TFP is multi-enzyme complex composed of four alpha-subunits (HADHA), which contains the long-chain 2-enoyl-CoA hydratase and the long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) domains, and four beta-subunits (HADHB), which contains the long-chain 3-ketoacyl-CoA thiolase (LKAT) domain [3-4]. Deficiency of these enzymes can result in diseases of the TFP complex with overlapping clinical symptoms: either the general TFP deficiency (described above) or isolated LCHAD deficiency (LCHADD). General TFP deficiency is defined by reduced activity of all three TFP enzymes. Isolated LCHAD deficiency is defined by reduced LCHAD activity resulting in accumulation of long-chain 3-hydroxy-fatty acids. The other two TFP enzymes might also be affected in LCHADD, but their activities are usually greater than 60% of normal (refer to the LCHAD test description for testing for LCHAD).
The TFP alpha- and beta-subunits are encoded by HADHA and HADHB, respectively, and genes both located in 2p23 . An isolated LCHAD presentation is associated with the common alpha-subunit mutation 1528G>C (E474Q) that is located directly within the catalytic region of the LCHAD domain, though other genotype-phenotype correlations are limited [7-8]. TFP deficiency due to alpha-subunit mutations has been described more often than cases due to beta-subunit mutations . Gene sequencing is available to test for mutations in the HADHA and HADHB genes (FZ). For patients with mutations not identified by full gene sequencing, a separate deletion/duplication assay is available using a targeted CGH array (GE).
1. Roe and Ding. Mitochondrial Fatty Acid Oxidation Disorders, in: C.R. Scriver, A.L. Beaudet, W. Sly, D. Valle (Eds.), The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001, pp. 2308-2310.
2. Den Boer et al. Long-chain 3-hydoxyacyl-CoA dehydro-genase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics 2002, 109:99-104.
3. Spiekerkoetter et al. Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations. Hum Mutat 2003, 21(6):598-607.
4. Choi et al. Identification of novel mutations of the HADHA and HADHB genes in patients with mitochondrial trifunctional protein deficiency. Int J Mol Med 2007, 19(1):81-7.
5. Yang et al. The genes for the [alpha] and [beta] subunits of the mitochondrial trifunctional protein are both located in the same region on human chromosome 2p23. Genomics 1996, 37:141-143.
6. Matern et al. Diagnosis of mitochondrial trifunctional protein deficiency in a blood spot from the newborn screening card by tandem mass spectrometry and DNA analysis. Pediatr Res 1999, 46:45-49.
7. Ushikubo et al. Molecular characterization of mitochondrial trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both [alpha] and [beta] subunits. Am J Hum Genet 1996, 58:979-988.
8. Ibdah et al. Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation. J Clin Invest 1998, 102(6):1193-9
9. Schulze et al. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics 2003, 111(6 Pt 1):1399-406.
- Confirmation of a clinical/biochemical diagnosis of TFP deficiency.
- Carrier testing in adults with a family history of TFP deficiency.
Clinical Sensitivity: 30/30 mutations identified in 15 patients , 8/8 mutations identified in 4 patients .
Analytical Sensitivity: ~99%
Prevalence: TFP is rare with incidence estimates of 1:250,000 live births . It is inherited in an autosomal recessive manner, therefore the recurrence risk for carrier parents of an affected child is 25%.
Submit only 1 of the following specimen types
Preferred specimen type: Whole Blood
Type: Whole Blood
Specimen Requirements:In EDTA (purple top) or ACD (yellow top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml
Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.
Specimen Requirements:OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.
Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.
- Urine Organic Acids (OA) and Plasma Acylcarnitine Profile (AR) are used in the diagnosis of a patient with TFP deficiency.
- Custom Diagnostics Known Mutation Analysis (KM) is available to family members if mutations are identified by sequencing.
- For comprehensive testing, a Trifunctional Protein Deficiency Deletion/Duplication Assay is available separately. This test is indicated 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 to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.