Pyridoxine-responsive Seizures Research Articles

Hypophosphatasia as a rare cause of neonatal seizures

Severe forms of hypophosphatasia due to loss-of-function in the ALPL gene may present with diverse neurological problems including pyridoxine-responsive seizures. We present a short report of pyridoxine-responsive neonatal seizures. Due to severe osteopenia with unmeasurable levels of alkaline phosphatase, targeted genetic screening was performed and two pathogenic variants in the gene for the nonspecific alkaline phosphatase confirmed the diagnosis of hypophosphatasia. We would like to emphasize the importance of considering infantile hypophosphatasia in the differential diagnosis of pyridoxine-responsive seizures with concomitant low alkaline phosphatase level and bone pathology, especially with the new treatments becoming available in the future.

Pyridoxine Responsive Seizures: Beyond Aldehyde Dehydrogenase 7A1.

Objective Pyridoxine responsive seizures (PDRs) are characterized by early-onset seizures and epileptic encephalopathy (neonates and infants) which respond to pyridoxine. Any type of seizures can be the first presentation of PDRs in these children. The aim of this 20-year retrospective study was to report the profile of 35 children with PDRs. Materials and Methods Neonatal and infantile seizures responding to pyridoxine were analyzed retrospectively from 1998 to 2018. Depending on the clinical features, laboratory results, and genetic study, they were divided into following four groups: (A) responders with α-aminoadipic semialdehyde dehydrogenase 7A1 ( ALDH7A1 ) mutation, (B) responders with pyridoxal phosphate homeostasis protein (PLPHP) mutation, (C) responders with none of these two known mutations, (D) and responders in combination with antiepileptic medications. Results Sixteen of 35 children had genetic mutation, 4 with ALDH7A1 mutation, and 12 with PLPHP mutation recently described. Nineteen of 35 children had no genetic positivity. Conclusion A large number of children with pyridoxine response do not have known genetic confirmation. Over time, new genes, responsible for pyridoxine dependency, may be identified or an unknown metabolic disorder may be seen in these children.

Pyridoxine-Responsive Seizures in Pyridoxamine Phosphate Oxidase Deficiency: Case Report and Review of the Literature

Pyridoxamine 5-phosphate oxidase (PNPO) deficiency results in a block in the final step of producing pyridoxal 5’- phosphate. This is expected to result in neuronal cell dysfunction that leads to the early neonatal encephalopathy and intractable seizures that are theorized to be resistant to pyridoxine and responsive to pyridoxal 5’-phosphate. As a matter of fact, the lack of response of the intractable seizures to high dose supplementation with pyridoxine is one of the main clinical clues for suspecting PNPO deficiency, although partial response can be observed. This is a case report of genetically confirmed PNPO deficiency that had complete response to high dose Intravenous and then oral pyridoxine after failure to control his seizures with of conventional anti-epileptic drugs. This case further supports the increasingly recognized phenotypic heterogeneity of PNPO deficiency and the potential pitfall of diagnosing pyridoxine responsive seizures proper related to ALDH7A1 (Aldehyde Dehydrogenase 7 family, member A1) pathogenic mutations solely on the bases of clinical response to pyridoxine.

Vitamin B-6 Metabolism and Interactions with TNAP.

Two observations stimulated the interest in vitamin B-6 and alkaline phosphatase in brain: the marked increase in plasma pyridoxal phosphate and the occurrence of pyridoxine responsive seizures in hypophosphatasia. The increase in plasma pyridoxal phosphate indicates the importance of tissue non-specific alkaline phosphatase (TNAP) in transferring vitamin B-6 into the tissues. Vitamin B-6 is involved in the biosynthesis of most of the neurotransmitters. Decreased gamma-aminobutyrate (GABA) appears to be most directly related to the development of seizures in vitamin B-6 deficiency. Cytosolic pyridoxal phosphatase/chronophin may interact with vitamin B-6 metabolism and neuronal development and function. Ethanolaminephosphate phospholyase interacts with phosphoethanolamine metabolism. Extracellular pyridoxal phosphate may interact with purinoceptors and calcium channels. In conclusion, TNAP clearly influences extracellular and intracellular metabolism of vitamin B-6 in brain, particularly during developmental stages. While effects on GABA metabolism appear to be the major contributor to seizures, multiple other intra- and extra-cellular metabolic systems may be affected directly and/or indirectly by altered vitamin B-6 hydrolysis and uptake resulting from variations in alkaline phosphatase activity.

