Trial Of Pyridoxine Research Articles

Utility and limitations of EEG in the diagnosis and management of ALDH7A1-related pyridoxine-dependent epilepsy. A retrospective observational study.

Pyridoxine-dependent epilepsy due to ALDH7A1 variants (PDE-ALDH7A1) is a rare disorder, presenting typically with severe neonatal, epileptic encephalopathy. Early diagnosis is imperative to prevent uncontrolled seizures. We have explored the role of EEG in the diagnosis and management of PDE. A total of 13 Norwegian patients with PDE-ALDH7A1 were identified, of whom five had reached adult age. Altogether 163 EEG recordings were assessed, 101 from the 1st year of life. Median age at seizure onset was 9 h (IQR 41), range 1 h-6 days. Median delay from first seizure to first pyridoxine injection was 2 days (IQR 5.5). An EEG burst suppression pattern was seen in eight patients (62%) during the first 5 days of life. Eleven patients had recordings during pyridoxine injections: in three, immediate EEG improvement correlated with seizure control, whereas in six, no change of epileptiform activity occurred. Of these six, one had prompt clinical effect, one had delayed effect (< 1 day), one had no effect, one had uncertain effect, and another had more seizures. A patient without seizures at time of pyridoxine trial remained seizure free for 6 days. Two patients with prompt clinical effect had increased paroxysmal activity, one as a conversion to burst suppression. Autonomic seizures in the form of apnoea appeared to promote respiratory distress and were documented by EEG in one patient. EEG follow-up in adult age did not show signs of progressing encephalopathy. A neonatal burst suppression EEG pattern should raise the suspicion of PDE-ALDH7A1. Respiratory distress is common; isolated apnoeic seizures may contribute. EEG responses during pyridoxine trials are diverse, often with poor correlation to immediate clinical effect. Reliance on single trials may lead to under-recognition of this treatable condition. Pyridoxine should be continued until results from biomarkers and genetic testing are available.

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures.

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.

Pyridoxine‐dependent epilepsy: Current perspectives and questions for future research

AbstractPyridoxine‐dependent epilepsy (PDE) was historically defined by a dramatic clinical response to a trial of pyridoxine and the re‐emergence of seizures after withdrawal of pyridoxine. Research conducted over the last seven decades has revealed that the phenotype of PDE results from multiple genetic disorders, and the most common disorder, PDE‐ALDH7A1, is caused by a deficiency of an enzyme involved in lysine metabolism. PDE‐ALDH7A1 is characterized by more than epilepsy, as many patients have abnormalities of brain development, and most patients have intellectual and developmental disability. Treatment aimed at the underlying metabolic defect, in addition to pyridoxine supplementation, has improved clinical outcomes. Recently discovered biomarkers and genetic testing allow for the diagnosis of PDE‐ALDH7A1 without the need of a pyridoxine trial and hold the promise for newborn screening. Despite these many advances, PDE‐ALDH7A1 remains a clinical and biochemical conundrum. The increasing use of model systems and an international collaboration of clinician‐scientists are among the reasons to be optimistic that these questions will be answered in the near future and that the clinical outcomes and quality of life will continue to improve for patients with PDE‐ALDH7A1.

