Mitochondrial Trifunctional Protein Deficiency (MTPD)

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Disease Ontology 12 DOID:0111277 OMIM 56 609015 KEGG 36 H01352 MeSH 43 C566945 D008052 D017240 NCIt 49 C98991 SNOMED-CT 67 237999008 MESH via Orphanet 44 D024741

ICD10 via Orphanet 33 G71.3 UMLS via Orphanet 72 C0342786 C1969443 Orphanet 58 ORPHA746 MedGen 41 C0342786 C1969443 SNOMED-CT via HPO 68 102594003 111287006 128613002 129565002 166603001 166643006 190882007 195021004 197446008 205091006 214264003 224958001 235886005 240131006 246545002 246586009 249808002 249945007 250018006 258211005 267044007 267258002 276508000 276610007 282195009 28835009 30144000 302226006 313307000 33688009 349006 36440009 366575004 36976004 371632003 37280007 386033004 397932003 398151007 398152000 399020009 409622000 409623005 42170009 42343007 42658009 432788009 44808001 48165008 48724000 5291005 55300003 55827005 57809008 68962001 698247007 75047002 75183008 84114007 84757009 85898001 89010004 91175000 91273001 9360008 more UMLS 71 C0000744 C1969443

NIH Rare Diseases : ⁵² The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 746 Definition A rare 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.. Epidemiology TFPD has been reported in less than 100 cases in the literature. Clinical description The 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. Etiology The 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 methods Urine 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 HADHB gene confirms diagnosis. Newborn screening is available in Austria, Czech Republic, Denmark, Germany, Hungary, Iceland, Netherlands and Portugal. Differential diagnosis Sudden 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 diagnosis Prenatal 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 counseling TFPD is an autosomal recessive disorder and genetic counseling is possible. Management and treatment Treatment 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. Prognosis Prognosis 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 tfp deficiency, is related to encephalopathy, progressive, early-onset, with episodic rhabdomyolysis 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 carnitine and Tocopherol have been mentioned in the context of this disorder. Affiliated tissues include liver, heart and retina, and related phenotypes are areflexia and exercise intolerance

Disease Ontology : ¹² A lipid metabolism disorder characterized by abnormal fatty acid oxidation resulting a wide range of clinical manifestations from servere neonatal symptoms including cardiomyopathy, hypoglycemia, metabolic acidosis, skeletal myopathy and neuropathy, liver disease and death to a more mild phenotype including peripheral polyneuropathy, episodic rhabdomyolysis and pigmentary retinopathy that has material basis in homozygous or compound heterozygous mutation in either of the subunits of the mitochondrial trifunctional protein; HADHA or HADHB on 2p23.3.

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). Signs and symptoms of mitochondrial trifunctional protein deficiency may begin during infancy or later in life. Features that occur during infancy include feeding difficulties, lack of energy (lethargy), low blood sugar (hypoglycemia), weak muscle tone (hypotonia), and liver problems. Infants with this disorder are also at high risk for serious heart problems, breathing difficulties, coma, and sudden death. Signs and symptoms of mitochondrial trifunctional protein deficiency that may begin after infancy include hypotonia, muscle pain, a breakdown of muscle tissue, and a loss of sensation in the extremities (peripheral neuropathy). Problems related to mitochondrial trifunctional protein deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.

OMIM : ⁵⁶ 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)

KEGG : ³⁶ Mitochondrial trifunctional protein (TFP) deficiency is a rare autosomal recessive disorder that is caused by mutations in HADHA and HADHB. TFP is a multienzyme complex of the fatty acid beta-oxidation cycle. Human TFP is an octamer composed of four alpha-subunits harboring long-chain enoyl-CoA hydratase and long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) and four beta-subunits encoding long-chain 3-ketoacyl-CoA thiolase (LCKAT). This disease includes a lethal neonatal phenotype with cardiomyopathy and Reye-like syndrome, an infantile hepatic phenotype with recurrent hypoketotic hypoglycemia, and a childhood or adolescent-onset neuromyopathic phenotype with peripheral neuropathy and recurrent rhabdomyolysis.

UniProtKB/Swiss-Prot : ⁷³ 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 : ⁷⁴ Mitochondrial trifunctional protein deficiency (MTP deficiency or MTPD) is an autosomal recessive fatty... more...

Clinical features from OMIM:

609015

Search NIH Clinical Center for Mitochondrial Trifunctional Protein Deficiency

Search GEO for disease gene expression data for Mitochondrial Trifunctional Protein Deficiency.