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Cornelis Jakobs - One of the best experts on this subject based on the ideXlab platform.
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Lysine restricted diet for Pyridoxine-Dependent Epilepsy: First evidence and future trials
Molecular genetics and metabolism, 2012Co-Authors: Clara D.m. Van Karnebeek, Curtis R. Coughlin, Sidney M. Gospe, Levinus A. Bok, Sravan Jaggumantri, Anibh M. Das, Mary B. Connolly, Hans Hartmann, Barb Cheng, Cornelis JakobsAbstract:Abstract Objective To evaluate the efficacy and safety of dietary lysine restriction as an adjunct to pyridoxine therapy on biochemical parameters, seizure control, and developmental/cognitive outcomes in children with Pyridoxine-Dependent Epilepsy (PDE) caused by antiquitin (ATQ) deficiency. Methods In this observational study, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring. Biochemical outcomes were evaluated using pipecolic acid and α-aminoadipic semialdehyde (AASA) levels in body fluids; developmental/cognitive outcomes were evaluated using age-appropriate tests and parental observations. Results Lysine restriction was well tolerated with good compliance; no adverse events were reported. Reduction in biomarker levels (measurement of the last value before and first value after initiation of dietary lysine restriction) ranged from 20 to 67% for plasma pipecolic acid, 13 to 72% for urinary AASA, 45% for plasma AASA and 42% for plasma P6C. For the 1 patient in whom data were available and who showed clinical deterioration upon interruption of diet, cerebrospinal fluid levels decreased by 87.2% for pipecolic acid and 81.7% for AASA. Improvement in age-appropriate skills was observed in 4 out of 5 patients showing pre-diet delays, and seizure control was maintained or improved in 6 out 7 children. Conclusions This observational study provides Level 4 evidence that lysine restriction is well tolerated with significant decrease of potentially neurotoxic biomarkers in different body compartments, and with the potential to improve developmental outcomes in children with PDE caused by ATQ deficiency. To generate a strong level of evidence before this potentially burdensome dietary therapy becomes the mainstay treatment, we have established: an international PDE consortium to conduct future studies with an all-inclusive integrated study design; a website containing up-to-date information on PDE; a methodological toolbox; and an online registry to facilitate the participation of interested physicians, scientists, and families in PDE research.
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Long-term outcome in Pyridoxine-Dependent Epilepsy
Developmental medicine and child neurology, 2012Co-Authors: Levinus A. Bok, Eduard A. Struys, Cornelis Jakobs, F.j. Halbertsma, Saskia Houterman, Ron A. Wevers, C.m.j.m. Vreeswijk, Johan H Van Der Hoeven, Deborah A Sival, Michèl A.a.p. WillemsenAbstract:Aim The long-term outcome of the Dutch Pyridoxine-Dependent Epilepsy cohort and correlations between patient characteristics and follow-up data were retrospectively studied. Method Fourteen patients recruited from a national reference laboratory were included (four males, 10 females, from 11 families; median age at assessment 6y; range 2y 6mo-16y). The following data were retrieved: sex; age at seizure onset; age at the start of pyridoxine therapy; level of urinary alpha-aminoadipic semialdehyde; antiquitin mutations; developmental milestones; evaluation of neurocognitive functioning and school career; magnetic resonance imaging (MRI) and electroencephalography (EEG) assessments. Results Pyridoxine was started antenatally in two children, in the first week of life in five, in the first month of life in three, or after the first month of life (range 2.5-8mo) in four. No child was physically disabled; however, only five walked at 2 years of age. Mental development was delayed in most: median IQ or developmental index was 72 (SD 19). Pyridoxine monotherapy controlled seizures in 10 of 14 children, whereas four needed additional antiepileptic drugs. Seizure persistence, antiepileptic drugs (other than pyridoxine), EEG background, and epileptiform activity were not associated with outcome. On neonatal MRI, structural and white matter abnormalities occurred in five of eight children; on follow-up, the number of abnormal MRIs was increased. Delayed initiation of pyridoxine medication and corpus callosum abnormalities were significantly associated with unfavourable neurodevelopmental outcome, but normal follow-up imaging did not predict a good outcome. Interpretation Outcome of patients with Pyridoxine-Dependent Epilepsy remains poor. Individual outcome cannot be predicted by the evaluated characteristics. We suggest that collaborated research in structured settings could help to improve treatment strategies and outcome for Pyridoxine-Dependent Epilepsy.
