Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging

Stivaros, Stavros; Alston, R. L.; Wright, Neville; Chandler, Kate; Bonney, Denise; Wynn, Robert; Will, Andrew; Punekar, Maqsood; Loughran, Sean; Kilday, John-Paul; Schindler, Detlev; Patel, Leena; Meyer, Stefan

doi:10.1259/bjr.20150088

Cited by 22 publications

(27 citation statements)

References 19 publications

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“…These changes did not cause neurological deficits or intellectual disability, such that she attends regular classes. This is consistent with the observation that minor brain malformations with little if any clinical manifestation are relatively frequent in FA patients (21). From age 10 her bone marrow was cytopenic with reduced hematopoiesis and increased fatty tissue.…”

Section: Resultssupporting

confidence: 91%

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Knies¹,

Inano²,

Ramı́rez³

et al. 2017

Journal of Clinical Investigation

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177

171

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The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by homologous recombination (HR). Here we have shown that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual presented with congenital abnormalities characteristic of FA. Cells from the patient carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3 showed increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival, and cell cycle arrest in G 2 phase. The cellular phenotype was mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or introduction of the patient-derived missense mutation, and the phenotype was rescued by expression of wild-type RFWD3 protein. HR was disrupted in RFWD3-mutant cells as a result of impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with replication protein A. Rfwd3 knockout mice appear to have increased embryonic lethality, are subfertile, show ovarian and testicular atrophy, and have a reduced lifespan resembling that of other FA mouse models. Although RFWD3 mutations have thus far been detected in a single child with FA, we propose RFWD3 as an FA gene, FANCW, supported by cellular paradigm systems and an animal model.

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Section: Resultssupporting

confidence: 91%

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Knies¹,

Inano²,

Ramı́rez³

et al. 2017

Journal of Clinical Investigation

Self Cite

177

171

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“…Previous case series have reported that CNS malformations in FA patients were present in 61%-90% of these patients, and pituitary abnormalities were the most common. [10][11][12] These reports have 36 cases with FA, revealed at least one congenital CNS or skull base abnormality in 61% of the patients. 12 In this report by Johnson-Tesch et al, FA patients had higher incidences of ectopic neurohypophysis, hypoplasia of the adenohypophysis, platybasia, and other midline CNS skull base posterior fossa abnormalities than age-and sex-matched controls.…”

Section: Discussionmentioning

confidence: 99%

“…12 A study compared neuroimaging findings in siblings from three families who are also affected with FA, and they noticed similar CNS findings and differences as well. 10 We were able to compare neuroimaging findings in siblings in two families. The congenital abnormalities were different, and acquired defects were similar in the first family (cases 6 and 7).…”

Section: Discussionmentioning

confidence: 99%

“…9 CNS malformations in patients with FA were reported to be as high as 90%, and pituitary abnormalities were the most common abnormalities. 10 A study that focused on pituitary size and abnormalities could not conclude that there was an association between pituitary abnormalities and endocrinopathies in FA patients. 11 However, congenital or acquired CNS abnormalities are poorly characterized.…”

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confidence: 99%

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Central nervous system lesions in Fanconi anemia: Experience from a research center for Fanconi anemia patients

Aksu

Gümrük

Bayhan

et al. 2020

Pediatric Blood & Cancer

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Background: Brain atrophy, abnormal pituitary morphology, corpus callosum, and posterior fossa abnormalities have been described in patients with Fanconi anemia (FA). We aimed to provide an overview of cranial neuroimaging findings and to evaluate the clinical implications in FA patients. Procedure: Cranial magnetic resonance imaging (MRI) studies of 34 patients with FA were retrospectively evaluated, and patients' clinical data were correlated with the imaging findings. Results: The patients' median age was 17.6 (range, 3.9-28) years. At least one pathological brain imaging finding was demonstrated in 22 (65%) patients. These findings included corpus callosum abnormalities and other related supratentorial malformations in nine, pituitary abnormalities in eight, craniovertebral junction and posterior fossa abnormalities in eight, vascular lesions in six, and intracerebral calcifications in two patients. Among the 22 patients who had abnormal cranial MRI findings, six (27%) had mild to moderate intellectual disability (ID), three (14%) had epilepsy, one (5%) had mild hearing loss, and one patient (5%) had hemiplegia. Among these 34 patients, 14 (41%) were transfusion dependent. There was no significant difference between patients with congenital and acquired neuroimaging findings and patients with normal neuroimaging regarding transfusion dependency. Conclusions: Acquired abnormalities in brain tissue, such as white matter intensity changes, white matter T2 hyperintense discrete foci, or infarcts along with congenital abnormalities, were identified in this study. Variable abnormal brain imaging findings in FA patients, although some were not associated with clinical neurological manifestations, suggest that brain imaging could be part of screening in FA. K E Y W O R D S acquired abnormalities, congenital abnormalities, Fanconi anemia, neuroimaging, vascular lesions 1 INTRODUCTION Fanconi anemia (FA), an inherited disorder due to a DNA repair defect, is associated with various congenital defects in multiple organs, pro-Abbreviations: CNS, central nervous system; DNA, deoxyribonucleic acid; FA, Fanconi anemia; ID, ıntellectual disability; MRI, magnetic resonance imaging; WM, white matter gressive bone marrow failure, increased risk of cancers, and endocrine disturbances. 1 To date, 22 genes have been identified, which encode FA subtype proteins that maintain genomic integrity. 2,3 FA is characterized by increased sensitivity to cross-linking agents, including diepoxybutane and mitomycin C. 1 Recent studies suggest that DNA damage via accumulation of endogenous aldehydes, inflammation,

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“…The nervous system features include microcephaly, brain and spinal cord abnormalities, and a medulloblastoma predisposition. However, recent clinical studies show that the incidence of CNS abnormalities in FA is higher than initially thought, and among the described alterations are pituitary and corpus callosum malformations, as well as cerebellar atrophy [233][234][235][236] ( Table 1).…”

Section: Fanconi Anemia-causing Genesmentioning

confidence: 97%

Protective Mechanisms Against DNA Replication Stress in the Nervous System

Charlier

Martins

2020

Genes

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The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed.

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Central nervous system abnormalities in Fanconi anaemia: patterns and frequency on magnetic resonance imaging

Cited by 22 publications

References 19 publications

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

Central nervous system lesions in Fanconi anemia: Experience from a research center for Fanconi anemia patients

Protective Mechanisms Against DNA Replication Stress in the Nervous System

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