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At least 19 recordsLinked to original sources
PubMed2006

Deep brain stimulation to treat hyperkinetic symptoms of Cockayne syndrome.

Cockayne syndrome manifests a spectrum of neurological dysfunction that includes medically intractable movement disorders. Deep brain stimulation has not been well studied in such rare neurodegenerative conditions. In this case, stimulation of the ventral intermediate nucleus of the thalamus was used to manage severe motor symptoms in a young man with Cockayne syndrome. There was a marked and progressive response to thalamic stimulation within weeks of surgery. These results suggest that patients with Cockayne syndrome should be considered for deep brain stimulation to treat refractory movement disorders.

Adolescent↗
PubMed1986

Distinctive skeletal dysplasia in Cockayne syndrome.

Cockayne syndrome is a well-known autosomal recessive form of dwarfism with senile-like appearance. Skeletal changes such as flattening of vertebral bodies, ivory epiphyses and thickening of cranial vault, have been observed in some patients with this condition. We describe here a 5.5-year-old girl with the typical clinical signs of Cockayne syndrome and a distinctive form of bone dysplasia with major involvement of the spine.

Bone Diseases, Developmental↗
PubMed2003

Spinal anaesthesia for caesarean section in a patient with Cockayne syndrome.

Cockayne syndrome is a rare inherited disorder with photosensitivity, dysmorphism, short stature and neurological deficits. Sufferers with this condition rarely survive into reproductive life. We report the successful delivery of a woman in her second pregnancy with Cockayne syndrome, her first pregnancy having resulted premature labour, caesarean section under spinal anaesthesia with considerable hypotension, and neonatal death. On this occasion she was hospitalised at 19 weeks' gestation and delivered by elective caesarean section at 34 weeks. She had a Mallampatti score of 3, so spinal anaesthesia using 1.8 mL of hyperbaric bupivacaine was given with good effect and mother and baby did well. The aetiology and clinical symptoms of this rare congenital syndrome, together with the anaesthetic implications and management, are described and discussed.

Journal Article↗
PubMed1996

Genetic analysis of twenty-two patients with Cockayne syndrome.

Cockayne syndrome (CS) is an autosomal recessive disorder with dwarfism, mental retardation, sun sensitivity and a variety of other features. Cultured CS cells are hypersensitive to ultraviolet (UV) light, and following UV irradiation, CS cells are unable to restore RNA synthesis rates to normal levels. This has been attributed to a specific deficiency in CS cells in the ability to repair damage in actively transcribed regions of DNA at the rapid rate seen in normal cells. We have used the failure of recovery of RNA synthesis, following UV irradiation of CS cells, in a complementation test. Cells of different CS donors are fused. Restoration of normal RNA synthesis rates in UV-irradiated heterodikaryons indicates that the donors are in different complementation groups, whereas a failure to effect this recovery implies that they are in the same group. In an analysis of cell strains from 22 CS donors from several countries and different racial groups, we have assigned five cell strains to the CS-A group and the remaining 17 to CS-B. No obvious racial, clinical or cellular distinctions could be made between individuals in the two groups. Our analysis will assist the identification of mutations in the recently cloned CSA and CSB genes and the study of structure-function relationships.

Adult↗
PubMed1998

Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome.

Cockayne syndrome is a multisystem sun-sensitive genetic disorder associated with a specific defect in the ability to perform transcription-coupled repair of active genes after UV irradiation. Two complementation groups (CS-A and CS-B) have been identified, and 80% of patients have been assigned to the CS-B complementation group. We have analyzed the sites of the mutations in the CSB gene in 16 patients, to determine the spectrum of mutations in this gene and to see whether the nature of the mutation correlates with the type and severity of the clinical symptoms. In nine of the patients, the mutations resulted in truncated products in both alleles, whereas, in the other seven, at least one allele contained a single amino acid change. The latter mutations were confined to the C-terminal two-thirds of the protein and were shown to be inactivating by their failure to restore UV-irradiation resistance to hamster UV61 cells, which are known to be defective in the CSB gene. Neither the site nor the nature of the mutation correlated with the severity of the clinical features. Severe truncations were found in different patients with either classical or early-onset forms of the disease.

