A C. elegans model for neurodegeneration in Cockayne syndrome.

Cockayne syndrome (CS) is a congenital syndrome characterized by growth and mental retardation, and premature ageing. The complexity of CS and mammalian models warrants simpler metazoan models that display CS-like phenotypes that could be studied in the context of a live organism. Here, we provide a characterization of neuronal and mitochondrial aberrations caused by a mutation in the csb-1 gene in Caenorhabditis elegans. We report a progressive neurodegeneration in adult animals that is enhanced upon UV-induced DNA damage. The csb-1 mutants show dysfunctional hyperfused mitochondria that degrade upon DNA damage, resulting in diminished respiratory activity. Our data support the role of endogenous DNA damage as a driving factor of CS-related neuropathology and underline the role of mitochondrial dysfunction in the disease.

DRP1 Inhibition Rescues Mitochondrial Integrity and Excessive Apoptosis in CS-A Disease Cell Models.

Cockayne syndrome group A (CS-A) is a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. Cells derived from CS-A patients present as pathological hallmarks excessive oxidative stress, mitochondrial fragmentation and apoptosis associated with hyperactivation of the mitochondrial fission dynamin related protein 1 (DRP1). In this study, by using human cell models we further investigated the interplay between DRP1 and CSA and we determined whether pharmacological or genetic inhibition of DRP1 affects disease progression. Both reactive oxygen and nitrogen species are in excess in CS-A cells and when the mitochondrial translocation of DRP1 is inhibited a reduction of these species is observed together with a recovery of mitochondrial integrity and a significant decrease of apoptosis. This study indicates that the CSA-driven modulation of DRP1 pathway is key to control mitochondrial homeostasis and apoptosis and suggests DRP1 as a potential target in the treatment of CS patients.

Early-onset nucleotide excision repair disorders with neurological impairment: Clues for early diagnosis and prognostic counseling.

Nucleotide excision repair associated diseases comprise overlapping phenotypes and a wide range of outcomes. The early stages still remain under-investigated and underdiagnosed, even although an early recognition of the first symptoms is of utmost importance for appropriate care and genetic counseling. We systematically collected clinical and molecular data from the literature and from newly diagnosed NER patients with neurological impairment, presenting clinical symptoms before the age of 12 months, including foetal cases. One hundred and eighty-five patients were included, 13 with specific symptoms during foetal life. Arthrogryposis, microcephaly, cataracts, and skin anomalies are the most frequently reported signs in early subtypes. Non ERCC6/CSB or ERCC8/CSA genes are overrepresented compared to later onset cohorts: 19% patients of this cohort presented variants in ERCC1, ERCC2/XPD, ERCC3/XPB or ERCC5/XPG. ERCC5/XPG is even the most frequently involved gene in foetal cases (10/13 cases, [4/7 families]). In this cohort, the mutated gene, the age of onset, the type of disease, severe global developmental delay, IUGR and skin anomalies were associated with earlier death. This large survey focuses on specific symptoms that should attract the attention of clinicians towards early-onset NER diagnosis in foetal and neonatal period, without waiting for the completeness of classical criteria.

Cockayne syndrome in adults: complete retinal dysfunction exploration of two case reports.

PURPOSE: Cockayne syndrome is a rare autosomal recessive disease, also known as a progeria disorder, causing dwarfism, senile appearance and multiple systemic affections. Ophthalmic abnormalities are frequent, for example, in the forms of pigmentary retinopathy with low visual acuity. We present two genetic-confirmed cases with a detailed electrophysiological exploration of their retinal findings. METHODS: Complete ophthalmic exploration is undertaken, including full-field electroretinogram under ISCEV guidelines and multifocal electroretinogram (RETI-scan science, Roland-Consult, Germany), ultra-wide-field retinography and autofluorescence (Optomap, Optos PLC, Dunfermline, Scotland, UK) and macular and retinal nerve fibre layer optical coherence tomography (Cirrus, Carl-Zeiss Meditec, Inc, Dublin, CA). RESULTS: Both cases presented with CSA/ERCC8 mutation and low visual acuity. Diffuse pigmentary retinopathy with macular atrophy was found in ultra-wide-field retinography and autofluorescence. Electrophysiological testing reported wide retinal dysfunction on both cone and rod system with macular involvement. CONCLUSIONS: Pigmentary retinopathy in CS could translate a wide dysfunction of the retina with major affection of external retinal layers of both cone and rod cells. Macular implication is also present and could explain progressive vision loss in such cases.

Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome.

BACKGROUND: Cockayne syndrome (CS) is a rare, autosomal recessive multisystem disorder characterised by prenatal or postnatal growth failure, progressive neurological dysfunction, ocular and skeletal abnormalities and premature ageing. About half of the patients with symptoms diagnostic for CS show cutaneous photosensitivity and an abnormal cellular response to UV light due to mutations in either the ERCC8/CSA or ERCC6/CSB gene. Studies performed thus far have failed to delineate clear genotype-phenotype relationships. We have carried out a four-centre clinical, molecular and cellular analysis of 124 patients with CS. METHODS AND RESULTS: We assigned 39 patients to the ERCC8/CSA and 85 to the ERCC6/CSB genes. Most of the genetic variants were truncations. The missense variants were distributed non-randomly with concentrations in relatively short regions of the respective proteins. Our analyses revealed several hotspots and founder mutations in ERCC6/CSB. Although no unequivocal genotype-phenotype relationships could be made, patients were more likely to have severe clinical features if the mutation was downstream of the PiggyBac insertion in intron 5 of ERCC6/CSB than if it was upstream. Also a higher proportion of severely affected patients was found with mutations in ERCC6/CSB than in ERCC8/CSA. CONCLUSION: By identifying >70 novel homozygous or compound heterozygous genetic variants in 124 patients with CS with different disease severity and ethnic backgrounds, we considerably broaden the CSA and CSB mutation spectrum responsible for CS. Besides providing information relevant for diagnosis of and genetic counselling for this devastating disorder, this study improves the definition of the puzzling genotype-phenotype relationships in patients with CS.

Cockayne syndrome-derived neurons display reduced synapse density and altered neural network synchrony.

Cockayne syndrome (CS) is a rare genetic disorder in which 80% of cases are caused by mutations in the Excision Repair Cross-Complementation group 6 gene (ERCC6). The encoded ERCC6 protein is more commonly referred to as Cockayne Syndrome B protein (CSB). Classical symptoms of CS patients include failure to thrive and a severe neuropathology characterized by microcephaly, hypomyelination, calcification and neuronal loss. Modeling the neurological aspect of this disease has proven difficult since murine models fail to mirror classical neurological symptoms. Therefore, a robust human in vitro cellular model would advance our fundamental understanding of the disease and reveal potential therapeutic targets. Herein, we successfully derived functional CS neural networks from human CS induced pluripotent stem cells (iPSCs) providing a new tool to facilitate studying this devastating disease. We identified dysregulation of the Growth Hormone/Insulin-like Growth Factor-1 (GH/IGF-1) pathway as well as pathways related to synapse formation, maintenance and neuronal differentiation in CSB neurons using unbiased RNA-seq gene expression analyses. Moreover, when compared to unaffected controls, CSB-deficient neural networks displayed altered electrophysiological activity, including decreased synchrony, and reduced synapse density. Collectively, our work reveals that CSB is required for normal neuronal function and we have established an alternative to previously available models to further study neural-specific aspects of CS.

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care.

PURPOSE: Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established. METHODS: One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians. RESULTS AND CONCLUSION: We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses.Genet Med 18 5, 483-493.

Auditory analysis of xeroderma pigmentosum 1971-2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration.