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Profound Neonatal Hypoglycemia and Lactic Acidosis Caused by Pyridoxine-Dependent Epilepsy
Pediatrics, 2012Co-Authors: Saadet Mercimek-mahmutoglu, Paula J Waters, Eduard A. Struys, Sylvia Stockler-ipsiroglu, Cornelis Jakobs, Gabriella Horvath, Marion B. Coulter-mackie, Tanya N. Nelson, Michael A. Sargent, Mary B. ConnollyAbstract:Pyridoxine-Dependent Epilepsy (PDE) was first described in 1954. The ALDH7A1 gene mutations resulting in α-aminoadipic semialdehyde dehydrogenase deficiency as a cause of PDE was identified only in 2005. Neonatal epileptic encephalopathy is the presenting feature in >50% of patients with classic PDE. We report the case of a 13-month-old girl with profound neonatal hypoglycemia (0.6 mmol/L; reference range >2.4), lactic acidosis (11 mmol/L; reference range A (p.Val278Val), and a novel putative pathogenic missense mutation c.1192G>C (p.Gly398Arg) in the ALDH7A1 gene. She has been seizure-free since 1.5 months of age on treatment with pyridoxine alone. She has motor delay and central hypotonia but normal language and social development at the age of 13 months. This case is the first description of a patient with PDE due to mutations in the ALDH7A1 gene who presented with profound neonatal hypoglycemia and lactic acidosis masquerading as a neonatal-onset gluconeogenesis defect. PDE should be included in the differential diagnosis of hypoglycemia and lactic acidosis in addition to medically refractory neonatal seizures.
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urinary aasa excretion is elevated in patients with molybdenum cofactor deficiency and isolated sulphite oxidase deficiency
Journal of Inherited Metabolic Disease, 2012Co-Authors: Philippa B Mills, Paula J Waters, Cornelis Jakobs, Peter E Clayton, Emma Footitt, Serkan Ceyhan, Eduard A. StruysAbstract:Analysis of α-aminoadipic semialdehyde is an important tool in the diagnosis of antiquitin deficiency (Pyridoxine-Dependent Epilepsy). However continuing use of this test has revealed that elevated urinary excretion of α-aminoadipic semialdehyde is not only found in patients with Pyridoxine-Dependent Epilepsy but is also seen in patients with molybdenum cofactor deficiency and isolated sulphite oxidase deficiency. This should be taken into account when interpreting the laboratory data. Sulphite was shown to inhibit α-aminoadipic semialdehyde dehydrogenase in vitro.
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Roth spots in pyridoxine dependent Epilepsy
BMJ case reports, 2011Co-Authors: Levinus A. Bok, Cornelis Jakobs, F.j. Halbertsma, F.t. Kerkhoff, Carola E. P. M. Duijsters, Michèl A.a.p. WillemsenAbstract:Pyridoxine dependent Epilepsy (PDE) is a rare metabolic defect in the degradation of lysine. The authors report a patient with metabolic and DNA confirmed PDE, on the fifth day of life ophthalmoscopy showed bilateral multiple white centred retinal haemorrhages, so called Roth spots. Roth spots are non-specific haemorrhagic signs that occur in a variety of conditions of acute systemic insults in homeostasis – most often infections- which relate to retinal capillary damage and the ensuing reparative process. No biochemical or microbiological signs of infection were present in blood and liquor. MRI of the brain showed an abnormal diffusion signal with increased apparent diffusion coefficient and little blood around the tentorium. The knowledge of the pathogenesis of PDE is still limited. The presence of Roth spots is suggestive for a pathogenic mechanism of vasogenic damage in PDE.
Eduard A. Struys - One of the best experts on this subject based on the ideXlab platform.
