First cases of pyridoxine-dependent epilepsy in Bulgaria: novel mutation in the ALDH7A1 gene

Tincheva, Savina; Todorov, Tihomir; Тодорова, Албена; Georgieva, Ralica; Stamatov, Dimitar; Yordanova, Iglika; Kadiyska, Tanya; Georgieva, Bilyana; Bojidarova, Maria; Tacheva, Genoveva; Litvinenko, Ivan; Mitev, Vanio

doi:10.1007/s10072-015-2338-3

Cited by 6 publications

(3 citation statements)

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“…2). Approximately 16 cases of patients harboring one of these mutations have been reported in the literature [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. All of these patients have biallelic mutations consistent with autosomal recessive inheritance, and the majority is compound heterozygous for one of the mutations studied here.…”

Section: Introductionmentioning

confidence: 97%

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Structural and biochemical consequences of pyridoxine‐dependent epilepsy mutations that target the aldehyde binding site of aldehyde dehydrogenase ALDH7A1

et al. 2019

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In humans, certain mutations in the gene encoding aldehyde dehydrogenase 7A1 are associated with pyridoxine‐dependent epilepsy (PDE). Understanding the impact of PDE‐causing mutations on the structure and activity of ALDH7A1 could allow for the prediction of symptom‐severity and aid the development of patient‐specific medical treatments. Herein, we investigate the biochemical and structural consequences of PDE missense mutations targeting residues in the aldehyde substrate binding site: N167S, P169S, A171V, G174V, and W175G. All but G174V could be purified for biochemical and X‐ray crystallographic analysis. W175G has a relatively mild kinetic defect, exhibiting a fivefold decrease in kcat with no change in Km. P169S and N167S have moderate defects, characterized by catalytic efficiencies of 20‐ and 100‐times lower than wild‐type, respectively. A171V has a profound functional defect, with catalytic efficiency 2000‐times lower than wild‐type. The crystal structures of the variants are the first for any PDE‐associated mutant of ALDH7A1. The structures show that missense mutations that decrease the steric bulk of the side chain tend to create a cavity in the active site. The protein responds by relaxing into the vacant space, and this structural perturbation appears to cause misalignment of the aldehyde substrate in W175G and N167S. The P169S structure is nearly identical to that of the wild‐type enzyme; however, analysis of B‐factors suggests the catalytic defect may result from altered protein dynamics. The A171V structure suggests that the potential for steric clash with Val171 prevents Glu121 from ion pairing with the amino group of the aldehyde substrate. Enzymes Aldehyde dehydrogenase 7A1 (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC1/2/1/31.html). Databases Coordinates have been deposited in the Protein Data Bank under the following accession codes: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6O4B, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6O4C, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6O4D, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6O4E, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6O4F, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6O4G, http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6O4H.

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Section: Introductionmentioning

confidence: 97%

“…Herein, we investigate the biochemical and structural consequences of PDE-associated mutations that affect residues in the substrate AASAL-binding site: N167S [14][15][16][17][18][19][20][21], P169S [22,23], A171V [13,24,25], G174V [24,26,27], and W175G [22,28,29] (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

Structural and biochemical consequences of pyridoxine‐dependent epilepsy mutations that target the aldehyde binding site of aldehyde dehydrogenase ALDH7A1

et al. 2019

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“…Our search strategy yielded 497 patients with a confirmed genetic diagnosis of B6-dependent epilepsies. Of these, 90.7% (431/497) were diagnosed with the following three disorders: ALDH deficiency (69.4%), PNPO deficiency (13.2%), and PLPBP deficiency (9.2%) ( Figure 1 ) [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , ...…”

Section: Resultsmentioning

confidence: 99%

Epilepsy Phenotypes of Vitamin B6-Dependent Diseases: An Updated Systematic Review

et al. 2023

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Background: Vitamin B6-dependent epilepsies include treatable diseases responding to pyridoxine or pyridoxal-5Iphosphate (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects). Patients and methods: We conducted a systematic review of published pediatric cases with a confirmed molecular genetic diagnosis of vitamin B6-dependent epilepsy according to PRISMA guidelines. Data on demographic features, seizure semiology, EEG patterns, neuroimaging, treatment, and developmental outcomes were collected. Results: 497 published patients fulfilled the inclusion criteria. Seizure onset manifested at 59.8 ± 291.6 days (67.8% of cases in the first month of life). Clonic, tonic-clonic, and myoclonic seizures accounted for two-thirds of the cases, while epileptic spasms were observed in 7.6%. Burst-suppression/suppression-burst represented the most frequently reported specific EEG pattern (14.4%), mainly in PLPB, ALDH7A1, and PNPO deficiency. Pyridoxine was administered to 312 patients (18.5% intravenously, 76.9% orally, 4.6% not specified), and 180 also received antiseizure medications. Pyridoxine dosage ranged between 1 and 55 mg/kg/die. Complete seizure freedom was achieved in 160 patients, while a significant seizure reduction occurred in 38. PLP, lysine-restricted diet, and arginine supplementation were used in a small proportion of patients with variable efficacy. Global developmental delay was established in 30.5% of a few patients in whom neurocognitive tests were performed. Conclusions: Despite the wide variability, the most frequent hallmarks of the epilepsy phenotype in patients with vitamin B6-dependent seizures include generalized or focal motor seizure semiology and a burst suppression/suppression burst pattern in EEG.

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Novel homozygous missense mutation in ALDH7A1 causes neonatal pyridoxine dependent epilepsy

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et al. 2017

Molecular and Cellular Probes

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First cases of pyridoxine-dependent epilepsy in Bulgaria: novel mutation in the ALDH7A1 gene

Cited by 6 publications

References 10 publications

Structural and biochemical consequences of pyridoxine‐dependent epilepsy mutations that target the aldehyde binding site of aldehyde dehydrogenase ALDH7A1

Structural and biochemical consequences of pyridoxine‐dependent epilepsy mutations that target the aldehyde binding site of aldehyde dehydrogenase ALDH7A1

Epilepsy Phenotypes of Vitamin B6-Dependent Diseases: An Updated Systematic Review

Novel homozygous missense mutation in ALDH7A1 causes neonatal pyridoxine dependent epilepsy

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