Alternative titles; symbols
HGNC Approved Gene Symbol: HADHA
SNOMEDCT: 237999008, 726021008;
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38): 2:26,190,635-26,244,632 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.3 | Fatty liver, acute, of pregnancy | 609016 | Autosomal recessive | 3 |
| HELLP syndrome, maternal, of pregnancy | 609016 | Autosomal recessive | 3 | |
| LCHAD deficiency | 609016 | Autosomal recessive | 3 | |
| Mitochondrial trifunctional protein deficiency 1 | 609015 | Autosomal recessive | 3 |
The HADHA and HADHB (143450) genes encode the alpha and beta subunits of the mitochondrial trifunctional protein, respectively. The heterocomplex contains 4 alpha and 4 beta subunits and catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids, including the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) step. The alpha subunit harbors the 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.211) and enoyl-CoA hydratase activities (EC 4.2.1.27) (Kamijo et al., 1994).
Kamijo et al. (1994) identified cDNAs for the genes encoding the alpha and beta subunits of the holoenzyme. The alpha-subunit cDNA encodes an 82.598-kD precursor, which ultimately becomes the 78.969-kD mature subunit.
Using rat Hadha to screen a human heart cDNA library, Sims et al. (1995) cloned HADHA, which encodes a 763-amino acid full-length protein, consisting of a 36-amino acid transit peptide and a 727-amino acid mature protein. HADHA shares 89% amino acid identity with its rat homolog.
Orii et al. (1999) determined that the HADHA and HADHB genes are linked in a head-to-head arrangement on opposite strands and that they have in common a 350-bp 5-prime flanking region. This region has bidirectional promoter activity with 2 critical cis elements that are activated by transcription factor SP1 (189906) binding. The authors concluded that expression of trifunctional protein subunits is probably coordinately regulated by a common promoter and by SP1.
Sims et al. (1995) determined that the HADHA gene contains 20 exons spanning over 52 kb.
By somatic cell hybrid studies, Craig et al. (1976) tentatively assigned the structural gene for trifunctional protein to chromosome 7. However, IJlst et al. (1996) localized the gene for the alpha subunit of the mitochondrial trifunctional protein to 2p24.1-p23.3 by fluorescence in situ hybridization (FISH). Yang et al. (1996) mapped both the HADHA and HADHB genes to 2p23 by FISH.
Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency
In LCHAD deficiency (609016), there is an isolated deficiency of the dehydrogenase activity with normal hydratase activity and moderately decreased thiolase activity (59% of control) (IJlst et al., 1996). In 24 of 26 unrelated Dutch patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, IJlst et al. (1994) identified a homozygous 1528G-C transversion in exon 15 of the HADHA gene, resulting in an E510Q substitution (600890.0001), based on numbering from the start codon. Two patients were compound heterozygous for E510Q and another pathogenic mutation in the HADHA gene (see, e.g., 600890.0006-600890.0007). IJlst et al. (1996) used S. cerevisiae for expression of wildtype and mutant protein to show that the E510Q mutation is directly responsible for the loss of LCHAD activity. Furthermore, they described a newly developed method allowing identification of the mutation in genomic DNA. The finding of an 87% allele frequency of this mutation in 34 LCHAD-deficient patients made this a valuable test for prenatal diagnosis. Sims et al. (1995) designated the 1528G-C mutation as E474Q based on numbering of the mature HADHA protein.
Ibdah et al. (1999) identified mutations in the HADHA gene in 19 children with LCHAD deficiency who presented with hypoketotic hypoglycemia and fatty liver. Eight children were homozygous for the E474Q mutation, while 11 were compound heterozygous for E474Q and another pathogenic mutation. While carrying fetuses with the E474Q mutation, 79% of the heterozygous mothers had fatty liver of pregnancy or the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets).
Mitochondrial Trifunctional Protein Deficiency 1
In mitochondrial trifunctional protein deficiency-1 (MTPD1; 609105), all 3 activities of the protein are deficient: dehydrogenase, hydratase, and thiolase (IJlst et al., 1996).