Vitamin responsive conditions in pediatric neurology

Vitamin responsive conditions can be either due to inherited defects in the metabolic pathways resulting in vitamin dependency or due to acquired deficiency states. Due to widespread malnutrition and predominantly vegetarian population in India, vitamin deficiency state is quite common and early identification is essential. Inherited defects, if treated earlier, lead to reduced morbidity and mortality and improvement in long-term neurocognitive outcomes. Various vitamin responsive conditions in pediatric neurology shall be discussed in this review. Infantile presentation of thiamine deficiency results in beriberi, and in adults, it leads to Wernicke’s encephalopathy and Korsakoff psychosis. Biotin thiamine-responsive basal ganglia disease is a defect of thiamine transporter 2, which leads to neuroregression and characteristic neuroimaging features of basal ganglia involvement, it responds to high doses of biotin and thiamine. Riboflavin is an enzyme involved in mitochondrial energy synthesis and is supplemented in various mitochondrial metabolic conditions. Brown-Vialetto-Van Laere syndrome is progressive pontobulbar palsy caused by defect in riboflavin transporters responsive to high doses of riboflavin. Pyridoxine responsive epilepsy presents with pharmacoresistant seizures in neonatal or early infantile age, biotinidase deficiency also presents with similar neurological manifestations, but typical cutaneous symptoms of rash and seborrheic dermatitis also occur. Both are epileptic encephalopathies and any infant presenting with epilepsy not responding to conventional AEDs must be given a trial of pyridoxine, biotin, and folinic acid. Vitamin B12 responsive conditions can include deficiency states, such as those manifesting with peripheral neuropathy and the syndrome of infantile tremor syndrome (developmental delay or regression, tremors, and megaloblastic anemia) as well as inherited disorders of homocysteine and cobalamin metabolism. These disorders are differentiated on the basis of clinical phenotype and laboratory parameters (serum B12, homocysteine levels, methylmalonic acid levels, etc.). Infantile tremor syndrome responds drastically to mega doses of Vitamin B12 and other multivitamins. Vitamin E deficiency causes ataxia with Vitamin E deficiency, other vitamins which can neurological symptoms include Vitamin C (pseudoparalysis) and Vitamin K (central nervous system bleeds). It is imperative for a practicing pediatrician to be well versed with these conditions, as these are potentially treatable conditions.

Amelioration of Levetiracetam-Induced Behavioral Side Effects by Pyridoxine. A Randomized Double Blind Controlled Study

BackgroundLevetiracetam is a relatively new-generation antiseizure drug approved for the treatment of focal and generalized seizures. Despite its favorable side effect profile and minimal drug-drug interactions, neuropsychiatric side effects are reported in up to 13% of children. A few case series have suggested that supplementation of pyridoxine may mitigate these side effects, but controlled trials are lacking. To address this issue, a randomized interventional study was carried out in a pediatric tertiary hospital to qualify and quantify the potential beneficial effect of pyridoxine in attenuating the neuropsychiatric side effects of levetiracetam in children. MethodsA total of 105 children with epilepsy who were taking levetiracetam (as a monotherapy or an adjunct) who showed behavioral symptoms coinciding with the start of levetiracetam, were included. Patients randomly and blindly received either a therapeutic (pyridoxine group, 46 of 105, 44%) or a homeopathic dose of pyridoxine (placebo, 59 of 105, 56%). A 30-item behavioral checklist was used to qualify and quantify the behavioral side effects at baseline and at different time points following initiation of treatment. ResultsBoth placebo and pyridoxine groups experienced a statistical reduction in behavioral scores when compared with baseline. Our study indicated that although there was a placebo effect, the improvement in neuropsychiatric symptoms was more prominent in children who received therapeutic doses of pyridoxine. ConclusionsThese data provide clinicians with pertinent evidence-based information that suggests that a trial of pyridoxine in patients who experience behavioral side effects due to the use of levetiracetam may avoid unnecessary change of antiseizure medications.

West Syndrome Is an Exceptional Presentation of Pyridoxine- and Pyridoxal Phosphate-Dependent Epilepsy: Data From a French Cohort and Review of the Literature.

Objective: To characterize the electro-clinical presentation of patients with pyridoxine-dependent epilepsy (PDE) and pyridoxal phosphate (PLP)-dependent epilepsy in order to determine whether some of them could be diagnosed as de novo West syndrome, i. e., West syndrome that starts after the age of 2 months without other types of seizures (focal seizures for instance) before the onset of epileptic spasms.Methods: We analyzed data from an unpublished cohort of 28 genetically confirmed cases of PDE with antiquitine (ATQ) deficiency and performed a review of the literature looking for description of West syndrome in patients with either PDE with ATQ deficiency or PLP-dependent epilepsy with Pyridox(am)ine phosphate oxidase (PNPO) deficiency.Results: Of the 28 cases from the ATQ deficiency French cohort, 5 had spasms. In four cases, spasms were associated with other types of seizures (myoclonus, focal seizures). In the last case, seizures started on the day of birth. None of these cases corresponded to de novo West syndrome. The review of the literature found only one case of PNPO deficiency presenting as de novo West syndrome and no case of ATQ deficiency.Significance: The presentation of PDE- and PLP-dependent epilepsy as de novo West syndrome is so exceptional that it probably does not justify a systematic trial of pyridoxine or PLP. We propose considering a therapeutic trial with these vitamins in West syndrome if spasms are associated with other seizure types or start before the age of 2 months.