Pyridoxine Responsiveness and PNPO Gene Mutations

Investigators at University Hospital, Zurich, Switzerland, and multiple centers in Europe and Canada, sequenced the pyridoxal 5-phosphate oxidase (PNPO) gene in 31 patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene.

Pyridoxine responsiveness in novel mutations of the PNPO gene

To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations. We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria. We 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). This 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.

Pyridoxine-dependent Epilepsy With Elevated Urinary α-Amino Adipic Semialdehyde in Molybdenum Cofactor Deficiency

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.

Hypophosphatasia Presenting with Pyridoxine-Responsive Seizures, Hypercalcemia, and Pseudotumor Cerebri: Case Report

Hypophosphatasia (HPP) is an inborn error of metabolism characterized by defective bone mineralization caused by a deficiency in alkaline phosphatase (ALP) activity due to mutations in the tissue-nonspecific ALP (TNALP) gene. The clinical expression of the disease is variable. Six forms of HPP are identified according to age at presentation and clinical features. Patients with the infantile form are normal at birth. First symptoms appear within the first 6 months of life. Along with skeletal findings, HPP patients may present with hypercalcemia, seizures, pseudotumor cerebri, and pulmonary insufficiency. Seizures in HPP are refractory to conventional antiepileptic drugs, but are responsive to pyridoxine. Herein, we report a case of HPP who presented with pyridoxine-responsive seizures in the early neonatal period and was found to have hypercalcemia, skeletal demineralization and increased intracranial pressure. Key words: Hypophosphatasia, pyridoxine-responsive seizures, bisphosphonates, alkaline phosphatase, bone resorption, hypercalcemia Conflict of interest:None declared.

Efficacy of Pyridoxine in Early-Onset Idiopathic Intractable Seizures in Children

To identify pyridoxine responsive seizures among children with early onset intractable seizures, and to identify pyridoxine-dependency as a subset in this group. Patients with neonatal onset idiopathic, intractable seizures were identified over a 6-month period and subjected to a 'pyridoxine trial', at the Pediatric Neurology Clinic of a tertiary-care teaching hospital in New Delhi, India. This consisted of an intravenous infusion of 100 mg of pyridoxine over 10-min with a simultaneous EEG monitoring. This procedure was carried out in the EEG laboratory with all appropriate precautions (including availability of resuscitation equipment and trained personnel). Continuous EEG monitoring was done throughout the infusion and till 20 min later, to look for correction of EEG abnormalities. All patients were then prescribed oral pyridoxine, 10-15 mg/kg/day divided TDS for 6 weeks, in addition to their current anticonvulsant therapy. Patients were reviewed every 15 days regarding compliance and change in seizure frequency. A reduction in seizure frequency by 50% of the baseline was considered as 'response' (significant change), meriting further continuation of pyridoxine therapy. In patients who remained seizure free on pyridoxine therapy, previous anti-epileptics were gradually tapered one by one. 621 children with active epilepsy were seen at the PNC, of which 48 had early-onset, medical intractable epilepsy, and 21 children (13 males and 8 females), aged between 11 month and 38 month were enrolled. The median age at onset of seizure was 5.1 months. The major seizure type was focal in 3 and generalized in 18 (including infantile spasm in 11). No patient had normalization of EEG during the 'trial'. Two patients (9.5%) had a response during the 2 weeks of oral treatment and oral therapy was continued. No toxicity or side-effects of pyridoxine were observed in these two patients over a follow-up of more than 18 months. Pyridoxine responsive seizures contribute a significant proportion to early-onset idiopathic intractable epilepsy in childhood. Routine use of pyridoxine in the management of early onset resistant seizures would go a long way in identifying these patients early.

