To assess the role of DNA repair in maintenance of hearing function and neurological integrity, we examined hearing status, neurological function, DNA repair complementation group and history of acute burning on minimal sun exposure in all patients with xeroderma pigmentosum, who had at least one complete audiogram, examined at the National Institutes of Health from 1971 to 2012. Seventy-nine patients, aged 1-61 years, were diagnosed with xeroderma pigmentosum (n = 77) or xeroderma pigmentosum/Cockayne syndrome (n = 2). A total of 178 audiograms were included. Clinically significant hearing loss (>20 dB) was present in 23 (29%) of 79 patients. Of the 17 patients with xeroderma pigmentosum-type neurological degeneration, 13 (76%) developed hearing loss, and all 17 were in complementation groups xeroderma pigmentosum type A or type D and reported acute burning on minimal sun exposure. Acute burning on minimal sun exposure without xeroderma pigmentosum-type neurological degeneration was present in 18% of the patients (10/55). Temporal bone histology in a patient with severe xeroderma pigmentosum-type neurological degeneration revealed marked atrophy of the cochlear sensory epithelium and neurons. The 19-year mean age of detection of clinically significant hearing loss in the patients with xeroderma pigmentosum with xeroderma pigmentosum-type neurological degeneration was 54 years younger than that predicted by international norms. The four frequency (0.5/1/2/4 kHz) pure-tone average correlated with degree of neurodegeneration (P < 0.001). In patients with xeroderma pigmentosum, aged 4-30 years, a four-frequency pure-tone average ≥10 dB hearing loss was associated with a 39-fold increased risk (P = 0.002) of having xeroderma pigmentosum-type neurological degeneration. Severity of hearing loss parallels neurological decline in patients with xeroderma pigmentosum-type neurological degeneration. Audiometric findings, complementation group, acute burning on minimal sun exposure and age were important predictors of xeroderma pigmentosum-type neurological degeneration. These results provide evidence that DNA repair is critical in maintaining neurological integrity of the auditory system.
"This 45-year-old female patient with XP had a history of progressive neurologic deficits [14,26] (Figure 1C and Table 1). She presented to the NIH at age 5 years with hearing difficulty and developmental delay. "
[Show abstract][Hide abstract] ABSTRACT: Background
To investigate the association of DNA nucleotide excision repair (NER) defects with neurological degeneration, cachexia and cancer, we performed autopsies on 4 adult xeroderma pigmentosum (XP) patients with different clinical features and defects in NER complementation groups XP-A, XP-C or XP-D.
The XP-A (XP12BE) and XP-D (XP18BE) patients exhibited progressive neurological deterioration with sensorineural hearing loss. The clinical spectrum encompassed severe cachexia in the XP-A (XP12BE) patient, numerous skin cancers in the XP-A and two XP-C (XP24BE and XP1BE) patients and only few skin cancers in the XP-D patient. Two XP-C patients developed internal neoplasms including glioblastoma in XP24BE and uterine adenocarcinoma in XP1BE. At autopsy, the brains of the 44 yr XP-A and the 45 yr XP-D patients were profoundly atrophic and characterized microscopically by diffuse neuronal loss, myelin pallor and gliosis. Unlike the XP-A patient, the XP-D patient had a thickened calvarium, and the brain showed vacuolization of the neuropil in the cerebrum, cerebellum and brainstem, and patchy Purkinje cell loss. Axonal neuropathy and chronic denervation atrophy of the skeletal muscles were observed in the XP-A patient, but not in the XP-D patient.
These clinical manifestations and autopsy findings indicate advanced involvement of the central and peripheral nervous system. Despite similar defects in DNA repair, different clinicopathological phenotypes are seen in the four cases, and therefore distinct patterns of neurodegeneration characterize XP-D, XP-A and XP-C patients.
[Show abstract][Hide abstract] ABSTRACT: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations resulting in defective repair of DNA damage. XP patients have a markedly increased risk of ultraviolet-induced neoplasms and premature aging of sun-exposed tissue. Approximately 25% of XP patients in the United States have neurologic abnormalities including progressive sensorineural hearing loss (SNHL).
To describe the temporal bone histopathology in 2 individuals with XP (XPA and XPD) with neurologic degeneration and to discuss the possible causes of deafness in these patients.
Temporal bones were removed at autopsy and studied using light microscopy.
In the case with XPD, the organ of Corti was missing throughout the cochlea, whereas the case with XPA demonstrated scattered presence of sensory cells in the middle and apical turns. In both cases, there was moderate-to-severe patchy atrophy of the stria vascularis in all turns, and cochlear neurons were severely atrophied compared with age-matched controls, with loss of both peripheral dendrites and central axons. There was severe degeneration of Scarpa's ganglion in the case with XPA.
Two cases of XP with neurologic degeneration are reported. The case with XPD demonstrated a more severe audiologic phenotype than XPA, although both had similar findings such as atrophy of the organ of Corti, stria vascularis, and spiral ganglia leading to severe or profound SNHL by the third decade of life. It is not clear if the neuronal degeneration in the inner ear was primary or secondary to loss of neuroepithelial cells.
Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 08/2013; 34(7). DOI:10.1097/MAO.0b013e31829795e9 · 1.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Xeroderma pigmentosum (XP) is a rare autosomal recessive disease of DNA repair with ultraviolet radiation (UV) sensitivity and a 10,000-fold increased risk of skin cancer. Symptoms include: freckle-like pigmentation in sun exposed skin before age 2 years, severe burns after minimal sun exposure (50% of patients) and damage to exposed surfaces of the eyes with loss of vision and ocular cancer. About 25% of patients develop a progressive neurodegeneration. The combination of an inherited inability to repair UV induced DNA damage and environmental exposure to UV must occur for cutaneous and ocular symptoms to develop. There is no cure for XP, but many of its manifestations may be reduced or prevented through consistent UV protection thus XP serves as a model for sun protection of patients with marked photosenstivity. Sun protective clothing including hats, sunglasses and face shields, sun screen lotions and avoidance of environmental sources of UV are cornerstones of prevention of skin and eye damage and cancer. Although XP is a serious disease with the potential for limitation of life expectancy, XP patients can live active lives while at the same time avoiding UV.
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