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Phenotype, biochemical features, genotype and treatment outcome of Pyridoxine-Dependent Epilepsy
Metabolic brain disease, 2016Co-Authors: Amal Al Teneiji, Eduard A. Struys, Theodora Bruun, Dawn Cordeiro, Jaina Patel, Michal Inbar-feigenberg, Shelly K. Weiss, Saadet Mercimek-mahmutogluAbstract:We report treatment outcome of eleven patients with Pyridoxine-Dependent Epilepsy caused by pathogenic variants in ALDH7A1 (PDE-ALDH7A1). We developed a clinical severity score to compare phenotype with biochemical features, genotype and delays in the initiation of pyridoxine. Clinical severity score included 1) global developmental delay/ intellectual disability; 2) age of seizure onset prior to pyridoxine; 3) current seizures on treatment. Phenotype scored 1–3 = mild; 4–6 = moderate; and 7–9 = severe. Five patients had mild, four patients had moderate, and two patients had severe phenotype. Phenotype ranged from mild to severe in eight patients (no lysine-restricted diet in the infantile period) with more than 10-fold elevated urine or plasma α-AASA levels. Phenotype ranged from mild to moderate in patients with homozygous truncating variants and from moderate to severe in patients with homozygous missense variants. There was no correlation between severity of the phenotype and the degree of α-AASA elevation in urine or genotype. All patients were on pyridoxine, nine patients were on arginine and five patients were on the lysine-restricted diet. 73% of the patients became seizure free on pyridoxine. 25% of the patients had a mild phenotype on pyridoxine monotherapy. Whereas, 100% of the patients, on the lysine-restricted diet initiated within their first 7 months of life, had a mild phenotype. Early initiation of lysine-restricted diet and/or arginine therapy likely improved neurodevelopmental outcome in young patients with PDE-ALDH7A1.
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A Prospective Case Study of the Safety and Efficacy of Lysine-Restricted Diet and Arginine Supplementation Therapy in a Patient With Pyridoxine-Dependent Epilepsy Caused by Mutations in ALDH7A1
Pediatric neurology, 2016Co-Authors: Muhammad Mahajnah, Eduard A. Struys, Dawn Corderio, Carly Mutch, Melissa T. Carter, Valerie Austin, Sarah Herd, Saadet Mercimek-mahmutogluAbstract:Abstract Background Pyridoxine-Dependent Epilepsy (PDE) is caused by mutations in ALDH7A1 (PDE- ALDH7A1 ), which encodes α-aminoadipic semialdehyde dehydrogenase in the lysine catabolic pathway, resulting in accumulation of α-aminoadipic-acid-semialdehyde. Patient Description and Results We present a three-year treatment outcome of a child with PDE- ALDH7A1 on pyridoxine (started at age three weeks of age), lysine-restricted diet (started at age seven months), and arginine supplementation therapy (started at age 26 months). He had a markedly elevated urinary α-aminoadipic-acid-semialdehyde (39.6 mmol/mol of creatinine; reference range = 0 to 2) and compound heterozygous mutations in ALDH7A1 (c.446C>A and c.919C>T). He has been seizure free since the age three weeks. He achieved normal cognitive function at age 3.5 years. He exhibited gross motor delay after the age 13 months. Tryptophan supplementation was added for the mild cerebral serotonin deficiency at the thirteenth month of therapy. Arginine supplementation was added to achieve further decrease in the cerebrospinal fluid α-aminoadipic-acid-semialdehyde levels at the 26th month of therapy. His cerebrospinal fluid α-aminoadipic-acid-semialdehyde levels were markedly decreased on this combined therapy. Conclusions This treatment was well tolerated. Mild cerebral serotonin deficiency was the only biochemical effect with no clinical features. Despite excellent compliance and strict treatment regimen, cerebrospinal fluid α-aminoadipic-acid-semialdehyde levels did not normalize.
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Novel therapy for pyridoxine dependent Epilepsy due to ALDH7A1 genetic defect: L-arginine supplementation alternative to lysine-restricted diet.
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2014Co-Authors: Saadet Mercimek-mahmutoglu, Keith Hyland, Eduard A. Struys, Dawn Cordeiro, Lianna Kyriakopoulou, Vivian Cruz, Eva MamakAbstract:Abstract Background and hypothesis Pyridoxine dependent Epilepsy (PDE) due to mutations in the ALDH7A1 gene (PDE- ALDH7A1 ) is caused by α-aminoadipic-semialdehyde-dehydrogenase enzyme deficiency in the lysine pathway resulting in the accumulation of α-aminoadipic acid semialdehyde (α-AASA). Classical presentation is neonatal intractable seizures with a dramatic response to pyridoxine. Pyridoxine therapy does not prevent developmental delays in the majority of the patients. We hypothesized that l -arginine supplementation will decrease accumulation of α-AASA by competitive inhibition of lysine transport into the central nervous system and improve neurodevelopmental and neurocognitive functions in PDE- ALDH7A1. Methods A 12-year-old male with PDE- ALDH7A1 was treated with l -arginine supplementation as an innovative therapy. Treatment outcome was monitored by cerebral-spinal-fluid (CSF) α-AASA measurements at baseline, 6th and 12th months of therapy. Neuropsychological assessments were performed at baseline and 12th months of therapy. Results l -arginine therapy was well tolerated without side effects. CSF α-AASA was decreased 57% at 12th months of therapy. Neuropsychological assessments revealed improvements in general abilities index from 108 to 116 and improvements in verbal and motor functioning at 12th months of therapy. Conclusion The short-term treatment outcome of this novel l -arginine supplementation therapy for PDE- ALDH7A1 was successful for biochemical and neurocognitive improvements.
