A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy.

Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness-causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOF. In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923delinsCTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy.

Intestinal permeability in children with trichuris dysentry syndrome - abstract

The status of the small intestine in 20 children with Trichuris dysentery syndrome was investigated, using a differential sugar absorption test on separate occasions, i.e., before treatment and after recovery during their growth spurt. Results from these tests were compared with results from 20 controls, matched for age , with no history of gastrointestinal disease. The sugar absorption test involved orally administering a moderately hypertonic sugar solution of rhamnose and lactulose after an overnight fast. Urine was collected in the subsequent 5 hours of the test and frozen -20§C until analysis by HPLC. Results were expressed as the ratio of lactulose/rhamnose excreted over this time period, the normal intestinal ratio of which is 0.05 ñ 0.02. All 20 children with the syndrome had significantly elevated, abnormal permeability ratios (0.37 ñ 0.18; p < 0.001). These ratios were seen to decrease in the children upon recovery (0.14 ñ 0.08) with 6 of the 18 children attaining normal ratios. The 20 controls had an intestinal permiability ratio of 0.10 ñ 0.08 with 10 of them having elevated permeability ratios. Healthy individuals excrete 12-14 percent of the rhamnose dose and less than 1 percent of the lactulose dose. All children with the syndrome excreted less than 12 percent of the oral dose of rhamnose while the amount of lactulose excreted was greater than 1 percent of the oral dose in 17 of the 20 subjects. Similarly, the amount of rhamnose excreted in the children upon recovery was less than 12 percent of the oral dose in 16 of 18 cases. For the controls, all children had a percentage of recovery for rhamnose less than 12 percent and a percentage recovery for lactulose less than 1 percent. The monosaccharide rhamnose demonstrates the degree of absorption through the abundant transcellular routes of the aqueous pores in the cell membrane while the disaccharide lactulose reflects the permeability through the fewer intercellular junctional complexes and extrusion zones. The Trichuris dysentery syndrome, previously known to be a colonic disease, appears from this study to be associated with inflammation of the small intestinal epithelium in man (AU)