Dependent Epilepsy Research Articles

The role of vitamin B6 deficiency in infantile epilepsies of unknown etiology

Aims: Pyridoxine dependent epilepsy (PDE) and pyridoxal-5'-phosphate deficiency are rare autosomal recessive enzyme defects in vitamin B6 metabolism due to mutations in the ALDH7A1 and PNPO gene. These disorders are typically characterized by severe, neonatal seizures that are resistant to anticonvulsant drugs but can be controlled by pyridoxine/pyridoxal phosphate. Recently, the phenotypic variability has been shown to be broader than previously assumed. The aim of this study was to further characterize the phenotypic spectrum of vitamin B6 dependent epilepsies.

Status epilepticus in a newborn – pyridoxine toxicity?

Aims: Pyridoxine dependent epilepsy (PDE) (MIM 266100) is a treatable neonatal encephalopathy with autosomal recessive inheritance. In view of possible positive effects on developmental outcome, antenatal and postnatal prophylactic treatment of siblings at risk has been recommended. Until now, no side effects of prophylactic treatment have been reported.

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.

Screening for pyridoxine dependent epilepsy (PDE) by Tandem Mass Spectrometry (HPLC-MS/MS)

Introduction: Pyridoxine dependent epilepsy (PDE; MIM:266100) is a rare, auto-somal-recessive inborn error of metabolism. More than 120 cases have been reported up to now. Neonatal seizures are caused by a secondary vitamin B6 deficiency due to a lack of 2-aminoadipic acid semialdehyde dehydrogenase activity (2-AASA, allysine). Lysine degradation is disturbed. Besides seizures mental retardation, in some cases microcephaly and disturbed brain development may occur.

Biochemical and molecular analysis of the ALDH7 A1 gene in 31 patients with Pyridoxine-dependent epilepsy

Most cases of pyridoxine dependent epilepsy (PDE) (MIM #266100) are caused by mutations of the antiquitin gene (ALDH7 A1), leading to α-aminoadipic acid semialdehyde dehydrogenase deficiency This enzyme is involved in the cerebral lysine degradation pathway. The accumulating compound piperideine 6-carboxylate (P6C) inactivates pyridoxalphosphate, causing severe cerebral pyridoxine deficiency. We report on biochemical and molecular findings in 31 Caucasian PDE patients with neonatal seizure onset, 13 of whom have not been reported previously. Pipecolic acid (PA) was measured by GCMS and α-aminoadipic acid semialdehyde (α-AASA) determined by LC-MS/MS. Mutation analysis was done by complete sequencing and confirming restriction fragment polymorphism analysis. In all patients with ALDH7 A1 mutations urinary α-AASA and plasma PA were elevated 1.6 to 62- fold and 1.5 to 38– fold, respectively. AASA and PA concentrations were higher in the 3 patients with pre-treatment sampling. Within 60 of the 62 alleles a total of 16 different mutations were identified. Several mutations had increased prevalence, as p.Glu399Gln (exon 14; 34%), c.1482–1G>T acceptor splice site mutation (intron 17, 12%), Arg82X (exon 4; 10%) and a „silent mutation“, p.V250V (exon 9; 9%). In 7 patients of 6 unrelated families 6 novel mutations were found: an insertion in exon 1, c.57insA (p.Arg20ThrfsX8), a donor splice site mutation, c.689+2T>C (intron 8), and 4 missense mutations (p.Arg82Gly (exon 4), p.Asn167Ser (exon 6), p.Asn420Lys (exon 15) and p.Gln425Pro (exon 15). All these mutations showed familiar cosegregation and were not present in 120 control alleles.

ETP03 EEG-amplitude response by pyridoxine-IV in children with pyridoxine dependent epilepsy and ALDH7A1-gene mutation.

ETP03 EEG-amplitude response by pyridoxine-IV in children with pyridoxine dependent epilepsy and ALDH7A1-gene mutation.

The importance of social support to chronically ill adolescents

Improvements in medicine have significantly prolonged life of chronically ill children and adolescents in the past several decades. There is a great variability in adaptation to illness among chronically ill persons--some of them seem to be very well adapted, with almost no problems. However, research results suggest that chronically ill children are more likely to have psychological problems than their healthy peers. Eightyfour subjects, all elementary school pupils, participated in the study. The first group included adolescents with chronical illness (malignant illness, insulin dependent diabetes mellitus, epilepsy, or asthma), and the second their healthy peers. Depression and social support were evaluated. The Birleson's Depression Scale and Perceived Social Support Scales (forms for friends and for family members) were used. The results show significant differences for two of the three variables: depression, and perceived social support from family, while there was no significant difference for perceived social support from friends. The results suggest that chronically ill adolescents are more depressed and that they perceive that the social support they receive from their families is lower when compared to their healthy peers. The results of this study showed that chronically ill adolescents are more depressed than their healthy peers. This group of adolescents also perceives that they have less social support from their families than their healthy peers. When it comes to perceived social support from friends, these two groups do not differ.

Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene

Patients with pyridoxine dependent epilepsy (PDE) present with early-onset seizures resistant to common anticonvulsants. According to the benefit of pyridoxine (vitamin B(6)) and recurrence of seizures on pyridoxine withdrawal, patients so far have been classified as having definite, probable, or possible PDE. Recently, PDE has been shown to be caused by a defect of alpha-amino adipic semialdehyde (AASA) dehydrogenase (antiquitin) in the cerebral lysine degradation pathway. The accumulating compound piperideine-6-carboxylic acid (P6C) was shown to inactivate pyridoxalphosphate (PLP) by a Knoevenagel condensation. Pipecolic acid (PA) and AASA are markedly elevated in urine, plasma, and cerebrospinal fluid (CSF) and thus can be used as biomarkers of the disease. We have investigated 18 patients with neonatal seizure onset, who have been classified as having definite (11), probable (four), or possible (three) PDE. All patients had elevated PA and AASA in plasma (and urine) while on treatment with individual dosages of pyridoxine. Within this cohort, molecular analysis identified 10 novel mutations (six missense mutations, one nonsense mutation, two splice site mutations) within highly conserved regions of the antiquitin gene. Seven mutations were located in exonic sequences and two in introns 7 and 17. Furthermore, a novel deletion of exon 7 was identified. Two of the 36 alleles investigated require further investigation. A known mutation (p.Glu399Gln) was found with marked prevalence, accounting for 12 out of 36 alleles (33%) within our cohort. Pyridoxine withdrawal is no longer needed to establish the diagnosis of "definite" PDE. Administration of pyridoxine in PDE may not only correct secondary PLP deficiency, but may also lead to a reduction of AASA (and P6C) as presumably toxic compounds.

DEVELOPMENT OF GABA (A) RECEPTOR ALPHA1 AND GAMMA2 SUBUNIT IN HUMAN TEMPORAL LOBE, HIPPOCAMPUS AND BASAL GANGLIA

Objectives: To examine the development of GABA (A) receptor alpha1 subunit (GABARA1) and gamma2 subunit (GABARG2) in human brain. Recently, the genes encoding GABARA1 and GABARG2 were found to be associated with age dependent epilepsy. Nevertheless, developmental and spatial changes of both subunits expression in human brain surprisingly had not been examined.

Epidemiology of pyridoxine dependent seizures in the Netherlands

Background: Pyridoxine dependent epilepsy is a rare cause of seizures in childhood. The diagnosis is made on clinical criteria, that in many cases are never met. Therefore, epidemiological data on...

Clinical aspects of the disorders of GABA metabolism in children.

There has been increased recognition of the pediatric neurotransmitter disorders. This review focuses on the clinical disorders of GABA metabolism. The known clinical disorders of GABA metabolism are pyridoxine dependent epilepsy, GABA-transaminase deficiency, SSADH deficiency, and homocarnosinosis. Pyridoxine dependent epilepsy is diagnosed clinically but potentially more common presentations, with later and atypical features, widen the spectrum. No gene locus has been confirmed; the pathophysiology may involve alterations in PLP transport, binding to GAD, or other PLP-dependent pathways. SSADH deficiency is associated with developmental delay, prominent language deficits, hypotonia, ataxia, hyporeflexia, and seizures. Increased detection is reported when specific ion monitoring is used for GHB on urine organic acids. The most consistent MRI abnormality is increased signal in the globus pallidus. MR spectroscopy has demonstrated the first example of increased endogenous GABA in human brain parenchyma in this disorder. GABA-transaminase deficiency and homocarnosinosis appear to be very rare but require CSF for detection, thus allowing for the possibility that these entities, as in the other pediatric neurotransmitter disorders, are underrecognized. The disorders of GABA metabolism require an increased index of clinical suspicion. Pyridoxine dependent epilepsy is a treatable condition with a potentially widening clinical spectrum, but with a prognosis dependent on early intervention. SSADH deficiency has a heterogeneous spectrum and requires careful urine organic acid testing for screening, followed by enzymatic confirmation allowing appropriate prognostic and genetic counseling.

Pyridoxine dependent epilepsy: a suggestive electroclinical pattern

AIMSTo determine if there is an electroencephalographic pattern suggestive of pyridoxine dependent epilepsy that could be used to improve the chances of early diagnosis.METHODSA retrospective study was made of all...

Pyridoxine Dependent Epilepsy with Iatrogenic Sensory Neuronopathy

An 18-year-old man was treated from birth with chronic high dose pyridoxine (vitamin B6) up to 2000 mg per day for pyridoxine-dependent seizures. Within two years of onset of treatment, he developed a sensory neuropathy which did not progress over the following 16 years. Electrophysiological studies were consistent with a pure sensory neuronopathy expressed as centripetal degeneration of processes of the dorsal root ganglion cells.

Calcium antagonistic effects of carbamazepine as a mechanism of action in neuropsychiatric disorders: studies in calcium dependent model epilepsies

Carbamazepine (CBZ) is used in neurology for the treatment of epilepsies and trigeminal neuralgia and in psychiatry for the prophylactic treatment of affective and schizoaffective psychoses. Since a common mechanism of epilepsies and affective psychoses might be increased intracelllular calcium ion levels, CBZ action was analyzed in penicillin, caffeine and low Mg 2+ induced model epilepsies which have been shown to be suppressed specifically by organic calcium antagonists. In CA3 and CA1 areas of hippocampal slice preparations of guinea pigs CBZ reduced paroxysmal depolarizations and extracellular field potentials (EFP) in a typical time and concentration dependent manner as it is known from calcium antagonists. Furthermore, subthreshold concentrations of the organic calcium antagonist verapamil intensified the action of CBZ. NMDA induced increases of the discharge rate of EFP were, however, unaffected by CBZ.