Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pyridoxine responsive epilepsy caused by a novel homozygous PNPO mutation.

ABSTRACT: We report a patient with anti-epileptic treatment refractory neonatal seizures responsive to pyridoxine. Biochemical analysis revealed normal markers for antiquitin deficiency and also mutation analysis of the ALDH7A1 (Antiquitin) gene was negative. Mutation analysis of the PNPO gene revealed a novel, homozygous, presumed pathogenic mutation (c.481C > T; p.(Arg161Cys)). Measurements of B6 vitamers in a CSF sample after pyridoxine administration revealed elevated pyridoxamine as the only metabolic marker for PNPO deficiency. With pyridoxine monotherapy the patient is seizure free and neurodevelopmental outcome at the age of 14 months is normal.

SUBMITTER: Jaeger B

PROVIDER: S-EPMC4789384 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Pyridoxine responsive epilepsy caused by a novel homozygous PNPO mutation.

Jaeger B B Abeling N G NG Salomons G S GS Struys E A EA Simas-Mendes M M Geukers V G VG Poll-The B T BT

Molecular genetics and metabolism reports 20160210

We report a patient with anti-epileptic treatment refractory neonatal seizures responsive to pyridoxine. Biochemical analysis revealed normal markers for antiquitin deficiency and also mutation analysis of the ALDH7A1 (Antiquitin) gene was negative. Mutation analysis of the PNPO gene revealed a novel, homozygous, presumed pathogenic mutation (c.481C > T; p.(Arg161Cys)). Measurements of B6 vitamers in a CSF sample after pyridoxine administration revealed elevated pyridoxamine as the only metaboli ...[more]

PMID: 27014579

Similar Datasets

Pyridoxine-Responsive Seizures in Infantile Hypophosphatasia and a Novel Homozygous Mutation in ALPL Gene.

Project description:Hypophosphatasia is a rare inherited disorder of bone and mineral metabolism caused by a number of loss-of-function mutations in the ALPL gene. It is characterized by defective bone and tooth mineralisation associated with low serum and bone alkaline phosphatase activity. The clinical presentation of this disease is extremely variable. For this reason, the diagnosis can be difficult and is often missed out or delayed. Hypophosphatasia is classified into subtypes based on the age of onset and clinical features. The clinical severity is associated with the age at diagnosis and the lack of tissue-nonspecific alkaline phosphatase activity; the severe forms of hypophosphatasia are primarily perinatal and infantile forms. Severe forms may present with many neurological problems such as seizures, hypotonia, irritability. Herein, we report the case of an infantile hypophosphatasia patient who presented with pyridoxine-responsive seizures and a novel homozygous mutation in the ALPL gene was detected. There is a limited number of hypophosphatasia patients with pyridoxine-responsive seizures in the literature, so early diagnosis of infantile hypophosphatasia in the clinically compatible patients allows more effective postnatal care/management and genetic counseling for further pregnancies.

| S-EPMC5096504 | biostudies-literature

Pyridoxine responsiveness in novel mutations of the PNPO gene.

Project description:ObjectiveTo determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations.MethodsWe sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria.ResultsWe were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5'-phosphate (PLP).ConclusionsThis study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5'-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug-resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis.

| S-EPMC4001193 | biostudies-literature

Pyridoxine-Dependent Epilepsy in Zebrafish Caused by Aldh7a1 Deficiency.

Project description:Pyridoxine-dependent epilepsy (PDE) is a rare disease characterized by mutations in the lysine degradation gene ALDH7A1 leading to recurrent neonatal seizures, which are uniquely alleviated by high doses of pyridoxine or pyridoxal 5'-phosphate (vitamin B6 vitamers). Despite treatment, neurodevelopmental disabilities are still observed in most PDE patients underlining the need for adjunct therapies. Over 60 years after the initial description of PDE, we report the first animal model for this disease: an aldh7a1-null zebrafish (Danio rerio) displaying deficient lysine metabolism and spontaneous and recurrent seizures in the larval stage (10 days postfertilization). Epileptiform electrographic activity was observed uniquely in mutants as a series of population bursts in tectal recordings. Remarkably, as is the case in human PDE, the seizures show an almost immediate sensitivity to pyridoxine and pyridoxal 5'-phosphate, with a resulting extension of the life span. Lysine supplementation aggravates the phenotype, inducing earlier seizure onset and death. By using mass spectrometry techniques, we further explored the metabolic effect of aldh7a1 knockout. Impaired lysine degradation with accumulation of PDE biomarkers, B6 deficiency, and low γ-aminobutyric acid levels were observed in the aldh7a1-/- larvae, which may play a significant role in the seizure phenotype and PDE pathogenesis. This novel model provides valuable insights into PDE pathophysiology; further research may offer new opportunities for drug discovery to control seizure activity and improve neurodevelopmental outcomes for PDE.

