#609015
ICD+
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| TRIFUNCTIONAL PROTEIN DEFICIENCY | |||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||
| MITOCHONDRIAL TRIFUNCTIONAL PROTEIN DEFICIENCY | |||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | |||||||||||||||||||||||||||||||||||||||||||||
| TRIFUNCTIONAL PROTEIN DEFICIENCY WITH MYOPATHY AND NEUROPATHY, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because mitochondrial trifunctional protein (MTP) deficiency can be caused by mutation in the genes encoding either the alpha (HADHA; 600890) or beta (HADHB; 143450) subunits of the mitochondrial trifunctional protein. | |||||||||||||||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||||||||||||||
| 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. | |||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||||||||
| 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). Purevsuren et al. (2009) reported the clinical and molecular features of 5 Japanese patients with MTP deficiency, including 3 who had previously been reported. 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. MTP Deficiency 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. Miyajima et al. (1997) reported a 23-year-old man with recurrent myoglobinuria, low muscle-free carnitine levels, and deficient fasting ketogenesis. 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. 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. | |||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | |||||||||||||||||||||||||||||||||||||||||||||
| 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. | |||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||
| 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 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. 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). | |||||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | |||||||||||||||||||||||||||||||||||||||||||||
| 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. 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 occurred in 2 mothers independently of the fetal phenotype. Mutation analysis revealed 16 different mutations, 12 of which were missense mutations. Based on homology to yeast thiolase, which had been characterized structurally, Spiekerkoetter et al. (2003) found that the location of the mutation within the protein correlated with the clinical phenotype. 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. 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 vitro functional expression studies 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. | |||||||||||||||||||||||||||||||||||||||||||||
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