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Lysine-restricted diet and mild cerebral serotonin deficiency in a patient with Pyridoxine-Dependent Epilepsy caused by ALDH7A1 genetic defect.
Molecular genetics and metabolism reports, 2014Co-Authors: Saadet Mercimek-mahmutoglu, Eduard A. Struys, Dawn Corderio, Laura Nagy, Carly Mutch, Melissa T. Carter, Lianna KyriakopoulouAbstract:Abstract Pyridoxine dependent Epilepsy (PDE) is caused by mutations in the ALDH7A1 gene (PDE-ALDH7A1) encoding α-aminoadipic-semialdehyde-dehydrogenase enzyme in the lysine catabolic pathway resulting in an accumulation of α-aminoadipic-acid-semialdehyde (α-AASA). We present the one-year treatment outcome of a patient on a lysine-restricted diet. Serial cerebral-spinal-fluid (CSF) α-AASA and CSF pipecolic-acid levels showed decreased levels but did not normalize. He had a normal neurodevelopmental outcome on a lysine-restricted diet. Despite normal CSF and plasma tryptophan levels and normal tryptophan intake, he developed mild CSF serotonin deficiency at one year of therapy. Stricter lysine restriction would be necessary to normalize CSF α-AASA levels, but might increase the risks associated with the diet. Patients are at risk of cerebral serotonin deficiency and should be monitored by CSF neurotransmitter measurements.
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Pyridoxine-Dependent Epilepsy with elevated urinary α-amino adipic semialdehyde in molybdenum cofactor deficiency.
Pediatrics, 2012Co-Authors: Eduard A. Struys, Gajja S. Salomons, B Nota, A Bakkali, Saad Al Shahwan, Brahim TabarkiAbstract:α-Amino adipic semialdehyde (α-AASA) accumulates in body fluids from patients with Pyridoxine-Dependent Epilepsy because of mutations in antiquitin (ALDH7A1) and serves as the biomarker for this condition. We have recently found that the urinary excretion of α-AASA was also increased in molybdenum cofactor and sulfite oxidase deficiencies. The seizures in Pyridoxine-Dependent Epilepsy are caused by lowered cerebral levels of pyridoxal-5-phosphate (PLP), the bioactive form of pyridoxine (vitamin B(6)), which can be corrected by the supplementation of pyridoxine. The nonenzymatic trapping of PLP by the cyclic form of α-AASA is causative for the lowered cerebral PLP levels. We describe 2 siblings with clinically evident pyridoxine-responsive seizures associated with increased urinary excretion of α-AASA. Subsequent metabolic investigations revealed several metabolic abnormities, all indicative for molybdenum cofactor deficiency. Molecular investigations indeed revealed a known homozygous mutation in the MOCS2 gene. Based upon the clinically evident pyridoxine-responsive seizures in these 2 siblings, we recommend considering pyridoxine supplementation to patients affected with molybdenum cofactor or sulfite oxidase deficiencies.
Levinus A. Bok - One of the best experts on this subject based on the ideXlab platform.
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Consensus guidelines for the diagnosis and management of Pyridoxine-Dependent Epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency
Journal of inherited metabolic disease, 2020Co-Authors: Curtis R. Coughlin, Levinus A. Bok, Peter E Clayton, Daniela Buhas, Laura A. Tseng, Jose E. Abdenur, Catherine Ashmore, François Boemer, Monica Boyer, Anibh M. DasAbstract:Pyridoxine-Dependent Epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided. This article is protected by copyright. All rights reserved.
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Geometric morphometrics reveal altered corpus callosum shape in Pyridoxine-Dependent Epilepsy.
