Autosomal Dominant Cerebellar Ataxia Research Articles

Spinocerebellar Ataxia Type 10: From Amerindians to Latin Americans

Autosomal dominant cerebellar ataxias, currently denominated spinocerebellar ataxias (SCAs), constitute a large, complex group of heterogeneous autosomal dominant degenerative diseases characterized by progressive degeneration of the cerebellum and its afferent and efferent connections [1, 2]. Other nervous system structures are usually affected, including the basal ganglia, brainstem nuclei, pyramidal tracts, and posterior column and anterior horn of the spinal cord, as well as the peripheral nerves. SCAs are clinically characterized by the presence of cerebellar gait, limb ataxia (with dysmetria, dysdiadochokinesia, intention tremor), scanning dysarthria, dysphagia, nystagmus, and ocular motility abnormalities, which may be accompanied by extracerebellar signs such as ophthalmoplegia, pyramidal signs, movement disorders (including parkinsonism, dystonia, myoclonus, and chorea), dementia, epilepsy, visual disorders (including pigmentary retinopathy), lower motor neuron disease, and peripheral neuropathy [1–4]. Magnetic resonance imaging has been useful to demonstrate cerebellar atrophy with or without brainstem and occasionally whole brain atrophy depending on the form of the SCA. The prevalence of SCAs differs widely, mainly according to the ethnic distribution in most areas of the world where it has been studied [1–4]. One epidemiological study from the Netherlands [5] erichsuggested that the prevalence of SCAs is 3/100,000 and another from Norway suggested it is 4.2/100,000 [6]. Approximately 36 distinct loci of SCAs have been recognized. Among them, SCA type 3 (or Machado–Joseph disease) is the commonest subtype of SCA in the world. SCA type 10 (SCA10) is a rare form of SCA, but it is the commonest SCA after SCA type 2 in Mexico and SCA type 3 in Brazil [1, 2].

Maculopathy and Spinocerebellar Ataxia Type 1

Autosomal dominant cerebellar ataxia is a rare heterogeneous group of diseases characterized by cerebellar symptoms, often associated with other multisystemic signs. Mild optic neuropathy has been associated with spinocerebellar ataxia type 1 (SCA1), but macular dysfunction has been reported in only 2 cases. We report the first family with SCA1 with several members affected by visual loss related to maculopathy. Cross-sectional clinical and electrophysiological study of a family with genetically confirmed SCA1. Patients with unexplained visual loss were included. Four patients from the same family, carrying the same genetic mutation, were examined. Testing revealed an increased CAG trinucleotide repeat number within the SCA1 gene. Genetic testing results for SCA7 were negative. Visual acuities ranged between 20/20 and 20/200. Visual fields revealed central scotomas in most of the eyes, and funduscopy was unremarkable in most patients. Central retinal thinning of the retina or disorganized photoreceptor layers were found with optical coherence tomography (OCT). In one patient, multifocal electroretinography (mfERG) revealed central retinal dysfunction. A clinically subtle or even occult maculopathy can occur in association with SCA1. Macular OCT and mfERG can be abnormal even in asymptomatic patients. Unexplained visual loss in SCA1 patients should prompt evaluation of macular function, even if clinical signs of maculopathy are absent.

The L450P mutation in KCND3 brings spinocerebellar ataxia and Brugada syndrome closer together

