Other entities represented in this entry:
DO: 0060999;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p23.3 | Mitochondrial trifunctional protein deficiency 2 | 620300 | Autosomal recessive | 3 | HADHB | 143450 |
A number sign (#) is used with this entry because of evidence that mitochondrial trifunctional protein deficiency-2 (MTPD2) is caused by homozygous or compound heterozygous mutation in the HADHB gene (143450), the beta subunit of the mitochondrial trifunctional protein, on chromosome 2p23.
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 (summary by 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 mitochondrial trifunctional protein deficiency-1 (609015), caused by mutation in the HADHA gene (600890), the alpha subunit of mitochondrial trifunctional protein.
Miyajima et al. (1997) reported a 23-year-old man with recurrent myoglobinuria, low muscle-free carnitine levels, deficient fasting ketogenesis, and mutation in the HADHB gene. Urinary organic acid analysis showed large amounts of C6-C14 3-hydroxydicarboxylic acids. The 3 activities of the mitochondrial trifunctional protein were markedly decreased, and the protein content was less than 2% of normal controls. Miyajima et al. (1997) concluded that MTP deficiency can also present in adolescence with recurrent myoglobinuria.
Spiekerkoetter et al. (2003) characterized 15 patients from 13 families with HADHB mutations of the mitochondrial trifunctional protein. Three clinical phenotypes were apparent: a severe neonatal presentation with cardiomyopathy, Reye-like symptoms, and early death in 4 patients; a hepatic form with recurrent hypoketotic hypoglycemia in 2 patients; and a milder, later-onset neuromyopathic phenotype with episodic myoglobinuria in 9 patients. Maternal HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) occurred in 2 mothers independently of the fetal phenotype.
Park et al. (2009) reported a Korean boy, born of unrelated parents, who presented at birth with severe metabolic acidosis, hypotension, oliguric renal failure, tachypnea, and decreased movements. Cardiac assessment showed left ventricular dilatation, cardiac dysfunction (ejection fraction of 25%), and mitral and tricuspid regurgitation. At age 5 days, he developed seizures. Laboratory studies showed increased lactate and ammonia and abnormal liver enzymes. Newborn screening tests showed abnormal accumulation of acylcarnitine species, and genetic analysis identified compound heterozygous mutations in the HADHB gene. The patient died of advanced cardiac failure at age 2 months.
Purevsuren et al. (2009) described the features of 5 Japanese patients with MTP deficiency, including 3 who had previously been reported, and mutation in the HADHB gene. Two had an early lethal phenotype, 2 had an intermediate hepatic phenotype, and 1 had a late-onset myopathic phenotype. The first 2 patients had onset within the first days of life of lactic acidosis, hyperketotic hypoglycemia, and hyperammonemia. Both died of cardiac arrest at ages 8 days and 3 months, respectively. The 2 patients with hepatic involvement had onset at ages 9 and 13 months, respectively. Both had delayed psychomotor development. One had increased liver enzymes, lactic acidemia, and recurrent rhabdomyolysis. The other had lethargy, hypotonia, recurrent respiratory infections, and liver dysfunction. The last patient, previously reported by Miyajima et al. (1997), had onset at age 15 years of muscle pain and weakness associated with rhabdomyolysis.
Mitochondrial Trifunctional Protein Deficiency 2 with Myopathy and Neuropathy
Naiki et al. (2014) reported a pair of Japanese dizygotic twins, born of consanguineous parents, with a protracted form of MTPD2. The patients were 18 years old at the time of the report. Both presented in early infancy with hypoparathyroidism with severely decreased serum calcium and increased serum phosphorus; 1 infant had seizures as a result, whereas the other was asymptomatic. Both subsequently had episodic rhabdomyolysis associated with infections, and developed a progressive peripheral neuropathy resulting in difficulty walking. Other features included distal muscle weakness, hyporeflexia, distal sensory impairment, and decreased nerve conduction velocities. Muscle biopsies showed denervation atrophy.
Reviews
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 progressive 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.
The mode of inheritance of MTPD2 in the patients reported by Ushikubo et al. (1996) was shown to be autosomal recessive.
In 2 unrelated patients with trifunctional protein deficiency, Ushikubo et al. (1996) identified homozygous or compound heterozygous mutations in the HADHB gene (143450.0001-143450.0003). This was the first demonstration of disease-causing mutations in the beta subunit. Using a vaccinia virus system and gel filtration analysis for cDNA expression experiments in patients' fibroblasts, Ushikubo et al. (1996) found that both normal alpha and beta subunits, and possibly their association, are important for stabilizing the trifunctional protein.