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 patients with MTP deficiency, Ibdah et al. (1998) identified biallelic mutations in the HADHA gene (600890.0008-600890.0010). The phenotype was characterized by slowly progressive chronic polyneuropathy and myopathy without hepatic or cardiac involvement. All 3 mutations were located in exon 9, which encodes a linker domain between the NH2-terminal hydratase and the COOH-terminal 3-hydroxyacyl-CoA dehydrogenase.
Ibdah et al. (1999) reported 5 children with complete MTP deficiency who presented with neonatal dilated cardiomyopathy or progressive neuromyopathy. None had the E474Q mutation common in isolated LCHAD deficiency, and none of their mothers had liver disease during pregnancy.
In 2 unrelated patients with lethal deficiency of trifunctional protein, Spiekerkoetter et al. (2002) delineated apparently homozygous alpha-subunit mutations that were present in heterozygous form in both mothers, but not in either biologic father. They performed a microsatellite repeat analysis of both patients and their parents using 7 chromosome 2-specific polymorphic DNA markers and 4 non-chromosome 2 markers. In both patients, 2 chromosome 2-specific markers demonstrated maternal isodisomy of chromosome 2. The other 5 chromosome 2-specific markers were noninformative in each patient. Inheritance of alleles from chromosomes 4, 5, and 7 was consistent with paternity. Spiekerkoetter et al. (2002) stated that 6 of 12 trifunctional protein-deficient patients with alpha-subunit mutations had disease due to homozygosity of mutations, and 2 of these 6 via the mechanism of uniparental disomy (UPD). For very rare autosomal recessive diseases, UPD greatly alters the empiric risk for the disorder from the 25% normally used. Spiekerkoetter et al. (2002) noted reports of 6 cases of maternal UPD of chromosome 2 and 2 cases of paternal UPD of chromosome 2.
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. The sibs died at 3 years of age and 7 months of age in the setting of illness with fever and diarrhea.
Ibdah et al. (2001) found that Mtpa-null mouse fetuses accumulated long-chain fatty acid metabolites and had low birth weight. Mtpa-null mice exhibited neonatal hypoglycemia, and all died suddenly within 6 to 36 hours after birth. Histopathologic analysis showed rapid development of hepatic steatosis after birth, and later showed significant necrosis and acute degeneration of the cardiac and diaphragmatic myocytes. The findings were similar to those observed in human trifunctional protein deficiency, indicating that long-chain fatty acid oxidation is essential for fetal development and survival after birth.
Based on numbering from the start codon, which was used by IJlst et al. (1994), this mutation is designated glu510-to-gln (E510Q). Sims et al. (1995) had designated the mutation GLU474GLN (E474Q) based on numbering of the mature protein.
LCHAD Deficiency with Maternal Acute Fatty Liver of Pregnancy
IJlst et al. (1994) identified a 1528G-C transversion in exon 15 of the HADHA gene, resulting in an E510Q substitution, in approximately 87% of the chromosomes in patients with LCHAD deficiency (609016).
Sims et al. (1995) used single-strand conformation variance (SSCV) analysis of the alpha subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase to determine the molecular basis of LCHAD deficiency in 3 families in which children presented with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mother had acute fatty liver and associated severe complications during pregnancy. The analysis in 2 affected children demonstrated homozygosity for the E474Q mutation. The third child was compound heterozygous for E474Q and Q342X (600890.0002).
IJlst et al. (1996) developed a PCR-RFLP method to identify the E474Q mutation in genomic DNA. Functional expression studies in S. cerevisiae showed that the mutation is directly responsible for the loss of LCHAD activity.
Tyni et al. (1997) discussed the clinical presentation of 13 patients with LCHAD deficiency due to a homozygous E474Q mutation. The patients had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Recurrent metabolic crises had occurred in 7 patients; the other 6 had a steadily progressive course. Cholestatic liver disease, which is uncommon in beta-oxidation defects, was found in 2 patients. One patient had peripheral neuropathy, and 6 had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. Radiologically, there was bilateral periventricular or focal cortical lesions in 3 patients and brain atrophy in 1. Only 1 patient, who had dietary treatment for 9 years, was alive at the age of 14 years; all others died before they were 2 years of age. The experience indicated the importance of recognizing the clinical features of LCHAD deficiency for the early institution of dietary management, which can alter the otherwise invariably poor prognosis.