The autosomal dominant cerebellar ataxias (SCAs) are progressive neurodegenerative disorders caused by atrophy of the cerebellum leading to progressive ataxia of gait and limbs, and speech and eye movement difficulties [1]. The SCAs are genetically heterogeneous and 22 causal genes have already been identified [1, 2].With the introduction of next-generation sequencing, novel SCA genes are being rapidly discovered and many more will certainly follow. Recently, we and others have identified loss-of-function mutations in KCND3 as causing SCA19 and SCA22 (SCA19/22) [3, 4], but gain-of-function mutations in KCND3 were also implicated in Brugada syndrome and atrial fibrillation [5, 6]. KCND3 encodes for the voltage-gated potassium channel Kv4.3, which mediates A-type potassium currents in neurons (IA) and in the heart (I to), although the disease mechanisms underlying these allelic disorders are not yet understood. To determine the disease frequency of SCA19/22 in Europe, we screened 366 familial ataxia cases. Most were of French origin and had tested negative for SCA1–3, SCA6, SCA7, SCA17, SCA23, and DRLPA mutations. The complete coding sequence and exon–intron boundaries ofKCND3 were screened using high-resolution melting (HRM) analysis (LightScanner, Bioke; for primer sequences, see Table S1). We discovered a French man (AAD-722-001) carrying the c.1348C>T, p.L450P mutation, which was reported to be associated with Brugada syndrome and was proven to result in a gain of Kv4.3 channel function [4]. This patient displayed a cerebellar gait ataxia at age 39, associated with pyramidal signs. However, at age 46 years, he has not yet presented with any heart problems. Since this man might be at risk for pathological heart palpitations and lethal ventricular arrhythmias, he should be screened for ECG abnormalities. This result emphasizes that the p.L450P mutation may predispose to both ataxia and ventricular arrhythmias, as might be the case for additional mutations associatedwith heritable heart syndromes such as Brugada syndrome and spinocerebellar ataxia that are located within the sixth transmembrane domain and the C-terminal tail of Kv4.3. Additionally, we identified a heterozygous variant, c. 1840C>T, p.P614S, in a French woman (AAD-114-009), who had developed a cerebellar gait ataxia with decreased reflexes and vibration sense in the ankles at the age of 59 years. This variant was not reported in any genetic database or in 400 Electronic supplementary material The online version of this article (doi:10.1007/s10048-013-0370-0) contains supplementary material, which is available to authorized users. A. Duarri : E. Nibbeling :M. R. Fokkens :D. S. Verbeek (*) Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands e-mail: d.s.verbeek@umcg.nl

A Novel de novo Exon 21 DNMT1 Mutation Causes Cerebellar Ataxia, Deafness, and Narcolepsy in a Brazilian Patient

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is caused by DNMT1 mutations. Diagnosing the syndrome can be difficult, as all clinical features may not be present at onset, HLA-DQB1*06:02 is often negative, and sporadic cases occur. We report on clinical and genetic findings in a 31-year-old woman with cerebellar ataxia, deafness, and narcolepsy, and discuss diagnostic challenges. Clinical and genetic investigation in a patient and family members. Ataxia clinic, São Paulo, Brazil. One patient and her family members. N/A. Narcolepsy was supported by polysomnographic and multiple sleep latency testing. HLA-DQB1*06:02 was positive. CSF hypocretin-1 was 191 pg/mL (normal values > 200 pg/mL). Mild brain atrophy was observed on MRI, with cerebellar involvement. The patient, her asymptomatic mother, and 3 siblings gave blood samples for genetic analysis. DNMT1 exons 20 and 21 were sequenced. Haplotyping of polymorphic markers surrounding the mutation was performed. The proband had a novel DNMT1 mutation in exon 21, p.Cys596Arg, c.1786T > C. All 4 parental haplotypes could be characterized in asymptomatic siblings without the mutation, indicating that the mutation is de novo in the patient. The Brazilian patient reported here further adds to the worldwide distribution of ADCA-DN. The mutation is novel, and illustrates a sporadic case with de novo mutation. We believe that many more cases with this syndrome are likely to be diagnosed in the near future, mandating knowledge of this condition and consideration of the diagnosis.