Alleles↗
PubMed1982

Excision repair in Cockayne syndrome.

Cockayne syndrome (CS) is a genetic disorder showing cellular sensitivity to the lethal effects of UV-irradiation. No defects in unscheduled DNA synthesis or in daughter-strand repair have been detected after UV-irradiation of CS cells. We have studied several aspects of excision repair, particularly at early times after UV-irradiation, and with one exception, we have not been able to detect any difference in the response of normal and CS cells to UV-irradiation, by measuring: (1) the rate of formation of incision breaks in the presence of 1-beta-D-arabinofuranosylcytosine (araC); (2) the amount of repair replication as measured by equilibrium centrifugation; (3) the ligation of repaired DNA to pre-existing DNA; (4) the digestibility of repaired DNA after treatment of nuclei with micrococcal nuclease. The single exception was a pair of CS strains from sibling donors in which the rate of uncoupled incision due to the presence of either araC or the specific inhibitor of DNA polymerase alpha, aphidicolin, was slightly faster than in other cells studied. This effect was absent in the heterozygous parents. However, since this was not seen in two other CS strains in the same genetic complementation group, we can not attribute this increased rate of incision to the defective CS gene. We conclude that, within the limits of resolution of these techniques, CS cells do not have a detectable defect in excision repair.

Cells, Cultured↗
PubMed1984

Use of lymphoblastoid cell lines to evaluate the hypersensitivity to ultraviolet radiation in Cockayne syndrome.

Cockayne syndrome (CS) is a rare autosomal recessive disease characterized by acute sun sensitivity, cachectic dwarfism, and neurologic and skeletal abnormalities. Cultured skin fibroblasts from patients with this disease are known to be hypersensitive to the lethal effects of 254-nm UV radiation. We have studied the sensitivity of 254-nm UV radiation of lymphoblastoid lines derived from 3 typical CS patients, 1 atypical CS patient who had a very late age of onset of clinical manifestations, 2 patients who had both xeroderma pigmentosum (XP) and typical CS, and 3 heterozygous parents of these patients. Post-UV survival was determined by the trypan-blue dye-exclusion method. The lymphoblastoid lines from the 3 typical CS patients, the atypical CS patient, and the 2 patients with both CS and XP had decreased post-UV viability in comparison with lines from normal donors. Lines from the heterozygous parents had normal post-UV viability. The post-UV viability of the typical CS lines was similar to that of a XP complementation group C line. The relative post-UV viability of lymphoblastoid lines from the typical CS patients was similar to the relative post-UV survival of their fibroblast lines. The lymphoblastoid line from the atypical CS patient had a post-UV viability similar to that of the typical CS patients. Thus, the relative hypersensitivity of CS patients' cells in vitro does not reflect the severity or age of onset of the patients' clinical manifestations. The lymphoblastoid lines from the 2 patients who had both CS and XP were significantly more sensitive to the UV radiation than those from patients with only CS. Our studies demonstrate that lymphoblastoid lines from patients with CS are appropriate and useful cell lines for the study of the inherited hypersensitivity to UV radiation.

Adolescent↗
PubMed1978

DNA repair in Cockayne syndrome.

Cockayne syndrome (CS) is a rare recessive genetic disease characterized in part by premature ageing and photosensitive skin. Because of the latter characteristic, this syndrome was considered to be an example of a UV-sensitive DNA repair-defective human disorder. We demonstrated normal levels of UV-induced unscheduled DNA synthesis (UDS) in four unrelated CS patients that show hypersensitivity to both UV and Mitomycin C (MMC). At low UV exposure, CS DNA shows a dose-dependent decrease in size. By contrast, heterozygotes appear to have a threshold below which there is little change in size of single strand DNA. Immediately following UV or MMC treatment, CS DNA is deficient in high molecular weight species, but undergoes a normal transition to larger DNA during a chase interval in the presence or absence of caffeine. This suggests a defect in replication or excision repair and no defect in post-replication repair (PRR). Pulse studies performed in the presence of hydroxyurea (HU) also reveal a deficient production of large DNA, suggesting the defect is in repair. As these cells have normal UDS and normal PRR, the basis for their UV sensitivity must be distinct from that observed in xeroderma pigmentosum (XP).

