Alternative titles; symbols
SNOMEDCT: 734434007; ORPHA: 3006; DO: 0070519;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
5q23.2 | Epilepsy, early-onset, 4, vitamin B6-dependent | 266100 | Autosomal recessive | 3 | ALDH7A1 | 107323 |
A number sign (#) is used with this entry because of evidence that early-onset vitamin B6-dependent epilepsy-4 (EPEO4) is caused by homozygous or compound heterozygous mutation in the ALDH7A1 gene (107323) on chromosome 5q23.
Early-onset vitamin B6-dependent epilespy-4 (EPEO4), characterized by a combination of various seizure types, usually occurs in the first hours of life and is unresponsive to standard anticonvulsants, responding only to immediate administration of pyridoxine hydrochloride. The dependence is permanent, and the interruption of daily pyridoxine supplementation leads to the recurrence of seizures. Some patients show developmental delay. The prevalence is estimated at 1 in 400,000 to 700,000 (Bennett et al., 2005).
For a discussion of genetic heterogeneity of EPEO, see 617290.
Pyridoxine-dependent epilepsy was first described by Hunt et al. (1954). Waldinger (1964) described 3 sibs of Italian ancestry in whom pyridoxine dependency was manifest by convulsions at birth. Four previously reported sibships with more than 1 affected sib were referred to. Bejsovec et al. (1967) described 3 sibs with intrauterine convulsions. The first 2 (females) died in status epilepticus. The third was shown to have pyridoxine dependency. Thus, this is one form of 'convulsive disorder, familial, with prenatal or early onset' (217200).
Goutieres and Aicardi (1985) reported 3 patients with atypical pyridoxine-dependent seizures. Each had either late onset of convulsions or seizure-free intervals of up to several months' duration without B6 supplementation. The findings, together with those in 9 previously reported cases, led the authors to urge a trial of pyridoxine in all cases of seizure disorders with onset before 18 months of age, regardless of type. Autosomal recessive inheritance was supported by parental consanguinity in the case of an affected female infant whose elder brother died at 8 months of age of unexplained status epilepticus.
Bennett et al. (2005) reported 6 Caucasian North American families with pyridoxine-dependent seizures. Two of the families had been reported by Battaglioli et al. (2000).
Mills et al. (2006) reported 13 patients from 8 unrelated families with pyridoxine-dependent epilepsy. Seizures usually started on the first day of life, but in 1 case were delayed until 3 weeks of age. Clonic seizures, generalized tonic seizures, and myoclonic jerks were all observed. Seizures were resistant to the usual anticonvulsant drugs in all but 1 case, but stopped completely and immediately upon treatment with pyridoxine. Plasma and cerebrospinal fluid levels of pipecolic acid were increased. Despite early and good control of seizures, all but 1 child showed developmental delay, ranging from mild to severe, with psychomotor difficulties and speech delay. Other features in the neonatal period included respiratory distress, acidosis, and abdominal distention and vomiting. The parents in 6 of the families were consanguineous; the families were of Dutch, Austrian, Bosnian, Turkish, Arab, and Asian origin.
Tseng et al. (2022) evaluated clinical outcomes in 37 patients, including 17 sib pairs and 1 sib trio, from 18 families with pyridoxine-dependent epilepsy. One sib of each family was treated early (2 sibs in the case of the sib trio) at an average age of 7 days, and one sib of each family was treated late, at an average age of 150 days. Nine of the sib pairs and the sib trio were treated with pyridoxine monotherapy and 8 sib pairs were treated with pyridoxine and lysine reduction therapies (LRT). Of the sib pairs treated with pyridoxine monotherapy, the early-treated sibs had better fine motor skills. Of the sib pairs treated with both pyridoxine and LRT, the early-treated sibs had fewer psychiatric/behavioral manifestations. There was not a significant difference between full-scale intelligence quotient (FSIQ) scores in early- versus late-treated patients in the 4 sib pairs who were tested. Fourteen percent of the entire cohort was assessed as normal in all domains.
Pyridoxine-dependent epilepsy shows autosomal recessive inheritance (Mills et al., 2006).
Plecko et al. (2007) noted that in pyridoxine-dependent epilepsy, pipecolic acid (PA) and alpha-amino adipic semialdehyde (AASA) are markedly elevated in urine, plasma, and cerebrospinal fluid, and thus can be used as biomarkers of the disorder. Pyridoxine withdrawal is no longer needed to establish the diagnosis of 'definite' EPD. Administration of pyridoxine may not only correct secondary pyridoxalphosphate (PLP) deficiency, but may also lead to a reduction of AASA and P6C (piperideine-6-carboxylate) as presumably toxic compounds.
