Journal of Neurology, Neurosurgery, and Psychiatry 1984;47:391-398 Hypersensitivity to DNA-damaging agents in cultured cells from patients with Usher's syndrome and Duchenne muscular dystrophy JAY H ROBBINS, DOMINIC A SCUDIERO,J FUJIO OTSUKA, ROBERT E TARONE,* ROGER A BRUMBACK,§ JONATHAN D WIRTSCHAFTER,II RONALD J POLINSKY,t SUSANNA F BARRETT, ALAN N MOSHELL, RONALD G SCARPINATO, MARY B GANGES, LINDA E NEE,t SHARON A MEYER,: BRIAN E CLATTERBUCKt From the Dermatology and Biometry* Branches, National Cancer Institute, Laboratory of Clinical Science, t National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, Chemical Carcinogenesis Program, t NCI-Frederick Cancer Research Facility, Frederick, Maryland, Muscular Dystrophy Association Clinic, § Fargo, North Dakota, Department of Ophthalmology, || University of Minnesota Hospitals, Minneapolis, Minnesota, USA SUMMARY Lymphoblastoid lines from nine Usher's syndrome (recessively inherited retinitis pig- mentosa and congenital sensorineural deafness) patients (representing eight kindreds) and from ten Duchenne muscular dystrophy patients (representing seven kindreds) showed a small but statistically significant hypersensitivity to the lethal effects of X-rays, as measured by the cellular ability to exclude the vital dye trypan blue, when compared with lines from 26 normal control subjects. Fibroblast lines from the Usher's syndrome patients, treated with X-rays or the radiomimetic, DNA-damaging chemical N-methyl-N'-nitro-N-nitrosoguanidine, also showed a statistically significant hypersensitivity when compared to normal fibroblast lines. These findings are consistent with the possibility that defective DNA repair mechanisms may be involved in the pathogenesis of these degenerative diseases. The term " abiotrophy" was introduced by WR Gowers in 1902 to signify the premature death of excitable tissues occurring in the absence of any histopathological evidence of the aetiology.' Gowers included primary neuronal degenerations and the muscular dystrophies among the abiotrophies. In 1919, E Treacher Collins classified retinitis pigmen- tosa, with its premature degeneration of photo- receptors, as an abiotrophy.2 The concept of abiot- rophy has recently been reviewed.3 The cause of the premature death of excitable tis- sue in these genetic disorders has long been unknown. We have suggested that the abiotrophic degeneration of neural, retinal, and muscle cells might result from the accumulation of damaged DNA.4-'3 This DNA-damage hypothesis is based Address for reprint requests: Jay H Robbins MD, Building 10, Room 12N238, National Institutes of Health, Bethesda, Maryland 20205, USA. Received 2 August 1983 and in revised form 23 October 1983. Accepted 5 November 1983 primarily on information obtained from the study of the autosomal recessive, sunlight-sensitivity disease xeroderma pigmentosum, one form of which involves a primary neuronal degeneration.4 Cul- tured cells from patients with xeroderma pigmen- tosum are hypersensitive to the lethal effects of ultraviolet radiation and ultraviolet-mimetic chemi- cals because of inherited defects in the repair of DNA.4 '4 Fibroblasts and lymphoblastoid lines from xeroderma pigmentosum patients with an early onset of neuronal degeneration are the most sensi- tive to the lethal effects of ultraviolet radiation, while cells from patients with later onset neurodegeneration or without neuronal degenera- tion are less sensitive.56 Cells from patients with ataxia telangiectasia, another inherited primary neuronal degeneration,'5 are hypersensitive to ioniz- ing radiation9 14 16-19 and to the radiomimetic chemical N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)'820 because of a defect in either DNA repair systems'4 1820 or some other system leading to secondary failure of DNA repair.2'23 More 391 group.bmj.com on March 3, 2013 - Published by jnnp.bmj.com Downloaded from