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Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2013

Open Access 01-12-2013 | 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)

Authors: Jin-Ping Lai, Yen-Chun Liu, Meghna Alimchandani, Qingyan Liu, Phyu Phyu Aung, Kant Matsuda, Chyi-Chia R Lee, Maria Tsokos, Stephen Hewitt, Elisabeth J Rushing, Deborah Tamura, David L Levens, John J DiGiovanna, Howard A Fine, Nicholas Patronas, Sikandar G Khan, David E Kleiner, J Carl Oberholtzer, Martha M Quezado, Kenneth H Kraemer

Published in: Acta Neuropathologica Communications | Issue 1/2013

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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.
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Literature
1.
Bradford PT, Goldstein AM, Tamura D, Khan SG, Ueda T, Boyle J, Oh KS, Imoto K, Inui H, Moriwaki S, Emmert S, Pike KM, Raziuddin A, Plona TM, DiGiovanna JJ, Tucker MA, Kraemer KH: Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J Med Genet 2011, 48: 168–176. 10.1136/jmg.2010.083022PubMedCentralCrossRefPubMed
2.
Kraemer KH, Lee MM, Andrews AD, Lambert WC: The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. Arch Dermatol 1994, 130: 1018–1021. 10.1001/archderm.1994.01690080084012CrossRefPubMed
3.
Kraemer KH, Lee MM, Scotto J: Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987, 123: 241–250. 10.1001/archderm.1987.01660260111026CrossRefPubMed
4.
Robbins JH, Kraemer KH, Lutzner MA, Festoff BW, Coon HG: Xeroderma pigmentosum. An inherited disease with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair. Ann Intern Med 1974, 80: 221–248. 10.7326/0003-4819-80-2-221CrossRefPubMed
5.
Anttinen A, Koulu L, Nikoskelainen E, Portin R, Kurki T, Erkinjuntti M, Jaspers NG, Raams A, Green MH, Lehmann AR, Wing JF, Arlett CF, Marttila RJ: Neurological symptoms and natural course of xeroderma pigmentosum. Brain 2008, 131: 1979–1989. 10.1093/brain/awn126CrossRefPubMed
6.
Itoh M, Hayashi M, Shioda K, Minagawa M, Isa F, Tamagawa K, Morimatsu Y, Oda M: Neurodegeneration in hereditary nucleotide repair disorders. Brain Dev 1999, 21: 326–333. 10.1016/S0387-7604(99)00033-9CrossRefPubMed
7.
Kanda T, Oda M, Yonezawa M, Tamagawa K, Isa F, Hanakago R, Tsukagoshi H: Peripheral neuropathy in xeroderma pigmentosum. Brain 1990, 113: 1025–1044. 10.1093/brain/113.4.1025CrossRefPubMed
8.
Robbins JH: Xeroderma pigmentosum. Defective DNA repair causes skin cancer and neurodegeneration. JAMA 1988, 260: 384–388. 10.1001/jama.1988.03410030100038CrossRefPubMed
9.
Robbins JH, Brumback RA, Mendiones M, Barrett SF, Carl JR, Cho S, Denckla MB, Ganges MB, Gerber LH, Guthrie RA: Neurological disease in xeroderma pigmentosum. Documentation of a late onset type of the juvenile onset form. Brain 1991, 114: 1335–1361.PubMed
10.
Robbins JH, Kraemer KH, Merchant SN, Brumback RA: Adult-onset xeroderma pigmentosum neurological disease–observations in an autopsy case. Clin Neuropathol 2002, 21: 18–23.PubMed
11.
12.
13.
Hoeijmakers JH: DNA damage, aging, and cancer. N Engl J Med 2009, 361: 1475–1485. 10.1056/NEJMra0804615CrossRefPubMed
14.
Totonchy MB, Tamura D, Pantell MS, Zalewski C, Bradford PT, Merchant SN, Nadol J, Khan SG, Schiffmann R, Pierson TM, Wiggs E, Griffith AJ, DiGiovanna JJ, Kraemer KH, Brewer CC: Auditory analysis of xeroderma pigmentosum 1971–2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration. Brain 2013, 136: 194–208.PubMedCentralCrossRefPubMed
15.
de Sanctis C, Cacchione A: L'idiozia xerodermica. Rivista Sperimentale di Freniatria e Medicina Legale delle Alienazioni Mentali 1932, 56: 269–292.
