Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 237999008; ORPHA: 746; DO: 0111277;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p23.3 | Mitochondrial trifunctional protein deficiency 1 | 609015 | Autosomal recessive | 3 | HADHA | 600890 |
A number sign (#) is used with this entry because of evidence that mitochondrial trifunctional protein deficiency-1 (MTPD1) is caused by homozygous or compound heterozygous mutation in the HADHA gene (600890), the alpha subunit of the mitochondrial trifunctional protein.
See also isolated LCHAD deficiency (609016), which is caused by mutation in the HADHA gene.
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).
Genetic Heterogeneity of Mitochondrial Trifunctional Protein Deficiency
See also MTPD2 (620300), caused by mutation in the HADHB gene, the beta subunit of the mitochondrial trifunctional protein.
Wanders et al. (1992) reported an infant, born of first-cousin parents, who presented with hypoglycemia and major hypotonia at 2 days of age. The infant developed respiratory failure and showed poor spontaneous motility and absence of suckling and archaic reflexes on day 8, had acute cardiac failure on day 28 related to a hypokinetic cardiomyopathy with distended wall, and died on day 30. Studies of fibroblasts from the patient demonstrated deficiency of all 3 activities of trifunctional protein.
Jackson et al. (1992) reported a young girl who presented with recurrent episodes of muscle weakness culminating in a severe attack of generalized muscle weakness. Muscle mitochondria from the patient demonstrated an abnormal pattern of intermediates of beta-oxidation with an accumulation of 3-hydroxyacyl- and 2-enoyl-CoA and carnitine esters, and 3-oxoacylcarnitines. The patient was shown to have a combined defect of long-chain 3-hydroxyacyl-CoA dehydrogenase, long-chain 3-oxoacyl-CoA thiolase, and long-chain 2-enoyl-CoA hydratase. In fibroblasts from both parents, intermediate levels of enzyme activity were found. The proband died at age 4.5 years after a brief illness. An earlier-born brother had died at the age of 2.5 years, probably of the same disorder. He showed terminally low-output cardiac failure with an enlarged dilated heart and generalized weakness.
Dionisi-Vici et al. (1996) described the clinical course of a girl diagnosed at the age of 15 months with a history of recurrent vomiting at birth. The patient presented with severe hypotonia, respiratory failure requiring assisted ventilation, and severe dilated cardiomyopathy. Urine organic acids were strongly suggestive of a fatty acid oxidation defect by characteristic excretion of 3-hydroxydicarboxylic acid; additional laboratory findings were consistent with hypoparathyroidism. Fibroblast analysis showed that all 3 MTP enzyme activities were affected, albeit to different degrees. In follow-up, additional episodes of metabolic decompensation were induced by intercurrent febrile illnesses.
Den Boer et al. (2003) found that 9 (42%) of 21 patients with MTP deficiency presented with rapidly progressive clinical deterioration. Eight of these patients died of cardiac complications within 8 weeks; the ninth patient died of liver failure within 4 weeks. Six of the 9 had hypoketotic hypoglycemia. Other clinical features of the rapidly progressive group included hypotonia, lethargy, liver disease, and peripheral neuropathy. One of 7 tested had pigmentary retinopathy. Two patients who were diagnosed prenatally died despite treatment; 1 of these patients had hydrops fetalis. Two (11%) of 19 pregnancies on which information was available were complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets).