Lessons from preclinical disease

Identifying individuals at risk of developing neurodegenerative conditions prior to clinical manifestation of disease, has become a popular subject for recent neurological research. It is well established that by the time patients present with these disorders, a significant degree of irreversible neuronal loss has already occurred. Understanding the evolution of preclinical disease may, therefore, highlight methods by which the pathological processes can be slowed or curtailed; either through modifying environmental factors or by the use of novel disease modifying agents. Encouragingly this approach already has a number of successful precedents and is widely employed in the prevention of heart disease and indeed in many other branches of medicine. An important first step in this process will be the ability to screen individuals at risk for predictive biomarkers of disease, but identifying the population at risk for sporadic neurodegenerative conditions has proved problematic. However, the study of fully penetrant autosomal dominant disorders, in which a reliable genetic test is currently available, offers an opportunity to identify specific predefined cohorts. These very specific cohorts can then be assessed in detail, if necessary over prolonged time periods, for a large range of potential clinical, biological and radiological biomarkers. Although the numbers of individuals at risk of these relatively rare genetic disorders are commonly limited, the hope is that studies of this important group of individuals may offer important insights into more common sporadic conditions. In this month’s journal club, we examine three articles; each one addressing these issues in seperate neurodegenerative disorders, all of which are autosomal dominant and fully penetrant conditions and in which the age at onset can be predicted with varying degrees of accuracy: Huntington’s disease (HD), autosomal dominant cerebellar ataxias (SCA) and presenilin 1 autosomal dominant Alzheimer’s disease. In the first paper Tabrizi et al., examine premanifest carriers of HD and early HD patients in a 36-month longitudinal study. The second paper by Jacobi et al., examines carriers of the SCA1, SCA2, SCA3 and SCA6 mutations prior to disease onset. The final paper describes a cross sectional analysis of a Colombian cohort of Presenilin 1 mutation carriers. All three studies have employed different methodologies in search of a common goal; to identify informative clinical, biological or radiological biomarkers for these diseases.

Origin of the Spinocerebellar Ataxia Type 7 Gene Mutation in Mexican Population

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by progressive cerebellar ataxia associated with macular degeneration that leads, in the majority of patients, to loss of autonomy and blindness. The cause of the disease has been identified as (CAG) n repeat expansion in the coding sequence of the ATXN7 gene on chromosome 3p21.1. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias found worldwide; however, we previously identified the Mexican population showing high prevalence of SCA7, suggesting the occurrence of a common founder effect. In this study, haplotype analysis using four SCA7 gene-linked markers revealed that all 72 SCA7 carriers studied share a common haplotype, A-254-82-98, for the intragenic marker 3145G/A and centromeric markers D3S1287, D3S1228, and D3S3635, respectively. This multiloci combination is uncommon in healthy relatives and Mexican general population, suggesting that a single ancestral mutation is responsible for all SCA7 cases in this population. Furthermore, genotyping using 17 short tandem repeat markers from the non-recombining region of the Y chromosome and further phylogenetic relationship analysis revealed that Mexican patients possess the Western European ancestry, which might trace the SCA7 ancestral mutation to that world region.

Experience in a short-term trial with 4-Aminopyridine in cerebellar ataxia

4-Aminopyridine (4-AP) is a reversible blocker of voltagegated potassium channels. Its slow release form has been approved for symptomatic treatment of gait disorder in multiple sclerosis [2]. In a number of small studies, 4-AP and the related compound 3,4-diaminopyridine (3,4-AP) improved downbeat nystagmus and reduced attack frequency in episodic ataxia [9]. In addition, 4-AP decreased gait variability in patients with chronic cerebellar ataxia of different origin [7, 8]. Chronic treatment with 3,4-AP had beneficial effects in a mouse model of spinocerebellar ataxia type 1 (SCA1) [3]. We here report our clinical experiences with 4-AP in 16 patients with chronic cerebellar ataxia. As 4-AP is thought to exert its effect on ataxia by interfering with the activity of cerebellar Purkinje neurons, we treated patients with SCA1, SCA3, SCA6 and sporadic adult-onset ataxia of unknown origin (SAOA), as well as one with a POLG mutation. These disorders are characterized by prominent cerebellar cortical degeneration with Purkinje cell involvement. Three centers participated in the observations. After giving informed consent, 16 patients were treated with the slow release form of 4-AP (Fampyra , 2 9 10 mg/day). Nine of the patients were female. Three patients were diagnosed SCA1, three SCA6, two SCA3, one genetically nonidentified autosomal dominant cerebellar ataxia, one POLG mutation and six of them a SAOA. Age was 60 ± 11.3 years (mean ± SD), disease duration 16.3 ± 17.1 years. To assess the severity of ataxia, we used the Scale for the Assessment and Rating of Ataxia (SARA) [5]. In addition, patients underwent three timed coordination tests, the 8 m walk (8 MW), the 9-hole pegboard (9HPT), and the speech rate test (PATA rate). Performance in these tests allows calculating the SCA Functional Index (SCAFI) [6]. Results of the timed tests are expressed as Z scores. Neurological symptoms other than ataxia were assessed with the Inventory of Non-Ataxia Signs (INAS) [4]. Patients estimated their health-related quality of life on the visual analogue scale of the EQ-5D (EQ-VAS) [1]. Assessments were done at baseline, 4 h and 14 days after treatment. Although two patients discontinued 4-AP due to side effects, the compound was generally well tolerated. This view is also supported by the trend towards an improvement of the EQ-VAS after 14 days. In the remaining 14 patients, SARA (range: 0–40) improved from 14.3 ± 4.7 to 13.0 ± 4.6 points after 4 h (n = 11) and to 13.7 ± 4.6 points after 14 days (n = 14), but these differences failed I. Giordano (&) H. Jacobi M. Minnerop T. Klockgether Department of Neurology, University Hospital of Bonn, Sigmund-Freud-Strase 25, 53105 Bonn, Germany e-mail: ilaria_anna.giordano@ukb.uni-bonn.de