To assess the role of DNA repair in maintenance of hearing function and neurological integrity, we examined hearing status, neurological function, DNA repair complementation group and history of acute burning on minimal sun exposure in all patients with xeroderma pigmentosum, who had at least one complete audiogram, examined at the National Institutes of Health from 1971 to 2012. Seventy-nine patients, aged 1-61 years, were diagnosed with xeroderma pigmentosum (n = 77) or xeroderma pigmentosum/Cockayne syndrome (n = 2). A total of 178 audiograms were included. Clinically significant hearing loss (>20 dB) was present in 23 (29%) of 79 patients. Of the 17 patients with xeroderma pigmentosum-type neurological degeneration, 13 (76%) developed hearing loss, and all 17 were in complementation groups xeroderma pigmentosum type A or type D and reported acute burning on minimal sun exposure. Acute burning on minimal sun exposure without xeroderma pigmentosum-type neurological degeneration was present in 18% of the patients (10/55). Temporal bone histology in a patient with severe xeroderma pigmentosum-type neurological degeneration revealed marked atrophy of the cochlear sensory epithelium and neurons. The 19-year mean age of detection of clinically significant hearing loss in the patients with xeroderma pigmentosum with xeroderma pigmentosum-type neurological degeneration was 54 years younger than that predicted by international norms. The four frequency (0.5/1/2/4 kHz) pure-tone average correlated with degree of neurodegeneration (P < 0.001). In patients with xeroderma pigmentosum, aged 4-30 years, a four-frequency pure-tone average ≥10 dB hearing loss was associated with a 39-fold increased risk (P = 0.002) of having xeroderma pigmentosum-type neurological degeneration. Severity of hearing loss parallels neurological decline in patients with xeroderma pigmentosum-type neurological degeneration. Audiometric findings, complementation group, acute burning on minimal sun exposure and age were important predictors of xeroderma pigmentosum-type neurological degeneration. These results provide evidence that DNA repair is critical in maintaining neurological integrity of the auditory system.

Cancer in xeroderma pigmentosum and related disorders of DNA repair.

Nucleotide-excision repair diseases exhibit cancer, complex developmental disorders and neurodegeneration. Cancer is the hallmark of xeroderma pigmentosum (XP), and neurodegeneration and developmental disorders are the hallmarks of Cockayne syndrome and trichothiodystrophy. A distinguishing feature is that the DNA-repair or DNA-replication deficiencies of XP involve most of the genome, whereas the defects in CS are confined to actively transcribed genes. Many of the proteins involved in repair are also components of dynamic multiprotein complexes, transcription factors, ubiquitylation cofactors and signal-transduction networks. Complex clinical phenotypes might therefore result from unanticipated effects on other genes and proteins.

[Clinical examination of renal function in Cockayne syndrome].

Cockayne syndrome (CS) is a rare hereditary disease, characterized by profound postnatal brain and somatic growth failure and by the degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. This syndrome is often associated with renal dysfunction, which usually correlates with the patient's prognosis. In the present study, we evaluated the longitudinal changes in serum creatinine and serum cystatin C levels in three patients with CS to examine whether these markers can help detect renal disorders at the earlier stages. The serum creatinine level in these CS patients gradually exceeded the reference level from 5 to 7 years of age, after correcting for body length. The cystatin C level of the CS patients increased to above the reference level while their estimated glomerular filtration rate remained within stage 2 or 3. Thus, we conclude that the serum creatinine level, following correction by body length, is very useful for the evaluation of renal function in CS. Moreover, the appropriate estimation of renal function facilities the administration of suitable medication, thus avoiding some harmful effects on the kidney.

Brain vascular changes in Cockayne syndrome.

Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are caused by deficient nucleotide excision repair. CS is characterized by cachectic dwarfism, mental disability, microcephaly and progeria features. Neuropathological examination of CS patients reveals dysmyelination and basal ganglia calcification. In addition, arteriosclerosis in the brain and subdural hemorrhage have been reported in a few CS cases. Herein, we performed elastica van Gieson (EVG) staining and immunohistochemistry for collagen type IV, CD34 and aquaporin 4 to evaluate the brain vessels in autopsy cases of CS, XP group A (XP-A) and controls. Small arteries without arteriosclerosis in the subarachnoid space had increased in CS cases but not in either XP-A cases or controls. In addition, string vessels (twisted capillaries) in the cerebral white matter and increased density of CD34-immunoreactive vessels were observed in CS cases. Immunohistochemistry findings for aquaporin 4 indicated no pathological changes in either CS or XP-A cases. Hence, the increased subarachnoid artery space may have caused subdural hemorrhage. Since such vascular changes were not observed in XP-A cases, the increased density of vessels in CS cases was not caused by brain atrophy. Hence, brain vascular changes may be involved in neurological disturbances in CS.