Neurology, 2018Co-Authors: Gabriela Oesch, Sandra L. Poliachik, Seth D. Friedman, Christopher B. Budech, Levinus A. Bok, A. Murat Maga, Jason N. Wright, Sidney M. GospeAbstract:Objective To evaluate the features and maturational changes in overall callosal shape in patients with Pyridoxine-Dependent Epilepsy (PDE). Methods Measurements were conducted through landmark-based geometric morphometrics applied on cerebral MRIs of patients with PDE and age-matched control subjects. The outline of the corpus callosum was manually traced in the midsagittal plane. Three hundred semi-landmarks along the outline were collected and underwent statistical generalized Procrustes analysis. An allometric regression was applied to evaluate the callosal shape due to growth over time. Results Thirty-eight patients with PDE and 38 age- and sex-matched control subjects were included. Mean age at the time of the MRI in the patient group was 9.3 years (median 6.3 years, range 0.01–48 years). Significant differences ( p p p Conclusions Patients with PDE show an altered callosal shape and variations in callosal ontogeny, which are likely secondary to the underlying genetic defect with abnormal function of antiquitin, the product of the ALDH7A1 gene.
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Callosal alterations in Pyridoxine-Dependent Epilepsy.
Developmental medicine and child neurology, 2014Co-Authors: Seth D. Friedman, Sandra L. Poliachik, Andrew Poliakov, Gisele E. Ishak, Dennis W. W. Shaw, Levinus A. Bok, Michèl A.a.p. Willemsen, Randolph K. Otto, Sidney M. GospeAbstract:AIM: While there have been isolated reports of callosal morphology differences in Pyridoxine-Dependent Epilepsy (PDE), a rare autosomal disorder caused by ALDH7A1 gene mutations, no study has systematically evaluated callosal features in a large sample of patients. This study sought to overcome this knowledge gap. METHOD: Spanning a wide age range from birth to 48 years, corpus callosum morphology and cross-sectional cerebral area were measured in 30 individuals with PDE (12 males, 18 females, median age 3.92y; 25th centile 0.27, 75th centile 15.25) compared to 30 age-matched comparison individuals (11 males, 19 females, median age 3.85y; 25th centile 0.26, 75th centile 16.00). Individuals with PDE were also divided into age groups to evaluate findings across development. As delay to treatment may modulate clinical severity, groups were stratified by treatment delay (less than or greater than 2wks from birth). RESULTS: Markedly reduced callosal area expressed as a ratio of mid-sagittal cerebral area was observed for the entire group with PDE (p 10y) demonstrated posterior abnormalities to be a consistent feature, with anterior regions increasingly involved across the developmental trajectory. Splitting the PDE group by treatment lag did not reveal overall or sub-region callosal differences. INTERPRETATION: Callosal abnormalities are a common feature of PDE not explained by treatment lag. Future work utilizing tract-based approaches to understand inter- and intra-hemispheric connectivity patterns will help in the better understanding the structural aspects of this disease.
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Lysine-Restricted Diet as Adjunct Therapy for Pyridoxine-Dependent Epilepsy: The PDE Consortium Consensus Recommendations
JIMD reports, 2014Co-Authors: Clara D.m. Van Karnebeek, Sylvia Stockler-ipsiroglu, Curtis R. Coughlin, Levinus A. Bok, Peter Baxter, Sravan Jaggumantri, Birgit Assmann, Daniela Buhas, Barbara Cheng, Anibh M. DasAbstract:Background: Seventy-five percent of patients with Pyridoxine-Dependent Epilepsy (PDE) due to Antiquitin (ATQ) deficiency suffer from developmental delay and/or intellectual disability (IQ < 70) despite seizure control. An observational study showed that adjunct treatment with a lysine-restricted diet is safe, results in partial normalization of lysine intermediates in body fluids, and may have beneficial effects on seizure control and psychomotor development.