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

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 Δ1 -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-oxo-pipecolate (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.

Pyridoxine-dependent seizures: an atypical case

Pyridoxine-dependent seizure (PDS) is a readily treatable cause of intractable seizures in childhood (1). Not more than 100 cases have been reported in the English language indexed journals. Delay in initiation of treatment could result in permanent mental handicap. It is generally recommended that a trial of pyridoxine should be given in all cases of intractable seizures below the age of 3 years (2). We report a case of 4-year-old boy with mental retardation and intractable seizures who, responded well to pyridoxine. This report emphasizes the importance of considering PDS in children with intractable seizures beyond 3 years. A 4-year-old boy was admitted to the pediatrics intensive care unit with status epilepticus. He was born to non-consanguineous parents with an Apgar score of 10 at 5 minutes. There was no family history of seizures or mental impairment. Child attained social smile at 4 months, turned over at 7 months, walked independently at 20 months, and started saying 2-3 words at 3 years. Generalized seizures (partial seizures with generalization and myoclonus) started at the age 2 years. Various antiepileptic drugs either as monotherapy or in combination resulted mild reduction in seizure frequency. At 4 years he could speak 3-4 words, could indicate toilet needs and walk with minimal difficulty. His vision and hearing were normal. Electroencephalogram (EEG) showed multifocal spike and wave discharges. MRI of brain showed mild diffuse cerebral atrophy with prominent ventricles. The following tests were normal or negative: hemogram, serum calcium and phosphorous, blood thyroid hormone profile, renal and liver function tests, serum ammonia, blood arterial pH, plasma organic acids, and urine homocysteine, reducing substances and organic acids. He was continued

Predictors of hand-foot syndrome (HFS) in randomised double-blind, placebo-controlled trial of pyridoxine for prevention of capecitabine induced HFS.

9596 Background: Hand-foot syndrome (HFS)is a common side effect of capecitabine, although East Asian patients appear to have better tolerability. Methods: This study aimed to evaluate the incidenc...

G66(P) Interesting cases of pyridoxine dependent epilepsy in late childhood

We report cases of two children with intractable epilepsy who responded to treatment with pyridoxine in late childhood. Case details Case 1: A 14 year old girl born following an uneventful pregnancy to non consanguinous parents. She has global developmental delay. She developed epilepsy at around 2 years of age. Her extensive investigations including an MRI of brain were normal. She had various types of seizures and these were refractory to antiepileptic medications. A trial of pyridoxine at around 13 years of age surprisingly had a very good effect on her seizure control. We are currently awaiting the result of urinary L-α-aminoadipic semialdehyde (AASA). Case 2: A 4 year old girl born following normal pregnancy developed infantile spasms at 4 months of age. She was treated with numerous courses of steroids with suboptimal response. Extended investigations including the MRI brain were normal. She eventually developed refractory epilepsy with cognitive decline. A trial of pyridoxine at 3 years of age achieved good control of epilepsy and improved her cognition as well. The urinary AASA was negative and the result of PNPO gene mutation is awaited. Discussion Pyridoxine dependent epilepsy is a syndrome that usually presents with neonatal intractable seizures. It may present later in infancy or early childhood. A variety of seizure types are reported, the most common being generalised tonic clonic seizures which progress to status epilepticus. Urinary AASA is usually elevated and the genetic testing is available for this condition now. Our cases responded to the empirical trial of Pyridoxine at a much later age. Conclusion We recommend testing for pyridoxine deficiency and therapeutic trial with pyridoxine in children with refractory epilepsy in all the age groups. Early detection and treatment of this condition not only achieves good seizure control but can possibly improve developmental outcome as well.

Cirrhosis associated with pyridoxal 5'-phosphate treatment of pyridoxamine 5'-phosphate oxidase deficiency.