Dagher et al. (2021) reviewed the clinical features of MTP deficiency and described 3 phenotypic groups: an early-onset cardiomyopathy associated with early death, an intermediate form with recurrent hypoketotic hypoglycemia, and a sensorimotor neuropathy with episodic rhabdomyolysis and hypoparathyroidism. The severity of disease presentation was found to be correlated with the degree of MTP enzyme deficiency. Dilated cardiomyopathy, which had the potential to develop across the life span, was the most common cardiomyopathy observed. However, the most severe form of cardiomyopathy was a rapidly progressing neonatal cardiomyopathy presenting around 3 months of age. Rhabdomyolysis in MTP deficiency was typically caused by prolonged activity, cold exposure, or infection. Peripheral neuropathy resembled axonal Charcot Marie Tooth disease (CMT2; see 118210) and could present without any other MTP deficiency symptoms. Early-onset liver disease was also reported in severe MTP enzyme deficiency, and was often diagnosed after patients presented with hypoketotic hypoglycemia. Dagher et al. (2021) noted that the hypoketotic hypoglycemia resulted from the inability to maintain substrates for ketogenesis via fatty acid oxidation and a lack of available ATP for gluconeogenesis.
MTP Deficiency 1 with Myopathy and Neuropathy
Dionisi Vici et al. (1991) described slowly progressive neuropathy and recurrent myoglobinuria in a boy whose sister had died at the age of 3 years, presumably of the same disorder.
Schaefer et al. (1996) reported 3 adults from a family with symptoms of recurrent exercise-induced rhabdomyolysis associated with peripheral neuropathy. Investigation of fatty acid oxidation in the patients revealed a deficiency of the mitochondrial trifunctional enzyme of beta-oxidation. The patients appeared to represent a novel phenotype of MTP deficiency characterized by recurrent rhabdomyolysis and peripheral neuropathy, but without involvement of other organs. This phenotype was associated with prolonged survival beyond the fourth decade. A low-fat/high-carbohydrate diet proved beneficial in one of the patients, drastically reducing the frequency of rhabdomyolytic episodes. Schaefer et al. (1996) noted that MTP deficiency should be considered in patients with recurrent episodes of myoglobinuria and peripheral neuropathy presenting in later life.
Den Boer et al. (2003) found that 12 (57%) of 21 patients with MTP deficiency presented with a slow, insidious disease characterized by hypotonia, muscle cramps, decreased tendon reflexes, and peripheral neuropathy. Other features included cardiomyopathy, liver disease, and feeding difficulties with failure to thrive. Seven of these patients died: 5 from progressive cardiomyopathy, 1 from severe infection and metabolic derangement, and 1 suddenly almost 14 years after onset. The 5 surviving patients were in relatively good clinical condition without cardiomyopathy. Three had developmental delay. Some had episodic rhabdomyolysis and/or myoglobinuria.
Liewluck et al. (2013) reported a man who presented in his late forties with exercise-induced rhabdomyolysis and was found to have features of a mild sensorimotor axonal peripheral neuropathy affecting the lower limbs. Laboratory studies showed an abnormal acylcarnitine profile, suggesting a defect in HADHA activity, although patient cells were not available for study. Genetic analysis revealed compound heterozygous mutations in the HADHA gene (600890.0001 and 600890.0004).
Yang et al. (2022) reported 2 Chinese sibs with MTPD who died at 3 years of age and 7 months of age in the setting of illness with fever and diarrhea. The younger sib had an autopsy which showed diffuse hepatocyte steatosis and cardiomyocyte steatosis.
Although the mortality rate among children with deficiency of LCHAD or complete deficiency of the trifunctional protein had been reported to be 75 to 90%, Ibdah et al. (1999) found that 67% of the affected children in their study were alive and receiving dietary treatment at the most recent follow-up, and most were able to attend school. Dietary treatment of children with fatty acid oxidation disorders dramatically reduced morbidity and mortality.
Guffon et al. (2021) described clinical response to treatment with triheptanoin in 18 patients with disorders of long chain fatty acid oxidation, including 5 with VLCAD deficiency (201475), 5 with LCHAD deficiency (609016), 3 with CACT deficiency, 3 with CPT II deficiency (600649), and 2 with MTP deficiency. Treatment duration was for an average of 22 months, with a range of 9 to 228 months. Ten of 12 pediatric patients and 4 of 6 adult patients reported reduction in fatigue and weakness. Eight of 12 pediatric patients and 3 of 6 adult patients experienced reduced intensity of myalgia. Episodes of rhabdomyolysis decreased in 8 of 12 pediatric patients and 3 of 6 adult patients. Of 3 patients who had severe hypoglycemic events in the year prior to starting triheptanoin, none had these events in the year following initiation of therapy. On average, emergency hospital care visits and days of emergency home care were also reduced.