Reactive Species in Progeroid Syndromes and Aging-Related Processes.

Significance: Reactive species have been classically considered causative of age-related degenerative processes, but the scenario appears considerably more complex and to some extent counterintuitive than originally anticipated. The impact of reactive species in precocious aging syndromes is revealing new clues to understand and perhaps challenge the resulting degenerative processes. Recent Advances: Our understanding of reactive species has considerably evolved, including their hormetic effect (beneficial at a certain level, harmful beyond this level), the occurrence of diverse hormetic peaks in different cell types and organisms, and the extended type of reactive species that are relevant in biological processes. Our understanding of the impact of reactive species has also expanded from the dichotomic damaging/signaling role to modulation of gene expression. Critical Issues: These new concepts are affecting the study of aging and diseases where aging is greatly accelerated. We discuss how notions arising from the study of the underlying mechanisms of a progeroid disease, Cockayne syndrome, represent a paradigm shift that may shed a new light in understanding the role of reactive species in age-related degenerative processes. Future Issues: Future investigations urge to explore established and emerging notions to elucidate the multiple contributions of reactive species in degenerative processes linked to pathophysiological aging and their possible amelioration. Antioxid. Redox Signal. 37, 208-228.

Identification and Characterization of a Novel Recurrent ERCC6 Variant in Patients with a Severe Form of Cockayne Syndrome B.

Cockayne syndrome (CS) is a rare disease caused by mutations in ERCC6/CSB or ERCC8/CSA. We report here the clinical, genetic, and functional analyses of three unrelated patients mutated in ERCC6/CSB with a severe phenotype. After clinical examination, two patients were investigated via next generation sequencing, targeting seventeen Nucleotide Excision Repair (NER) genes. All three patients harbored a novel, c.3156dup, homozygous mutation located in exon 18 of ERCC6/CSB that affects the C-terminal region of the protein. Sanger sequencing confirmed the mutation and the parental segregation in the three families, and Western blots showed a lack of the full-length protein. NER functional impairment was shown by reduced recovery of RNA synthesis with proficient unscheduled DNA synthesis after UV-C radiations in patient-derived fibroblasts. Despite sharing the same mutation, the clinical spectrum was heterogeneous among the three patients, and only two patients displayed clinical photosensitivity. This novel ERCC6 variant in Tunisian patients suggests a founder effect and has implications for setting-up prenatal diagnosis/genetic counselling in North Africa, where this disease is largely undiagnosed. This study reveals one of the rare cases of CS clinical heterogeneity despite the same mutation. Moreover, the occurrence of an identical homozygous mutation, which either results in clinical photosensitivity or does not, strongly suggests that this classic CS symptom relies on multiple factors.

The Ercc1-/Δ mouse model of accelerated senescence and aging for identification and testing of novel senotherapeutic interventions.

Progeroid murine models represent an emerging tool to investigate mechanisms of aging in an expedient and efficient manner. One prominent mechanism of aging is the accumulation of DNA damage and subsequent increase in cellular senescence, leading to age related pathologies. Ercc1-/Δ hypomorphic mice, which have a reduced level of the ERCC1-XPF DNA repair endonuclease complex, accumulate spontaneously occurring endogenous DNA damage similar to naturally aged mice, but at a faster rate. The resulting genomic damage gives rise to a senescent cell burden that is comparable to that of a naturally aged mouse. In fact, the expression of senescence and senescence-associated secretory phenotype (SASP) markers in 4-5-month-old Ercc1-/Δ mice, along with other measurements of senescence, were equivalent and never exceeded the extent of that found in naturally aged mice. Furthermore, many features of both natural murine aging and human aging are present in Ercc1-/Δ mice. An emerging use of these mice is the ability to study age-related signaling pathways, including identifying different types of senescent cells and their key senescent cell anti-apoptotic pathways (SCAPs). Most importantly, this model represents a rapid, cost-effective mouse model for the evaluation in vivo of senolytic drugs and other gerotherapeutics.

