Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: l-arginine supplementation alternative to lysine-restricted diet

Mercimek-Mahmutoglu, Saadet; Cordeiro, Dawn; Cruz, Vivian; Hyland, Keith; Struys, Eduard A.; Kyriakopoulou, Lianna; Mamak, Eva

doi:10.1016/j.ejpn.2014.07.001

Cited by 63 publications

(68 citation statements)

References 20 publications

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“…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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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: 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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“…This supports the hypothesis that supplemental arginine can decrease brain lysine metabolism through competitive inhibition, and suggests an additive benefit of both a lysine-restricted diet and arginine fortification in cerebral lysine disorders. Recently arginine supplementation was used as an alternative to the lysine-restricted diet in a child with PDE with a decrease in cerebral lysine and urine and CSF α-AASA levels as well as neurologic improvement [25].…”

mentioning

confidence: 99%

Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome

Coughlin

Karnebeek

Al-Hertani

et al. 2015

Molecular Genetics and Metabolism

107

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“…A lysine‐restricted diet has the potential to lower neurotoxic AASA concentrations and has become an additional treatment option for PDE (Gallagher et al ., ; Stockler et al ., ; van Karnebeek et al ., ). High‐dose arginine supplementation might be an additional option, working by competitive inhibition of lysine uptake in the gut and at the blood/brain barrier (Mercimek‐Mahmutoglu et al ., ).…”

Section: Defects Of Vitamin Metabolismmentioning

confidence: 99%

Treatable newborn and infant seizures due to inborn errors of metabolism

Campistol

Plecko

2015

Epileptic Disorders

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About 25% of seizures in the neonatal period have causes other than asphyxia, ischaemia or intracranial bleeding. Among these are primary genetic epileptic encephalopathies with sometimes poor prognosis and high mortality. In addition, some forms of neonatal infant seizures are due to inborn errors of metabolism that do not respond to common AEDs, but are amenable to specific treatment. In this situation, early recognition can allow seizure control and will prevent neurological deterioration and long‐term sequelae. We review the group of inborn errors of metabolism that lead to newborn/infant seizures and epilepsy, of which the treatment with cofactors is very different to that used in typical epilepsy management.

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Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: l-arginine supplementation alternative to lysine-restricted diet

Cited by 63 publications

References 20 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

Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome

Treatable newborn and infant seizures due to inborn errors of metabolism

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