Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome.

The first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or pyridoxal 5'-phosphate and many of them showed residual enzyme activity. One sequence change (R116Q), predicted to affect flavin mononucleotide binding and binding of the two PNPO dimers, and with high residual activity was found in Groups (ii) and (iii). This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy.

The predictive value of early neurological examination in neonatal hypoxic-ischaemic encephalopathy and neurodevelopmental outcome at 24 months.

AIM: The clinical and electrographic signs of hypoxic-ischaemic encephalopathy (HIE) evolve over the first days of life. We examined the evolution of neurological signs over the first 3 days of life, and determined whether serial administration of the Amiel-Tison Neurological Assessment at Term (ATNAT) would predict neurodevelopmental outcome at 24 months. METHOD: Term (>37 wks' gestation) neonates born with suspected HIE between May 2003 and May 2005 in a Cork maternity unit were recruited prospectively. Modified Sarnat grading was assigned. The ATNAT was administered on days 1, 2, and 3 of life and a discharge neurological examination. Time to oral feeding and demographic variables were recorded. Developmental status was assessed using the revised Griffiths Mental Development Scales at 6, 12, and 24 months. RESULTS: Fifty-seven infants were recruited, with 51 (31 males, 20 females) included for follow-up. Neurological examination evolved and normalized over the first 3 days of life in many cases. At 24 months, 21 children had an adverse outcome, including six deaths. Examination at all time points correlated significantly with neurological outcome at 24 months. The best correlations were found to be (1) neurological examination at discharge (r=0.65, p<0.001), (2) Sarnat grading (r=0.64, p<0.001), and (3) ATNAT on day 3 (r=0.46, p<0.001). The best predictive value was seen with neurological examination at discharge (positive and negative predictive values of 86% and 72% respectively). INTERPRETATION: Persistence of abnormal neurological signs correlates significantly with adverse outcome. The later a neonatal neurological examination was performed, the better its predictive ability.

Bruising: when it is spontaneous and not idiopathic thrombocytopenia purpura.

Bruising is a presentation that often causes concern. There are many causes of bruising in children, including non-accidental injury, which must be excluded. We report a case of a 22-month-old boy where all the common diagnoses were excluded. We highlight the need to be aware of transient acquired inhibitors of coagulation that can cause spontaneous bleeding.