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Lysine restricted diet for Pyridoxine-Dependent Epilepsy: First evidence and future trials
Molecular genetics and metabolism, 2012Co-Authors: Clara D.m. Van Karnebeek, Curtis R. Coughlin, Sidney M. Gospe, Levinus A. Bok, Sravan Jaggumantri, Anibh M. Das, Mary B. Connolly, Hans Hartmann, Barb Cheng, Cornelis JakobsAbstract:Abstract Objective To evaluate the efficacy and safety of dietary lysine restriction as an adjunct to pyridoxine therapy on biochemical parameters, seizure control, and developmental/cognitive outcomes in children with Pyridoxine-Dependent Epilepsy (PDE) caused by antiquitin (ATQ) deficiency. Methods In this observational study, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring. Biochemical outcomes were evaluated using pipecolic acid and α-aminoadipic semialdehyde (AASA) levels in body fluids; developmental/cognitive outcomes were evaluated using age-appropriate tests and parental observations. Results Lysine restriction was well tolerated with good compliance; no adverse events were reported. Reduction in biomarker levels (measurement of the last value before and first value after initiation of dietary lysine restriction) ranged from 20 to 67% for plasma pipecolic acid, 13 to 72% for urinary AASA, 45% for plasma AASA and 42% for plasma P6C. For the 1 patient in whom data were available and who showed clinical deterioration upon interruption of diet, cerebrospinal fluid levels decreased by 87.2% for pipecolic acid and 81.7% for AASA. Improvement in age-appropriate skills was observed in 4 out of 5 patients showing pre-diet delays, and seizure control was maintained or improved in 6 out 7 children. Conclusions This observational study provides Level 4 evidence that lysine restriction is well tolerated with significant decrease of potentially neurotoxic biomarkers in different body compartments, and with the potential to improve developmental outcomes in children with PDE caused by ATQ deficiency. To generate a strong level of evidence before this potentially burdensome dietary therapy becomes the mainstay treatment, we have established: an international PDE consortium to conduct future studies with an all-inclusive integrated study design; a website containing up-to-date information on PDE; a methodological toolbox; and an online registry to facilitate the participation of interested physicians, scientists, and families in PDE research.
Saadet Mercimek-mahmutoglu - One of the best experts on this subject based on the ideXlab platform.
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Phenotype, biochemical features, genotype and treatment outcome of Pyridoxine-Dependent Epilepsy
Metabolic brain disease, 2016Co-Authors: Amal Al Teneiji, Eduard A. Struys, Theodora Bruun, Dawn Cordeiro, Jaina Patel, Michal Inbar-feigenberg, Shelly K. Weiss, Saadet Mercimek-mahmutogluAbstract:We report treatment outcome of eleven patients with Pyridoxine-Dependent Epilepsy caused by pathogenic variants in ALDH7A1 (PDE-ALDH7A1). We developed a clinical severity score to compare phenotype with biochemical features, genotype and delays in the initiation of pyridoxine. Clinical severity score included 1) global developmental delay/ intellectual disability; 2) age of seizure onset prior to pyridoxine; 3) current seizures on treatment. Phenotype scored 1–3 = mild; 4–6 = moderate; and 7–9 = severe. Five patients had mild, four patients had moderate, and two patients had severe phenotype. Phenotype ranged from mild to severe in eight patients (no lysine-restricted diet in the infantile period) with more than 10-fold elevated urine or plasma α-AASA levels. Phenotype ranged from mild to moderate in patients with homozygous truncating variants and from moderate to severe in patients with homozygous missense variants. There was no correlation between severity of the phenotype and the degree of α-AASA elevation in urine or genotype. All patients were on pyridoxine, nine patients were on arginine and five patients were on the lysine-restricted diet. 73% of the patients became seizure free on pyridoxine. 25% of the patients had a mild phenotype on pyridoxine monotherapy. Whereas, 100% of the patients, on the lysine-restricted diet initiated within their first 7 months of life, had a mild phenotype. Early initiation of lysine-restricted diet and/or arginine therapy likely improved neurodevelopmental outcome in young patients with PDE-ALDH7A1.