Clinical features and the management of pyridoxine-dependent and pyridoxine-responsive seizures: review of 63 North American cases submitted to a patient registry

To facilitate clinical research on pyridoxine-dependent seizures (PDS), a rare disease registry was established for affected patients in the United States and Canada. From 1999 to 2007, 63 cases, ranging in age from 11 months to 40 years, were registered. All registered cases were diagnosed with PDS by their physicians using clinical criteria. Seventy percent of the cases presented with neonatal seizures, and the mean lag time between presentation and diagnosis was 313 days. Pyridoxine treatment regimens were varied, ranging from 50 to 2,500 mg per day (1.4 to 67.8 mg/kg/day). While 47 of the cases were seizure-free on pyridoxine monotherapy, over time, eight other cases also required the concomitant use of anticonvulsants for effective seizure control, while the remainder continued to have recurrent seizures, despite the use of pyridoxine and multiple anticonvulsants. Our review of this collection of cases suggests that, for some registered individuals, either pyridoxine may be acting as an adjunctive anticonvulsant or the patient may have developed a secondary etiology for seizures. In addition, some of these cases may have pyridoxine-responsive seizures (PRS) rather than pyridoxine-dependency. Four adult and seven school-aged cases were described as developmentally normal, while the other cases had a variety of neurodevelopmental handicaps. Twenty-five percent of the cases required the pharmacologic treatment of behavioral symptoms. Clinicians caring for neonates and other young patients with intractable seizures do not necessarily consider PDS as an etiology; therefore, certain cases may be undiagnosed or diagnosed late in the course of their evaluation and treatment. As the diagnosis of PDS can now be confirmed by genetic and biochemical testing, formal screening protocols for this disorder should be developed. Patients previously diagnosed with PDS by clinical criteria should also receive confirmatory testing.

Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T > C, p.M226T; c.1112C > T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene

Pyridoxine-responsive seizures (PRS) and the role of pyridoxine (PN, vitamin B 6) in hypophosphatasia (HPP) are incompletely understood. Typically, PRS and HPP are rare, independent, metabolic disorders. In PRS, seizures resist standard anticonvulsants apart from PN, yet have a good prognosis. In HPP, inactivation of the tissue nonspecific isoenzyme of alkaline phosphatase (TNSALP) impairs skeletal mineralization and causes rickets in infants that can be fatal. Here, we report a 7-month-old girl, newly diagnosed with infantile HPP, who presented as a neonate with PRS but without bony abnormalities. Analysis of biogenic amines in cerebrospinal fluid (CSF) suggested brain pyridoxal 5′-phosphate (PLP) deficiency, although PLP in CSF was not decreased. She had normal cognitive milestones but failure to thrive and rickets. Nearly undetectable serum ALP activity, elevated plasma PLP and urinary phosphoethanolamine (PEA) and inorganic pyrophosphate (PPi) levels, hypercalcemia, hypercalciuria and nephrocalcinosis were consistent with infantile HPP. Only prednisolone reduced serum calcium levels. Despite improved growth and weight gain, she developed rib fractures and died from respiratory failure at age 9 months. Sequence analysis of the TNSALP gene revealed novel missense mutations in exon 7 (c.677T > C, p.M226T) and exon 10 (c.1112C > T, p.T371I). Our patient demonstrated that PRS in neonates may not necessarily be “idiopathic”; instead, such seizures can be caused by severe HPP that becomes clinically apparent later in infancy. The pathophysiology of PRS in HPP differs from the three other genetic defects known to cause PRS, but all may lead to brain PLP deficiency reducing seizure thresholds. All reported HPP patients with neonatal seizures died within 18 months of birth, suggesting that PRS is an indicator of HPP severity and lethal prognosis. We recommend that assessment of any neonate with PRS should include measurement of serum ALP activity.

Hospital Pharmacy and Emergency Department Availability of Parenteral Pyridoxine

Pyridoxine is a recommended antidote that should be available in emergency departments (EDs). A pediatric use of this preparation is the treatment of acute seizures secondary to pyridoxine dependency or responsiveness. Two cases of children with pyridoxine-dependent and pyridoxine-responsive seizures whose treatment was affected by the unavailability of pyridoxine in local EDs are presented. These cases prompted the development of a survey to ascertain the availability of parenteral pyridoxine in the pharmacies and EDs of both children's and general hospitals in the United States. A survey of 203 pharmacy directors in 100 pediatric hospitals (42 self-governing and 58 within a hospital) and 103 general hospitals was conducted. The questionnaire asked for the number of licensed beds and whether injectable pyridoxine was on the formulary and stocked by the ED. The overall response rate was 73% (83% pediatric and 64% general hospitals). Injectable pyridoxine was on the formulary of 99% of pediatric hospitals and 91% of general hospitals (P = 0.044). Of those hospitals that had pyridoxine on the formulary, the availability of injectable pyridoxine in EDs was low in both pediatric (20.7%) and general hospitals (16.7%). Given the number of possible uses of parenteral pyridoxine in the ED, it is suggested that there is a case for all pediatric and general hospital pharmacies to have it on the formulary and further for all EDs in these hospitals to have injectable pyridoxine available for immediate use.