We report the case of an 8-year-old boy with pyridoxamine 5'-phosphate oxidase (PNPO) deficiency. He developed seizures at 24h of age that were refractory to standard anticonvulsant therapy and a trial of pyridoxine but responded to pyridoxal phosphate (PLP) at 28days of life. Genetic testing identified compound heterozygous mutations in the PNPO gene. Management of encephalopathic episodes required escalation of PLP dose to 100 mg/kg/day by 2 years of age. Routine blood tests at this time showed significantly deranged liver function tests (LFTs). A wedge liver biopsy showed early cirrhosis with marked elevation of pyridoxal and pyridoxic acid levels in the liver sample. Despite extensive investigation, no cause other than PLP therapy could be identified for the cirrhosis. The PLP dose was weaned to 50mg/kg/day before episodes of encephalopathy recurred. Concurrent with the reduction of his PLP dose, LFTs showed improvement. However, at 8 years of age, there is persistent evidence of hepatic fibrosis and early portal hypertension. We hypothesise that hepatic toxicity due to PLP or its degradation products is the cause of cirrhosis in this boy. Until further evidence becomes available, we would suggest that people with PNPO deficiency are treated with the minimum dose of PLP required to prevent episodes of encephalopathy.

Positive Outcome following Early Diagnosis and Treatment of Pyridoxal-5′-Phosphate Oxidase Deficiency: A Case Report

Pyridoxal-5'-phosphate oxidase (PNPO) deficiency is a rare autosomal recessive, vitamin-responsive metabolic disorder causing refractory neonatal seizures that respond to the administration of pyridoxal-5'-phosphate (PLP). There are currently few case studies that have documented the functional outcome in PNPO deficiency, which remains poor in the majority of cases. We present the case of a male infant born at 35 weeks gestation who promptly responded to oral administration of PLP, following resistance to common anticonvulsive therapy and to a pyridoxine trial. Neurological outcome at 21 months is favorable and illustrates the importance of standardized vitamin trials in the acute setting of "therapy-resistant" neonatal seizures. Early recognition of PNPO deficiency and appropriate intervention might be associated with a more favorable outcome than initially considered.

Clinical Spectrum in Children With Pyridoxine-Dependent Epilepsy

Research Article| May 01 2013 Clinical Spectrum in Children With Pyridoxine-Dependent Epilepsy AAP Grand Rounds (2013) 29 (5): 55. https://doi.org/10.1542/gr.29-5-55 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Clinical Spectrum in Children With Pyridoxine-Dependent Epilepsy. AAP Grand Rounds May 2013; 29 (5): 55. https://doi.org/10.1542/gr.29-5-55 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: epilepsy, pyridoxine dependency syndrome, seizures, pyridoxine Source: Perez B, Gutierrez-Solana LG, Verdu A, et al. Clinical, biochemical, and molecular studies in pyridoxine-dependent epilepsy: antisense therapy as possible new therapeutic option. Epilepsia. 2013; 54(2): 239– 248; doi: https://doi.org/10.1111/epi.12083Google Scholar Researchers in Spain and India studied the clinical, biochemical, and genetic spectrum in children with pyridoxine-dependent epilepsy (PDE). The disease was confirmed based on the presence of α-aminoadipic semialdehyde (α-AASA) in urine and pipecolic acid (PA) in plasma and/or cerebrospinal fluid, and by DNA analysis. A total of 12 children were included in the case series. Onset of seizures varied from the neonatal period to the first months of life. Seizures were focal or multifocal, clonic or myoclonic, and generalized tonic; 50% of study patients had status epilepticus. Seizures were controlled transiently with conventional antiepileptic drugs (AED) for 15 or more days in 8 of 12 patients, leading to a delay in diagnosis. The effective dose of pyridoxine (vitamin B6) to suppress seizures ranged from 10 to 30 mg/kg per day. Refractory neonatal seizures were the main indications for suspecting and starting treatment for PDE. Neurologic symptoms in addition to seizures included hypotonia, irritability, and psychomotor retardation. EEG abnormalities were variable in the study children; the EEG was normal in 1 patient. All EEGs became normal after pyridoxine therapy. MRI abnormalities included mega cisterna magna, Dandy Walker syndrome, ventriculomegaly, and corpus callosum dysgenesis. Six study children, followed for more than 5 years, had evidence of cognitive dysfunction. Delay in treatment and dysgenesis of the corpus callosum were risk factors for neurodevelopmental delay. Treatment with pyridoxine failed to normalize IQ. The authors conclude that, despite pyridoxine therapy, there remains a need to reduce persistent neurologic damage in PDE, and that the diagnosis of PDE should be considered in infants with intractable or poorly controlled seizures. Dr Millichap has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. PDE is an autosomal recessive inherited disorder caused by mutations in the ALDH7A1 gene, which encodes antiquitin protein. The clinical spectrum of antiquitin deficiency extends from ventriculomegaly detected on fetal ultrasound, through abnormal fetal movements, to the onset of seizures after birth.1 Clinical diagnosis of PDE can be challenging, because (1) there may be some response to AEDs, (2) response to pyridoxine may not be instantaneous, and (3) structural brain abnormalities may coexist.1 PDE should be considered in the differential diagnosis of any infant with intractable seizures, including patients with MRI abnormalities such as corpus callosum dysgenesis or Dandy Walker syndrome. In suspected cases of PDE, the use of biochemical and DNA tests for antiquitin deficiency is recommended together with a clinical trial of pyridoxine.1 The long-term outcome of PDE is often poor. In a Dutch PDE cohort of 14 patients,2 mental development was delayed in the majority of children, with a median IQ of 72; only 5 walked at 2... You do not currently have access to this content.