Oxidative stress in developmental brain disorders.

Oxidative stress is one of the predisposing factors in adult neurological disorders. We have examined the involvement of oxidative stress in child-onset neurodegenerative disorders, and here we review the findings from our analysis. In cases of Cockayne syndrome, the oxidative products of lipids and proteins were increased in the globus pallidus; however, oxidative nucleotide damage that coincided with reduced copper/zinc superoxide dismutase (Cu/ZnSOD) expression was observed in cases of xeroderma pigmentosum, and these patients also presented increased oxidative stress markers in urine samples. In spinal muscular atrophy, lipid peroxidation in conjunction with oxidative DNA damage was observed in motor neurons. Cases of subacute sclerosing panencephalitis presented oxidative nucleoside damage in cerebral cortical neurons at early disease stages, which were subsequently replaced by lipid peroxidation in glial cells of cerebral white matter. In relation to progressive myoclonic epilepsy, oxidative damage to DNA, proteins, and lipids appeared to coincide with cerebral and cerebellar cortical lesions of neuronal ceroid-lipofuscinosis. Patients with Lafora disease also presented an increase in oxidative stress markers for DNA and/or lipids in the brain and urine. These findings imply involvement of oxidative stress in developmental brain disorders; antioxidant agents could prove to be useful for treating patients with those disorders.

Rat Model of Cockayne Syndrome Neurological Disease.

Cockayne syndrome (CS) is a rare genetic neurodevelopmental disorder, characterized by a deficiency in transcription-coupled subpathway of nucleotide excision DNA repair (TC-NER). Mutation of the Cockayne syndrome B (CSB) gene affects basal transcription, which is considered a major cause of CS neurologic dysfunction. Here, we generate a rat model by mimicking a nonsense mutation in the CSB gene. In contrast to that of the Csb-/- mouse models, the brains of the CSB-deficient rats are more profoundly affected. The cerebellar cortex shows significant atrophy and dysmyelination. Aberrant foliation of the cerebellum and deformed hippocampus are visible. The white matter displays high glial fibrillary acidic protein (GFAP) staining indicative of reactive astrogliosis. RNA sequencing (RNA-seq) analysis reveals that CSB deficiency affects the expression of hundreds of genes, many of which are neuronal genes, suggesting that transcription dysregulation could contribute to the neurologic disease seen in the CSB rat models.

A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome.

Missense variants located to the "molecular brake" in the tyrosine kinase hinge region of platelet-derived growth factor receptor-ß, encoded by PFGFRB, can cause Penttinen-type (Val665Ala) and Penttinen-like (Asn666His) premature ageing syndromes, as well as infantile myofibromatosis (Asn666Lys and Pro660Thr). We have found the same de novo PDGFRB c.1997A>G p.(Asn666Ser) variants in two patients with lipodystrophy, acro-osteolysis and severely reduced vision due to corneal neovascularisation, reminiscent of a severe form of Penttinen syndrome with more pronounced connective tissue destruction. In line with this phenotype, patient skin fibroblasts were prone to apoptosis. Both in patient fibroblasts and stably transduced HeLa and HEK293 cells, autophosphorylation of PDGFRß was observed, as well as increased phosphorylation of downstream signalling proteins such as STAT1, PLCγ1, PTPN11/SHP2-Tyr580 and AKT. Phosphorylation of MAPK3 (ERK1) and PTPN11/SHP2-Tyr542 appeared unaffected. This suggests that this missense change not only weakens tyrosine kinase autoinhibition, but also influences substrate binding, as both PTPN11 tyrosines (Tyr542 and Tyr580) usually are phosphorylated upon PDGFR activation. Imatinib was a strong inhibitor of phosphorylation of all these targets, suggesting an option for precision medicine based treatment.

