RESUMEN
A patient undergoing chemotherapy for treatment of acute lymphocytic leukemia developed septicemia that was treated with linezolid for 16 days. The patient subsequently reported reduced vision in both eyes and was found to have bilateral optic neuropathy. After the discontinuation of linezolid treatment, both the optic neuropathy and visual impairment resolved without sequelae.
Asunto(s)
Acetamidas/efectos adversos , Antibacterianos/efectos adversos , Enfermedades del Nervio Óptico/inducido químicamente , Oxazolidinonas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Sepsis/tratamiento farmacológico , Acetamidas/uso terapéutico , Adulto , Antibacterianos/uso terapéutico , Femenino , Humanos , Linezolid , Oxazolidinonas/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND/AIMS: Dent's disease is caused by mutations in the chloride/proton antiporter, CLC-5, or oculo-cerebro-renal-syndrome-of-Lowe (OCRL1) genes. METHODS: Eighteen probands with Dent's disease were investigated for mutations in CLC-5 and two of its interacting proteins, CLC-4 and cofilin. Wild-type and mutant CLC-5s were assessed in kidney cells. Urinary calcium excretion following an oral calcium challenge was studied in one family. RESULTS: Seven different CLC-5 mutations consisting of two nonsense mutations (Arg347Stop and Arg718Stop), two missense mutations (Ser244Leu and Arg516Trp), one intron 3 donor splice site mutation, one deletion-insertion (nt930delTCinsA) and an in-frame deletion (523delVal) were identified in 8 patients. In the remaining 10 patients, DNA sequence abnormalities were not detected in the coding regions of CLC-4 or cofilin, and were independently excluded for OCRL1. Patients with CLC-5 mutations were phenotypically similar to those without. The donor splice site CLC-5 mutation resulted in exon 3 skipping. Electrophysiology demonstrated that the 523delVal CLC-5 mutation abolished CLC-5-mediated chloride conductance. Sixty percent of women with the CLC-5 deletion-insertion had nephrolithiasis, although calcium excretion before and after oral calcium challenge was similar to that in unaffected females. CONCLUSIONS: Three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent's disease in this patient cohort.
Asunto(s)
Canales de Cloruro/genética , Cofilina 1/genética , Enfermedades Renales/genética , Mutación , Secuencia de Aminoácidos , Secuencia de Bases , Calcio/administración & dosificación , Calcio/farmacocinética , Calcio/orina , Línea Celular , Canales de Cloruro/fisiología , Codón sin Sentido , Análisis Mutacional de ADN , Electrofisiología , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Humanos , Enfermedades Renales/fisiopatología , Masculino , Mutagénesis Insercional , Mutación Missense , Linaje , Eliminación de Secuencia , TransfecciónRESUMEN
BACKGROUND & AIMS: Crohn's disease is a common inflammatory disorder of the gut characterized by variation in both location and behavior. Chromosome 16 and the HLA region on chromosome 6 have been implicated in susceptibility to disease. Mutations in the NOD2/CARD15 gene, recently identified on chromosome 16, have been associated with disease overall but are found in only 25% of patients. No data regarding their contribution to specific disease subtypes exist. Here we report a detailed genotype-phenotype analysis of 244 accurately characterized patients. METHODS: A total of 244 white patients with Crohn's disease recruited from a single center in the United Kingdom were studied. All patients were rigorously phenotyped and followed-up for a median time of 16 years. By using linkage disequilibrium mapping we studied 340 polymorphisms in 24 HLA genes and 3 NOD2/CARD15 polymorphisms. RESULTS: We show that NOD2/CARD15 mutations determine ileal disease only. We confirm that alleles on specific long-range HLA haplotypes determine overall susceptibility and describe novel genetic associations with susceptibility, location, and behavior of Crohn's disease. CONCLUSIONS: The clinical pattern of Crohn's disease may be defined by specific genotypes. This study may provide the basis for a future molecular classification of disease.