Molecular epidemiology of hereditary ataxia in Finland

Abstract Background The genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population. Patients and methods All patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced. Results A genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms. Conclusions Expansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuropathy.

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Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion

Brain ◽

10.1093/brain/awz418 ◽

2020 ◽

Vol 143 (2) ◽

pp. 480-490 ◽

Cited By ~ 22

Author(s):

Andrea Cortese ◽

Stefano Tozza ◽

Wai Yan Yau ◽

Salvatore Rossi ◽

Sarah J Beecroft ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Late Onset ◽

Sensory Neuropathy ◽

Repeat Expansion ◽

Cerebellar Dysfunction ◽

Full Spectrum ◽

Ataxic Neuropathy ◽

Walking Aids ◽

Repeat Expansions ◽

Walking Difficulty

Abstract Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.

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CANVAS is a common form of late-onset hereditary ataxia

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.04.51-52 ◽

2020 ◽

pp. 51-52

Author(s):

Е.П. Нужный ◽

Н.Ю. Абрамычева ◽

Е.Г. Воробьева ◽

Е.О. Иванова ◽

Ю.А. Шпилюкова ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Clinical Picture ◽

Autosomal Recessive ◽

Late Onset ◽

Repeat Expansion ◽

Hereditary Ataxia ◽

Recessive Ataxia ◽

Autosomal Recessive Ataxia

Синдром CANVAS (мозжечковая атаксия, невропатия и вестибулярная арефлексия) - аутосомно-рецессивная атаксия с поздним дебютом, обусловленная носительством биаллельной экспансии (AAGGG)n во 2-м интроне гена RFC1. До настоящего момента отсутствуют сведения о распространенности данного заболевания в российских семьях. Нами был проведен поиск биаллельной экспансии AAGGG-повторов у 35 российских пациентов с поздней мозжечковой атаксией. Верифицированы 5 пациентов (14,3%) с синдромом CANVAS и характерной клинической картиной. CANVAS (cerebellar ataxia, neuropathy and vestibular areflexia) is a late-onset autosomal recessive ataxia due to biallelic (AAGGG)n repeat expansion in the 2nd intron of the RFC1 gene. There is no information on the CANVAS prevalence in Russian families. We searched for biallelic expansion of AAGGG repeats in 35 Russian patients with late-onset cerebellar ataxia. Five patients (14.3%) with CANVAS syndrome and a characteristic clinical picture were verified.

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REscan: inferring repeat expansions and structural variation in paired-end short read sequencing data

Bioinformatics ◽

10.1093/bioinformatics/btaa753 ◽

2020 ◽

Author(s):

Russell Lewis McLaughlin

Keyword(s):

Structural Variation ◽

Sequence Data ◽

Neurological Diseases ◽

Repeat Expansion ◽

Sequencing Data ◽

Short Read ◽

Short Read Sequencing ◽

Repeat Expansions ◽

Paired End Sequencing

Abstract Motivation Repeat expansions are an important class of genetic variation in neurological diseases. However, the identification of novel repeat expansions using conventional sequencing methods is a challenge due to their typical lengths relative to short sequence reads and difficulty in producing accurate and unique alignments for repetitive sequence. However, this latter property can be harnessed in paired-end sequencing data to infer the possible locations of repeat expansions and other structural variation. Results This article presents REscan, a command-line utility that infers repeat expansion loci from paired-end short read sequencing data by reporting the proportion of reads orientated towards a locus that do not have an adequately mapped mate. A high REscan statistic relative to a population of data suggests a repeat expansion locus for experimental follow-up. This approach is validated using genome sequence data for 259 cases of amyotrophic lateral sclerosis, of which 24 are positive for a large repeat expansion in C9orf72, showing that REscan statistics readily discriminate repeat expansion carriers from non-carriers. Availabilityand implementation C source code at https://github.com/rlmcl/rescan (GNU General Public Licence v3).

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Charcot-Marie-Tooth disease type 1A: morphological phenotype of the 17p duplication versus PMP22 point mutations

Acta Neuropathologica ◽

10.1007/bf00318579 ◽

1995 ◽

Vol 90 (6) ◽

pp. 645-649 ◽

Cited By ~ 75

Author(s):

A. A. W. M. Gabre�ls-Festen ◽

P. A. Bolhuis ◽

J. E. Hoogendijk ◽

L. J. Valentijn ◽

E. J. H. M. Eshuis ◽

...

