Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy

Laura A. Tseng; Jose E. Abdenur; Ashley Andrews; Verena G. Aziz; Levinus A. Bok; Monica Boyer; Daniela Buhas; Hans Hartmann; Emma J. Footitt; Sabine Gronborg; Mirian C. H. Janssen; Nicola Longo; Roelineke J. Lunsing; Alex E. MacKenzie; Frits A. Wijburg; Sidney M. Gospe; Curtis R. Coughlin; Clara D. M. van Karnebeek

doi:10.1016/j.ymgme.2022.02.005

Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy

Laura A. Tseng, Jose E. Abdenur, Ashley Andrews, Verena G. Aziz, Levinus A. Bok, Monica Boyer, Daniela Buhas, Hans Hartmann, Emma J. Footitt, Sabine Gronborg, Mirian C. H. Janssen, Nicola Longo, Roelineke J. Lunsing, Alex E. MacKenzie, Frits A. Wijburg, Sidney M. Gospe, Curtis R. Coughlin, Clara D. M. van Karnebeek^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to a-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function.

Methods: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities.

Results: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains.

Conclusion: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature.

Take- home message: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome. (C) 2022 Published by Elsevier Inc.

Original language	English
Pages (from-to)	350-356
Number of pages	7
Journal	Molecular Genetics and Metabolism
Volume	135
Issue number	4
DOIs	https://doi.org/10.1016/j.ymgme.2022.02.005
Publication status	Published - Apr-2022

Keywords

Pyridoxine-dependent epilepsy
PDE-ALDH7A1
Lysine reduction therapies
Lysine-restricted diet
Arginine supplementation
Sibling study
Neurodevelopmental outcome
ARGININE SUPPLEMENTATION
ANTIQUITIN DEFICIENCY
FEATURES
DIAGNOSIS
CHILDREN
SIBLINGS
SEIZURES
SPECTRUM
DIET

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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., Coughlin, C. R., & van Karnebeek, C. D. M. (2022). Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy. Molecular Genetics and Metabolism, 135(4), 350-356. https://doi.org/10.1016/j.ymgme.2022.02.005

@article{63d3053c677f4f34a202342e3b33b377,

title = "Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy",

abstract = "Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to a-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function.Methods: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities.Results: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains.Conclusion: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature.Take- home message: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome. (C) 2022 Published by Elsevier Inc.",

keywords = "Pyridoxine-dependent epilepsy, PDE-ALDH7A1, Lysine reduction therapies, Lysine-restricted diet, Arginine supplementation, Sibling study, Neurodevelopmental outcome, ARGININE SUPPLEMENTATION, ANTIQUITIN DEFICIENCY, FEATURES, DIAGNOSIS, CHILDREN, SIBLINGS, SEIZURES, SPECTRUM, DIET",

author = "Tseng, {Laura A.} and Abdenur, {Jose E.} and Ashley Andrews and Aziz, {Verena G.} and Bok, {Levinus A.} and Monica Boyer and Daniela Buhas and Hans Hartmann and Footitt, {Emma J.} and Sabine Gronborg and Janssen, {Mirian C. H.} and Nicola Longo and Lunsing, {Roelineke J.} and MacKenzie, {Alex E.} and Wijburg, {Frits A.} and Gospe, {Sidney M.} and Coughlin, {Curtis R.} and {van Karnebeek}, {Clara D. M.}",

year = "2022",

month = apr,

doi = "10.1016/j.ymgme.2022.02.005",

language = "English",

volume = "135",

pages = "350--356",

journal = "Molecular Genetics and Metabolism",

issn = "1096-7192",

publisher = "ACADEMIC PRESS INC ELSEVIER SCIENCE",

number = "4",

}

Tseng, LA, Abdenur, JE, Andrews, A, Aziz, VG, Bok, LA, Boyer, M, Buhas, D, Hartmann, H, Footitt, EJ, Gronborg, S, Janssen, MCH, Longo, N, Lunsing, RJ, MacKenzie, AE, Wijburg, FA, Gospe, SM, Coughlin, CR & van Karnebeek, CDM 2022, 'Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy', Molecular Genetics and Metabolism, vol. 135, no. 4, pp. 350-356. https://doi.org/10.1016/j.ymgme.2022.02.005

TY - JOUR

T1 - Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy

AU - Tseng, Laura A.

AU - Abdenur, Jose E.

AU - Andrews, Ashley

AU - Aziz, Verena G.

AU - Bok, Levinus A.

AU - Boyer, Monica

AU - Buhas, Daniela

AU - Hartmann, Hans

AU - Footitt, Emma J.

AU - Gronborg, Sabine

AU - Janssen, Mirian C. H.

AU - Longo, Nicola

AU - Lunsing, Roelineke J.

AU - MacKenzie, Alex E.

AU - Wijburg, Frits A.

AU - Gospe, Sidney M.

AU - Coughlin, Curtis R.

AU - van Karnebeek, Clara D. M.

PY - 2022/4

Y1 - 2022/4

N2 - Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to a-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function.Methods: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities.Results: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains.Conclusion: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature.Take- home message: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome. (C) 2022 Published by Elsevier Inc.

AB - Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to a-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function.Methods: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities.Results: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains.Conclusion: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature.Take- home message: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome. (C) 2022 Published by Elsevier Inc.

KW - Pyridoxine-dependent epilepsy

KW - PDE-ALDH7A1

KW - Lysine reduction therapies

KW - Lysine-restricted diet

KW - Arginine supplementation

KW - Sibling study

KW - Neurodevelopmental outcome

KW - ARGININE SUPPLEMENTATION

KW - ANTIQUITIN DEFICIENCY

KW - FEATURES

KW - DIAGNOSIS

KW - CHILDREN

KW - SIBLINGS

KW - SEIZURES

KW - SPECTRUM

KW - DIET

U2 - 10.1016/j.ymgme.2022.02.005

DO - 10.1016/j.ymgme.2022.02.005

M3 - Article

SN - 1096-7192

VL - 135

SP - 350

EP - 356

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

IS - 4

ER -