Deep Brain Stimulation of the Internal Globus Pallidus for Generalized Dystonia Associated with Spinocerebellar Ataxia Type 1: A Case Report

Ataxia is a common movement disorder affecting primarily balance and coordination. The cerebellar circuitry is most commonly involved, but there can also be involvement of connected structures, including the thalamus, globus pallidus, and striatum ( 1. Schöls L Bauer P Schmidt T Schulte T Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004; 3: 291-304 Abstract Full Text Full Text PDF PubMed Scopus (793) Google Scholar , 2. Rüb U Del Turco D Del Tredici K et al. Thalamic involvement in a spinocerebellar ataxia type 2 (SCA2) and a spinocerebellar ataxia type 3 (SCA3) patient, and its clinical relevance. Brain. 2003; 126: 2257-2272 Crossref PubMed Scopus (65) Google Scholar ). There is a subset of ataxic syndromes that are inherited in an autosomal dominant fashion. Spinocerebellar ataxia type 1 (SCA1) is an inherited form of ataxia associated with abnormal CAG repeats on the ataxin 1 gene on chromosome 6 ( 3. Zoghbi HY Orr HT. Spinocerebellar ataxias. in: Scriver CR Beaudt AL Valle D The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill, New York2001: 5741-5758 Google Scholar ). The highly variable clinical features of this disorder are well documented and may include dystonia, parkinsonism, cognitive dysfunction, and other movement disorders in addition to ataxia ( 1. Schöls L Bauer P Schmidt T Schulte T Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004; 3: 291-304 Abstract Full Text Full Text PDF PubMed Scopus (793) Google Scholar , 4. Bu?rk K Globas C Bösch S et al. Cognitive deficits in spinocerebellar ataxia types 1, 2, and 3. J Neurol. 2003; 250: 207-211 Crossref PubMed Scopus (163) Google Scholar ). Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been established as a treatment for generalized dystonia. Recent imaging techniques, such as diffusion tensor imaging (DTI), provide an in vivo estimation of the anatomical tracts affected by DBS ( 5. Butson CR Cooper SE Henderson JM McIntyre CC. Patient-specific analysis of the volume of tissue activated during deep brain stimulation. Neuroimage. 2007; 34: 661-670 Crossref PubMed Scopus (350) Google Scholar ). We present a case of generalized dystonia in a patient with genetically confirmed SCA1 who responded well to bilateral deep brain stimulation of the GPi.

An Out-of-frame Overlapping Reading Frame in the Ataxin-1 Coding Sequence Encodes a Novel Ataxin-1 Interacting Protein