16.
Hayashi M: Roles of oxidative stress in xeroderma pigmentosum. Adv Exp Med Biol 2008, 637: 120–127.CrossRefPubMed
17.
Hayashi M: Oxidative stress in developmental brain disorders. Neuropathology 2009, 29: 1–8. 10.1111/j.1440-1789.2008.00888.xCrossRefPubMed
18.
Hayashi M, Araki S, Kohyama J, Shioda K, Fukatsu R: Oxidative nucleotide damage and superoxide dismutase expression in the brains of xeroderma pigmentosum group A and Cockayne syndrome. Brain Dev 2005, 27: 34–38. 10.1016/j.braindev.2004.04.001CrossRefPubMed
19.
Hayashi M, Araki S, Kohyama J, Shioda K, Fukatsu R, Tamagawa K: Brainstem and basal ganglia lesions in xeroderma pigmentosum group A. J Neuropathol Exp Neurol 2004, 63: 1048–1057.PubMed
20.
Hayashi M, Itoh M, Araki S, Kumada S, Shioda K, Tamagawa K, Mizutani T, Morimatsu Y, Minagawa M, Oda M: Oxidative stress and disturbed glutamate transport in hereditary nucleotide repair disorders. J Neuropathol Exp Neurol 2001, 60: 350–356.PubMed
21.
Hayashi M, Miwa-Saito N: Tanuma N. Neuropathology: Kubota M Brain vascular changes in Cockayne syndrome; 2011.
22.
Hayashi M, Ohto T: Shioda K. Brain Dev: Fukatsu R Lesions of cortical GABAergic interneurons and acetylcholine neurons in xeroderma pigmentosum group A; 2011.
23.
Kenyon GS, Booth JB, Prasher DK: Rudge P Neuro-otological abnormalities in xeroderma pigmentosum with particular reference to deafness. Brain 1985,108(Pt 3):771–784.CrossRefPubMed
24.
Kohji T, Hayashi M, Shioda K, Minagawa M, Morimatsu Y, Tamagawa K, Oda M: Cerebellar neurodegeneration in human hereditary DNA repair disorders. Neurosci Lett 1998, 243: 133–136. 10.1016/S0304-3940(98)00109-8CrossRefPubMed
25.
Okayasu I, Satoh Y, Irimajiri T, Mitoh Y: Fetal case of xeroderma pigmentosum–first report of an autopsy case. Acta Pathol Jpn 1978, 28: 459–464.PubMed
26.
Ramkumar HL, Brooks BP, Cao X, Tamura D, DiGiovanna JJ, Kraemer KH, Chan CC: Ophthalmic manifestations and histopathology of xeroderma pigmentosum: two clinicopathological cases and a review of the literature. Surv Ophthalmol 2011, 56: 348–361. 10.1016/j.survophthal.2011.03.001PubMedCentralCrossRefPubMed
27.
Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH: Cockayne syndrome and xeroderma pigmentosum. Neurology 2000, 55: 1442–1449. 10.1212/WNL.55.10.1442PubMedCentralCrossRefPubMed
28.
Reed WB, Landing B, Sugarman G, Cleaver JE, Melnyk J: Xeroderma pigmentosum. Clinical and laboratory investigation of its basic defect. JAMA 1969, 207: 2073–2079.PubMed
29.
Reed WB, MARY SB, NICKEL WR: Xeroderma pigmentosum with neurological complications: The deSanctis-Cacchione syndrome. Arch Dermatol 1965, 91: 224–226. 10.1001/archderm.1965.01600090032005CrossRefPubMed
30.
Reed WB, Sugarman GI, Mathis RA: DeSanctis-Cacchione syndrome. A case report with autopsy findings. Arch Dermatol 1977, 113: 1561–1563. 10.1001/archderm.1977.01640110081013CrossRefPubMed
31.
Roytta M, Anttinen A: Xeroderma pigmentosum with neurological abnormalities. A clinical and neuropathological study. Acta Neurol Scand 1986, 73: 191–199. 10.1111/j.1600-0447.1986.tb10586.xCrossRefPubMed
32.
Takagi M: Xeroderma pigmentosum–report of two autopsy cases (author's transl). Kokubyo Gakkai Zasshi 1979, 46: 389–396.CrossRefPubMed
33.
