagnostic Mutation Analysis (KM) is available to family members if mutations are identified by sequencing.
- Deletion/Duplication Assay is available separately for individuals where mutations are not identified by sequence analysis. Refer to the test requisition or contact the laboratory for more information.
- Prenatal testing is available for known familial mutations only. Please call the Laboratory Genetic Counselor before collecting a fetal sample.