Spinocerebellar ataxia type 1 is an autosomal dominant cerebellar ataxia associated with the expansion of a polyglutamine tract within the ataxin-1 (ATXN1) protein. Recent studies suggest that understanding the normal function of ATXN1 in cellular processes is essential to decipher the pathogenesis mechanisms in spinocerebellar ataxia type 1. We found an alternative translation initiation ATG codon in the +3 reading frame of human ATXN1 starting 30 nucleotides downstream of the initiation codon for ATXN1 and ending at nucleotide 587. This novel overlapping open reading frame (ORF) encodes a 21-kDa polypeptide termed Alt-ATXN1 (Alternative ATXN1) with a completely different amino acid sequence from ATXN1. We introduced a hemagglutinin tag in-frame with Alt-ATXN1 in ATXN1 cDNA and showed in cell culture the co-expression of both ATXN1 and Alt-ATXN1. Remarkably, Alt-ATXN1 colocalized and interacted with ATXN1 in nuclear inclusions. In contrast, in the absence of ATXN1 expression, Alt-ATXN1 displays a homogenous nucleoplasmic distribution. Alt-ATXN1 interacts with poly(A)(+) RNA, and its nuclear localization is dependent on RNA transcription. Polyclonal antibodies raised against Alt-ATXN1 confirmed the expression of Alt-ATXN1 in human cerebellum expressing ATXN1. These results demonstrate that human ATXN1 gene is a dual coding sequence and that ATXN1 interacts with and controls the subcellular distribution of Alt-ATXN1.

Abnormal RNA structures (RNA foci) containing a penta‐nucleotide repeat (UGGAA)n in the Purkinje cell nucleus is associated with spinocerebellar ataxia type 31 pathogenesis

Spinocerebellar ataxia type 31 (SCA31) is an autosomal-dominant cerebellar ataxia showing a Purkinje cell (PC)-predominant neurodegeneration in humans. The mutation is a complex penta-nucleotide repeat containing (TGGAA)n , (TAGAA)n , (TAAAA)n and (TAGAATAAAA)n inserted in an intron shared by two different genes BEAN1 and TK2 located in the long arm of the human chromosome 16. Previous studies have shown that (TGGAA)n is the critical component of SCA31 pathogenesis while the three other repeats, also present in normal Japanese, are not essential. Importantly, it has been shown that BEAN1 and TK2 are transcribed in mutually opposite directions in the human brain. Furthermore, abnormal RNA structures called "RNA foci" are observed by a probe against (UAGAAUAAAA)n in SCA31 patients' PC nuclei, indicating that the BEAN1-direction mutant transcript appears instrumental for the pathogenesis. However, it is not known whether the critical repeat (TGGAA)n contributes to the formation of RNA foci, neither do we understand how the RNA foci formation is relevant to the pathogenesis. To address these issues, we investigated two SCA31 cerebella by fluorescence in situ hybridization using a probe against (UGGAA)n . We also asked whether the mutant BEAN1-transcript containing (UGGAA)n exerts toxicity compared to the other three repeats in cultured cells. Histopathologically, we confirm that the PC is the main target of SCA31 pathogenesis. We find that the RNA foci containing (UGGAA)n are indeed observed in PC nuclei of both SCA31 patients, whereas similar foci were not observed in control individuals. In both transiently and stably expressed cultured cell models, we also find that the mutation transcribed in the BEAN1-direction yields more toxicity than control transcripts and forms RNA foci detected with probes against (UGGAA)n and (UAGAAUAAAA)n . Taking these findings together, we conclude that the RNA foci containing BEAN1-direction transcript (UGGAA)n are associated with PC degeneration in SCA31.

Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE

DNMT1, encoding DNA methyltransferase 1 (Dnmt1), is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. To date, two phenotypes produced by DNMT1 mutations have been reported, including hereditary sensory and autonomic neuropathy (HSAN) type IE with mutations in exon 20, and autosomal dominant cerebellar ataxia, deafness, and narcolepsy caused by mutations in exon 21. We report a sporadic case in a Japanese patient with loss of pain and vibration sense, chronic osteomyelitis, autonomic system dysfunctions, hearing loss, and mild dementia, but without definite cerebellar ataxia. Electrophysiological studies revealed absent sensory nerve action potential with nearly normal motor nerve conduction studies. Brain magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy. Using a next-generation sequencing system, 16 candidate genes were analyzed and a novel missense mutation, c.1706A>G (p.His569Arg), was identified in exon 21 of DNMT1. Our findings suggest that mutation in exon 21 of DNMT1 may also produce a HSAN phenotype. Because all reported mutations of DNMT1 are concentrated in exons 20 and 21, which encode the replication focus targeting sequence (RFTS) domain of Dnmt1, the RFTS domain could be a mutation hot spot.

Autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy (ADCA-DN): An Emerging Syndrome Caused by DNMT1 Mutations (S43.003)

Autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy (ADCA-DN): An Emerging Syndrome Caused by DNMT1 Mutations (S43.003)

Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics

Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments.