| S-EPMC5714462 | biostudies-literature

Global Metabolomics Discovers Two Novel Biomarkers in Pyridoxine-Dependent Epilepsy Caused by ALDH7A1 Deficiency.

Project description:Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive developmental and epileptic encephalopathy caused by pathogenic variants in the ALDH7A1 gene (PDE-ALDH7A1), which mainly has its onset in neonates and infants. Early diagnosis and treatment are crucial to prevent severe neurological sequelae or death. Sensitive, specific, and stable biomarkers for diagnostic evaluations and follow-up examinations are essential to optimize outcomes. However, most of the known biomarkers for PDE lack these criteria. Additionally, there is little discussion regarding the interdependence of biomarkers in the PDE-ALDH7A1 metabolite profile. Therefore, the aim of this study was to understand the underlying mechanisms in PDE-ALDH7A1 and to discover new biomarkers in the plasma of patients using global metabolomics. Plasma samples from 9 patients with genetically confirmed PDE-ALDH7A1 and 22 carefully selected control individuals were analyzed by ultra high performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS). Two novel and reliable pyridoxine-independent diagnostic markers, 6-hydroxy-2-aminocaproic acid (HACA) and an isomer of C9H11NO4, were identified. Furthermore, a possible reaction mechanism is proposed for HACA. This study demonstrates the capability of global metabolomics in disease screening to detect established and novel biomarkers.

| S-EPMC9784804 | biostudies-literature

Pyridoxine-Dependent Epilepsy: A Treatable Epilepsy Syndrome Presenting with Dystonia and Congenital Cataracts with a Novel Mutation.

Project description: Not available

| S-EPMC10026274 | biostudies-literature

Biochemical data from the characterization of a new pathogenic mutation of human pyridoxine-5'-phosphate oxidase (PNPO).

Project description:PNPO deficiency is responsible of severe neonatal encephalopathy, responsive to pyridoxal-5'-phosphate (PLP) or pyridoxine. Recent studies widened the phenotype of this condition and detected new genetic variants on PNPO gene, whose pathogenetic role and clinical expression remain to be established. One of these mutations, Arg116Gln, is of particular interest because of its later onset of symptoms (beyond the first months of life) and its peculiar epileptic manifestations in patients. This protein variant was expressed as recombinant protein in E coli, purified to homogeneity, and characterized with respect to structural and kinetic properties, stability, binding constants of cofactor flavin mononucleotide (FMN) and product (PLP) in order to define the molecular and structural bases of its pathogenicity. For interpretation and discussion of reported data, together with the description of clinical studies, refer to the article [1] (doi: 10.1016/j.ymgme.2017.08.003).

| S-EPMC5779537 | biostudies-literature

Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination.

Project description:ObjectiveTo investigate the role of intragenic deletions of ALDH7A1 in patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single identifiable mutation in ALDH7A1.MethodsWe designed a custom oligonucleotide array with high-density probe coverage across the ALDH7A1 gene. We performed array comparative genomic hybridization in 6 patients with clinical and biochemical evidence of pyridoxine-dependent epilepsy but only a single detectable mutation in ALDH7A1 by sequence analysis.ResultsWe found partial deletions of ALDH7A1 in 5 of 6 patients. Breakpoint analysis reveals that the deletions are likely a result of Alu-Alu recombination in all cases. The density of Alu elements within introns of ALDH7A1 suggests susceptibility to recurrent rearrangement.ConclusionPatients with clinical pyridoxine-dependent epilepsy and a single identifiable mutation in ALDH7A1 warrant further investigation for copy number changes involving the ALHD7A1 gene.

| S-EPMC4553021 | biostudies-literature

Protein-losing enteropathy and joint contractures caused by a novel homozygous ANTXR2 mutation.