In a patient with MTP deficiency, Brackett et al. (1995) identified compound heterozygosity for 2 mutations in the HADHA gene (600890.0003 and 600890.0004). The patient presented in the neonatal period with hypoglycemia and cardiomyopathy and later died unexpectedly at the age of 18 months.
In 2 Chinese sibs with MTPD, Yang et al. (2022) identified compound heterozygous mutations in the HADHA gene (R235W, 600890.0011; G703R, 600890.0012). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family.
In 2 unrelated patients with slowly progressive neuropathy and recurrent myoglobinuria, Ibdah et al. (1998) confirmed MTP deficiency and identified biallelic mutations in exon 9 of the HADHA gene (600890.0008-600890.0010). One of the patients had been reported by Dionisi Vici et al. (1991); both patients survived into their early teens. Ibdah et al. (1998) suggested that the relatively milder phenotype in these patients may be correlated with mutations in exon 9 of the HADHA gene, which encodes a linker domain between 2 regions of enzyme activity.
Ibdah et al. (1999) reported 5 children with complete MTP deficiency who presented with neonatal dilated cardiomyopathy or progressive neuromyopathy. None had the common HADHA mutation (E474Q; 600890.0001) often seen in isolated LCHAD deficiency, and none of their mothers had liver disease during pregnancy. Similarly, Chakrapani et al. (2000) reported 5 families with trifunctional protein deficiency in which 3 mothers experienced significant hepatic disease while carrying an affected fetus. Diagnoses were based on increased levels of long-chain hydroxyacylcarnitines and deficiencies of 3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase activity in fibroblasts. None of these affected infants had the E474Q mutation.
Brackett, J. C., Sims, H. F., Rinaldo, P., Shapiro, S., Powell, C. K., Bennett, M. J., Strauss, A. W. Two alpha subunit donor splice site mutations cause human trifunctional protein deficiency. J. Clin. Invest. 95: 2076-2082, 1995. [PubMed: 7738175] [Full Text: https://doi.org/10.1172/JCI117894]
Chakrapani, A., Olpin, S., Cleary, M., Walter, J. H., Wraith, J. E., Besley, G. T. N. Trifunctional protein deficiency: three families with significant maternal hepatic dysfunction in pregnancy not associated with E474Q mutation. J. Inherit. Metab. Dis. 23: 826-834, 2000. [PubMed: 11196108] [Full Text: https://doi.org/10.1023/a:1026712719416]
Dagher, R., Massie, R., Gentil, B. J. MTP deficiency caused by HADHB mutations: pathophysiology and clinical manifestations. Molec. Genet. Metab. 133: 1-7, 2021. [PubMed: 33744096] [Full Text: https://doi.org/10.1016/j.ymgme.2021.03.010]
den Boer, M. E. J., Dionisi-Vici, C., Chakrapani, A., van Thuijl, A. O. J., Wanders, R. J. A., Wijburg, F. A. Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement. J. Pediat. 142: 684-689, 2003. [PubMed: 12838198] [Full Text: https://doi.org/10.1067/mpd.2003.231]
Dionisi Vici, C., Burlina, A. B., Bertini, E., Bachmann, C., Mazziotta, M. R. M., Zacchello, F., Sabetta, G., Hale, D. E. Progressive neuropathy and recurrent myoglobinuria in a child with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. J. Pediat. 118: 744-746, 1991. [PubMed: 2019931] [Full Text: https://doi.org/10.1016/s0022-3476(05)80039-3]