Acute onset of cerebellar ataxia in a spinocerebellar ataxia type 10 patient after use of steroids

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder caused by an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of the ATXN10 gene on chromosome 22q13.31,2. SCA10 gene encodes a 475 KD protein of largely undetermined function. The pathogenic number of ATTCT repeat units ranges from 800 to 4,500 repeats. SCA10 represents a rare form of SCA, described only in Latin America1,2. While clinical manifestations of families described in Brazil are those of a predominantly “pure” cerebellar syndrome, it is often accompanied by epilepsy and occasionally peripheral neuropathy in the Mexican ones1,2. Here, we presented the case of a patient with genetically confirmed SCA10, who developed sudden onset of cerebellar ataxia after a course of corticosteroid therapy. A 34-year-old previously asymptomatic Brazilian woman suddenly developed gait ataxia and dysarthria two weeks after a pulse therapy with methylprednisolone for the treatment of idiopathic thrombocytopenic purpura. The patient was admitted with a clinical picture of body petechiae, gingival bleeding, and hematochezia, which started four days earlier. She had a platelet count of 1,000, which improved with the use of corticosteroids. Neurological assessment revealed gait ataxia, dysarthria, and ocular dysmetria. The Scale for the Assessment and Rating of Ataxia (SARA) was 7.5. Brain magnetic resonance imaging (MRI) showed moderate cerebellar atrophy. Family history was positive for SCA10, including previously reported relatives (aunt and two cousins), whose symptoms were initially manifested during pregnancy3. Interestingly, this same family has also reported the occurrence of cerebellar symptoms triggered by ingestion of small amounts of alcohol, which was previously also published by the authors4. SCA10 is the second most common autosomal dominant cerebellar ataxia in Brazil (after SCA type 3) and in Mexico (after SCA 2). To our knowledge, there is no report of acute cerebellar ataxia development after steroid therapy in patients with SCAs. Based on the case reported here and on family history of onset of symptoms during pregnancy and on postpartum period3, the authors hypothesized that hormonal factors may have a role in the emergence of SCA10 clinical symptoms and signs in previously asymptomatic patients in this family. The mechanisms by which hormones act on cerebellar function and its afferent and efferent connections remain unknown. Previously established genetic variables could be responsible for a lower threshold for manifestation of SCA10 in the course of steroid therapy, and additional studies are necessary to confirm this finding. On the other hand, it is widely known that stress seems to cause acute neuronal death or dysfunction5. Therefore, another possibility is that factors related to stress, involved in acute medical situations, such as pregnancy and postpartum period, could have a pivotal role in the development of acute symptoms of cerebellar ataxia in patients with asymptomatic cerebellar atrophy due to SCA10.

Spinocerebellar ataxia type 7: Report of an Indian family

Spinocerebellar ataxia type 7 (SCA7) is a form of autosomal dominant cerebellar ataxia which is associated with pigmentary retinal degeneration. It is known for its world-wide rarity except in the Scandinavian countries. It is very rarely reported from India and the neighbouring Asian countries. The present report describes the neurogenetic findings of a family of SCA7, from the northern part of Karnataka in South India. It documents the wide intrafamilial phenotypic variability, which could be correlated with the CAG repeat counts and phenomenon of anticipation. Genotype phenotype correlation highlighted certain disparities in comparison with the previous studies. The report highlights the need for multiethnic population studies and the role of genetic counseling and prenatal testing in SCA7 patients.

Mutations in KCND3 cause spinocerebellar ataxia type 22

To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23. We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions. We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame 3-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K(+) channel conductance in whole cell patch-clamp recordings. Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration.