Wang Y, Tan XH, DiGiovanna JJ, Lee CC, Stern JB, Raffeld M, Jaffe ES, Kraemer KH: Genetic diversity in melanoma metastases from a patient with xeroderma pigmentosum. J Invest Dermatol 2010, 130: 1188–1191. 10.1038/jid.2009.377PubMedCentralCrossRefPubMed
34.
Yano K: Xeroderma pigmentosum with disorders of the central nervous system; a histopathological study. Folia Psychiatr Neurol Jpn 1950, 4: 143–175.PubMed
35.
Kraemer KH, Coon HG, Petinga RA, Barrett SF, Rahe AE, Robbins JH: Genetic heterogeneity in xeroderma pigmentosum: complementation groups and their relationship to DNA repair rates. Proc Natl Acad Sci U S A 1975, 72: 59–63. 10.1073/pnas.72.1.59PubMedCentralCrossRefPubMed
36.
Kraemer KH, DiGiovanna JJ, Moshell AN, Tarone RE, Peck GL: Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 1988, 318: 1633–1637. 10.1056/NEJM198806233182501CrossRefPubMed
37.
States JC, Myrand SP: Splice site mutations in a xeroderma pigmentosum group A patient with delayed onset of neurological disease. Mutat Res 1996, 363: 171–177. 10.1016/0921-8777(96)00004-3CrossRefPubMed
38.
Terunuma A, Ye J, Emmert S, Khan SG, Kraemer KH, Vogel JC: Ultraviolet light selection assay to optimize oligonucleotide correction of mutations in endogenous xeroderma pigmentosum genes. Gene Ther 2004, 11: 1729–1734. 10.1038/sj.gt.3302344CrossRefPubMed
39.
Kraemer KH, De Weerd-Kastelein EA, Robbins JH, Keijzer W, Barrett SF, Petinga RA, Bootsma D: Five complementation groups in xeroderma pigmentosum. Mutat Res 1975, 33: 327–340. 10.1016/0027-5107(75)90208-0CrossRefPubMed
40.
Petinga RA, Andrews AD, Tarone RE, Robbins JH: Typical xeroderma pigmentosum complementation group A fibroblasts have detectable ultraviolet light-induced unscheduled DNA synthesis. Biochim Biophys Acta 1977, 479: 400–410. 10.1016/0005-2787(77)90033-8CrossRefPubMed
41.
Andrews AD, Barrett SF, Robbins JH: Xeroderma pigmentosum neurological abnormalities correlate with colony-forming ability after ultraviolet radiation. Proc Natl Acad Sci U S A 1978, 75: 1984–1988. 10.1073/pnas.75.4.1984PubMedCentralCrossRefPubMed
42.
DiGiovanna JJ, Patronas N, Katz D, Abangan D, Kraemer KH: Xeroderma pigmentosum: spinal cord astrocytoma with 9-year survival after radiation and isotretinoin therapy. J Cutan Med Surg 1998, 2: 153–158.PubMed
43.
Khan SG, Oh KS, Shahlavi T, Ueda T, Busch DB, Inui H, Emmert S, Imoto K, Muniz-Medina V, Baker CC, DiGiovanna JJ, Schmidt D, Khadavi A, Metin A, Gozukara E, Slor H, Sarasin A, Kraemer KH: Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients. Carcinogenesis 2006, 27: 84–94.CrossRefPubMed
44.
Robbins JH, Brumback RA, Moshell AN: Clinically asymptomatic xeroderma pigmentosum neurological disease in an adult: evidence for a neurodegeneration in later life caused by defective DNA repair. Eur Neurol 1993, 33: 188–190. 10.1159/000116932CrossRefPubMed
45.
Robbins JH, Polinsky RJ, Moshell AN: Evidence that lack of deoxyribonucleic acid repair causes death of neurons in xeroderma pigmentosum. Ann Neurol 1983, 13: 682–684. 10.1002/ana.410130621CrossRefPubMed
46.
Stern JB, Peck GL, Haupt HM, Hollingsworth HC, Beckerman T: Malignant melanoma in xeroderma pigmentosum: search for a precursor lesion. J Am Acad Dermatol 1993, 28: 591–594. 10.1016/0190-9622(93)70079-9CrossRefPubMed
47.
