Mitochondrial Trifunctional Protein Deficiency

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OMIM 57 609015 Orphanet 59 ORPHA746 UMLS via Orphanet 74 C1969443 C0342786 MESH via Orphanet 45 D024741 ICD10 via Orphanet 34 G71.3

MedGen 42 C1969443 C0342786 MeSH 44 D008052 D017240 KEGG 37 H01352 SNOMED-CT via HPO 69 258211005 28835009 398151007 398152000 224958001 36440009 432788009 267258002 276610007 42170009 42343007 84114007 195021004 399020009 276508000 9360008 409623005 409622000 166603001 166643006 75183008 48165008 190882007 91273001 240131006 89010004 68962001 302226006 386033004 42658009 more UMLS 73 C1969443

NIH Rare Diseases : ⁵³ The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 746Disease definitionMitochondrial trifunctional protein (TFP) deficiency (TFPD) is a disorder of fatty acid oxidation characterized by a wide clinical spectrum ranging from severe neonatal manifestations including cardiomyopathy, hypoglycemia, metabolic acidosis, skeletal myopathy and neuropathy, liver disease and death to a mild phenotype with peripheral polyneuropathy, episodic rhabdomyolysis and pigmentary retinopathy..EpidemiologyTFPD has been reported in less than 100 cases in the literature.Clinical descriptionThe neonatal onset, severe form manifests as hepatic steatosis, cardiomyopathy, skeletal myopathy and neuropathy and is usually fatal. A moderately severe form, with onset usually from the neonatal period to 18 months of age, presents primarily with hypoketotic hypoglycemia and metabolic acidosis which is often precipitated by prolonged fasting and/or intercurrent illness. Both forms can manifest with neuropathy with or without cardiomyopathy and can be fatal. The mild form merges with the moderately severe infantile form and can present from a few months of age until adolescence as a peripheral polyneuropathy with episodic rhabdomyolysis triggered by prolonged fasting, illness, exercise or exposure to heat or cold. There is respiratory failure associated with the episodes of rhabdomyolysis. A pigmentary retinopathy may also develop over time. Very occasionally, adults presenting for the first time with a previously unrecognized disease are described.EtiologyThe TFP, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids which are the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase (LCEH), and long-chain thiolase (LCTH) steps. The HADHA gene (2p23) encodes the LCEH and LCHAD enzymes and the HADHB gene (2p23) encodes the LCTH enzyme. Two mutations in either one of these two genes causes TFPD.Diagnostic methodsUrine organic acids may show a C6-C14 (hydroxy) dicarboxylic aciduria, and blood acylcarnitine analysis often shows increased long chain hydroxyacyl carnitine species (C14-OH, C16-OH, C18-OH, C18:1-OH). Both urine and blood markers are less reliable and more variable than those seen in LCHAD deficiency (see this term). This is because defects in LCEH may block the formation of hydroxy-metabolites. Reduced enzyme activity in at least two (usually all 3) enzymes in cultured fibroblasts is seen. Molecular analysis confirming bi-allelic non-1528C>G mutations in the HADHA gene or bi-allelic mutations in the HADHBgene confirms diagnosis. Newborn screening is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands and Portugal.Differential diagnosisSudden infant death syndrome and isolated LCHAD deficiency (see this term) form part of the differential diagnosis. LCHAD deficiency is clinically indistinguishable from severe TFPD.Antenatal diagnosisPrenatal diagnosis is possible by analyzing enzyme activity in chorionic villi samples, once a deficiency of TFP has been established in the index case/family. Molecular analysis is the preferred option when two mutations have been identified in a family.Genetic counselingTFPD is an autosomal recessive disorder and genetic counseling is possible.Management and treatmentTreatment involves adherence to a low fat diet with restriction of long chain fatty acid intake and substitution with medium chain fatty acids. Fasting and exposure to environmental extremes must be strictly avoided and exercise should be limited.PrognosisPrognosis for the severe neonatal form of TFPD is very poor. The later onset mild form has a far more favorable prognosis.Visit the Orphanet disease page for more resources.

MalaCards based summary : Mitochondrial Trifunctional Protein Deficiency, also known as trifunctional protein deficiency with myopathy and neuropathy, is related to long-chain 3-hydroxyacyl-coa dehydrogenase deficiency and abetalipoproteinemia, and has symptoms including ataxia, myalgia and weakness. An important gene associated with Mitochondrial Trifunctional Protein Deficiency is HADHA (Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunit Alpha), and among its related pathways/superpathways are Fatty acid degradation and Fatty acid metabolism. The drugs Heparin and Glycerol have been mentioned in the context of this disorder. Affiliated tissues include liver, heart and skin, and related phenotypes are pigmentary retinopathy and muscular hypotonia

Genetics Home Reference : ²⁵ Mitochondrial trifunctional protein deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting).

OMIM : ⁵⁷ The mitochondrial trifunctional protein, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by decreased activity of all 3 enzymes. Clinically, classic trifunctional protein deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden unexplained infant death (SIDS; 272120), infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy (Spiekerkoetter et al., 2003). Some patients with MTP deficiency show a protracted progressive course associated with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy. These patients tend to survive into adolescence and adulthood (den Boer et al., 2003). See also isolated LCHAD deficiency (609016), which is caused by mutation in the HADHA gene. (609015)

UniProtKB/Swiss-Prot : ⁷⁵ Mitochondrial trifunctional protein deficiency: A disease biochemically characterized by loss of all enzyme activities of the mitochondrial trifunctional protein complex. Variable clinical manifestations include hypoglycemia, cardiomyopathy, delayed psychomotor development, sensorimotor axonopathy, generalized weakness, hepatic dysfunction, respiratory failure. Sudden infant death may occur. Most patients die from heart failure.

Wikipedia : ⁷⁶ Mitochondrial trifunctional protein deficiency is an autosomal recessive fatty acid oxidation disorder... more...

Clinical features from OMIM:

609015

#	Description	GenomeRNAi Source Accession	Score	Top Affiliating Genes
1	Increased shRNA abundance (Z-score > 2)	GR00366-A-100	9.53	EHHADH
2	Increased shRNA abundance (Z-score > 2)	GR00366-A-11	9.53	EHHADH
3	Increased shRNA abundance (Z-score > 2)	GR00366-A-130	9.53	EHHADH
4	Increased shRNA abundance (Z-score > 2)	GR00366-A-138	9.53	EHHADH
5	Increased shRNA abundance (Z-score > 2)	GR00366-A-161	9.53	HADHB
6	Increased shRNA abundance (Z-score > 2)	GR00366-A-194	9.53	HADHB
7	Increased shRNA abundance (Z-score > 2)	GR00366-A-46	9.53	EHHADH GAREM2
8	Increased shRNA abundance (Z-score > 2)	GR00366-A-56	9.53	HADHB
9	Increased shRNA abundance (Z-score > 2)	GR00366-A-63	9.53	HADHB
10	Increased shRNA abundance (Z-score > 2)	GR00366-A-67	9.53	HADHB
11	Increased shRNA abundance (Z-score > 2)	GR00366-A-76	9.53	EHHADH GAREM2 HADHB
12	Increased shRNA abundance (Z-score > 2)	GR00366-A-79	9.53	EHHADH
13	Increased shRNA abundance (Z-score > 2)	GR00366-A-81	9.53	EHHADH
14	Increased G1 length, increased G2 length	GR00237-A	8.96	HADHA HADHB

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