Struys (2007) pointed out that in pyridoxine-dependent epilepsy, plasma pipecolic acid is only modestly elevated and that the elevation of AASA in urine, plasma, and cerebral spinal fluid is the most reliable basis for diagnosis. AASA dehydrogenase deficiency is the cause of pyridoxine-dependent epilepsy in a vast majority of cases; some cases are caused by hyperprolinemia II (239510).
Bok et al. (2007) reevaluated the diagnosis of pyridoxine-dependent seizures in 11 Dutch patients who had been previously been diagnosed with 'definite' (4), 'probable' (3) or 'possible' (4) EPD using clinical criteria based on questionnaires (Been et al., 2005). Using metabolic parameters, Bok et al. (2007) confirmed the disorder in all 4 with definite, 2 with probable, and 3 with possible EPD. Patients with EPD had increased plasma and urinary AASA, whereas those without the disorder had normal AASA levels. Plasma PA levels were also increased in these patients, but urinary PA was normal. Bok et al. (2007) concluded that noninvasive urinary screening for AASA accumulation is a reliable tool to diagnose EPD and can thus avoid the potentially dangerous pyridoxine withdrawal test.
Cormier-Daire et al. (2000) performed genetic linkage analysis in 5 affected families, 4 with consanguineous parents and 1 with nonconsanguineous parents. They excluded the GAD1 gene on chromosome 2q31 and the GAD2 gene (138275) on 10p23 as candidates for mutation in the disorder. A genomewide search using microsatellite markers revealed linkage to a 5.1-cM interval on chromosome 5q31.2-q31.3 (maximum lod score of 8.43 at marker D5S2017).
Bennett et al. (2005) reported 6 small Caucasian North American families with pyridoxine-dependent seizures. Haplotype analysis of 2 families with evidence suggestive of linkage to chromosome 5q31, including 1 reported by Battaglioli et al. (2000), allowed refinement of the candidate disease interval to a 2.2-cM (2.0-Mb) region between markers D5S2011 and D5S2859. Five of the 6 families showed haplotype segregation consistent with linkage to chromosome 5q31, although the lod score did not reach significance (lod of 1.87 at marker D5S2011). Linkage to chromosome 5 was excluded in 1 family, indicating genetic heterogeneity.
In affected infants from 8 unrelated families with pyridoxine-dependent epilepsy, Mills et al. (2006) identified homozygous or compound heterozygous mutations in the ALDH7A1 gene (107323.0001-107323.0007).
In 7 patients from 4 apparently unrelated Dutch families with pyridoxine-dependent epilepsy (Been et al., 2005; Bok et al., 2007), Salomons et al. (2007) identified a homozygous mutation in the ALDH7A1 gene (E399Q; 107323.0001).
Mills et al. (2006) determined that the ALDH7A1 gene product is an AASA dehydrogenase in the pipecolic acid pathway of lysine catabolism. Deficiency of the enzyme results in seizures because accumulating P6C condenses with and inactivates PLP, an essential cofactor in neurotransmitter metabolism.
Bennett et al. (2005) stated that the prevalence of pyridoxine-dependent epilepsy is estimated at 1 in 400,000 to 700,000.
Bok et al. (2007) estimated the incidence of pyridoxine-dependent seizures in the Netherlands to be 1 in 276,000.
Using CRISPR/Cas9 gene editing, Pena et al. (2017) generated an aldh7a1-null zebrafish model that recapitulated the clinical and biochemical features of EPD. Beginning at 10 days postfertilization, mutant larvae displayed features consistent with an epilepsy phenotype, including spontaneous and recurrent seizures, epileptoform electrographic activity, and early death. Treatment with pyridoxine and PLP extended life span in mutant larvae, and pyridoxine treatment also alleviated the manifestation of seizures. Mass spectrometry revealed accumulation of EPD biomarkers, including AASA and P6C, B6 vitamin deficiency, and low gamma-aminobutyric acid levels in mutant fish, indicating that the ablation of aldh7a1 disrupted lysine degradation. Lysine supplementation aggravated the epilepsy phenotype in mutant larvae, inducing earlier seizure onset and death. Combination supplementation with pyridoxine and lysine suggested the existence of a critical 'seizure-inducing' level for AASA/P6C that was reached more rapidly with lysine supplementation.
