Prevalence of RFC1-mediated spinocerebellar ataxia in a North American ataxia cohort

ObjectiveWe evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 (RFC1) and disabled adaptor protein 1 (DAB1) in an undiagnosed ataxia cohort from North America.MethodsA cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for RFC1, resulting in a combined 911 subjects tested.ResultsIn the initial cohort, 41 samples were identified with 1 expanded allele in the RFC1 gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in RFC1 (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the DAB1 gene (spinocerebellar ataxia type 37).ConclusionsIn a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in RFC1 was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.

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Prevalence of RFC1-Mediated Spinocerebellar Ataxia in a United States Ataxia Cohort

10.1101/790006 ◽

2019 ◽

Author(s):

Dona Aboud Syriani ◽

Darice Wong ◽

Claudio M. De Gusmao ◽

Sameer Andani ◽

Yuanming Mao ◽

...

Keyword(s):

United States ◽

Cerebellar Ataxia ◽

Spinocerebellar Ataxia ◽

The United States ◽

Tertiary Referral ◽

Expanded Allele ◽

Initial Cohort ◽

Heterozygous Sample ◽

Repeat Expansions ◽

Polymerase Chain

ABSTRACTObjectiveRepeat expansions in RFC1 and DAB1 have recently been identified as causing cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) and spinocerebellar ataxia 37 (SCA37), respectively. We evaluated the prevalence of these repeat-expansions in an undiagnosed ataxia cohort from the United States.MethodsA cohort of 596 patients with undiagnosed familial or sporadic cerebellar ataxia were evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat primed polymerase chain reaction (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 96 and 13 patients respectively, were subsequently screened for RFC1 resulting in a combined 705 subjects tested.ResultsIn the initial cohort, 42 samples were identified with one expanded allele in the RFC1 gene (7.0%), and 9 had two expanded alleles (1.5%). For the additional cohorts, we found 12 heterozygous samples (12.5%) and 7 biallelic samples (7.3%) in the larger cohort, and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 19 patients were identified with biallelic repeat expansions in RFC1 (2.7%). Of these 19 patients, 6 (32%) had a clinical diagnosis of CANVAS, 10 had cerebellar ataxia with neuropathy (53%), and 3 had spinocerebellar ataxia (16%). No patients were identified with expansions in the DAB1 gene.ConclusionIn a large undiagnosed ataxia cohort from the United States, biallelic pathogenic repeat expansion in RFC1 was observed in 2.7%. Testing should be strongly considered in ataxia patients, especially those with CANVAS or neuropathy.

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Spinocerebellar ataxia type 28: A novel autosomal dominant cerebellar ataxia characterized by slow progression and ophthalmoparesis

The Cerebellum ◽

10.1007/s12311-008-0053-9 ◽

2008 ◽

Vol 7 (2) ◽

pp. 184-188 ◽

Cited By ~ 42

Author(s):

Caterina Mariotti ◽

Alfredo Brusco ◽

Daniela Di Bella ◽

Claudia Cagnoli ◽

Marco Seri ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Spinocerebellar Ataxia ◽

Autosomal Dominant ◽

Autosomal Dominant Cerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Slow Progression

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Spinocerebellar ataxia type 6 in Brazil

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2008000500015 ◽

2008 ◽

Vol 66 (3b) ◽

pp. 691-694 ◽

Cited By ~ 13

Author(s):

Hélio A.G. Teive ◽

Renato Puppi Munhoz ◽

Salmo Raskin ◽

Lineu César Werneck

Keyword(s):

Cerebellar Ataxia ◽

Spinocerebellar Ataxia ◽

Late Onset ◽

Cag Repeat ◽

Autosomal Dominant Cerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 6 ◽

Voltage Dependent ◽

Pure Cerebellar Ataxia ◽

Japanese Ancestry

Spinocerebellar ataxia type 6 (SCA 6) is an autosomal dominant cerebellar ataxia caused by CAG repeat expansion in the SCA6 gene, a alpha 1A voltage-dependent calcium channel subunit gene on chromosome 19p13. SCA-6 is characterized predominantly by slowly progressive pure cerebellar ataxia with late onset. We report three index patients, with pure, late onset, cerebellar ataxia, belonging to three different Brazilian families, all of them with Japanese ancestry, from Hokkaido island of Japan.

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Genetic Rhabdomyolysis within the Spectrum of the Spinocerebellar Ataxia Type 2 Responsive to Pregabalin

10.21203/rs.3.rs-125754/v1 ◽

2021 ◽

Author(s):

Fabian Rossi ◽

Joe Ma ◽

Nina Tsakadze ◽

Lourdes Benes-Lima ◽

Julio Araque Gonzalez ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Spinocerebellar Ataxia ◽

Clinical Presentation ◽

Spinocerebellar Ataxia Type ◽

Adult Onset ◽

Spinocerebellar Ataxia Type 2 ◽

First Report ◽

Recurrent Rhabdomyolysis

Abstract BackgroundSpinocerebellar Ataxia type 2 is a slowly progressive adult onset ataxia with a broad clinical presentation. Case presentationWe describe a man with Spinocerebellar Ataxia type 2 with chronic, severe, and recurrent rhabdomyolysis, as part of the cerebellar ataxia genetic spectrum. Initially rhabdomyolysis was refractory to multiple medications, but entirely resolved and remained in chronic remission with pregabalin. ConclusionThis is the first report of Spinocerebellar Ataxia type 2 associated with chronic, severe, recurrent rhabdomyolysis as part of its genetic phenotype responsive to pregabalin.