10 Epidemiology of Pyridoxine-Dependent Seizures in the Netherlands

Top of pageAbstract Background: Pyridoxine-dependent epilepsy is a rare cause of seizures in childhood and epidemiologic data on pyridoxine dependency are scarce. Classically, the diagnosis is definitely established when convulsions recur after withdrawal of pyridoxine and cease again after a second trial of pyridoxine (Baxter P. Pyridoxine-dependent and pyridoxine-responsive seizures. Dev Med Child Neurol 2001:416–20). Objectives: To study the epidemiology of pyridoxine-dependent epilepsy in the Netherlands, and to determine whether the diagnosis is based upon the appropriate criteria. Methods: Nationwide all university hospitals (n=10) and departments of paediatric or neonatal neurology (n=17) were asked to report known cases of pyridoxine-dependent seizures. Birth incidences were calculated using national data on life births from 1991 to 2003. The criteria of definite, probable, and possible cases of pyridoxine-dependent seizures were applied as published by Baxter (Baxter P. Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch Dis Child 1999:431–3). Results: Response was received from all 10 university hospitals and 94% of paediatric or neonatal neurology departments. Thirteen patients were reported. Five definite (38%), two probable (15%), and four possible cases (31%) were identified. Two cases (15%) did not meet criteria for either of these groups. The birth incidence was 1:396 000 for definite and probable cases and 1:252 000 when possible cases are included. Conclusions: Thus far, epidemiologic data on pyridoxine-dependent seizures were only available from the UK and Ireland. A higher incidence is found in the Netherlands, in accordance to earlier suggestions of a regional difference. The study shows that the diagnosis is often made without performance of a formal trial of withdrawal. We want to emphasize the importance of confirming the diagnosis, concerning the consequences as for individual prognosis, the potential side effects of prolonged pyridoxine substitution, and the possibility of treating the mother in case of future pregnancies.

Pyridoxine-responsive seizures in a patient with infantile hypophosphatasia

Pyridoxine-responsive seizures in a patient with infantile hypophosphatasia

Amplitude‐integrated encephalography in pyridoxine‐dependent seizures and pyridoxine‐responsive seizures

Pyridoxine‐dependent seizures are rare in newborn infants, although recent data suggest that the prevalence probably is underestimated. In all newborn infants with recurrent epileptic seizures the general recommendation is to administer pyridoxine and simultaneously record an electroencephalogram (EEG). Conclusion: One infant with pyridoxine‐responsive seizures and another with pyridoxine‐dependent seizures had different electroclinical responses on amplitude‐integrated EEG monitoring (aEEG) when pyridoxine was administered.

‘Pyridoxine treatment in a subgroup of children with pervasive developmental disorders’

‘Pyridoxine treatment in a subgroup of children with pervasive developmental disorders’

Amplitude-integrated encephalography in pyridoxine-dependent seizures and pyridoxine-responsive seizures

Pyridoxine-dependent seizures are rare in newborn infants, although recent data suggest that the prevalence probably is underestimated. In all newborn infants with recurrent epileptic seizures the general recommendation is to administer pyridoxine and simultaneously record an electroencephalogram (EEG). One infant with pyridoxine-responsive seizures and another with pyridoxine-dependent seizures had different electroclinical responses on amplitude-integrated EEG monitoring (aEEG) when pyridoxine was administered.

Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK

OBJECTIVETo study the epidemiology of pyridoxine dependent seizures and other forms of pyridoxine responsive seizures.DESIGNMonthly notifications to the British Paediatric Surveillance Unit over two years. Questionnaire follow up.SETTINGUK and the...