The defect in pyridoxine-dependent epilepsy had initially been proposed to reside in the glutamic acid decarboxylase-1 gene (GAD1; 605363) (Scriver and Whelan, 1969; Yoshida et al., 1971).
Bachman, D. S. Late-onset pyridoxine-dependency convulsions. Ann. Neurol. 14: 692-693, 1983. [PubMed: 6651254] [Full Text: https://doi.org/10.1002/ana.410140618]
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Been, J. V., Bok, L. A., Andriessen, P., Renier, W. O. Epidemiology of pyridoxine dependent seizures in the Netherlands. Arch. Dis. Child. 90: 1293-1296, 2005. [PubMed: 16159904] [Full Text: https://doi.org/10.1136/adc.2005.075069]
Bejsovec, M., Kulenda, Z., Ponca, E. Familial intrauterine convulsions in pyridoxine dependency. Arch. Dis. Child. 42: 201-207, 1967. [PubMed: 6024470] [Full Text: https://doi.org/10.1136/adc.42.222.201]
Bennett, C. L., Huynh, H. M., Chance, P. F., Glass, I. A., Gospe, S. M., Jr. Genetic heterogeneity for autosomal recessive pyridoxine-dependent seizures. Neurogenetics 6: 143-149, 2005. [PubMed: 16075246] [Full Text: https://doi.org/10.1007/s10048-005-0221-8]
Bok, L. A., Struys, E., Willemsen, M. A. A. P., Been, J. V., Jakobs, C. Pyridoxine-dependent seizures in Dutch patients: diagnosis by elevated urinary alpha-aminoadipic semialdehyde levels. Arch. Dis. Child. 92: 687-689, 2007. [PubMed: 17088338] [Full Text: https://doi.org/10.1136/adc.2006.103192]
Cormier-Daire, V., Dagoneau, N., Nabbout, R., Burglen, L., Penet, C, Soufflet, C., Desguerre, I., Munnich, A., Dulac, O. A gene for pyridoxine-dependent epilepsy maps to chromosome 5q31. Am. J. Hum. Genet. 67: 991-993, 2000. [PubMed: 10978228] [Full Text: https://doi.org/10.1086/303087]
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Pena, I. A., Roussel, Y., Daniel, K., Mongeon, K., Johnstone, D., Weinschutz Mendes, H., Bosma, M., Saxena, V., Lepage, N., Chakraborty, P., Dyment, D. A., van Karnebeek, C. D. M., Verhoeven-Duif, N., Bui, T. V., Boycott, K. M., Ekker, M., MacKenzie, A. Pyridoxine-dependent epilepsy in zebrafish caused by Aldh7a1 deficiency. Genetics 207: 1501-1518, 2017. [PubMed: 29061647] [Full Text: https://doi.org/10.1534/genetics.117.300137]
Plecko, B., Paul, K., Paschke, E., Stoeckler-Ipsiroglu, S., Struys, E., Jakobs, C., Hartmann, H., Luecke, T., di Capua, M., Korenke, C., Hikel, C., Reutershahn, E., Freilinger, M., Baumeister, F., Bosch, F., Erwa, W. Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Hum. Mutat. 28: 19-26, 2007. [PubMed: 17068770] [Full Text: https://doi.org/10.1002/humu.20433]
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Scriver, C. R., Whelan, D. T. Glutamic acid decarboxylase (GAD) in mammalian tissue outside the central nervous system, and its possible relevance to hereditary vitamin B6 dependency with seizures. Ann. N.Y. Acad. Sci. 166: 83-96, 1969. [PubMed: 5262035] [Full Text: https://doi.org/10.1111/j.1749-6632.1969.tb54259.x]
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Tseng, L. A., Abdenur, J. E., Andrews, A., Aziz, V. G., Bok, L. A., Boyer, M., Buhas, D., Hartmann, H., Footitt, E. J., Gronborg, S., Janssen, M. C. H., Longo, N., Lunsing, R. J., MacKenzie, A. E., Wijburg, F. A., Gospe, S. M., Jr., Coughlin, C. R., II, van Karnebeek, C. D. M. Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy. Molec. Genet. Metab. 135: 350-356, 2022. [PubMed: 35279367] [Full Text: https://doi.org/10.1016/j.ymgme.2022.02.005]
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