Dionisi-Vici, C., Garavaglia, B., Burlina, A. B., Bertini, E., Saponara, I., Sabetta, G., Taroni, F. Hypoparathyroidism in mitochondrial trifunctional protein deficiency. J. Pediat. 129: 159-162, 1996. [PubMed: 8757579] [Full Text: https://doi.org/10.1016/s0022-3476(96)70206-8]
Guffon, N., Mochel, F., Schiff, M., De Lonlay, P., Douillard, C., Vianey-Saban, C. Clinical outcomes in a series of 18 patients with long chain fatty acids oxidation disorders treated with triheptanoin for a median duration of 22 months. Molec. Genet. Metab. 132: 227-233, 2021. [PubMed: 33610471] [Full Text: https://doi.org/10.1016/j.ymgme.2021.02.003]
Ibdah, J. A., Bennett, M. J., Rinaldo, P., Zhao, Y., Gibson, B., Sims, H. F., Strauss, A. W. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. New Eng. J. Med. 340: 1723-1731, 1999. [PubMed: 10352164] [Full Text: https://doi.org/10.1056/NEJM199906033402204]
Ibdah, J. A., Tein, I., Dionisi-Vici, C., Bennett, M. J., IJlst, L., Gibson, B., Wanders, R. J. A., Strauss, A. W. Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation. J. Clin. Invest. 102: 1193-1199, 1998. [PubMed: 9739053] [Full Text: https://doi.org/10.1172/JCI2091]
Jackson, S., Kler, R. S., Bartlett, K., Briggs, H., Bindoff, L. A., Pourfarzam, M., Gardner-Medwin, D., Turnbull, D. M. Combined enzyme defect of mitochondrial fatty acid oxidation. J. Clin. Invest. 90: 1219-1225, 1992. [PubMed: 1401059] [Full Text: https://doi.org/10.1172/JCI115983]
Liewluck, T., Mundi, M. S., Mauermann, M. L. Mitochondrial trifunctional protein deficiency: a rare cause of adult-onset rhabdomyolysis. Muscle Nerve 48: 989-991, 2013. [PubMed: 23868323] [Full Text: https://doi.org/10.1002/mus.23959]
Miyajima, H., Orii, K. E., Shindo, Y., Hashimoto, T., Shinka, T., Kuhara, T., Matsumoto, I., Shimizu, H., Kaneko, E. Mitochondrial trifunctional protein deficiency associated with recurrent myoglobinuria in adolescence. Neurology 49: 833-837, 1997. [PubMed: 9305349] [Full Text: https://doi.org/10.1212/wnl.49.3.833]
Schaefer, J., Jackson, S., Dick, D. J., Turnbull, D. M. Trifunctional enzyme deficiency: adult presentation of a usually fatal beta-oxidation defect. Ann. Neurol. 40: 597-602, 1996. [PubMed: 8871579] [Full Text: https://doi.org/10.1002/ana.410400409]
Spiekerkoetter, U., Sun, B., Khuchua, Z., Bennett, M. J., Strauss, A. W. Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations. Hum. Mutat. 21: 598-607, 2003. [PubMed: 12754706] [Full Text: https://doi.org/10.1002/humu.10211]
Wanders, R. J. A., IJlst, L., Poggi, F., Bonnefont, J. P., Munnich, A., Brivet, M., Rabier, D., Saudubray, J. M. Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Biochem. Biophys. Res. Commun. 188: 1139-1145, 1992. [PubMed: 1445348] [Full Text: https://doi.org/10.1016/0006-291x(92)91350-y]
Yang, J., Yuan, D., Tan, X., Zeng, Y., Tang, N., Chen, D., Tan, J., Cai, R., Huang, J., Yan, T. Analysis of a family with mitochondrial trifunctional protein deficiency caused by HADHA gene mutations. Molec. Med. Rep. 25: 47, 2022. [PubMed: 34878152] [Full Text: https://doi.org/10.3892/mmr.2021.12563]