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Journal Article•DOI•

Infantile Onset Spinocerebellar Ataxia 2 (SCA2): A Clinical Report With Review of Previous Cases

Ankur Singh1, Mohammed Faruq2, Mitali Mukerji2, Manish Kumar Dwivedi2, Sumit Pruthi3, Seema Kapoor1 •
Madigan Army Medical Center1, Institute of Genomics and Integrative Biology2, Monroe Carell Jr. Children's Hospital at Vanderbilt3
01 Jan 2014-Journal of Child Neurology (SAGE Publications)-Vol. 29, Iss: 1, pp 139-144
TL;DR: A patient with infantile-onset spinocerebellar ataxia type 2 who inherited the disease from his father (47 CAG repeats) is described to help treating clinicians to suspect this disorder and to offer timely genetic counseling for a currently potentially untreatable disorder.
Abstract: Autosomal dominant cerebellar ataxia type I is a heterogeneous group of spinocerebellar ataxias with variable neurologic presentations, with age of onset varying from infancy to adulthood Autosomal dominant cerebellar ataxia type I is composed mainly of 3 prevalent spinocerebellar ataxia types with different pathogenic loci, specifically spinocerebellar ataxia 1 (6p24-p23), spinocerebellar ataxia 2 (12q241), and spinocerebellar ataxia 3 (14q321) The shared pathogenic mutational event is the expansion of the CAG repeat that results in polyglutamine extended stretches in the encoded proteins CAG repeat disorders generally show the phenomenon of anticipation, which is more often associated with paternal transmission In this report, we describe a patient with infantile-onset spinocerebellar ataxia type 2 (~320 CAG repeat) who inherited the disease from his father (47 CAG repeats) We have summarized the clinical, neuroimaging, electroencephalographic (EEG), and molecular data of previous cases and attempt to highlight the most consistent findings Our intent is to help treating clinicians to suspect this disorder and to offer timely genetic counseling for a currently potentially untreatable disorder
Citations
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Journal Article•DOI•
What’s new in pontocerebellar hypoplasia? An update on genes and subtypes

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Tessa van Dijk1, Frank Baas1, Peter G. Barth, Bwee Tien Poll-The•
Leiden University Medical Center1
15 Jun 2018-Orphanet Journal of Rare Diseases
TL;DR: The clinical, neuroradiological and genetic characteristics of the different PCH subtypes are described, the differential diagnosis is summarized, and the discovery of new pathways involved in PCH is still symptomatic.
Abstract: Pontocerebellar hypoplasia (PCH) describes a rare, heterogeneous group of neurodegenerative disorders mainly with a prenatal onset. Patients have severe hypoplasia or atrophy of cerebellum and pons, with variable involvement of supratentorial structures, motor and cognitive impairments. Based on distinct clinical features and genetic causes, current classification comprises 11 types of PCH. In this review we describe the clinical, neuroradiological and genetic characteristics of the different PCH subtypes, summarize the differential diagnosis and reflect on potential disease mechanisms in PCH. Seventeen PCH-related genes are now listed in the OMIM database, most of them have a function in RNA processing or translation. It is unknown why defects in these apparently ubiquitous processes result in a brain-specific phenotype. Many new PCH related genes and phenotypes have been described due to the appliance of next generation sequencing techniques. By including such a broad range of phenotypes, including non-degenerative and postnatal onset disorders, the current classification gives rise to confusion. Despite the discovery of new pathways involved in PCH, treatment is still symptomatic. However, correct diagnosis of PCH is important to provide suitable care and counseling regarding prognosis, and offer appropriate (prenatal) genetic testing to families.

95 citations

Journal Article•DOI•
A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: Expanding the phenotype of ITPR1-related spinocerebellar ataxia's.