Ibdah et al. (1999) reported a patient who presented at 2 months of age with generalized tonic-clonic seizure due to an acute infantile hypocalcemia and vitamin D deficiency. He also had occult, unexplained cholestatic liver disease and impairment of 25-hydroxylation of vitamin D secondary to hepatic steatosis. Sudden unexpected death occurred at 8 months. Molecular analysis revealed homozygosity for the E474Q mutation. The mother had preeclampsia during the third trimester of her pregnancy.
Mitochondrial Trifunctional Protein Deficiency 1
In a man with mitochondrial trifunctional protein deficiency (MTPD1; 609015), Liewluck et al. (2013) identified compound heterozygous mutations in the HADHA gene: E510Q and a splice site mutation (600890.0004). The patient 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.
In 1 family studied by Sims et al. (1995), a child with LCHAD deficiency (609016) was compound heterozygous for 2 mutations in the HADHA gene: E474Q (600890.0001) and a 1132C-T transition, resulting in a gln342-to-ter (Q342X) substitution within the cofactor NAD-binding domain of the mature protein. A truncated alpha subunit produced by this mutant allele would not contain the LCHAD active site.
In an infant with neonatal presentation of hypoglycemia and lactic aciduria and sudden unexplained death (MTPD1; 609015) at the age of 18 months, Brackett et al. (1995) demonstrated compound heterozygosity for 2 different mutations in the 5-prime donor splice site following exon 3 of the HADHA gene: a paternally inherited G-to-A transition at the invariant position +1 and a maternally inherited A-to-G mutation at position +3 (600890.0004). Both allelic mutations apparently caused skipping of exon 3 (71 bp), resulting in universal deletion of exon 3 in the patient's mRNA, undetectable levels of alpha-subunit protein, and complete loss of trifunctional protein.
For discussion of the maternally inherited A-to-G mutation at position +3 of the HADHA gene that was found in compound heterozygous state in an infant with neonatal presentation of hypoglycemia and lactic aciduria and sudden unexplained death (MTPD1; 609015) by Brackett et al. (1995), see 600890.0003.
In a man with MTPD1 manifest as adult-onset exercise-induced rhabdomyolysis and mild sensorimotor axonal peripheral neuropathy, Liewluck et al. (2013) identified compound heterozygous mutations in the HADHA gene: c.180+3A-G in intron 3 and E510Q (600890.0001).
Isaacs et al. (1996) described an infant with trifunctional protein deficiency-1 (MTPD1; 609015) who was compound heterozygous for the common E474Q mutation (600890.0001) causing LCHAD deficiency (609016) and a novel 1678C-T transition in exon 16 of the HADHA gene that results in an arg524-to-ter (R524X) substitution of the mature protein. The mother was heterozygous for the R524X mutation, and the infant's father and 2 phenotypically normal brothers were heterozygous for the E474Q mutation. Pregnancies were normal with the heterozygous sons but complicated by acute fatty liver of pregnancy with the affected son. The exon 16 mutation was confirmed by SSCV and nucleotide sequencing while both mutations were evident by ASO analysis. Quantification of the mRNA transcript from the premature termination codon mutation in exon 16 showed greatly reduced cytoplasmic levels as expected. The authors suggested that any child born to a mother with acute fatty liver of pregnancy should be screened for LCHAD or MTP deficiency.
Most patients with a defect in the mitochondrial trifunctional protein complex have an isolated deficiency of LCHAD activity (609016). In a group of 46 LCHAD-deficient patients studied enzymatically, IJlst et al. (1997) found 12 to be compound heterozygous for the common 1528G-C mutation (600890.0001) and another mutation in HADHA. IJlst et al. (1997) described 2 new mutations found in this compound heterozygous group. One was an insertion of a C at position 2129, changing the reading frame for the alpha subunit and creating a premature stop codon at residue 733, resulting in a truncated protein that was presumed to be unstable. The second was a 1025T-C transition, resulting in a leu342-to-pro (L342P; 600890.0007) substitution.
