Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine‐dependent epilepsy and pyridoxine phosphate oxidase deficiency

Abstract

AIM We report on seizures, paroxysmal events, and electroencephalogram (EEG) findings in four female infants with pyridoxine-dependent epilepsy (PDE) and in one female with pyridoxine phosphate oxidase deficiency (PNPO).METHOD Videos and EEGs were analysed and compared with videos of seizures and paroxysmal events archived from 140 neonates. PDE and PNPO were proven by complete control of seizures once pyridoxine or pyridoxal 5¢-phosphate was administered and by recurrence when withdrawn. Mutations in the antiquitin gene were found in three patients and in the PNPO gene in one child.RESULTS Seizures began within 48 hours after birth in four newborns and at age 3 weeks in one.Frequent multifocal and generalized myoclonic jerks, often intermixed with tonic symptoms, abnormal eye movement, grimacing, or irritability, were observed in all infants with PDE and PNPO, but rarely in the other archived videos of neonates. EEGs were inconstant and frequently no discernable ictal changes were recorded during the seizures and the paroxysmal events. In addition, interictal EEGs were inconclusive, with normal and abnormal recordings. In older children tonic-clonic seizures, abnormal behaviour, inconsolable crying, frightened facial expression, sleep disturbance, loss of consciousness, paraesthesia, or intermittent visual symptoms were described during controlled and uncontrolled withdrawal or insufficient dosage.INTERPRETATION PDE or PNPO should be considered in infants with prolonged episodes of mixed multifocal myoclonic tonic symptoms, notably when associated with grimacing and abnormal eye movements.Pyridoxine-dependent epilepsy (PDE) and pyridoxine phosphate oxidase deficiency (PNPO) are rare diseases that necessitate rapid diagnosis and appropriate treatment. Recently, genetic and biochemical diagnostic tools have become available to confirm the diagnosis. 1-3 However, as these results are not available for several hours, administration of pyridoxine and pyridoxal 5¢-phosphate is still the method of choice to treat patients suspected of having the diseases and to make a preliminary diagnosis (folinic acid-responsive seizures have recently been shown to be identical to PDE and to respond to pyridoxine). 4 Administration of pyridoxine in neonates with drug refractory seizures is widely accepted. However, pyridoxal 5¢-phosphate is not licensed in many countries and often not readily available in the hospitals.In 2004 we retrospectively reviewed 105 neonatal seizures and paroxysmal events archived in our video database. 5 Videos of two patients differed markedly from the others and both patients became free from symptoms immediately after administration of pyridoxine. Their unique pattern of paroxysmal events prompted us to suspect PDE in other neonates with similar symptoms. Since 2004 we have identified two additional children with PDE and one with PNPO. The diagnosis of PNPO was made because the paroxysmal events were typical of PDE but were unresponsive to pyridoxine. Here we report on the seizures, paroxysmal symptoms,...

Partial Pyridoxine Responsiveness in PNPO Deficiency

“…The seizure semiology in our patient is notably similar to the recently reported signs in four patients with pyridoxineresponsive epilepsy and one patient with PNPO deficiency (Schmitt et al 2010). The features of neonatal and infantile irritability, inconsolable crying, facial grimacing, abnormal eye movements, eye twitching, multifocal myoclonias and erratic movements, and tonic seizures are characteristic of both diagnoses.…”

Normal Neurodevelopmental Outcomes in PNPO Deficiency: A Case Series and Literature Review

“…Details of the initial presentation of case 4 have been reported previously (Hoffmann et al 2007;Schmitt et al 2010;Sudarsanam et al 2014). Intractable neonatal seizures occurred, with a number of different seizure types seenabnormal eye movements, abnormal smiling, multifocal myoclonic jerks, focal clonic seizures and spasms associated with screaming and irritability.…”

“…To date there have been <40 cases reported in the medical literature (Mills et al 2005Hoffmann et al 2007;Bagci et al 2008;Ruiz et al 2008;Schmitt et al 2010;Veerapandiyan et al 2011;Ware et al 2014;Plecko et al 2014;Porri et al 2014). The initial clinical reported phenotype of PNPO deficiency included prematurity, early-onset neonatal encephalopathy and seizures that are resistant to conventional anticonvulsants and pyridoxine.…”

Cirrhosis Associated with Pyridoxal 5′-Phosphate Treatment of Pyridoxamine 5′-Phosphate Oxidase Deficiency

“…The initial clinical details have been previously reported (Hoffmann et al 2007;Schmitt et al 2010). In summary, this boy was born at term and developed seizures at 24 h of age.…”