Wide clinical variability among 13 new Cockayne syndrome cases confirmed by biochemical assays

Pasquier, Laurent

doi:10.1136/adc.2005.080473

Cited by 41 publications

(24 citation statements)

References 11 publications

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“…The XP-C patients display extreme UV sensitivity and are highly prone to develop skin, corneal, and eyelid cancers because of their defects in GGR. CS patients, defective in the TCR branch of NER (1,27), present a very different clinical picture, one of developmental defects and neurodegeneration; many but not all patients are also photosensitive, some developing blistering sunburns (5,28). In contrast to XP-C patients, no known CS patient has ever developed cancer (4,5,8).…”

Section: Discussionmentioning

confidence: 98%

Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency

Reid-Bayliss

Arron

Loeb

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are human photosensitive diseases with mutations in the nucleotide excision repair (NER) pathway, which repairs DNA damage from UV exposure. CS is mutated in the transcription-coupled repair (TCR) branch of the NER pathway and exhibits developmental and neurological pathologies. The XP-C group of XP patients have mutations in the global genome repair (GGR) branch of the NER pathway and have a very high incidence of UV-induced skin cancer. Cultured cells from both diseases have similar sensitivity to UV-induced cytotoxicity, but CS patients have never been reported to develop cancer, although they often exhibit photosensitivity. Because cancers are associated with increased mutations, especially when initiated by DNA damage, we examined UV-induced mutagenesis in both XP-C and CS cells, using duplex sequencing for high-sensitivity mutation detection. Duplex sequencing detects rare mutagenic events, independent of selection and in multiple loci, enabling examination of all mutations rather than just those that confer major changes to a specific protein. We found telomerase-positive normal and CS-B cells had increased background mutation frequencies that decreased upon irradiation, purging the population of subclonal variants. Primary XP-C cells had increased UV-induced mutation frequencies compared with normal cells, consistent with their GGR deficiency. CS cells, in contrast, had normal levels of mutagenesis despite their TCR deficiency. The lack of elevated UV-induced mutagenesis in CS cells reveals that their TCR deficiency, although increasing cytotoxicity, is not mutagenic. Therefore the absence of cancer in CS patients results from the absence of UV-induced mutagenesis rather than from enhanced lethality.

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Section: Discussionmentioning

confidence: 98%

Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency

Reid-Bayliss

Arron

Loeb

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Some individuals may have anatomical abnormalities such as unilateral or hypoplastic kidneys, but in the majority of patients with renal dysfunction it is thought to be secondary to hypertension and atherosclerosis/arteriolosclerosis (Bartenjev et al, 2000; Higginbottom et al, 1979; Hirooka et al, 1988; Pasquier et al, 2006). Renal failure may be a marker of poor prognosis, and may indicate impending death (Kubota et al, 2015).…”

Section: 0 Clinical Features Of Csmentioning

confidence: 99%

Cockayne syndrome: Clinical features, model systems and pathways

Karikkineth

Scheibye‐Knudsen

Fivenson

et al. 2017

Ageing Research Reviews

208

157

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Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including microcephaly and cognitive deficits, pigmentary retinopathy, cataracts, sensorineural deafness, and ambulatory and feeding difficulties, leading to death by 12 years of age on average. It is an autosomal recessive disorder, with a prevalence of approximately 2.5 per million. There are several phenotypes (1, 2 and 3) and complementation groups (CSA and CSB), and overlaps with xeroderma pigmentosum (XP). It has been considered a progeria, and many of the clinical features resemble accelerated aging. As such, the study of CS affords an opportunity to better understand the underlying mechanisms of aging. The molecular basis of CS has traditionally been considered to be due to defects in transcription and transcription-coupled nucleotide excision repair (TC-NER). However, recent work suggests that defects in base excision DNA repair and mitochondrial functions may also play key roles. This opens up the possibility of molecular interventions in CS, and by extrapolation, possibly in aging.

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“…Some physical characteristics such as general body habitus (Cockayne syndrome),7 8 facial dysmorphism (Cohen syndrome),9 polydactyly (Bardet–Biedl syndrome),10 or neurological regression (neuronal ceroid lipofuscinosis)11 or hypotonia and the molar tooth sign on brain MRI (Joubert syndrome) will give away the underlying syndrome. Deafness may indicate Usher syndrome 12.…”

Section: Clinical Workup and Molecular Testingmentioning

confidence: 99%

The Marshall M. Parks memorial lecture: making sense of early-onset childhood retinal dystrophies--the clinical phenotype of Leber congenital amaurosis

Traboulsi

2009

British Journal of Ophthalmology

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A correct diagnosis of the early-onset childhood retinal dystrophies requires careful clinical evaluation, the detection of suggestive or pathognomonic ophthalmoscopic clues, the use of electrophysiology to document characteristic electroretinographic findings and, in some cases, the utilisation of newer diagnostic modalities such as optical coherence tomography. Molecular diagnosis confirms the clinical diagnosis and provides the basis for possible future gene therapy. A strict definition of early-onset childhood retinal dystrophies (EOCRDs) does not exist, but inherited retinal dystrophies that are diagnosed in the first few years of life could be included under this umbrella terminology. The clinical ophthalmological manifestations of these diseases may or may not be detected at birth, and include the triad of severe vision loss, sensory nystagmus and electroretinographic abnormalities. Their clinical manifestations are light sensitivity, night blindness, fundus pigmentary changes and other psychophysical and retinal anatomic abnormalities. Diseases that could be included in the EOCRDs are Leber congenital amaurosis, achromatopsia, congenital stationary night blindness, X-linked juvenile retinoschisis, Goldmann-Favre disease and other NR2E3-related disorders, and possibly some very early-onset forms of Stargardt disease and juvenile retinitis pigmentosa. In this paper, phenotypic clues to the diagnosis of the underlying molecular defect in patients with Leber congenital amaurosis are discussed and an overview of the clinical workup of the child with a retinal dystrophy is presented. An accurate diagnosis of individual EOCRD allows a better prediction of the clinical course and the planning of possible and emerging therapies.

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Wide clinical variability among 13 new Cockayne syndrome cases confirmed by biochemical assays

Cited by 41 publications

References 11 publications

Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency

Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency

Cockayne syndrome: Clinical features, model systems and pathways

The Marshall M. Parks memorial lecture: making sense of early-onset childhood retinal dystrophies--the clinical phenotype of Leber congenital amaurosis

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