Cells, Cultured↗
PubMed2004

Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.

UV-sensitive syndrome (UVsS) is a rare autosomal recessive disorder characterized by photosensitivity and mild freckling but without neurological abnormalities or skin tumors. UVsS cells show UV hypersensitivity and defective transcription-coupled DNA repair of UV damage. It was suggested that UVsS does not belong to any complementation groups of known photosensitive disorders such as xeroderma pigmentosum and Cockayne syndrome (CS). To identify the gene responsible for UVsS, we performed a microcell-mediated chromosome transfer based on the functional complementation of UV hypersensitivity. We found that one of the UVsS cell lines, UVs1KO, acquired UV resistance when human chromosome 10 was transferred. Because the gene responsible for CS group B (CSB), which involves neurological abnormalities and photosensitivity as well as a defect in transcription-coupled DNA repair of UV damage, is located on chromosome 10, we sequenced the CSB gene from UVs1KO and detected a homozygous null mutation. Our results indicate that previous complementation analysis of UVs1KO was erroneous. This finding was surprising because a null mutation of the CSB gene would be expected to result in CS features such as severe developmental and neurological abnormalities. On the other hand, no mutation in the CSB cDNA and a normal amount of CSB protein was detected in Kps3, a UVsS cell line obtained from an unrelated patient, indicating genetic heterogeneity in UVsS. Possible explanations for the discrepancy in the genotype-phenotype relationship in UVs1KO are presented.

Base Sequence↗
PubMedDate not supplied

Detection of UV-induced K-ras codon 12 mutation by PCR and differential dot-blot hybridization in cells from Down syndrome and Cockayne syndrome.

By means of the polymerase chain reaction (PCR) and differential dot-blot hybridization, base substitution mutations of K-ras codon 12 were investigated in skin fibroblast cells from Down syndrome (DS) patients. Mutations were identified in DS cells after UV irradiation, predominantly in cells from younger patients. In contrast, no mutation was detected in cells from Cockayne syndrome (CS) patients who had the same features of premature aging as in DS but were not prone to cancer. This association of DS cells, but not CS cells, with inducibility of the K-ras codon 12 mutation may imply the proneness of DS patients to cancer development but a lack of proneness of CS patients.

Aging↗
PubMed2006

A novel splice site mutation in the Cockayne syndrome group A gene in two siblings with Cockayne syndrome.

Cockayne syndrome (CS) is mainly caused by mutations in the Cockayne syndrome group A or B (CSA or CSB) genes which are required for a sub-pathway of nucleotide excision repair entitled transcription coupled repair. Approximately 20% of the CS patients have mutations in CSA, which encodes a 44 kDa tryptophane (Trp, W) and aspartic acid (Asp, D) amino acids (WD) repeat protein. Up to now, nine different CSA mutations have been identified. We examined two Somali siblings 9 and 12 years old with clinical features typical of CS including skin photosensitivity, progressive ataxia, spasticity, hearing loss, central and peripheral demyelination and intracranial calcifications. Molecular analysis showed a novel splice acceptor site mutation, a G to A transition in the -1 position of intervening sequence 6 (g.IVS6-1G>A), in the CSA (excision repair cross-complementing 8 (ERCC8)) gene. IVS6-1G>A results in a new 28 amino acid C-terminus and premature termination of the CSA protein (G184DFs28X). A review of the CSA protein and the 10 known CSA mutations is also presented.

Amino Acid Sequence↗
PubMed1994

A new UV-sensitive syndrome not belonging to any complementation groups of xeroderma pigmentosum or Cockayne syndrome: siblings showing biochemical characteristics of Cockayne syndrome without typical clinical manifestations.

We report here on two siblings who show no clinical manifestations except for slight cutaneous photosensitivity and cutaneous pigmentation but have biochemical characteristics of Cockayne syndrome (CS). Fibroblasts derived from the patients (Kps2 and Kps3) were 3-4 times more sensitive to UV than normal cells. Although unscheduled DNA synthesis (UDS) in these cells was at a normal level, recovery of RNA synthesis (RRS) after UV irradiation was severely depressed. Microinjection of bacteriophage T4 endonuclease V into the cells corrected RRS after UV irradiation to a level near normal. These results indicate that DNA repair of cyclobutane-type pyrimidine dimers is impaired in the cells and the biochemical characteristics are similar to those of CS cells. However, cell fusion complementation tests with CS group A and B cells resulted in correction of RRS after UV irradiation. Cell fusion with XP group A, B, D, F and G cells also corrected RRS after UV irradiation, and microinjection of cell extracts prepared from Kps3 cells corrected UDS in XP group C and E cells, indicating that the patients do not belong to any complementation group of XP or CS. These results suggest that the patients have a new UV-sensitive syndrome with a biochemical phenotype of CS.

Adolescent↗
PubMed1986

Serum lipid and lipoprotein levels in premature ageing syndromes: total lipodystrophy and Cockayne syndrome.

Serum lipids and lipoproteins were investigated in two girls who suffered from total lipodystrophy, in their family members, and in two brothers suffering from Cockayne syndrome. Hyperlipoproteinemia type IIb (Fredrickson) was detected in one case with total lipodystrophy. Very low levels of serum high density lipoprotein cholesterol (HDL-Ch) were observed in both of total lipodystrophic cases, in most of their first degree relatives, and in one of patients with Cockayne syndrome. Because total lipodystrophy and the Cockayne syndrome belong to ageing syndromes they can serve as a useful model of premature arteriosclerosis and the defect lipid metabolism.

Adult↗
PubMedDate not supplied

[Clinical and neuropathological study of two brothers with Cockayne syndrome].

INTRODUCTION: Cockayne syndrome (CS) is a rare autosomal recessive disease which is characterized by physical and mental retardation, progressive neurological disfunction, photosensitivity and other cutaneous features. Usually they present ophthalmologic abnormalities as well as other heterogenous clinical, radiological and pathologic features as leucodistrophy and calcifications in central nervous system and segmental demyelination in peripheral nervous system. CLINICAL CASES: Two brothers, sons of healthy unrelated parents, are presented. The first patient was referred at 8 months of age because of psychomotor retardation and the second one at 5 months old because of a cataract. At the age of 2 years both presented a complex clinical picture with photosensitivity, growth and mental retardation, peripheral neuropathy, neurosensorial deafness, and cerebral atrophy and calcifications in neuroimaging diagnosis tests. In the following years the older brother presented signs of renal failure, cataracts and retinopathy, and died at 9 years old because of a respiratory infection. The neuropathologic study showed a discrete neuronal loss and diffuse demyelination with calcium deposits in cerebral white matter and basal ganglia. Today the second patient is 8 years old and shows a clinical course similar to that of his brother. CONCLUSIONS: Clinical, radiologic and pathologic features in our patients support the diagnosis of CS type II.

Basal Ganglia↗
PubMed2003

Three novel mutations responsible for Cockayne syndrome group A.

Cockayne syndrome (CS) is a rare autosomal recessive disease, which shows diverse clinical symptoms such as photosensitivity, severe mental retardation and developmental defects. CS cells are hypersensitive to killing by UV-irradiation and defective in transcription-coupled repair. Two genetic complementation groups in CS (CS-A and CS-B) have been identified. We analyzed mutations of the CSA gene in 5 CS-A patients and identified 3 types of mutations. Four unrelated CS-A patients (CS2OS, CS2AW, Nps2 and CS2SE) had a deletion including exon 4, suggesting that there is a founder effect on the CSA mutation in Japanese CS-A patients. Patient CS2SE was a compound heterozygote for this deletion and an amino acid substitution at the 106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein, which resulted in a defective nucleotide excision repair. Patient Mps1 had a large deletion in the upstream region including exon 1 of the CSA gene. Our results indicate that a rapid and reliable diagnosis of CSA mutations could be achieved in CS-A patients by PCR or PCR-RFLP and that the Q106P mutation could alter the propeller structure of the CSA protein which is important for the formation of the CSA protein complex.

