Antenatal treatment in two Dutch families with pyridoxine-dependent seizures

Contains fulltext : 88199.pdf (publisher's version ) (Closed access)Incidental reports suggest that antenatal treatment of pyridoxine dependent seizures (PDS) may improve neurodevelopmental outcome of affected patients. Two families with PDS are reported, both with two affected siblings. Antenatal treatment with pyridoxine was instituted during the second pregnancy in each family (50 and 60 mg daily from 3 and 10 weeks of gestation, respectively). Perinatal characteristics and neurodevelopmental outcome at 4 (Family A) and 12 (Family B) years of age were compared between the untreated and treated child within each family. Meconium-stained amniotic fluid was present in both first pregnancies and abnormal foetal movements were noticed in one. In the treated infants, pregnancy and birth were uncomplicated. In family A, postnatal pyridoxine supplementation prevented neonatal seizures. Both children in family A were hypotonic and started walking after 2 years of age; both had white matter changes on MRI, and the first child was treated for squint. IQ was 73 and 98 in the antenatally untreated and treated child, respectively. The second child in family B developed seizures on the seventh day, because pyridoxine maintenance therapy had not been instituted after birth. Seizures responded rapidly to pyridoxine supplementation. MRI showed large ventricles and a mega cisterna magna. IQ was 80 and 106 in the antenatally untreated and treated child respectively. Both children had normal motor development. These results suggest that antenatal pyridoxine supplementation may be effective in preventing intrauterine seizures, decreasing the risk of complicated birth and improving neurodevelopmental outcome in PDS.1 maart 201

Pyridoxine-dependent epilepsy initially responsive to phenobarbital Epilepsia por dependência de piridoxina inicialmente responsiva ao fenobarbital

Pyridoxine-dependent epilepsy is a rare autossomal recessive disorder characterized by recurrent seizures that are not controlled by anticonvulsant medications but remits after administration of pyridoxine. We report on a 30 day-old girl who presented with seizures during the first day of life, initially responsive to anticonvulsant therapy, which remitted within two weeks. Seizures were characterized as multifocal myoclonic jerks of upper and lower limbs associated with buccal-lingual oral movements and eyelid blinking. Laboratory and neuroimaging studies were normal. Electroencephalographic record demonstrated a abnormal background activity with high-voltage epileptic discharges and a burst-suppression pattern. The seizures ceased after oral administration of pyridoxine, but recurred after withdrawal, confirming the diagnosis.<br>A epilepsia por dependência de piridoxina é uma doença autossômica recessiva rara caracterizada por crises recorrentes refratárias a tratamento medicamentoso, mas que remitem após a administração de piridoxina. Relatamos o caso de menina de 30 dias de vida que iniciou crises convulsivas desde o primeiro dia de vida, inicialmente responsivas a tratamento com drogas anticonvulsivantes, mas que reiniciaram após a segunda semana de vida. As crises eram caracterizadas por movimentos clônicos erráticos de membros superiores e inferiores associados a movimentos oromandibulares e piscamentos. Exames laboratoriais e de neuroimagem foram normais. O exame eletrencefalográfico evidenciou atividade de base desorganizada com descargas epilépticas de alta voltagem associadas a um padrão de surto-supressão. As crises cessaram após a administração de piridoxina e recorreram após a sua retirada, confirmando o diagnóstico

Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients

Purpose: Pyridoxine-dependent seizure (PDS) is a rare disorder characterized by seizures that are resistant to common anticonvulsants, and that are ultimately controlled by daily pharmacologic doses of pyridoxine (vitamin B6). Mutations of the antiquitin gene (ALDH7A1) are now recognized as the molecular basis of cases of neonatal-onset PDS.\ud \ud Methods: Bidirectional DNA sequence analysis of ALDH7A1 was undertaken along with plasma pipecolic acid (PA) measurements to determine the prevalence of ALDH7A1 mutations in a cohort of 18 North American patients with PDS.\ud \ud Results: In patients with neonatal-onset PDS, compound heterozygous or homozygous ALDH7A1 mutations were detected in 10 of 12 cases, and a single mutation was found in the remaining 2. In later-onset cases, mutations in ALDH7A1 were detected in three of six cases. In two patients with infantile spasms responsive to pyridoxine treatment and with good clinical outcomes, no mutations were found and PA levels were normal. In total, 13 novel mutations were identified.\ud \ud Discussion: Our study advances previous findings that defects of ALDH7A1 are almost always the cause of neonatal-onset PDS and that defects in this gene are also responsible for some but not all later-onset cases. Later-onset cases of infantile spasms with good outcomes lacked evidence for antiquitin dysfunction, suggesting that this phenotype is less compelling for PDS

Callosal alterations in pyridoxine-dependent epilepsy

Item does not contain fulltextAIM: While there have been isolated reports of callosal morphology differences in pyridoxine-dependent epilepsy (PDE), a rare autosomal disorder caused by ALDH7A1 gene mutations, no study has systematically evaluated callosal features in a large sample of patients. This study sought to overcome this knowledge gap. METHOD: Spanning a wide age range from birth to 48 years, corpus callosum morphology and cross-sectional cerebral area were measured in 30 individuals with PDE (12 males, 18 females, median age 3.92y; 25th centile 0.27, 75th centile 15.25) compared to 30 age-matched comparison individuals (11 males, 19 females, median age 3.85y; 25th centile 0.26, 75th centile 16.00). Individuals with PDE were also divided into age groups to evaluate findings across development. As delay to treatment may modulate clinical severity, groups were stratified by treatment delay (less than or greater than 2wks from birth). RESULTS: Markedly reduced callosal area expressed as a ratio of mid-sagittal cerebral area was observed for the entire group with PDE (p10y) demonstrated posterior abnormalities to be a consistent feature, with anterior regions increasingly involved across the developmental trajectory. Splitting the PDE group by treatment lag did not reveal overall or sub-region callosal differences. INTERPRETATION: Callosal abnormalities are a common feature of PDE not explained by treatment lag. Future work utilizing tract-based approaches to understand inter- and intra-hemispheric connectivity patterns will help in the better understanding the structural aspects of this disease

Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy

BACKGROUND: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function. METHODS: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities. RESULTS: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains. CONCLUSION: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature. TAKE- HOME MESSAGE: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome