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.

Síndrome de Progeria Hutchinson-Gilford / Hutchinson-Gilford Progeria síndrome

El Síndrome de Progeria de Hutchinson-Gilford es una enfermedad que se caracteriza por el envejecimiento prematuro en niños, debido a una mutación en el gen de Lámina tipo A involucrado en la mitosis celular. En el presente trabajo, con el objetivo de dar difusión al conocimiento de esta enfermedad, se señalan los procesos involucrados en su desarrollo, así como los avances científicos y el alcance de nuevas ventanas terapéuticas. La revisión se realizó consultando artículos en español e inglés empleando los motores de búsqueda Pubmed y Google Académico. La actualización del personal de salud sobre las enfermedades genéticas congénitas es de vital importancia para mejorar su detección, atención y manejo(AU)

Hutchinson-Gilford Progeria Syndrome is a disease characterized by premature aging in children, due to a mutation in the Lamina type A, gene involved in cellular mitosis. In the present work, with the aim of spreading the knowledge of this disease, the processes involved in its development, the scientific advances, and the scope of new therapeutic treatments were summarized. The review was carried out by consulting articles in Spanish and English using the Pubmed and Google Academic search engines. The updating of health personnel on congenital genetic diseases is of vital importance to improve their detection, care and management(EU)

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.

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.

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.

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.

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.

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.

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.

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.

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: Clinical features, model systems and pathways.

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 (1-3) and two complementation groups (CSA and CSB), and CS 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 ascribed 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 for molecular interventions in CS, and by extrapolation, possibly in aging.

Neurodegeneration in accelerated aging.

The growing proportion of elderly people represents an increasing economic burden, not least because of age-associated diseases that pose a significant cost to the health service. Finding possible interventions to age-associated disorders therefore have wide ranging implications. A number of genetically defined accelerated aging diseases have been characterized that can aid in our understanding of aging. Interestingly, all these diseases are associated with defects in the maintenance of our genome. A subset of these disorders, Cockayne syndrome, Xeroderma pigmentosum group A and ataxia-telangiectasia, show neurological involvement reminiscent of what is seen in primary human mitochondrial diseases. Mitochondria are the power plants of the cells converting energy stored in oxygen, sugar, fat, and protein into ATP, the energetic currency of our body. Emerging evidence has linked this organelle to aging and finding mitochondrial dysfunction in accelerated aging disorders thereby strengthens the mitochondrial theory of aging. This theory states that an accumulation of damage to the mitochondria may underlie the process of aging. Indeed, it appears that some accelerated aging disorders that show neurodegeneration also have mitochondrial dysfunction. The mitochondrial alterations may be secondary to defects in nuclear DNA repair. Indeed, nuclear DNA damage may lead to increased energy consumption, alterations in mitochondrial ATP production and defects in mitochondrial recycling, a term called mitophagy. These changes may be caused by activation of poly-ADP-ribose-polymerase 1 (PARP1), an enzyme that responds to DNA damage. Upon activation PARP1 utilizes key metabolites that attenuate pathways that are normally protective for the cell. Notably, pharmacological inhibition of PARP1 or reconstitution of the metabolites rescues the changes caused by PARP1 hyperactivation and in many cases reverse the phenotypes associated with accelerated aging. This implies that modulation of PARP1 or the downstream metabolites may be a therapeutic strategy for treating accelerated aging disorders and potentially age-associated neurological decline seen in the normal population.

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.

Progressive demyelinating neuropathy correlates with clinical severity in Cockayne syndrome.

OBJECTIVE: Cockayne syndrome (CS) is characterized by postnatal growth failure and progressive multi-organ dysfunctions. CSA and CSB gene mutations account for the majority of cases and three degrees of severity are delineated. A peripheral neuropathy is known to be associated with CS but the type, severity and correlation of the nerve involvement with CS subtypes remain unknown in genetically identified patients. METHODS: Clinical and nerve conduction studies (NCS) in 25 CS patients with CSA (n=13) CSB (n=12) mutations. RESULTS: NCS show a widespread decrease in motor and sensory conduction velocities (CV) in all severe and classical form of CS. In one patient, CV were normal at age 8months but severe slowing was detected at 2years. Conduction block and/or temporal dispersion were observed in 68% of patients. CONCLUSIONS: CS is associated with a progressive sensory and motor neuropathy. Signs of segmental demyelination, including conduction blocks, may not be obvious before the age of 2years. CV slowing is correlated with the CS clinical severity. SIGNIFICANCE: NCS should be performed in patients with suspected CS as an additional tool to guide the diagnosis before molecular studies. Further studies focused on NCS course are required in order to assess its relevance as a biomarker in research therapy projects.

[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.

Dermatologic findings in 16 patients with Cockayne syndrome and cerebro-oculo-facial-skeletal syndrome.

IMPORTANCE: Cockayne syndrome (CS) and cerebro-oculo-facial-skeletal (COFS) syndrome are autosomal recessive diseases that belong to the family of nucleotide excision repair disorders. Our aim was to describe the cutaneous phenotype of patients with these rare diseases. OBSERVATIONS: A systematic dermatologic examination of 16 patients included in a European study of CS was performed. The patients were aged 1 to 28 years. Six patients (38%) had mutations in the Cockayne syndrome A (CSA) gene, and the remaining had Cockayne syndrome B (CSB) gene mutations. Fourteen patients were classified clinically as having CS and 2 as having COFS syndrome. Photosensitivity was present in 75% of the patients and was characterized by sunburn after brief sun exposure. Six patients developed symptoms after short sun exposure through a windshield. Six patients had pigmented macules on sun-exposed skin, but none developed a skin neoplasm. Twelve patients (75%) displayed cyanotic acral edema of the extremities. Eight patients had nail dystrophies and 7 had hair anomalies. CONCLUSIONS AND RELEVANCE: The dermatologic findings of 16 cases of CS and COFS syndrome highlight the high prevalence of photosensitivity and hair and nail disorders. Cyanotic acral edema was present in 75% of our patients, a finding not previously reported in CS.

Lifespan extension by dietary intervention in a mouse model of Cockayne syndrome uncouples early postnatal development from segmental progeria.

Cockayne syndrome (CS) is a rare autosomal recessive segmental progeria characterized by growth failure, lipodystrophy, neurological abnormalities, and photosensitivity, but without skin cancer predisposition. Cockayne syndrome life expectancy ranges from 5 to 16 years for the two most severe forms (types II and I, respectively). Mouse models of CS have thus far been of limited value due to either very mild phenotypes, or premature death during postnatal development prior to weaning. The cause of death in severe CS models is unknown, but has been attributed to extremely rapid aging. Here, we found that providing mutant pups with soft food from as late as postnatal day 14 allowed survival past weaning with high penetrance independent of dietary macronutrient balance in a novel CS model (Csa(-/-) | Xpa(-/-)). Survival past weaning revealed a number of CS-like symptoms including small size, progressive loss of adiposity, and neurological symptoms, with a maximum lifespan of 19 weeks. Our results caution against interpretation of death before weaning as premature aging, and at the same time provide a valuable new tool for understanding mechanisms of progressive CS-related progeroid symptoms including lipodystrophy and neurodysfunction.