By exome sequencing, Spiekerkoetter et al. (2003) identified biallelic mutations in the HADHB gene in 15 patients from 13 families with MTP deficiency. Of the 16 identified mutations, 12 were missense mutations.
Orii et al. (1997) identified 2 Japanese patients in whom the 3 enzyme activities of the trifunctional protein were undetectable in fibroblasts. The patients were homozygous or compound heterozygous for mutations in the HADHB gene (143450.0004; 143450.0005).
In a Korean boy with MTP deficiency, Park et al. (2009) identified compound heterozygous mutations in the HADHB gene (143450.0008) and (143450.0009).
Purevsuren et al. (2009) reported 5 Japanese patients with trifunctional protein deficiency due to homozygous or compound heterozygous mutations in the HADHB gene (see, e.g., 143450.0004 and 143450.0006).
In a pair of dizygotic Japanese twins, born of consanguineous parents, with the neuromyopathic form of MTPD2, Naiki et al. (2014) identified a homozygous missense mutation in the HADHB gene (A392V; 143450.0007). Western blot analysis of patient cells showed decreased or absent levels of the alpha and beta subunits of the mitochondrial trifunctional protein. The mutant HADHB protein failed to form an active heterooctamer with the wildtype alpha subunit.
Reviews
Dagher et al. (2021) reviewed the pathophysiology, clinical phenotype, and molecular findings in MTP deficiency caused by biallelic mutations in the HADHB gene. The authors noted that mutations in the HADHB gene often lead to deficiency of all 3 enzymatic functions of the mitochondrial trifunctional protein because the mutations frequently affect amino acid residues located at the interface of the dimerization domains between HADHB and HADHA.
Based on homology to yeast thiolase, which had been characterized structurally, Spiekerkoetter et al. (2003) found that the location of the mutations within the HADHB protein correlated with the clinical phenotype in the patients with MTP deficiency. Outer loop mutations that were expected to alter protein stability were present only in milder forms. The degree of reduction in thiolase antigen also correlated with the severity of clinical presentation. Thus, although MTP deficiency is highly heterogeneous, some genotype-phenotype correlation could be established.
In vitro functional expression studies in the 5 patients with MTP deficiency reported by Purevsuren et al. (2009) indicated a genotype/phenotype correlation: patients whose mutations resulted in no residual protein activity had a more severe phenotype than those whose mutations had residual activity.
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]
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]
Naiki, M., Ochi, N., Kato, Y. S., Purevsuren, J., Yamada, K., Kimura, R., Fukushi, D., Hara, S., Yamada, Y., Kumagai, T., Yamaguchi, S., Wakamatsu, N. Mutations in HADHB, which encodes the beta-subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy. Am. J. Med. Genet. 164A: 1180-1187, 2014. [PubMed: 24664533] [Full Text: https://doi.org/10.1002/ajmg.a.36434]
Orii, K. E., Aoyama, T., Wakui, K., Fukushima, Y., Miyajima, H., Yamaguchi, S., Orii, T., Kondo, N., Hashimoto, T. Genomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency. Hum. Molec. Genet. 6: 1215-1224, 1997. [PubMed: 9259266] [Full Text: https://doi.org/10.1093/hmg/6.8.1215]
Park, H.-D., Kim, S. R., Ki, C.-S., Lee, S.-Y., Chang, Y. S., Jin, D.-K., Park, W. S. Two novel HADHB gene mutations in a Korean patient with mitochondrial trifunctional protein deficiency. Ann. Clin. Lab. Sci. 39: 399-404, 2009. [PubMed: 19880769]
Purevsuren, J., Fukao, T., Hasegawa, Y., Kobayashi, H., Li, H., Mushimoto, Y., Fukuda, S., Yamaguchi, S. Clinical and molecular aspects of Japanese patients with mitochondrial trifunctional protein deficiency. Molec. Genet. Metab. 98: 372-377, 2009. [PubMed: 19699128] [Full Text: https://doi.org/10.1016/j.ymgme.2009.07.011]
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]
Ushikubo, S., Aoyama, T., Kamijo, T., Wanders, R. J. A., Rinaldo, P., Vockley, J., Hashimoto, T. 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. 58: 979-988, 1996. [PubMed: 8651282]