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Tessa van Dijk1, Peter G. Barth1, Liesbeth Reneman1, Bart Appelhof1, Frank Baas1, Bwee Tien Poll-The1 •
University of Amsterdam1
01 Jan 2017-American Journal of Medical Genetics Part A
TL;DR: A de novo missense mutation in the inositol, 1,4,5 triphosphate receptor type 1 (ITPR1) gene is reported in a patient with severe pontocerebellar hypoplasia, which further expands the spectrum of ITPR1‐related ataxias.
Abstract: We report a de novo missense mutation (c.7649T>A) in the inositol, 1,4,5 triphosphate receptor type 1 (ITPR1) gene in a patient with severe pontocerebellar hypoplasia. The mutation results in an amino acid substitution of a highly conserved isoleucine by asparagine (p. I2550N) in the transmembrane domain. Mutations and deletions of the ITPR1 gene are associated with several types of autosomal dominant spinocerebellar ataxia, varying in age of onset and severity. Patients have signs of cerebellar ataxia and at most, a mild cerebellar atrophy on MRI. In contrast, the patient we report here has profound cerebellar and pontine hypoplasia. Our finding therefore further expands the spectrum of ITPR1-related ataxias. © 2016 Wiley Periodicals, Inc.

27 citations

Cites background from "Infantile Onset Spinocerebellar Ata..."

  • ...Typically, other clinical findings like retinitis pigmentosa or cone-rod dystrophy are present in these conditions [Singh et al., 2014; Donis et al., 2015]....

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Journal Article•DOI•
The Multiple Faces of Spinocerebellar Ataxia type 2.

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Antonella Antenora1, Carlo Rinaldi2, Alessandro Roca1, Chiara Pane1, Maria Lieto1, Maria Lieto2, Francesco Saccà1, Silvio Peluso1, Giuseppe De Michele1, Alessandro Filla1 •
University of Naples Federico II1, University of Oxford2
10 Aug 2017-Annals of clinical and translational neurology
TL;DR: Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families, and occurrence is higher in specific populations such as the Cuban and Southern Italian.
Abstract: Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin-2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available. Although the functions of ataxin-2 have not been completely elucidated, the protein is involved in mRNA processing and control of translation. Recently, it has also been shown that the size of the CAG repeat in normal alleles represents a risk factor for ALS, suggesting that ataxin-2 plays a fundamental role in maintenance of neuronal homeostasis.

24 citations

Journal Article•DOI•
Massive CAG repeat expansion and somatic instability in maternally transmitted infantile spinocerebellar ataxia type 7.

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Heather Trang1, Sabrina Y. Stanley1, Paul S. Thorner1, Hannaneh Faghfoury1, Andreas Schulze1, Cynthia Hawkins1, Christopher E. Pearson1, Grace Yoon1 •
University of Toronto1
01 Feb 2015-JAMA Neurology
TL;DR: The first case to date of maternally transmitted infantile spinocerebellar ataxia type 7 (SCA7), in which a tract of CAG45 expands to lengths as large as (CAG)92-250 is reported, which has implications for diagnosis and counseling among families of patients with SCA7.
Abstract: Importance We report the first case to date of maternally transmitted infantile spinocerebellar ataxia type 7 (SCA7), in which a tract of (CAG)45 expands to lengths as large as (CAG)92-250. Observations A 38-year-old woman with classic SCA7 (and a son, who died at age 3 years) had pronounced cerebellar atrophy and a renal biopsy specimen that showed focal segmental glomerulosclerosis with abnormal podocytes containing cytoplasmic inclusions. Polymerase chain reaction amplification across the SCA7 repeat tract assessed expansion levels in tissues of the affected son. High levels of somatic CAG instability were observed in blood, kidney, and skeletal muscle. This transmitted expansion is considerably larger than previously reported maternal transmission expansions of 5 to 10 gained repeats. Conclusions and Relevance We document the first intertissue CAG instability reported to date in patients with SCA7, similar to SCA7 mouse models. Infantile SCA7, which is often paternally transmitted, can rarely arise by maternal transmission, which has implications for diagnosis and counseling among families of patients with SCA7.

24 citations

Journal Article•DOI•
A clinical report of the massive CAG repeat expansion in spinocerebellar ataxia type 2: Severe onset in a Mexican child and review previous cases.