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A Prospective Case Study of the Safety and Efficacy of Lysine-Restricted Diet and Arginine Supplementation Therapy in a Patient With Pyridoxine-Dependent Epilepsy Caused by Mutations in ALDH7A1
Pediatric neurology, 2016Co-Authors: Muhammad Mahajnah, Eduard A. Struys, Dawn Corderio, Carly Mutch, Melissa T. Carter, Valerie Austin, Sarah Herd, Saadet Mercimek-mahmutogluAbstract:Abstract Background Pyridoxine-Dependent Epilepsy (PDE) is caused by mutations in ALDH7A1 (PDE- ALDH7A1 ), which encodes α-aminoadipic semialdehyde dehydrogenase in the lysine catabolic pathway, resulting in accumulation of α-aminoadipic-acid-semialdehyde. Patient Description and Results We present a three-year treatment outcome of a child with PDE- ALDH7A1 on pyridoxine (started at age three weeks of age), lysine-restricted diet (started at age seven months), and arginine supplementation therapy (started at age 26 months). He had a markedly elevated urinary α-aminoadipic-acid-semialdehyde (39.6 mmol/mol of creatinine; reference range = 0 to 2) and compound heterozygous mutations in ALDH7A1 (c.446C>A and c.919C>T). He has been seizure free since the age three weeks. He achieved normal cognitive function at age 3.5 years. He exhibited gross motor delay after the age 13 months. Tryptophan supplementation was added for the mild cerebral serotonin deficiency at the thirteenth month of therapy. Arginine supplementation was added to achieve further decrease in the cerebrospinal fluid α-aminoadipic-acid-semialdehyde levels at the 26th month of therapy. His cerebrospinal fluid α-aminoadipic-acid-semialdehyde levels were markedly decreased on this combined therapy. Conclusions This treatment was well tolerated. Mild cerebral serotonin deficiency was the only biochemical effect with no clinical features. Despite excellent compliance and strict treatment regimen, cerebrospinal fluid α-aminoadipic-acid-semialdehyde levels did not normalize.
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Pyridoxine dependent Epilepsy: Seizure onset, seizure types and EEG features
Journal of Pediatric Epilepsy, 2015Co-Authors: Amrita Machado, Serap Vural, Saadet Mercimek-mahmutogluAbstract:Pyridoxine dependent Epilepsy (PDE) is an autosomal recessively inherited disorder. It is caused by mutations in the ALDH7A1 gene (PDE-ALDH7A1) encoding the alpha-aminoadipic semialdehyde dehydrogenase enzyme in the lysine catabolic pathway. The alpha-aminoadipic semialdehyde dehydrogenase enzyme deficiency leads to accumulation of alpha-aminoadipic semialdehyde and piperidine 6-carboxylic acid, the latter inactivates pyridoxal-5-phosphate. The majority of the patients present with neonatal onset intractable seizures with a dramatic response to pyridoxine therapy. Later seizure onset up to 3 yr of age has been reported too. Generalized tonic-clonic seizures are the most common seizure type. The treatment of PDE consists of high dose pyridoxine supplementation therapy. Since the underlying genetic defect was identified in the lysine catabolic pathway, few patients were treated with lysine-restricted diet to decrease, likely neurotoxic, alpha-aminoadipic semialdehyde and piperidine 6-carboxylic acid accumulation in the central nervous system.
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Novel therapy for pyridoxine dependent Epilepsy due to ALDH7A1 genetic defect: L-arginine supplementation alternative to lysine-restricted diet.
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2014Co-Authors: Saadet Mercimek-mahmutoglu, Keith Hyland, Eduard A. Struys, Dawn Cordeiro, Lianna Kyriakopoulou, Vivian Cruz, Eva MamakAbstract:Abstract Background and hypothesis Pyridoxine dependent Epilepsy (PDE) due to mutations in the ALDH7A1 gene (PDE- ALDH7A1 ) is caused by α-aminoadipic-semialdehyde-dehydrogenase enzyme deficiency in the lysine pathway resulting in the accumulation of α-aminoadipic acid semialdehyde (α-AASA). Classical presentation is neonatal intractable seizures with a dramatic response to pyridoxine. Pyridoxine therapy does not prevent developmental delays in the majority of the patients. We hypothesized that l -arginine supplementation will decrease accumulation of α-AASA by competitive inhibition of lysine transport into the central nervous system and improve neurodevelopmental and neurocognitive functions in PDE- ALDH7A1. Methods A 12-year-old male with PDE- ALDH7A1 was treated with l -arginine supplementation as an innovative therapy. Treatment outcome was monitored by cerebral-spinal-fluid (CSF) α-AASA measurements at baseline, 6th and 12th months of therapy. Neuropsychological assessments were performed at baseline and 12th months of therapy. Results l -arginine therapy was well tolerated without side effects. CSF α-AASA was decreased 57% at 12th months of therapy. Neuropsychological assessments revealed improvements in general abilities index from 108 to 116 and improvements in verbal and motor functioning at 12th months of therapy. Conclusion The short-term treatment outcome of this novel l -arginine supplementation therapy for PDE- ALDH7A1 was successful for biochemical and neurocognitive improvements.