Turner ML, Moshell AN, Corbett DW, Stern JB, Roth MJ, DiGiovanna J, Horn TD, Kraemer KH: Clearing of melanoma in situ with intralesional interferon alfa in a patient with xeroderma pigmentosum. Arch Dermatol 1994, 130: 1491–1494. 10.1001/archderm.1994.01690120027003CrossRefPubMed
48.
Gaasterland DE, Rodrigues MM, Moshell AN: Ocular involvement in xeroderma pigmentosum. Ophthalmology 1982, 89: 980–986.CrossRefPubMed
49.
Li L, Bales ES, Peterson CA, Legerski RJ: Characterization of molecular defects in xeroderma pigmentosum group C. Nat Genet 1993, 5: 413–417. 10.1038/ng1293-413CrossRefPubMed
50.
51.
Fukuhara N, Kumamoto T, Takasawa H, Tsubaki T, Origuchi Y: The peripheral neuropathy in De Sanctis-Cacchione syndrome. Histological, ultrastructural, and morphometric studies. Acta Neuropathol (Berl) 1982, 56: 194–200. 10.1007/BF00690635CrossRef
52.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD: IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009, 360: 765–773. 10.1056/NEJMoa0808710PubMedCentralCrossRefPubMed
53.
Robbins JH, Moshell AN: DNA repair processes protect human beings from premature solar skin damage: evidence from studies on xeroderma pigmentosum. J Invest Dermatol 1979, 73: 102–107. 10.1111/1523-1747.ep12532789CrossRefPubMed
54.
Kraemer KH, Patronas NJ, Schiffmann R, Brooks BP, Tamura D, DiGiovanna JJ: Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: A complex genotype-phenotype relationship. Neuroscience 2007, 145: 1388–1396. 10.1016/j.neuroscience.2006.12.020PubMedCentralCrossRefPubMed
55.
Jaarsma D, Van DP I, De Waard MC, Haasdijk ED, Brandt R, Vermeij M, Rijksen Y, Maas A, Van SH, Hoeijmakers JH: Van der Horst GT Age-related neuronal degeneration: complementary roles of nucleotide excision repair and transcription-coupled repair in preventing neuropathology. PLoS Genet 2011, 7: 1002405. 10.1371/journal.pgen.1002405CrossRef
56.
Faghri S, Tamura D, Kraemer KH, DiGiovanna JJ: Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations. J Med Genet 2008, 45: 609–621. 10.1136/jmg.2008.058743PubMedCentralCrossRefPubMed
57.
Daya-Grosjean L, Sarasin A: The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors. Mutat Res 2005, 571: 43–56. 10.1016/j.mrfmmm.2004.11.013CrossRefPubMed
58.
Wang Y, DiGiovanna JJ, Stern JB, Hornyak TJ, Raffeld M, Khan SG, Oh KS, Hollander MC, Dennis PA, Kraemer KH: Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas. Proc Natl Acad Sci U S A 2009, 106: 6279–6284. 10.1073/pnas.0812401106PubMedCentralCrossRefPubMed
59.
Brooks PJ: The case for 8,5'-cyclopurine-2'-deoxynucleosides as endogenous DNA lesions that cause neurodegeneration in xeroderma pigmentosum. Neuroscience 2007, 145: 1407–1417. 10.1016/j.neuroscience.2006.10.025PubMedCentralCrossRefPubMed
60.
de Waard MC, van dP I, Zuiderveen BN, Comley LH, Haasdijk ED, Rijksen Y, Ridwan Y, Zondag G, Hoeijmakers JH, Elgersma Y, Gillingwater TH, Jaarsma D: Age-related motor neuron degeneration in DNA repair-deficient Ercc1 mice. Acta Neuropathol 2010, 120: 461–475. 10.1007/s00401-010-0715-9PubMedCentralCrossRefPubMed
Metadata
Title
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)
Authors
Jin-Ping Lai
Yen-Chun Liu
Meghna Alimchandani
Qingyan Liu
Phyu Phyu Aung
Kant Matsuda
Chyi-Chia R Lee
Maria Tsokos
Stephen Hewitt
Elisabeth J Rushing
Deborah Tamura
David L Levens
John J DiGiovanna
Howard A Fine
Nicholas Patronas
Sikandar G Khan
David E Kleiner
J Carl Oberholtzer
Martha M Quezado
Kenneth H Kraemer
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2013
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/2051-5960-1-4

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