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José Sánchez-Corona1, Sergio Alberto Ramirez-Garcia, Gema Castañeda-Cisneros1, Susan Andrea Gutierrez-Rubio2, Víctor Volpini, Diana M Sánchez-Garcia3, José Elías García-Ortiz1, Diana García-Cruz2 •
Mexican Social Security Institute1, University of Guadalajara2, Western Institute of Technology and Higher Education3
21 Aug 2020-Genetics and Molecular Biology
TL;DR: A Mexican child affected by SCA2 with an infantile onset, associated with a high number of CAG repeats previously no reported and anticipation phenomenon is described.
Abstract: The spinocerebellar ataxia type 2 is a neurodegenerative disease with autosomal dominant inheritance; clinically characterized by progressive cerebellar ataxia, slow ocular saccades, nystagmus, ophthalmoplegia, dysarthria, dysphagia, cognitive deterioration, mild dementia, peripheral neuropathy. Infantile onset is a rare presentation that only has been reported in four instances in the literature. In the present work a boy aged 5 years 7 months was studied due to horizontal gaze-evoked nystagmus, without saccades, ataxic gait, dysarthria, dysphagia, dysmetria, generalized spasticity mainly pelvic, bilateral Babinsky. The mother aged 27 years-old presented progressive cerebellar ataxia, dysarthria, dysmetria, dysdiadochokinesis, limb ataxia and olivopontocerebellar atrophy. The molecular analysis was made by identifying the expansion repeats in tandem by long PCR to analyze the repeats in the ATXN2 gene. We found an extreme CAG expansion repeats of ~884 repeats in the child. We describe a Mexican child affected by SCA2 with an infantile onset, associated with a high number of CAG repeats previously no reported and anticipation phenomenon.

7 citations

Cites background from "Infantile Onset Spinocerebellar Ata..."

  • ...The most frequent signs in infantile onset are developmental delay, visual impairment usually dependent on retinitis pigmentosa or optic atrophy, hypotonia, seizures with infantile spasms or myoclonic seizures, facial dysmorphism, dystonic features and early death (Tables 1 and 2) (Singh et al., 2014; Antenora et al., 2017)....

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  • ...Brain MRI scans showed extreme cerebellar and brainstem atrophy, but also different degrees of supratentorial atrophy, ventricular enlargement, and white matter signal abnormalities probably attributable to dysmyelination and/or delayed myelination (Singh et al., 2014; Antenora et al., 2017)....

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  • ..., 2017), and meiotic instability a general feature of SCA2 without a familial history (Babovic et al., 1998; Mao et al., 2002; Moretti et al., 2004; Dirik et al., 2007; Abdel and Zaki, 2008; Paciorkowski et al., 2011; Di Fabio et al., 2012; Vinther-Jensen et al., 2013; Singh et al., 2014)....

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  • ...The present case presented gaze-evoked nystagmus without retinitis pigmentosa common in childhood SCA2 due to long CAG repeats in ATXN2 gene (see Table 2), greater than one hundred repeats (Babovic et al., 1998; Mao et al., 2002; Paciorkowski et al., 2011; Di Fabio et al., 2012; Vinther-Jensen et al., 2013; Avelino et al., 2014; Singh et al., 2014)....

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  • ...So, the range in 19 reported cases with SCA2 with age of onset in childhood was 0-48 months, which were carriers of the heterozygous genotype (22/X), in which X corresponds to an allele with abnormal expansion repeats with an average range of 62-841 repeats (Table 1) (Babovic et al., 1998; Mao et al., 2002; Moretti et al., 2004; Dirik et al., 2007; Abdel and Zaki, 2008; Paciorkowski et al., 2011; Di Fabio et al., 2012; Vinther-Jensen et al., 2013; Avelino et al., 2014; Singh et al., 2014)....

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References
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Journal Article•DOI•
Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

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Andrew Elden1, Hyung-Jun Kim2, Michael P. Hart1, Alice Chen-Plotkin1, Brian S. Johnson1, Xiaodong Fang1, Maria Armakola1, Felix Geser1, Robert W. Greene1, Min Min Lu1, Arun Padmanabhan1, Dana Clay-Falcone1, Leo McCluskey1, Lauren Elman1, Denise Juhr3, Peter J. Gruber3, Udo Rüb4, Georg Auburger4, John Q. Trojanowski1, Virginia M.-Y. Lee1, Vivianna M. Van Deerlin1, Nancy M. Bonini2, Aaron D. Gitler1 •
University of Pennsylvania1, Howard Hughes Medical Institute2, Children's Hospital of Philadelphia3, Goethe University Frankfurt4
26 Aug 2010-Nature
TL;DR: It is shown that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models.
Abstract: The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27-33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43-ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.

