Phenotype, biochemical features, genotype and treatment outcome of pyridoxine-dependent epilepsy

Teneiji, Amal Al; Bruun, Theodora; Cordeiro, Dawn; Patel, Jaina; Inbar‐Feigenberg, Michal; Weiss, Shelly K.; Struys, Eduard A.; Mercimek-Mahmutoglu, Saadet

doi:10.1007/s11011-016-9933-8

Cited by 52 publications

(69 citation statements)

References 19 publications

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“…8 Proven or predicted loss-of-function variants were usually associated with a severe phenotype, while missense variants not interfering with protein stability or PLP-binding seem to associate to milder phenotypes. Patient 1 in this study, homozygous for the splice-site variant c.207+1G>A, shows a severe phenotype according to the adapted clinical severity score 8,15 (score 7-8 dependent on the further course of epilepsy), supporting these observations. Compound heterozygosity for c.207+1G>A and c.320-2A>G, has previously been described in a case with similar severity and clinical course.…”

Section: Discussionsupporting

confidence: 79%

“…The splice‐site and null variants were associated with the most severe phenotypic presentations . By applying an adapted clinical severity score a genotype‐phenotype correlation for this patient group was recently established . Proven or predicted loss‐of‐function variants were usually associated with a severe phenotype, while missense variants not interfering with protein stability or PLP‐binding seem to associate to milder phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic pitfalls in vitamin B6‐dependent epilepsy caused by mutations in the PLPBP gene

et al. 2019

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Vitamin B6‐responsive epilepsies are a group of genetic disorders including ALDH7A1 deficiency, PNPO deficiency, and others, usually causing neonatal onset seizures resistant to treatment with common antiepileptic drugs. Recently, biallelic mutations in PLPBP were shown to be a novel cause of vitamin B6‐dependent epilepsy with a variable phenotype. The different vitamin B6‐responsive epilepsies can be detected and distinguished by their respective biomarkers and genetic analysis. Unfortunately, metabolic biomarkers for early detection and prognosis of PLPBP deficiency are currently still lacking. Here, we present data from two further patients with vitamin B6‐dependent seizures caused by variants in PLPBP, including a novel missense variant, and compare their genotype and phenotypic presentation to previously described cases. Hyperglycinemia and hyperlactatemia are the most consistently observed biochemical abnormalities in pyridoxal phosphate homeostasis protein (PLPHP) deficient patients and were present in both patients in this report within the first days of life. Lactic acidemia, the neuroradiological, and clinical presentation led to misdiagnosis of a mitochondrial encephalopathy in two previously published cases with an early fatal course. Similarly, on the background of glycine elevation in plasma, glycine encephalopathy was wrongly adopted as diagnosis for a patient in our report. In this regard, lactic acidemia as well as hyperglycinemia appear to be diagnostic pitfalls in patients with vitamin B6‐responsive epilepsies, including PLPHP deficiency. Synopsis In vitamin B6‐responsive epilepsies, including PLPHP deficiency, there are several diagnostic pitfalls, including lactic acidemia as well as hyperglycinemia, highlighting the importance of a pyridoxine trial, and genetic testing.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Diagnostic pitfalls in vitamin B6‐dependent epilepsy caused by mutations in the PLPBP gene

et al. 2019

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“…Recent treatment paradigms have attempted to reduce the accumulation of α‐AASA and Δ 1 ‐P6C through a lysine‐restricted diet and competitive inhibition of lysine‐transport . These lysine restriction therapies result in significant reduction of α‐AASA/Δ 1 ‐P6C and improved cognitive outcome, although treatment must be initiated within the first year of life for optimal developmental outcome . Unfortunately, the diagnosis of PDE is often delayed .…”

Section: Introductionmentioning

confidence: 86%

Identification of a novel biomarker for pyridoxine‐dependent epilepsy: Implications for newborn screening

