Lysine-restricted diet and mild cerebral serotonin deficiency in a patient with pyridoxine-dependent epilepsy caused by ALDH7A1 genetic defect

Mercimek-Mahmutoglu, Saadet; Corderio, Dawn; Nagy, Laura; Mutch, Carly; Carter, Melissa; Struys, Eduard A.; Kyriakopoulou, Lianna

doi:10.1016/j.ymgmr.2014.02.001

Cited by 23 publications

(27 citation statements)

References 11 publications

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“…The treated PNPO deficient patient has normal neurodevelopment at the age of 1 year and has been seizure‐free on pyridoxal‐5‐phosphate monotherapy since the neonatal period . The PDE‐ ALDH7A1 patient has mild gait ataxia with normal cognitive functions at the age of 2 and a half years and has been seizure‐free on pyridoxine monotherapy and lysine‐restricted diet . The cobalamin G–deficient patient has mild GDD at the age of 3 years and has been seizure‐free since 4 months of age on hydroxycobalamin and betaine therapy.…”

Section: Resultsmentioning

confidence: 99%

“…9 The PDE-ALDH7A1 patient has mild gait ataxia with normal cognitive functions at the age of 2 and a half years and has been seizure-free on pyridoxine monotherapy and lysinerestricted diet. 11 The cobalamin G-deficient patient has mild GDD at the age of 3 years and has been seizure-free since 4 months of age on hydroxycobalamin and betaine therapy. The severe MTHFR-deficient patient showed improvements in developmental milestones after commencing of betaine therapy, but has subsequently moved to another part of the country and lost to follow-up.…”

Section: Resultsmentioning

confidence: 99%

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Diagnostic yield of genetic testing in epileptic encephalopathy in childhood

et al. 2015

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Summary Objective Epilepsy is a common neurologic disorder of childhood. To determine the genetic diagnostic yield in epileptic encephalopathy, we performed a retrospective cohort study in a single epilepsy genetics clinic. Methods We included all patients with intractable epilepsy, global developmental delay, and cognitive dysfunction seen between January 2012 and June 2014 in the Epilepsy Genetics Clinic. Electronic patient charts were reviewed for clinical features, neuroimaging, biochemical investigations, and molecular genetic investigations including targeted next‐generation sequencing of epileptic encephalopathy genes. Results Genetic causes were identified in 28% of the 110 patients: 7% had inherited metabolic disorders including pyridoxine dependent epilepsy caused by ALDH7A1 mutation, Menkes disease, pyridox(am)ine‐5‐phosphate oxidase deficiency, cobalamin G deficiency, methylenetetrahydrofolate reductase deficiency, glucose transporter 1 deficiency, glycine encephalopathy, and pyruvate dehydrogenase complex deficiency; 21% had other genetic causes including genetic syndromes, pathogenic copy number variants on array comparative genomic hybridization, and epileptic encephalopathy related to mutations in the SCN1A, SCN2A, SCN8A, KCNQ2, STXBP1, PCDH19, and SLC9A6 genes. Forty‐five percent of patients obtained a genetic diagnosis by targeted next‐generation sequencing epileptic encephalopathy panels. It is notable that 4.5% of patients had a treatable inherited metabolic disease. Significance To the best of our knowledge, this is the first study to combine inherited metabolic disorders and other genetic causes of epileptic encephalopathy. Targeted next‐generation sequencing panels increased the genetic diagnostic yield from <10% to >25% in patients with epileptic encephalopathy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Diagnostic yield of genetic testing in epileptic encephalopathy in childhood

et al. 2015

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“…6 This could be due to AASA, which is highly reactive and possibly neurotoxic and which levels do not normalize. [7][8][9][10][11] In the search for new treatment modalities, the lysine degradation pathway has gained new attention and the activity of the PA pathway has been brought into question by recent isotopic tracing studies. In fibroblasts from ATQ-deficient patients, PA derived only from the saccharopine pathway.…”

Section: Introductionmentioning

confidence: 99%

New insights into human lysine degradation pathways with relevance to pyridoxine‐dependent epilepsy due to antiquitin deficiency

Crowther

Mathis

Poms

et al. 2019

J of Inher Metab Disea

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Deficiency of antiquitin (ATQ), an enzyme involved in lysine degradation, is the major cause of vitamin B6‐dependent epilepsy. Accumulation of the potentially neurotoxic α‐aminoadipic semialdehyde (AASA) may contribute to frequently associated developmental delay. AASA is formed by α‐aminoadipic semialdehyde synthase (AASS) via the saccharopine pathway of lysine degradation, or, as has been postulated, by the pipecolic acid (PA) pathway, and then converted to α‐aminoadipic acid by ATQ. The PA pathway has been considered to be the predominant pathway of lysine degradation in mammalian brain; however, this was refuted by recent studies in mouse. Consequently, inhibition of AASS was proposed as a potential new treatment option for ATQ deficiency. It is therefore of utmost importance to determine whether the saccharopine pathway is also predominant in human brain cells. The route of lysine degradation was analyzed by isotopic tracing studies in cultured human astrocytes, ReNcell CX human neuronal progenitor cells and human fibroblasts, and expression of enzymes of the two lysine degradation pathways was determined by Western blot. Lysine degradation was only detected through the saccharopine pathway in all cell types studied. The enrichment of 15N‐glutamate as a side product of AASA formation through AASS furthermore demonstrated activity of the saccharopine pathway. We provide first evidence that the saccharopine pathway is the major route of lysine degradation in cultured human brain cells. These results support inhibition of the saccharopine pathway as a new treatment option for ATQ deficiency.

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“…Later on in a case study, the lysine-restricted diet resulted in normal neurodevelopmental outcome and decreased CSF alpha-AASA and PA levels on this treatment. This treatment was well tolerated without major clinical side effects and normal growth in this patient, but caused mild serotonin deficiency in the CNS [63]. Both studies provided the first evidences that accumulation of alpha-AASA and PA in the CNS might be the likely explanation of neurotoxic effects of these metabolites causing developmental delays, cognitive dysfunction and probably responsible for progressive neurodegenerative disease course.…”

Section: Treatment Of Pde and Pde-aldh7a1mentioning

confidence: 57%

Pyridoxine dependent epilepsy: Seizure onset, seizure types and EEG features

2015

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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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Lysine-restricted diet and mild cerebral serotonin deficiency in a patient with pyridoxine-dependent epilepsy caused by ALDH7A1 genetic defect

Cited by 23 publications

References 11 publications

Diagnostic yield of genetic testing in epileptic encephalopathy in childhood

Diagnostic yield of genetic testing in epileptic encephalopathy in childhood

New insights into human lysine degradation pathways with relevance to pyridoxine‐dependent epilepsy due to antiquitin deficiency

Pyridoxine dependent epilepsy: Seizure onset, seizure types and EEG features

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