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Long-Term Treatment Outcome of two Patients With Pyridoxine-Dependent Epilepsy Caused byALDH7A1 Mutations: Normal Neurocognitive Outcome
Journal of child neurology, 2014Co-Authors: Enas Nasr, Eva Mamak, Anette Feigenbaum, Elizabeth J. Donner, Saadet Mercimek-mahmutogluAbstract:Pyridoxine-Dependent Epilepsy is an autosomal recessively inherited disorder of lysine catabolism caused by mutations in the ALDH7A1 gene. We report 2 patients with normal neurocognitive outcome (full-scale IQ of 108 and 74) and their more than 10 years’ treatment outcome on pyridoxine monotherapy. Both patients had specific borderline impairments in visual processing speed. More long-term treatment outcome reports will increase our knowledge about the natural history of the disease.
Gabriele Wohlrab - One of the best experts on this subject based on the ideXlab platform.
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Seizures and paroxysmal events: symptoms pointing to the diagnosis of Pyridoxine-Dependent Epilepsy and pyridoxine phosphate oxidase deficiency.
Developmental medicine and child neurology, 2010Co-Authors: Bernhard Schmitt, Matthias R. Baumgartner, Cornelis Jakobs, Peter E Clayton, Philippa B Mills, Elmar Keller, Gabriele WohlrabAbstract:AimWe report on seizures, paroxysmal events, and electroencephalogram (EEG) findings in four female infants with Pyridoxine-Dependent Epilepsy (PDE) and in one female with pyridoxine phosphate oxidase deficiency (PNPO).MethodVideos and EEGs were analysed and compared with videos of seizures and paroxysmal events archived from 140 neonates. PDE and PNPO were proven by complete control of seizures once pyridoxine or pyridoxal 5'-phosphate was administered and by recurrence when withdrawn. Mutations in the antiquitin gene were found in three patients and in the PNPO gene in one child.ResultsSeizures began within 48 hours after birth in four newborns and at age 3 weeks in one. Frequent multifocal and generalized myoclonic jerks, often intermixed with tonic symptoms, abnormal eye movement, grimacing, or irritability, were observed in all infants with PDE and PNPO, but rarely in the other archived videos of neonates. EEGs were inconstant and frequently no discernable ictal changes were recorded during the seizures and the paroxysmal events. In addition, interictal EEGs were inconclusive, with normal and abnormal recordings. In older children tonic-clonic seizures, abnormal behaviour, inconsolable crying, frightened facial expression, sleep disturbance, loss of consciousness, paraesthesia, or intermittent visual symptoms were described during controlled and uncontrolled withdrawal or insufficient dosage.InterpretationPDE or PNPO should be considered in infants with prolonged episodes of mixed multifocal myoclonic tonic symptoms, notably when associated with grimacing and abnormal eye movements.
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V11 Poster location 011 Seizures in infants with Pyridoxine-Dependent Epilepsy and pyridoxine phosphate oxidase deficiency
European Journal of Paediatric Neurology, 2009Co-Authors: Bernhard Schmitt, Matthias R. Baumgartner, Ph. Mills, Elmar Keller, Gabriele WohlrabAbstract:Introduction: We report on seizure symptoms and EEGfindings in 4 infants with Pyridoxine-Dependent Epilepsy (PDE) and in one with pyridoxine phosphate oxidase deficiency (PNPO). Methods: Seizure videos and EEG were analysed and compared with seizure videos from our neonatal archive. PDE and PNPO was proven by response to pyridoxine or pyridoxal 5′-phosphate and by relapse after withdrawal. Mutations in the antiquitin gene were found in 3 patients and in the PNPO gene in 1 child. Results: Prolonged erratic multifocal or generalised myoclonic jerks were observed in all infants as well as abnormal eye movements, grimacing, focal or generalised tonic symptoms, crying and irritability. Symptoms often occurred intermixed and with variable intensity. None of >100 archived neonatal seizures of different aetiologies showed a comparable mix of seizure symptoms. In 2 older infants irritability, inconsolable crying and frightful facial expression was the prominent symptom during withdrawal. Divers visual symptoms occurred in a 4 year old child with PNPO (probably because of underdosing) and were suspected in a 14 month old child with PDE during withdrawal. Ictal EEG was very variable. Beside continuous spike wave discharges or suppression burst pattern we registered multifocal sharp waves, intermittent prolonged periods of suppression or even normal EEG activity during the seizures. Conclusion: PDE or PNPO should be considered in infants with prolonged seizures with mixed multifocal myoclonic tonic symptoms, often associated with grimacing and abnormal eye movements.