Amino Acid Substitution↗
PubMed2007

Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice.

Cockayne syndrome (CS) is a rare recessive childhood-onset neurodegenerative disease, characterized by a deficiency in the DNA repair pathway of transcription-coupled nucleotide excision repair. Mice with a targeted deletion of the CSB gene (Csb-/-) exhibit a much milder ataxic phenotype than human patients. Csb-/- mice that are also deficient in global genomic repair [Csb-/-/xeroderma pigmentosum C (Xpc)-/-] are more profoundly affected, exhibiting whole-body wasting, ataxia, and neural loss by postnatal day 21. Cerebellar granule cells demonstrated high TUNEL staining indicative of apoptosis. Purkinje cells, identified by the marker calbindin, were severely depleted and, although not TUNEL-positive, displayed strong immunoreactivity for p53, indicating cellular stress. A subset of animals heterozygous for Csb and Xpc deficiencies was more mildly affected, demonstrating ataxia and Purkinje cell loss at 3 months of age. Mouse, Csb-/-, and Xpc-/- embryonic fibroblasts each exhibited increased sensitivity to UV light, which generates bulky DNA damage that is a substrate for excision repair. Whereas Csb-/-/Xpc-/- fibroblasts were more UV-sensitive than either single knockout, double-heterozygote fibroblasts had normal UV sensitivity. Csb-/- mice crossed with a strain defective in base excision repair (Ogg1) demonstrated no enhanced neurodegenerative phenotype. Complete deficiency in nucleotide excision repair therefore renders the brain profoundly sensitive to neurodegeneration in specific cell types of the cerebellum, possibly because of unrepaired endogenous DNA damage that is a substrate for nucleotide but not base excision repair.

Animals↗
PubMed1991

Evidence for defective repair of cyclobutane pyrimidine dimers with normal repair of other DNA photoproducts in a transcriptionally active gene transfected into Cockayne syndrome cells.

Cockayne syndrome (CS) and xeroderma pigmentosum (XP), autosomal recessive diseases with clinical and cellular hypersensitivity to UV radiation, differ in ability to repair UV DNA photoproducts in their overall genome: normal repair in CS, defective repair in XP. In order to characterize a DNA repair defect in an active gene in CS, we measured the capacity of cells from patients with CS and XP to reactivate 2 major types of UV-induced DNA damage, photoreactivatable (i.e., cyclobutane pyrimidine dimers) and non-photoreactivatable (primarily pyrimidine-(6-4)pyrimidone photoproducts), in the actively transcribing chloramphenicol acetyltransferase (cat) gene of the plasmid expression vector pRSV-cat. Epstein-Barr virus-transformed lymphoblast lines from 4 normal persons and from 3 patients with CS and from two with XP were transiently transfected with the plasmid, and the cat activity in cell extracts was determined. When the cells were transfected with UV-irradiated plasmid, expression was abnormally decreased in both the CS and XP cells. When the cyclobutane pyrimidine dimers in the UV-irradiated plasmid were removed by photoreactivation prior to transfection, cat expression in the CS, but not in the XP, lines reached normal levels. These data imply that both the XP and CS cells are unable to repair normally the cyclobutane pyrimidine dimer photoproducts which block transcription of cat. However, the CS, but not XP, cells can repair normally the other UV-induced photoproducts which block transcription. The ability of CS, but not XP, cells to repair these non-dimer photoproducts indicates that the active gene repair mechanism treats the cyclobutane pyrimidine dimer differently from the non-dimer photoproducts.

Cell Line↗