1,117 citations

"Infantile Onset Spinocerebellar Ata..." refers background in this paper

  • ...The intermediate-repeat CAG length (27-33 CAG/CAA) has been recently documented in association with amyotrophic lateral sclerosis.(4) The expansion length of >100 is associated with the juvenile onset of the spinocerebellar ataxia type 2 and presents with multisystem involvement beyond the aforementioned neurologic symptoms, such as developmental delay, hypotonia, retinal degeneration, infantile spasm, and epilepsy....

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Journal Article•DOI•
Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats

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Georges Imbert1, Frédéric Saudou2, Frédéric Saudou1, Gaël Yvert2, Gaël Yvert1, Didier Devys2, Didier Devys1, Yvon Trottier2, Yvon Trottier1, Jean-Marie Garnier1, Jean-Marie Garnier2, Chantal Weber2, Chantal Weber1, Jean-Louis Mandel1, Jean-Louis Mandel2, Géraldine Cancel1, Géraldine Cancel2, Nacer Abbas1, Nacer Abbas2, Alexandra Durr1, Alexandra Durr2, Olivier Didierjean1, Olivier Didierjean2, Giovanni Stevanin2, Giovanni Stevanin1, Yves Agid1, Yves Agid2, Alexis Brice1, Alexis Brice2 •
French Institute of Health and Medical Research1, Harvard University2
01 Nov 1996-Nature Genetics
TL;DR: The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglUTamine expansion diseases.
Abstract: Two forms of the neurodegenerative disorder spinocerebellar ataxia are known to be caused by the expansion of a CAG (polyglutamine) trinucleotide repeat. By screening cDNA expression libraries, using an antibody specific for polyglutamine repeats, we identified six novel genes containing CAG stretches. One of them is mutated in patients with spinocerebellar ataxia linked to chromosome 12q (SCA2). This gene shows ubiquitous expression and encodes a protein of unknown function. Normal SCA2 alleles (17 to 29 CAG repeats) contain one to three CAAs in the repeat. Mutated alleles (37 to 50 repeats) appear particularly unstable, upon both paternal and maternal transmissions. The sequence of three of them revealed pure CAG stretches. The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglutamine expansion diseases.

859 citations

"Infantile Onset Spinocerebellar Ata..." refers background in this paper

  • ...1).(1) Normal CAG alleles range from 15 to 32 repeats, with 22 repeats being the most common in healthy individuals....

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  • ...Minimal CAG repeat length in affected infants was 62, whereas all affected parents had 140 Journal of Child Neurology 29(1)...

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  • ...com Journal of Child Neurology 2014, Vol 29(1) 139-144 a The Author(s) 2013 Reprints and permission: sagepub....

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Journal Article•DOI•
A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families)

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N. H. Wadia, R. K. Swami
01 Jan 1971-Brain

166 citations

"Infantile Onset Spinocerebellar Ata..." refers background in this paper

  • ...There have been reports of numerous families affected with spinocerebellar ataxia type 2 since the first report in the literature.(14) Infantile onset of spinocerebellar ataxia type 2 has been rarely reported in the literature....

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Journal Article•DOI•
Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism

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P. Charles, Agnès Camuzat, Nawal Benammar, François Sellal, Alain Destée, A. M. Bonnet, Suzanne Lesage, I. Le Ber, Giovanni Stevanin, Alexandra Durr, Alexis Brice 
20 Nov 2007-Neurology
TL;DR: Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins.
Abstract: Background: Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2 . Methods: We screened 164 families with ADP for expansions in the SCA2, 3 , and 17 genes and for the G2019S mutation in LRRK2 . The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2 , LRRK2 , and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size. Results: Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2 . In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs. Conclusion: These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.

