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 - Grønborg, 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.
N1 - Funding Information:
The authors thank all patients and families for participating in the international PDE registry. We are grateful to the clinicians and laboratory specialists involved in the care for these patients, and to Mr. Roderick Houben (Health2Media) for the design of the supplementary figures. Funding support for this study was granted by Stichting Metakids NL.
Funding Information:
This project/publication is supported in part by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535. Contents are the authors' sole responsibility and do not necessarily represent official NIH views. CvK received a salary award from Stichting Metakids.
Publisher Copyright:
© 2022
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-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.
AB - Background: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-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.
KW - Arginine supplementation
KW - Lysine reduction therapies
KW - Lysine-restricted diet
KW - Neurodevelopmental outcome
KW - PDE-ALDH7A1
KW - Pyridoxine-dependent epilepsy
KW - Sibling study
UR - https://www.scopus.com/pages/publications/85125995885
U2 - 10.1016/j.ymgme.2022.02.005
DO - 10.1016/j.ymgme.2022.02.005
M3 - Article
C2 - 35279367
SN - 1096-7192
VL - 135
SP - 350
EP - 356
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 4
ER -
SDG 3 Good Health and Well-being