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Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): from clinical diagnosis towards genetic testing

Medizinische Genetik ◽

10.1515/medgen-2021-2098 ◽

2021 ◽

Vol 33 (4) ◽

pp. 301-310

Author(s):

Andreas Thieme ◽

Christel Depienne ◽

Dagmar Timmann

Keyword(s):

Cerebellar Ataxia ◽

Chronic Cough ◽

Late Onset ◽

Neurological Diseases ◽

Brain Mri ◽

Genetic Research ◽

Sensory Nerve ◽

Repeat Expansions ◽

Factor C ◽

Pentanucleotide Repeat

Abstract The cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset and recessively inherited ataxia. For many years, CANVAS has been diagnosed based on the clinical phenotype. Only recently, a large biallelic pentanucleotide repeat expansion in the replication factor C subunit 1 (RFC1) gene has been identified as the underlying genetic cause for the large majority of CANVAS cases. Subsequently, other phenotypes such as ataxia with chronic cough, incomplete CANVAS and MSA-C-like phenotypes have been associated with biallelic RFC1 repeat expansions. Because of this heterogeneity it has been suggested to change the name of the disease to “RFC1 disease”. Chronic cough is characteristic and can precede neurological symptoms by years or decades. In the neurological examination signs of cerebellar, sensory, and vestibular ataxia are frequently observed. Nerve conduction studies usually show absent or markedly reduced sensory nerve action potentials. On brain MRI cerebellar degeneration and spinal cord alterations are common. In later disease stages more widespread neurodegeneration with additional involvement of the brainstem and basal ganglia is possible. As yet, the exact incidence of RFC1-associated neurological diseases remains uncertain although first studies suggest that RFC1-related ataxia is common. Moreover, the pathophysiological mechanisms caused by the large biallelic pentanucleotide repeat expansions in RFC1 remain elusive. Future molecular and genetic research as well as natural history studies are highly desirable to pave the way towards personalized treatment approaches.

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Minidumbbell structures formed by ATTCT pentanucleotide repeats in spinocerebellar ataxia type 10

Nucleic Acids Research ◽

10.1093/nar/gkaa495 ◽

2020 ◽

Cited By ~ 1

Author(s):

Pei Guo ◽

Sik Lok Lam

Keyword(s):

Spinocerebellar Ataxia ◽

Dna Polymerase ◽

Dna Sequences ◽

Solution Structure ◽

Large Scale ◽

Genetic Disorder ◽

Spinocerebellar Ataxia Type ◽

Klenow Fragment ◽

Repeat Expansions

Abstract Spinocerebellar ataxia type 10 (SCA10) is a progressive genetic disorder caused by ATTCT pentanucleotide repeat expansions in intron 9 of the ATXN10 gene. ATTCT repeats have been reported to form unwound secondary structures which are likely linked to large-scale repeat expansions. In this study, we performed high-resolution nuclear magnetic resonance spectroscopic investigations on DNA sequences containing two to five ATTCT repeats. Strikingly, we found the first two repeats of all these sequences well folded into highly compact minidumbbell (MDB) structures. The 3D solution structure of the sequence containing two ATTCT repeats was successfully determined, revealing the MDB comprises a regular TTCTA and a quasi TTCT/A pentaloops with extensive stabilizing loop-loop interactions. We further carried out in vitro primer extension assays to examine if the MDB formed in the primer could escape from the proofreading function of DNA polymerase. Results showed that when the MDB was formed at 5-bp or farther away from the priming site, it was able to escape from the proofreading by Klenow fragment of DNA polymerase I and thus retained in the primer. The intriguing structural findings bring about new insights into the origin of genetic instability in SCA10.

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CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

Journal of Neurology ◽

10.1007/s00415-020-10183-0 ◽

2020 ◽

Author(s):

Natalia Dominik ◽

Valentina Galassi Deforie ◽

Andrea Cortese ◽

Henry Houlden

Keyword(s):

Late Onset ◽

Replication Factor C ◽

Common Cause ◽

Progressive Ataxia ◽

The World ◽

Recent Developments ◽

C Subunit ◽

Repeat Expansions ◽

Visual Problems ◽

Factor C

Abstract The ataxias are a group of disorders that manifest with balance, movement, speech and visual problems. They can arise due to dysfunction of the cerebellum, the vestibular system and/or the sensory neurons. Genetic defects are a common cause of chronic ataxia, particularly common are repeat expansions in this group of conditions. Co-occurrence of cerebellar ataxia with neuropathy and vestibular areflexia syndrome has been termed CANVAS. Although CANVAS is a rare syndrome, on discovery of biallelic expansions in the second intron of replication factor C subunit 1 (RFC1) gene, we and others have found the phenotype is broad and RFC1 expansions are a common cause of late-onset progressive ataxia. We aim to provide a review and update on recent developments in CANVAS and populations, where the disorder has been reported. We have also optimised a protocol for RFC1 expansion screening which is described herein and expanded phenotype after analysing late-onset ataxia patients from around the world.

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