Keyword(s):

Point Mutations ◽

Disease Type ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Tooth Disease ◽

Morphological Phenotype

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Familial adult myoclonic epilepsy (FAME): clinical features, molecular characteristics, pathophysiological aspects and diagnostic work-up

Medizinische Genetik ◽

10.1515/medgen-2021-2100 ◽

2021 ◽

Vol 33 (4) ◽

pp. 311-318

Author(s):

Lorenz Peters ◽

Christel Depienne ◽

Stephan Klebe

Keyword(s):

Clinical Features ◽

Neurological Disorders ◽

Genetic Disorder ◽

Repeat Expansion ◽

Myoclonic Epilepsy ◽

Molecular Characteristics ◽

Autosomal Dominant Disorder ◽

Repeat Expansions ◽

Diagnostic Work ◽

Work Up

Abstract Familial adult myoclonic epilepsy (FAME) is a rare autosomal dominant disorder characterized by myoclonus and seizures. The genetic variant underlying FAME is an intronic repeat expansion composed of two different pentamers: an expanded TTTTA, which is the motif originally present at the locus, and an insertion of TTTCA repeats, which is usually located at the 3′ end and likely corresponds to the pathogenic part of the expansion. This repeat expansion has been identified so far in six genes located on different chromosomes, which remarkably encode proteins with distinct cellular localizations and functions. Although the exact pathophysiological mechanisms remain to be clarified, it is likely that FAME repeat expansions lead to disease independently of the gene where they occur. We herein review the clinical and molecular characteristics of this singular genetic disorder, which interestingly shares clinical features with other more common neurological disorders whose etiology remains mainly unsolved.

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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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Characteristics of mutational signatures of unknown etiology

NAR Cancer ◽

10.1093/narcan/zcaa026 ◽

2020 ◽

Vol 2 (3) ◽

Author(s):

Xiaoju Hu ◽

Zhuxuan Xu ◽

Subhajyoti De

Keyword(s):

Dna Damage ◽

Point Mutations ◽

Gc Content ◽

Unknown Origin ◽

Unknown Etiology ◽

Mutational Signatures ◽

Dna Damage And Repair ◽

Disease Etiology ◽

Repair Processes ◽

A Genome

Abstract Although not all somatic mutations are cancer drivers, their mutational signatures, i.e. the patterns of genomic alterations at a genome-wide scale, provide insights into past exposure to mutagens, DNA damage and repair processes. Computational deconvolution of somatic mutation patterns and expert curation pan-cancer studies have identified a number of mutational signatures associated with point mutations, dinucleotide substitutions, insertions and deletions, and rearrangements, and have established etiologies for a subset of these signatures. However, the mechanisms underlying nearly one-third of all mutational signatures are not yet understood. The signatures with established etiology and those with hitherto unknown origin appear to have some differences in strand bias, GC content and nucleotide context diversity. It is possible that some of the hitherto ‘unknown’ signatures predominantly occur outside gene regions. While nucleotide contexts might be adequate to establish etiologies of some mutational signatures, in other cases additional features, such as broader (epi)genomic contexts, including chromatin, replication timing, processivity and local mutational patterns, may help fully understand the underlying DNA damage and repair processes. Nonetheless, remarkable progress in characterization of mutational signatures has provided fundamental insights into the biology of cancer, informed disease etiology and opened up new opportunities for cancer prevention, risk management, and therapeutic decision making.

