Cockayne syndrome and xeroderma pigmentosum - DNA repair disorders with overlaps and paradoxes

Objectives: To review genetic variants of Cockayne syndrome (CS) and xerode rma pigmentosum (XP), autosomal recessive disorders of DNA repair that affe ct the nervous system, and to illustrate them by the first case of xeroderm a pigmentosum-Cockayne syndrome (XP-CS) complex to undergo neuropathologic examination. Methods: Published reports of clinical, pathologic, and molecu lar studies of CS, XP neurologic disease, and the XP-CS complex were review ed, and a ninth case of XP-CS is summarized. Results: CS is a multisystem d isorder that causes both profound growth failure of the soma and brain and progressive cachexia, retinal, cochlear, and neurologic degeneration, with a leukodystrophy and demyelinating neuropathy without an increase in cancer . XP presents as extreme photosensitivity of the skin and eyes with a 1000- fold increased frequency of cutaneous basal and squamous cell carcinomas an d melanomas and a small increase in nervous system neoplasms. Some 20% of p atients with XP incur progressive degeneration of previously normally devel oped neurons resulting in cortical, basal ganglia, cerebellar, and spinal a trophy, cochlear degeneration, and a mixed distal axonal neuropathy. Cultur ed cells from patients with CS or XP are hypersensitive to killing by ultra violet (UV) radiation. Both CS and most XP cells have defective DNA nucleot ide excision repair of actively transcribing genes; in addition, XP cells h ave defective repair of the global genome. There are two complementation gr oups in CS and seven in XP. Patients with the XP-CS complex fall into three XP complementation groups. Despite their XP genotype, six of nine individu als with the XP-CS complex, including the boy we followed up to his death a t age 6, had the typical clinically and pathologically severe CS phenotype. Cultured skin and blood cells had extreme sensitivity to killing by UV rad iation, DNA repair was severely deficient, post-UV unscheduled DNA synthesi s was reduced to less than 5%, and post-UV plasmid mutation frequency was i ncreased. Conclusions: The paradoxical lack of parallelism of phenotype to genotype is unexplained in these disorders. Perhaps diverse mutations respo nsible for UV sensitivity and deficient DNA repair may also produce profoun d failure of brain and somatic growth, progressive cachexia and premature a ging, and tissue-selective neurologic deterioration by their roles in regul ation of transcription and repair of endogenous oxidative DNA damage.