Pyridoxine‐dependent epilepsy: An under‐recognised cause of intractable seizures

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder causing intractable seizures in neonates and infants. PDE patients are typically resistant to anti-epileptic treatment but respond to the administration of pyridoxine. Different seizure types have been reported in PDE, and episodes of status epilepticus are common. Electroencephalographic or neuroimaging abnormalities are not pathognomonic for this disorder. Intellectual disability is frequent at the follow-up. Recently, elevated urinary α-aminoadipic semialdehyde has been shown to be a reliable biomarker of this disorder, and mutations in the ALDH7A1 gene, encoding α-aminoadipic semialdehyde dehydrogenase, have been demonstrated in the large majority of PDE patients. However, early consideration of a pyridoxine trial remains the most important issue in a neonate or in an infant with intractable early onset seizures.

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.

A double‐blind, randomized trial of pyridoxine versus placebo for the prevention of pegylated liposomal doxorubicin‐related hand‐foot syndrome in gynecologic oncology patients

The objective of this study was to compare the incidence of hand-foot syndrome (HFS) in patients who received pyridoxine versus placebo during pegylated liposomal doxorubicin (PLD) chemotherapy for recurrent ovarian, breast, or endometrial cancer. Patients received PLD 40 mg/m(2) for a maximum of 6 cycles. Patients were assigned randomly to receive pyridoxine 100 mg twice daily (Group A) or placebo (Group B) and received standard HFS education. Patients completed the Functional Assessment of Cancer Therapy quality-of-life (QOL) questionnaire. The incidence of HFS as measured by common toxicity criteria was compared between groups. Analyses were conducted according to an intent-to-treat basis. Chi-square tests or Fisher exact tests were used. Thirty-four patients were enrolled (18 in Group A and 16 in Group B), and 5 patients were unevaluable for HFS assessment. Overall, 15 of 29 patients (52%) had HFS (all grades), and 10 of 29 patients (35%) had grade 2/3 events. Eight of 15 patients in Group A (53%) and 7 of 14 patients in Group B (50%) had HFS (P = .857). For grade 2/3 events, there was no difference between groups: Six of 15 events (40%) occurred in Group A, and 4 of 14 events (29%) occurred in Group B (P = .70). There was no difference in QOL scores between patients who had grade 2/3 HFS and patients who had grade 0/1 HFS. QOL analysis revealed that all patients had elevated social well being. Pyridoxine as administered in the current study did not prevent HFS in patients who received PLD. It is possible that QOL is not compromised in patients with HFS because they may have increased social well being while coping with their disease.

Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-α-aminoadipic semialdehyde/l-Δ1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine l-α-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary l-α-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios.

Two novel ALDH7A1 (antiquitin) splicing mutations associated with pyridoxine‐dependent seizures

Pyridoxine-dependent seizures (PDS) is a rare autosomal recessive disorder causing intractable seizures in neonates and infants. Patients are typically resistant to conventional anticonvulsants but respond well to the administration of pyridoxine. We report two unrelated patients affected with PDS as a result of alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency caused by pathogenic ALDH7A1/antiquitin mutations. Two of the three reported mutations are novel and result in erroneous splicing, as showed by messenger RNA (mRNA) studies. So far, the vast majority of the patients clinically diagnosed as PDS show alpha-AASA dehydrogenase deficiency, caused by mutations in the ALDH7A1 gene. However, despite the availability of reliable biomarkers, early consideration of a pyridoxine trial is still the most important issue in a child with therapy-resistant seizures.

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.

Sideroblastic anaemias.

Sideroblastic anaemias.