Project description:Infantile systemic hyalinosis (ISH) is a rare autosomal recessive disorder and an allelic form of hyaline fibromatosis syndrome that is caused by mutations in the ANTRX2 gene encoding the transmembrane anthrax toxin receptor 2. Its main features include characteristic skin lesions, joint contractures, persistent diarrhea, and failure to thrive due to accumulation of hyaline material in multiple organs. The resulting severe malnutrition can cause death in early infancy. Because of its rarity and high fatality rate, timely diagnosis is difficult and ISH may be underdiagnosed. In this report, we describe a 10-month-old male with severe protein-losing enteropathy, skin lesions, and painful joint contractures, diagnosed with ISH based on skin his-topathology and identification of a novel homozygous ANTRX2 mutation, c.1127_1128delTG (p.V376Gfs*14). While its clinical outcome is poor without curative treatment, establishing a diagnosis of ISH starting from clinical suspicion to molecular analysis is important for appropriate medical management and for risk and carrier assessment of family members.

| S-EPMC6057141 | biostudies-literature

The first family with adult osteogenesis imperfecta caused by a novel homozygous mutation in CREB3L1.

Project description:BackgroundOsteogenesis imperfecta (OI) is a clinically heterogeneous disease characterized by extreme skeletal fragility. It is caused by mutations in genes frequently affecting collagen biosynthesis. Mutations in CREB3L1 encoding the ER stress transducer OASIS are very rare and are only reported in pediatric patients. We report a large family with a novel CREB3L1 mutation, with severe adult clinical presentation.MethodsClinical examination was performed on the family members. Next generation sequencing was performed for the causative genes for OI. The mutation was confirmed in other family members with Sanger sequencing.ResultsA novel homozygous mutation in CREB3L1 was identified in the three affected patients. The parents and siblings who carry the mutation in heterozygous state were clinically unaffected. The three affected siblings, who were reported to have been born healthy, presented very severe progressive skeletal malformations and joint contractures but absence of common OI characteristics including blue sclerae, deafness, and dentinogenesis imperfecta. Resorption of a part of the humerus presumably associated with fracture nonunion and pseudarthrosis.ConclusionWe report a novel homozygous CREB3L1 mutation in a large Indonesian family; the homozygous affected members have survived to adulthood and they present a more severe phenotype than previously reported, expanding the clinical spectrum of OI for this gene.

| S-EPMC6687637 | biostudies-literature

Metabolite Identification Using Infrared Ion Spectroscopy─Novel Biomarkers for Pyridoxine-Dependent Epilepsy.

Project description:Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics strategies are being increasingly applied in metabolite screening for a wide variety of medical conditions. The long-standing "grand challenge" in the utilization of this approach is metabolite identification─confidently determining the chemical structures of m/z-detected unknowns. Here, we use a novel workflow based on the detection of molecular features of interest by high-throughput untargeted LC-MS analysis of patient body fluids combined with targeted molecular identification of those features using infrared ion spectroscopy (IRIS), effectively providing diagnostic IR fingerprints for mass-isolated targets. A significant advantage of this approach is that in silico-predicted IR spectra of candidate chemical structures can be used to suggest the molecular structure of unknown features, thus mitigating the need for the synthesis of a broad range of physical reference standards. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine metabolism, resulting from a mutation in the ALDH7A1 gene that leads to an accumulation of toxic levels of α-aminoadipic semialdehyde (α-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While α-AASA and P6C are known biomarkers for PDE in urine, their instability makes them poor candidates for diagnostic analysis from blood, which would be required for application in newborn screening protocols. Here, we use combined untargeted metabolomics-IRIS to identify several new biomarkers for PDE-ALDH7A1 that can be used for diagnostic analysis in urine, plasma, and cerebrospinal fluids and that are compatible with analysis in dried blood spots for newborn screening. The identification of these novel metabolites has directly provided novel insights into the pathophysiology of PDE-ALDH7A1.

| S-EPMC8613736 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data