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

Department of Neurology, University Children's Hospital, Steinwiesstrasse 75, Zurich, Switzerland.
Developmental Medicine & Child Neurology (Impact Factor: 3.51). 03/2010; 52(7):e133-42. DOI: 10.1111/j.1469-8749.2010.03660.x
Source: PubMed


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).
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by complete control of seizures once pyridoxine or pyridoxal 5'-phosphate was administered and by recurrence when withdrawn.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.
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.
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.

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Available from: Matthias R Baumgartner, Dec 27, 2014
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    • "Early reports have suggested that the common clinical features in the reported PNPO cases thus far include (1) neonatal encephalopathy, seizures resistant to multiple anticonvulsants (Mills et al. 2005; Schmitt et al. 2010), (2) burst suppression EEG pattern (Veerapandiyan et al. 2011), (3) non-responsiveness to pyridoxine (Clayton 2006), (4) complete or partial responsiveness to PLP (Pearl et al. 2013), (5) prematurity (Veerapandiyan et al. 2011) and (6) neonatal lethality if the diagnosis is not suspected and PLP administered (Khayat et al. 2008). Early diagnosis and treatment with PLP have been linked with improved neurodevelopmental outcomes (Hoffmann et al. 2007; Plecko et al. 2014) with more recent reports supporting that normal neurodevelopmental outcomes can occur (Khayat et al. 2008; Mills et al. 2014; Plecko et al. 2014). "
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    ABSTRACT: Pyridox(am)ine 5'-phosphate oxidase deficiency results in an early-onset neonatal encephalopathy that can be fatal if not detected and treated early. The condition is rare, can result in preterm delivery, and can mimic hypoxic ischemic encephalopathy. Thus, suspicion of the diagnosis, appropriate investigations, and therapeutic trials with pyridoxal-5'-phosphate are often delayed. In this paper we report four cases of pyridox(am)ine 5'-phosphate oxidase deficiency, two of whom are siblings. Three were treated with pyridoxal-5'-phosphate in the first few days of life and the fourth within the first month. One of the siblings was electively treated from birth until a diagnosis was secured. Our cases demonstrate that early diagnosis and treatment can be associated with normal neurodevelopment in childhood. We suggest that a low threshold for investigating for pyridox(am)ine 5'-phosphate oxidase deficiency and electively treating with pyridoxal-5'-phosphate is considered in any neonate with encephalopathy, including those with presumed hypoxic ischemic encephalopathy in whom the degree of encephalopathy is not expected from perinatal history, cord gases and/or neuroimaging.
    Full-text · Article · Aug 2015
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    • "PNPO deficiency is a rare disorder with less than 50 reported cases in the literature. Common clinical features in reported cases thus far include (1) neonatal encephalopathy with seizures resistant to multiple anticonvulsants (Mills et al. 2005; Schmitt et al. 2010), (2) burst suppression EEG pattern (Veerapandiyan et al. 2011), (3) nonresponsiveness to pyridoxine (Clayton 2006), (4) complete or partial responsiveness to PLP (Pearl et al. 2013), (5) prematurity (Veerapandiyan et al. 2011), and (6) neonatal lethality if the diagnosis was not suspected and P5P administered (Khayat et al. 2008). Recently three groups of PNPO deficiency clinical phenotypes have been postulated: (1) early-onset neonatal seizures responsive to PLP, (2) infantile spasms in infancy, and (3) seizures beginning in the first three months of life responsive to pyridoxine (Mills et al. 2014). "
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    ABSTRACT: We report the case of a 4-year-old boy with pyridoxamine 5-phosphate oxidase deficiency, now the second reported case to develop hepatic cirrhosis. He presented with an encephalopathy in the first 1.5 h of life and received a first dose of PLP at 40 h of life. PNPO gene sequencing identified homozygosity for a novel variant in exon 7, c.637C>T (p.Pro213Ser). Persistent elevations in alanine transferase and aspartate transferase combined with an echogenic liver on ultrasound prompted performance of a liver biopsy which demonstrated hepatic cirrhosis. This is the second reported case of hepatic cirrhosis in PNPO deficiency. The pathogenesis is unclear but may be related to epigenetic activation of purinergic signaling in the hepatic stellate cells. PNPO deficiency may in time prove to be a suitable candidate for consideration of therapeutic orthotropic liver transplantation in select patients.
    Full-text · Article · Jun 2015
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    • "They observed continuous or intermittent focal or generalized discharges of sharp waves or rhythmic sharp theta waves during the seizures, but more frequently, there was no discernible ictal change. They concluded that lack of ictal EEG discharge during distinct paroxysmal events is perhaps more suggestive of PDE or PLP dependent epilepsy than the inconstantly obvious ictal discharges [22]. Genetically, PLP dependent epilepsy is related to PNPO gene mutation located on chromosome 17 and is inherited in an autosomal recessive manner. "
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    ABSTRACT: Untreated epileptic encephalopathies in children may potentially have disastrous outcomes. Treatment with antiepileptic drugs (AEDs) often may not control the seizures, and even if they do, this measure is only symptomatic and not specific. It is especially valuable to identify potential underlying conditions that have specific treatments. Only a few conditions have definitive treatments that can potentially modify the natural course of disease. In this paper, we discuss the few such conditions that are responsive to vitamin or vitamin derivatives.
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