Down syndrome is caused by trisomy of chromosome 21 and is comprised of a constellation of abnormalities including neuropathological features that closely resemble those characterizing the neurodegeneration of Alzheimer disease. Because cultured cell lines from patients with Alzheimer disease and other neurodegenerations have a hypersensitivity to the lethal effects of DNA-damaging agents, we studied the response of Down syndrome lymphoblastoid lines to the lethal effects of ionizing and ultraviolet radiation. Lines from the four Down syndrome patients were more sensitive to X-rays than lines from 28 normal donors (P = 10(-4)), while survival of the Down syndrome lines after ultraviolet irradiation was not significantly different from normal. This hypersensitivity to X-rays, which may reflect defective repair of X-ray-induced DNA damage, represents the first abnormality common to cultured cells from both Down syndrome and Alzheimer disease patients.

Alzheimer Disease↗

PubMedDate not supplied

Alzheimer disease fibroblasts are hypersensitive to the lethal effects of a DNA-damaging chemical.

A group of fibroblast lines from three patients with the sporadic form of Alzheimer disease (AD) showed a small but statistically significant hypersensitivity to the lethal effects of the DNA-damaging chemical N-methyl-N'-nitro-nitrosoguanidine (MNNG) when compared with lines from eight normal control subjects. A fibroblast line from a patient with a dominantly inherited form of familial AD had a hypersensitivity similar to that of the three sporadic AD lines. However, fibroblast lines from a group of five patients with spinal muscular atrophy (SMA) were not hypersensitive to the chemical, demonstrating that not every primary neuronal degeneration manifests hypersensitivity to this chemical. These findings are consistent with the possibility that a defect in DNA-repair mechanisms may be the cause of the in vitro hypersensitivity, as well as the premature death of neurons in vivo, in both the sporadic and familial forms of AD.

Alzheimer Disease↗

PubMedDate not supplied

Adult-onset xeroderma pigmentosum neurological disease--observations in an autopsy case.

Xeroderma pigmentosum (XP) is an inherited disease with defective DNA repair. Patients develop skin cancer because of unrepaired DNA damage produced by the ultraviolet radiation (UV) in sunlight. Many XP children also develop XP neurological disease (ND), consisting of sensorineural hearing loss (SNHL) and a primary neuronal degeneration of the central and peripheral nervous systems. Since the harmful UV in sunlight cannot reach the nervous system, the cause of the death of XP neurons has been hypothesized to result from the inability to repair their DNA that has been damaged by endogenous metabolites. Progressive XP ND originating in an adult has been identified in only a single case. Although clinically asymptomatic at the age of 47 years, the patient had audiometric evidence of a developing mild SNHL together with elicited signs and electrophysiologic evidence of a peripheral neuropathy. She died of metastatic endocervical adenocarcinoma at 49 years of age. We describe here the neuropathological findings in this patient, including examination of the inner ear. Despite clinical evidence of SNHL, there were no anatomic abnormalities of the inner ear. However, the dorsal root ganglia (DRG) showed ongoing neuronal loss. Our findings indicate that XP ND originating in this adult is, like XP ND in children, a primary neuronal degeneration that manifests first in the peripheral nervous system.

Age of Onset↗