Open Access Research

The influence of DNA repair on neurological degeneration, cachexia, skin cancer and internal neoplasms: autopsy report of four xeroderma pigmentosum patients (XP-A, XP-C and XP-D)

Jin-Ping Lai1, Yen-Chun Liu1, Meghna Alimchandani1, Qingyan Liu1, Phyu Phyu Aung1, Kant Matsuda1, Chyi-Chia R Lee1, Maria Tsokos1, Stephen Hewitt1, Elisabeth J Rushing2, Deborah Tamura3, David L Levens1, John J DiGiovanna3, Howard A Fine4, Nicholas Patronas5, Sikandar G Khan3, David E Kleiner1, J Carl Oberholtzer1, Martha M Quezado1 and Kenneth H Kraemer3*

  • * Corresponding author: Kenneth H Kraemer kraemerk@nih.gov

  • † Equal contributors

Author Affiliations

1 Laboratory of Pathology; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

2 Institute of Neuropathology, University of Zurich, Zurich, Switzerland, USA

3 DNA Repair Section, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

4 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

5 Radiology and Imaging Sciences, Clinical Center National Institutes of Health, Bethesda, MD, 20892, USA

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Acta Neuropathologica Communications 2013, 1:4  doi:10.1186/2051-5960-1-4

Published: 8 May 2013

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.

Results

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.

Conclusions

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.

Keywords:
DNA damage; DNA repair; Neurodegeneration; Glioblastoma; Cachexia