Deletion of 5' sequences of the CSB gene provides insight into the pathophysiology of Cockayne syndrome.

Cockayne syndrome is an autosomal recessive neurodegenerative disorder characterized by a specific defect in the repair of UV-induced DNA lesions. Most cases of Cockayne syndrome are caused by mutations in the CSB gene but the pathophysiological mechanisms are poorly understood. We report the clinical and molecular data of two severely affected Cockayne patients with undetectable CSB protein and mRNA. Both patients showed severe growth failure, microcephaly, mental retardation, congenital cataracts, retinal pigmentary degeneration, photosensitivity and died at the ages of 6 and 8 years. UV irradiation assays demonstrated that both patients had the classical DNA repair defect. Genomic DNA sequencing of the CSB gene showed a homozygous deletion involving non-coding exon 1 and upstream regulatory sequences, but none of the coding exons. Functional complementation using a wild-type CSB expression plasmid fully corrected the DNA repair defect in transfected fibroblasts. Horibata et al recently proposed that all type of CSB mutations result in a defect in UV damage repair that is responsible for the photosensitivity observed in the syndrome, but that only truncated CSB polypeptides generated by nonsense mutations have some additional inhibitory functions in transcription or in oxidative damage repair, which are necessary to lead to the other features of the phenotype. Our patients do not fit the proposed paradigm and new hypotheses are required to account for the pathophysiology of Cockayne syndrome, at the crossroads between DNA repair and transcription.

Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair.

Cockayne syndrome (CS) is a progressive childhood neurodegenerative disorder associated with a DNA repair defect caused by mutations in either of two genes, CSA and CSB. These genes are involved in nucleotide excision repair (NER) of DNA damage from ultraviolet (UV) light, other bulky chemical adducts and reactive oxygen in transcriptionally active genes (transcription-coupled repair, TCR). For a long period it has been assumed that the symptoms of CS patients are all due to reduced TCR of endogenous DNA damage in the brain, together with unexplained unique sensitivity of specific neural cells in the cerebellum. Not all the symptoms of CS patients are however easily related to repair deficiencies, so we hypothesize that there are additional pathways relevant to the disease, particularly those that are downstream consequences of a common defect in the E3 ubiquitin ligase associated with the CSA and CSB gene products. We have found that the CSB defect results in altered expression of anti-angiogenic and cell cycle genes and proteins at the level of both gene expression and protein lifetime. We find an over-abundance of p21 due to reduced protein turnover, possibly due to the loss of activity of the CSA/CSB E3 ubiquitylation pathway. Increased levels of p21 can result in growth inhibition, reduced repair from the p21-PCNA interaction, and increased generation of reactive oxygen. Consistent with increased reactive oxygen levels we find that CS-A and -B cells grown under ambient oxygen show increased DNA breakage, as compared with xeroderma pigmentosum cells. Thus the complex symptoms of CS may be due to multiple, independent downstream targets of the E3 ubiquitylation system that results in increased DNA damage, reduced transcription coupled repair, and inhibition of cell cycle progression and growth.

Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship.

Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair (NER). The NER pathway involves at least 28 genes. Three NER genes are also part of the basal transcription factor, TFIIH. Mutations in 11 NER genes have been associated with clinical diseases with at least eight overlapping phenotypes. The clinical features of these patients have some similarities but also have marked differences. NER is involved in protection against sunlight-induced DNA damage. While XP patients have 1000-fold increase in susceptibility to skin cancer, TTD and CS patients have normal skin cancer risk. Several of the genes involved in NER also affect somatic growth and development. Some patients have short stature and immature sexual development. TTD patients have sulfur deficient brittle hair. Progressive sensorineural deafness is an early feature of XP and CS. Many of these clinical diseases are associated with developmental delay and progressive neurological degeneration. The main neuropathology of XP is a primary neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the brain. These complex neurological abnormalities are not related to sunlight exposure but may be caused by developmental defects as well as faulty repair of DNA damage to neuronal cells induced by oxidative metabolism or other endogenous processes.