126 citations

Journal Article•DOI•
Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion.

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Dusica Babovic-Vuksanovic1, Karen Snow1, Marc C. Patterson1, Virginia V. Michels1•
Mayo Clinic1
12 Oct 1998-American Journal of Medical Genetics
TL;DR: Testing for dominant ataxias should be included in the evaluation of infants with nonspecific progressive neurologic symptoms and retinitis pigmentosa, especially in cases with a positive family history for spinocerebellar ataxia.
Abstract: Autosomal dominant cerebellar ataxias are a heterogeneous group of neurodegenerative disorders that generally present in adulthood. Spinocerebellar ataxia type 2 typically presents with progressive cerebellar symptoms, slow ocular saccades, and peripheral neuropathy. The onset of symptoms is usually between 20 and 40 years. We describe an infant who presented with neonatal hypotonia, developmental delay, and dysphagia. Ocular findings of retinitis pigmentosa were noted at 10 months. Her father had mild spinocerebellar ataxia first noted at age 22 years. Molecular studies of the SCA2 gene showed a CAG expansion of 43 repeats in the father and an extreme CAG repeat expansion of more than 200 in the baby. Our report expands the known phenotype and genotype of SCA2. Testing for dominant ataxias should be included in the evaluation of infants with nonspecific progressive neurologic symptoms and retinitis pigmentosa, especially in cases with a positive family history for spinocerebellar ataxia.

99 citations

"Infantile Onset Spinocerebellar Ata..." refers background in this paper

  • ...The expansion length of >100 is associated with the juvenile onset of the spinocerebellar ataxia type 2 and presents with multisystem involvement beyond the aforementioned neurologic symptoms, such as developmental delay, hypotonia, retinal degeneration, infantile spasm, and epilepsy.(5-12) In India, spinocerebellar ataxia type 2 represents the commonest subtype described,(13) and it is expected that in large, multigenerational families, phenotypic and genetic variability will be encountered....

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  • ...Infantile onset of spinocerebellar ataxia type 2 has been rarely reported in the literature.(5-12) Clinical presentation in the proband was of a neurodegenerative phenotype with onset in infancy....

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Related Papers (5)
Childhood‐onset ataxia: Testing for large CAG‐repeats in SCA2 and SCA7

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15 Jul 2002-American Journal of Medical Genetics
Rong Mao, Arthur S. Aylsworth, Nicholas T. Potter, William G. Wilson, Galen Breningstall, Myra J. Wick, Dusica Babovic-Vuksanovic, Martha Nance, Marc C. Patterson, Christopher M. Gomez, Karen Snow 
Spinocerebellar ataxia type 6.

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01 Jun 2005
K K Lau, K M Au, M L Chen, H L Li, B Sheng, A Y W Chan 
A comprehensive clinical and genetic study of a large Mexican population with spinocerebellar ataxia type 7

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01 Jan 2015-Neurogenetics
Luis Velázquez-Pérez, César M Cerecedo-Zapata, Oscar Hernández-Hernández, Emilio Martínez-Cruz, Y. S. Tapia-Guerrero, Rigoberto González-Piña, J. Salas-Vargas, Roberto Rodríguez-Labrada, R. Gurrola-Betancourth, Norberto Leyva-García, Bulmaro Cisneros, Jonathan J. Magaña 
A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21‐q23

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01 Jun 2003-Brain
Ming Yi Chung, Yi-Chun Lu, Nai Chia Cheng, Bing-Wen Soong 
'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization.

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01 May 2012-Brain
María García-Murias, Beatriz Quintáns, Manuel Arias, Ana I. Seixas, Pilar Cacheiro, Rosa Tarrío, Rosa Tarrío, Julio Pardo, María J. Millán, Susana Arias-Rivas, Patricia Blanco-Arias, Patricia Blanco-Arias, Dapena D, Ramón Moreira, Francisco Rodríguez-Trelles, Jorge Sequeiros, Jorge Sequeiros, Angel Carracedo, Angel Carracedo, Isabel Silveira, María Jesús Sobrido, María Jesús Sobrido