For discussion of the leu342-to-pro (L342P) mutation in the HADHA gene that was found in compound heterozygous state in patients with LCHAD deficiency (609016) by IJlst et al. (1997), see 600890.0006.
In a patient with trifunctional protein deficiency-1 with myopathy and neuropathy (see 609015), Ibdah et al. (1998) identified a homozygous 845T-A transversion in exon 9 of the HADHA gene, resulting in a val246-to-asp (V246D) substitution of the mature protein. The patient was a 13-year-old boy who was born to asymptomatic first-cousin parents. He had delayed gross motor milestones and, beginning at age 20 months, he had the first of many episodes of profound weakness precipitated by fever, vomiting, or dehydration. His subsequent clinical course was characterized by slowly progressive limb-girdle myopathy with mild facial weakness and a symmetric peripheral sensorimotor axonopathy with secondary demyelination. In addition, the patient had recurrent episodes of myoglobinuria (up to 5 times per year) precipitated by prolonged exertion, infection, cold exposure, fasting, and/or stress. Muscle biopsy revealed a mild lipid-accumulative myopathy. With the introduction of frequent feeding, a high-carbohydrate low-fat diet, and preventive fatty acid oxidation measures at age 7.5 years, there was a marked reduction in the frequency of myoglobinuric episodes. There was, however, no improvement in power or endurance, and these continued to deteriorate. A trial of prednisone resulted in significant improvement in the limb-girdle myopathy, which had been sustained over 5 years, as well as a transient improvement in his peripheral neuropathy. Myoglobinuric episodes were reduced to once every 1 to 2 years and were less severe.
In a patient with trifunctional protein deficiency-1 with myopathy and neuropathy (see 609015), Ibdah et al. (1998) identified compound heterozygosity for 2 mutations in the HADHA gene: an ile269-to-asn (I269N) substitution and an arg255-to-ter substitution (600890.0010) in the mature protein. Both mutations were in exon 9. The patient was a 12-year-old boy who was born to unrelated healthy parents. The first episode of muscle weakness occurred at 13 months of age, precipitated by an upper respiratory tract infection. Thereafter there were recurrent episodes of muscle weakness and myoglobinuria precipitated by infection, fasting, exertion, or cold exposure. At long-term follow-up, the patient had slowly progressive sensorimotor polyneuropathy characterized by bilateral foot drop, contracture of the Achilles tendons, and symmetric weakness in wrist and finger extension. He did not have pigmentary retinopathy or cardiomyopathy. A high-carbohydrate/low-fat diet failed to prevent the progression of the neuromuscular manifestations. This patient had previously been reported by Dionisi Vici et al. (1991). In that report it was stated that a sister had died at the age of 3 years, probably of the same disorder.
For discussion of the arg255-to-ter (R255X) mutation in the HADHA gene that was found in compound heterozygous state in a patient with trifunctional protein deficiency-1 with myopathy and neuropathy (see 609015) by Ibdah et al. (1998), see 600890.0009.
In 2 Chinese sibs with trifunctional protein deficiency-1 (MTPD1; 609015), Yang et al. (2022) identified compound heterozygous mutations in the HADHA gene: a c.703C-T transition at a conserved site, resulting in an arg235-to-trp (R235W) substitution, and a c.2107G-A transition at a conserved site, resulting in a gly703-to-arg (G703R; 600890.0012) substitution. The mutations, which were identified by whole-exome sequencing and Sanger sequencing, segregated with disease in the family. The R235W mutation was predicted to affect the enoyl-CoA hydratase/isomerase domain and the G703R mutation was predicted to affect the 3-hydroxyacyl-CoA-dehydrogenase C-terminal domain.
For discussion of the c.2107G-A transition in the HADHA gene, resulting in a gly703-to-arg (G703R) substitution, that was identified in compound heterozygous state in 2 Chinese sibs with trifunctional protein deficiency-1 (MTPD1; 609015) by Yang et al. (2022), see 600890.0011.
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