Investigation of SCA10 in the Cypriot population: Further exclusion of SCA dynamic repeat mutations

Autosomal dominant cerebellar ataxias (ADCAs) encompass a heterogeneous group of rare diseases that affect the cerebellum and its connections. The most common forms have been associated with dynamic mutations while some rarer forms with conventional mutations. Studies in different populations revealed differences in their relative frequencies both within and between the studied populations, showing that the frequencies are depended on ethnic and geographical factors. Previous investigation of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in the Cypriot population, revealed no pathogenic expansion in the Cypriot SCA patients. We hereby present our recent investigation of the SCA10 pentanucleotide repeat expansion. Forty-two ascertained Cypriot sporadic ataxia patients, the index case from 1 ADCA and 14 ARCA families and a cohort of normal population individuals were included in the study. All our patients have normal range ATXN10 gene ATTCT repeat numbers (10–19). In the normal population group, repeat lengths ranged from 11 to 20 with the 14 repeats allele being the most frequent. Therefore, all currently established dynamic repeat SCA mutations are absent from the Cypriot population, indicating distinct genetic causes.

A case of nocturnal frontal lobe epilepsy in a patient with spinocerebellar ataxia type 17

Nocturnal frontal lobe epilepsy (NFLE) comprises a complex spectrum of distinct paroxysmal sleep-related attacks of variable intensity, including paroxysmal arousals, nocturnal paroxysmal dystonias and epileptic nocturnal wanderings. Scalp EEG and brain MRI are unable to reveal abnormalities in a considerable amount of patients. In those cases the epileptic nature of NFLE is supported by the stereotypical clinical presentation of the episodes and the often dramatic response to antiepileptic drugs (AEDs) like Carbamazepine, Clonazepam or Topiramate. Spinocerebellar ataxia type 17 (SCA 17) is a neurodegenerative disease caused by the expansion above 44 units of a CAG/CAA repeat in the coding region of the TATA box binding protein (TBP) gene. It is one of the rarer forms amongst autosomal dominant cerebellar ataxias, with extreme variable age at onset and clinical phenotype. Epilepsy is quite commonly observed among SCA 17 patients, however it is exclusively described in terms of generalized tonic–clonic seizures. We report a case of NFLE occurring in a SCA 17 patient and brilliantly responsive to Topiramate after failure of the first line therapy with Carbamazepine.

A Family with Spinocerebellar Ataxia Type 5 Found to Have a Novel Missense Mutation within a SPTBN2 Spectrin Repeat

A family with late-onset autosomal dominant pure cerebellar ataxia, consistent with spinocerebellar ataxia type 5 (SCA5) but lacking previously reported SPTBN2 mutations, was identified. DNA was collected from seven individuals across two generations and the SPTBN2 gene on chromosome 11 was sequenced. A nonsynonymous heterozygous substitution in exon 12 was detected in individuals diagnosed with SCA5 while unaffected family members did not possess this variant. The identified c.1415C>T variant results in a p.T472M substitution in the second SPEC domain of the beta-III spectrin protein. The threonine at position 472 is not in close proximity to the characteristic residues that define the SPEC domain and is variable across diverse SPEC domains, yet is highly conserved in SPTBN2. Consistent with these observations, bioinformatic analysis of the p.T472M variant suggests it to be pathological. Two deletions within the SPTBN2 SPEC domains (E532_M544del and L629_R634delinsW) have been previously reported to cause SCA5, but this is the first missense mutation in this region of the protein shown to likely be pathogenic.

Dentatorubral Pallidoluysian Atrophy (DRPLA)-A Rare Neurological Disorder

Dentatorubral pallidoluysian atrophy (DRPLA) is a rare type of an autosomal dominant progressive late onset cerebellar ataxia. It is caused by a defect in a gene [CAG repeat in atrophin-1 (ATN1) on chromosome 12] and results in damage to the cerebellum, and to its connections within the central nervous system. It is also known as Haw River Syndrome and Naito-Oyanagi disease. This disorder seems to be very rare except in Japan. Patients with DRPLA can exhibit a variety of psychiatric symptoms in addition to extrapyramidal and cerebellar symptoms. We report a case who was 28 years old unmarried man presented at BSMMU, Dhaka in 2010. The present work highlights the variable mode of presentation of DRPLA and the difficulty of an early diagnosis without facility of genetic analysis. The aim of our report was to describe typical clinical presentations of the disease without positive family history. Our patient presented with unsteadiness during walking, irrelevant behavior and talking, incontinence of urine and stool with occasional myoclonic seizure and dementia. DOI: http://dx.doi.org/10.3329/jbcps.v30i1.11367 J Bangladesh Coll Phys Surg 2012; 30: 48-52