Mutations in the USH1C gene associated with sector retinitis pigmentosa and hearing loss.

PURPOSE: To determine the molecular cause of sector retinitis pigmentosa and hearing loss in two affected siblings. METHODS: Direct DNA sequencing of the USH1C gene was performed in two affected siblings. Putative pathogenic sequence changes were assayed in their parent's chromosomes and in control chromosomes. Clinical examination included visual acuity measurement, visual field measurement, electrophysiologic assessment, and fine matrix mapping. Retinal imaging with fundus photography, scanning laser ophthalmoscope (fundus autofluorescence), and optical coherence tomography was performed. Hearing and vestibular function was also assessed. RESULTS: The siblings were aged 42 years and 40 years, and both were compound heterozygotes for the p.R103H missense change and the novel splice site change c.2227-1G>A in the USH1C gene. Both alleles were found to be in trans. Neither allele was identified in a panel of 866 control chromosomes, and both were considered pathogenic. Both siblings had sector retinitis pigmentosa restricted to the inferior and nasal retina. Fundus autofluorescence imaging showed a clear demarcation between normal and abnormal areas of retina, which corresponded to areas of reduced sensitivity on fine matrix mapping and loss of visual field. Both siblings had severe hearing loss but were able to develop language. CONCLUSION: We report a novel molecular cause of sector retinitis pigmentosa associated with hearing loss representing a new phenotype associated with mutations in the USH1C gene.

Seizures Due to a KCNQ2 Mutation: Treatment with Vitamin B6.

There is increasing evidence that vitamin B6, given either as pyridoxine or pyridoxal 5'-phosphate, can sometimes result in improved seizure control in idiopathic epilepsy. Whole-exome sequencing was used to identify a de novo mutation (c.629G>A; p.Arg210His) in KCNQ2 in a 7-year-old patient whose neonatal seizures showed a response to pyridoxine and who had a high plasma to CSF pyridoxal 5'-phosphate ratio, usually indicative of an inborn error of vitamin B6 metabolism. This mutation has been described in three other patients with neonatal epileptic encephalopathy. A review of the literature was performed to assess the effectiveness of vitamin B6 treatment in patients with a KCNQ2 channelopathy. Twenty-three patients have been reported to have been trialled with B6; in three of which B6 treatment was used alone or in combination with other antiepileptic drugs to control seizures. The anticonvulsant effect of B6 vitamers may be propagated by multiple mechanisms including direct antagonist action on ion channels, antioxidant action on excess reactive oxygen species generated by increased neuronal firing and replenishing the pool of pyridoxal 5'-phosphate needed for the synthesis of some inhibitory neurotransmitters. Vitamin B6 may be a promising adjunctive treatment for patients with channelopathies and the wider epileptic population. This report also demonstrates that an abnormal plasma to CSF pyridoxal 5'-phosphate ratio may not be exclusive to inborn errors of vitamin B6 metabolism.