Wempe

Kumar

et al. 2019

J of Inher Metab Disea

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Pyridoxine-dependent epilepsy (PDE) is often characterized as an early onset epileptic encephalopathy with dramatic clinical improvement following pyridoxine supplementation. Unfortunately, not all patients present with classic neonatal seizures or respond to an initial pyridoxine trial, which can result in the under diagnosis of this treatable disorder. Restriction of lysine intake and transport is associated with improved neurologic outcomes, although treatment should be started in the first year of life to be effective. Because of the documented diagnostic delay and benefit of early treatment, we aimed to develop a newborn screening method for PDE. Previous studies have demonstrated the accumulation of Δ 1 -piperideine-6-carboxylate and α-aminoadipic semialdehyde in individuals with PDE, although these metabolites are unstable at room temperature (RT) limiting their utility for newborn screening. As a result, we sought to identify a biomarker that could be applied to current newborn screening paradigms. We identified a novel metabolite, 6-oxopipecolate (6-oxo-PIP), which accumulates in substantial amounts in blood, plasma, urine, and cerebral spinal fluid of individuals with PDE. Using a stable isotope-labeled internal standard, we developed a nonderivatized liquid chromatography tandem mass spectrometry-based method to quantify 6-oxo-PIP. This method replicates the analytical techniques used in many laboratories and could be used with few modifications in newborn screening programs. Furthermore, 6-oxo-PIP was measurable in urine for 4 months even when stored at RT. Herein, we report a novel biomarker for PDE that is stable at RT and can be quantified using current newborn screening techniques. K E Y W O R D S6-hydroxy-pipecolate, 6-oxo-pipecolate, ALDH7A1, alpha aminoadipic semialdehyde, pyridoxinedependent epilepsy

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“…Current treatment paradigms aim to reduce putative neurotoxic metabolites through a lysine restricted diet and competitive inhibition of lysine transport . These therapies have been associated with improved neurologic outcomes, although optimal development is dependent on an early diagnosis and initiation of treatment in the first year of life …”

Section: Introductionmentioning

confidence: 99%

“…5,6 These therapies have been associated with improved neurologic outcomes, although optimal development is dependent on an early diagnosis and initiation of treatment in the first year of life. 5,7 PDE results from a deficiency of α-aminoadipic semialdehyde (α-AASA) dehydrogenase (E.C. 1.2.1.3), a key enzyme in lysine metabolism.…”

Section: Introductionmentioning

confidence: 99%

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy

Coughlin

Swanson

Spector

et al. 2019

J of Inher Metab Disea

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Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the importance of an early diagnosis. As genetic testing is increasingly accepted as first tier testing for epileptic encephalopathies, we aimed to provide a comprehensive overview of ALDH7A1 mutations that cause PDE. The genotypes, ethnic origin and reported gender was collected from 185 subjects with a diagnosis of PDE. The population frequency for the variants in this report and the existing literature were reviewed in the Genome Aggregation Database (gnomAD). Novel variants identified in population databases were also evaluated through in silico prediction software and select variants were over‐expressed in an E.coli‐based expression system to measure α‐aminoadipic semialdehyde dehydrogenase activity and production of α‐aminoadipic acid. This study adds 47 novel variants to the literature resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, we estimate an incidence of approximately 1:64,352 live births. This report provides a comprehensive overview of known ALDH7A1 mutations that cause PDE, and suggests that PDE may be more common than initially estimated. Due to the relative high frequency of the disease, the likelihood of under‐diagnosis given the wide clinical spectrum and limited awareness among clinicians as well as the cognitive improvement noted with early treatment, newborn screening for PDE may be warranted.

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Phenotype, biochemical features, genotype and treatment outcome of pyridoxine-dependent epilepsy

Cited by 52 publications

References 19 publications

Diagnostic pitfalls in vitamin B6‐dependent epilepsy caused by mutations in the PLPBP gene

Diagnostic pitfalls in vitamin B6‐dependent epilepsy caused by mutations in the PLPBP gene

Identification of a novel biomarker for pyridoxine‐dependent epilepsy: Implications for newborn screening

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy

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