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Long-Chain 3-Hydroxyacyl-Coenzyme A Dehydrogenase (LCHAD) Deficiency / Mitochondrial Trifunctional Protein (MTP) Deficiency
HADHA and HADHB genes
LCHAD deficiency and MTP deficiency, are rare disorder of fatty acid oxidation (FAO), due to different defects in the MTP, caused by mutations in the HADHA and HADHB genes. LCHAD deficiency and MTP deficiency, have overlapping clinical presentations. The presentations are characterized by variable symptoms including infantile hypoketotic hypoglycemia, vomiting, lethargy, hypotonia, and failure to thrive. Additional presentations are cardiomyopathy and cardiac conduction defects, severe liver disease, recurrent muscle cramps, seizures, coma or sudden death (SIDS). Peripheral neuromyopathy, and pigmentary retinopathy may develop at a later age. The high mortality rate for these disorders, estimated at 38%, is usually due to a Reye-like illness or fatal cardiomyopathy. Syndromes of maternal illness, HELLP (hypertension, elevated liver enzymes, low platelets) and AFLP (acute fatty liver of pregnancy) may occur in a pregnancy carrying a fetus with LCHAD/MTP deficiency.
Most individuals with defects in MTP have isolated LCHAD deficiency that is due to mutations in the HADHA gene. Less commonly, individuals are found with defects in all three MTP activities; these can be due to mutations in HADHA or HADHB. Even more rare, mutations in HADHB that cause isolated 3-keto acyl CoA thiolase deficiency can be observed. Mutations in these genes cause the accumulation of long-chain fatty acids and their metabolites. Although newborn screening for these disorders is done in many states, some cases of LCHAD/MTP deficiency are not detected by newborn screens.
Using genomic DNA obtained from buccal swabs (not accepted on infants) or blood (2mL for infants, 5mL for adults in EDTA), mutation analysis of the HADHA gene is performed. GeneDx offers the option of first testing for the common LCHAD deficiency HADHA mutation (c.1528 G->C) that is found in approximately 87% of alleles. If homozygosity for this mutation is not observed, the entire coding sequence and intron/exon boundaries of the 20 exon HADHA gene will be analyzed by bi-directional sequencing. If two mutations are not identified in the HADHA gene, sequencing of the HADHB gene (exons 1-16) can be done as a tiered test, or upon request. Alternatively, both tests can be ordered simultaneously. Carrier testing and prenatal diagnosis is available once the mutation in the family has been defined.
Information Sheet, including prices and CPT codes
Consent Document
Genetic Test Sample Submission Form (Test Requisition Form) including Payment Options
MTP deficiency, MTP, TFP, TPA, trifunctional protein deficiency, coma, fasting, fatty acids, hypoglycemia, hypotonia, lethargy, neuropathy, newborn screening, oxidation, recessive, mitochondria, mitochondrial, Reye syndrome, HAD, hydroxylacyl-CoA, dehydrogenase, 3-ketoacyl-CoA, thiolase, enoyl-Coa, hydratase, alpha subunit, beta subunit, coenzyme A, newborn screening
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