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Identification of GGC repeat expansion in the NOTCH2NLC gene in amyotrophic lateral sclerosis

Neurology ◽

10.1212/wnl.0000000000010945 ◽

2020 ◽

Vol 95 (24) ◽

pp. e3394-e3405 ◽

Cited By ~ 1

Author(s):

Yanchun Yuan ◽

Zhen Liu ◽

Xuan Hou ◽

Wanzhen Li ◽

Jie Ni ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Mainland China ◽

Repeat Expansion ◽

Fisher Exact Test ◽

Healthy Controls ◽

Exact Test ◽

Repeat Expansions ◽

Neuronal Intranuclear Inclusion ◽

Electrophysiologic Studies ◽

Lateral Sclerosis

ObjectiveTo determine whether the GGC repeats in the NOTCH2NLC gene contribute to amyotrophic lateral sclerosis (ALS).MethodsIn this study, 545 patients with ALS and 1,305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes (including C9ORF72 and ATXN2) and polynucleotide repeat expansions in NOP56 and AR genes were excluded. Repeat-primed PCR and GC-rich PCR were performed to determine the GGC repeat size in NOTCH2NLC. Systematic and targeted clinical evaluations and investigations, including skin biopsy and dynamic electrophysiologic studies, were conducted in the genetically affected patients.ResultsGGC repeat expansion was observed in 4 patients (numbers of repeats 44, 54, 96, and 143), accounting for ≈0.73% (4 of 545) of all patients with ALS. A comparison with 1,305 healthy controls revealed that GGC repeat expansion in NOTCH2NLC was associated with ALS (Fisher exact test, 4 of 545 vs 0 of 1,305, p = 0.007). Compared to patients with the neuronal intranuclear inclusion disease (NIID) muscle weakness–dominant subtype, patients with ALS phenotype carrying the abnormal repeat expansion tended to have a severe phenotype and rapid deterioration.ConclusionOur results suggest that ALS is a specific phenotype of NIID or that GGC expansion in NOTCH2NLC is a factor that modifies ALS. These findings may help clarify the pathogenic mechanism of ALS and may expand the known clinical spectrum of NIID.

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Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106409 ◽

2019 ◽

Vol 57 (4) ◽

pp. 274-282 ◽

Cited By ~ 1

Author(s):

Shereen Georges Ghosh ◽

Lu Wang ◽

Martin W Breuss ◽

Joshua D Green ◽

Valentina Stanley ◽

...

Keyword(s):

Disulfide Bonds ◽

Protein Disulfide Isomerase ◽

Transmembrane Protein ◽

Repeat Expansion ◽

Global Developmental Delay ◽

Disulfide Isomerase ◽

Whole Exome ◽

Brain Malformations ◽

Repeat Expansions ◽

Protein Disulfide

BackgroundProtein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.MethodsEight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.ResultsAn identical homozygous variant in TMX2 (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While TMX2 is an activator of cellular C9ORF72 repeat expansion toxicity, patients showed no evidence of C9ORF72 repeat expansions.ConclusionThe TMX2 c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of C9ORF72 expansions. TMX2 is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.

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Unusual structures of CCTG repeats and their participation in repeat expansion

BioMolecular Concepts ◽

10.1515/bmc-2016-0024 ◽

2016 ◽

Vol 7 (5-6) ◽

pp. 331-340 ◽

Cited By ~ 3

Author(s):

Pei Guo ◽

Sik Lok Lam

Keyword(s):

Conformational Dynamics ◽

Structural Diversity ◽

Repeat Expansion ◽

Nucleic Acid Binding ◽

Myotonic Dystrophy Type 2 ◽

Unusual Structure ◽

Intron 1 ◽

Repeat Expansions ◽

Cctg Repeat ◽

The One

AbstractCCTG repeat expansion in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene has been identified to be the genetic cause of myotonic dystrophy type 2 (DM2). Yet the underlying reasons for the genetic instability in CCTG repeats remain elusive. In recent years, CCTG repeats have been found to form various types of unusual secondary structures including mini-dumbbell (MDB), hairpin and dumbbell, revealing that there is a high structural diversity in CCTG repeats intrinsically. Upon strand slippage, the formation of unusual structures in the nascent strand during DNA replication has been proposed to be the culprit of CCTG repeat expansions. On the one hand, the thermodynamic stability, size, and conformational dynamics of these unusual structures affect the propensity of strand slippage. On the other hand, these structural properties determine whether the unusual structure can successfully escape from DNA repair. In this short overview, we first summarize the recent advances in elucidating the solution structures of CCTG repeats. We then discuss the potential pathways by which these unusual structures bring about variable sizes of repeat expansion, high strand slippage propensity and efficient repair escape.

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