Early-onset phenotype in a patient with an intermediate allele and a large SCA1 expansion: a case report.
Case report
Cerebellar ataxia
DNA repeat expansion
Phenotype
Polyglutamine disease
SCA1
Spinocerebellar degenerations
Journal
BMC neurology
ISSN: 1471-2377
Titre abrégé: BMC Neurol
Pays: England
ID NLM: 100968555
Informations de publication
Date de publication:
17 Sep 2024
17 Sep 2024
Historique:
received:
06
06
2024
accepted:
03
09
2024
medline:
18
9
2024
pubmed:
18
9
2024
entrez:
17
9
2024
Statut:
epublish
Résumé
Spinocerebellar ataxia type 1, is a rare neurodegenerative disorder with autosomal dominant inheritance belonging to the polyglutamine diseases. The diagnosis of this disease requires genetic testing that may also include the search for CAT interruption of the CAG repeat tract. One 23-years-old patient suffers from a severe ataxia, with early-onset and rapid progression of the disease. His father might have been affected, but no molecular confirmation has been performed. The genetic results were negative for the Friedreich's ataxia, spinocerebellar ataxia type 2, 3, 6, 7 and 17. The numbers of CAG repeats in the ATXN1 gene was assessed by fluorescent PCR, tripled-primed PCR and enzymatic digestion for the search of sequence interruption in the CAG repeats. The patient carried one pathogenic allele of 61 CAG and one intermediate allele of 37 CAG in the ATXN1 gene. Both alleles were uninterrupted. We report a rare case of spinocerebellar ataxia type 1 with an intermediate allele and a large SCA1 expansion. The determination of the absence of CAT interruption brought crucial information concerning this molecular diagnosis, the prediction of the disease and had practical consequences for genetic counseling.
Sections du résumé
BACKGROUND
BACKGROUND
Spinocerebellar ataxia type 1, is a rare neurodegenerative disorder with autosomal dominant inheritance belonging to the polyglutamine diseases. The diagnosis of this disease requires genetic testing that may also include the search for CAT interruption of the CAG repeat tract.
CASE PRESENTATION
METHODS
One 23-years-old patient suffers from a severe ataxia, with early-onset and rapid progression of the disease. His father might have been affected, but no molecular confirmation has been performed. The genetic results were negative for the Friedreich's ataxia, spinocerebellar ataxia type 2, 3, 6, 7 and 17. The numbers of CAG repeats in the ATXN1 gene was assessed by fluorescent PCR, tripled-primed PCR and enzymatic digestion for the search of sequence interruption in the CAG repeats. The patient carried one pathogenic allele of 61 CAG and one intermediate allele of 37 CAG in the ATXN1 gene. Both alleles were uninterrupted.
CONCLUSIONS
CONCLUSIONS
We report a rare case of spinocerebellar ataxia type 1 with an intermediate allele and a large SCA1 expansion. The determination of the absence of CAT interruption brought crucial information concerning this molecular diagnosis, the prediction of the disease and had practical consequences for genetic counseling.
Identifiants
pubmed: 39289638
doi: 10.1186/s12883-024-03846-2
pii: 10.1186/s12883-024-03846-2
doi:
Substances chimiques
Ataxin-1
0
ATXN1 protein, human
0
Nerve Tissue Proteins
0
Ataxins
0
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
348Informations de copyright
© 2024. The Author(s).
Références
Opal P, Ashizawa T. Spinocerebellar Ataxia type 1. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, et al. editors. GeneReviews
Chung M, Ranum LPW, Duvick LA, Servadio A, Zoghbi HY, Orr HT. Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I. Nat Genet. 1993;5:254–8.
pubmed: 8275090
doi: 10.1038/ng1193-254
Capacci E, Bagnoli S, Giacomucci G, Rapillo CM, Govoni A, Bessi V, et al. The frequency of intermediate alleles in patients with cerebellar phenotypes. Cerebellum. 2023;23:1135–45.
pubmed: 37906407
pmcid: 11102406
doi: 10.1007/s12311-023-01620-7
Schmitz-Hübsch T, Du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66:1717–20.
pubmed: 16769946
doi: 10.1212/01.wnl.0000219042.60538.92
Carvalho DR, La Rocque-Ferreira A, Rizzo IM, Imamura EU, Speck-Martins CE. Homozygosity enhances severity in Spinocerebellar Ataxia Type 3. Pediatr Neurol. 2008;38:296–9.
pubmed: 18358414
doi: 10.1016/j.pediatrneurol.2007.12.006
Takahashi H, Ishikawa K, Tsutsumi T, Fujigasaki H, Kawata A, Okiyama R, et al. A clinical and genetic study in a large cohort of patients with spinocerebellar ataxia type 6. J Hum Genet. 2004;49:256–64.
pubmed: 15362569
doi: 10.1007/s10038-004-0142-7
Zühlke CH, Spranger M, Spranger S, Voigt R, Lanz M, Gehlken U, et al. SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6. Eur J Hum Genet. 2003;11:629–32.
pubmed: 12891385
doi: 10.1038/sj.ejhg.5201018
Sato K, Kashihara K, Okada S, Ikeuchi T, Tsuji S, Shomori T, et al. Does homozygosity advance the onset of dentatorubral-pallidoluysian atrophy? Neurology. 1995;45:1934–6.
pubmed: 7477999
doi: 10.1212/WNL.45.10.1934
Lee J-M, Ramos EM, Lee J-H, Gillis T, Mysore JS, Hayden MR, et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology. 2012;78:690–5.
pubmed: 22323755
pmcid: 3306163
doi: 10.1212/WNL.0b013e318249f683
Tojima M, Murakami G, Hikawa R, Yamakado H, Yamashita H, Takahashi R, et al. Homozygous 31 trinucleotide repeats in the SCA2 allele are pathogenic for cerebellar ataxia. Neurol Genet. 2018;4:e283.
pubmed: 30533529
pmcid: 6244019
doi: 10.1212/NXG.0000000000000283
Mariotti C, Gellera C, Grisoli M, Mineri R, Castucci A, Di Donato S. Pathogenic effect of an intermediate-size SCA-6 allele (CAG)
pubmed: 11673601
doi: 10.1212/WNL.57.8.1502
Goldfarb LG, Vasconcelos O, Platonov FA, Lunkes A, Kipnis V, Kononova S, et al. Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1. Ann Neurol. 1996;39:500–6.
pubmed: 8619528
doi: 10.1002/ana.410390412
Sharma P, Sonakar AK, Tyagi N, Suroliya V, Kumar M, Kutum R, et al. Genetics of Ataxias in Indian Population: a collative insight from a Common Genetic Screening Tool. Adv Genet. 2022;3:2100078.
pubmed: 36618024
pmcid: 9744545
doi: 10.1002/ggn2.202100078
Schöls L, Amoiridis G, Büttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Ann Neurol. 1997;42:924–32.
pubmed: 9403486
doi: 10.1002/ana.410420615
Menon RP, Nethisinghe S, Faggiano S, Vannocci T, Rezaei H, Pemble S, et al. The role of interruptions in polyQ in the Pathology of SCA1. PLoS Genet. 2013;9:e1003648.
pubmed: 23935513
pmcid: 3723530
doi: 10.1371/journal.pgen.1003648
Jacobi H, Du Montcel ST, Bauer P, Giunti P, Cook A, Labrum R, et al. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol. 2015;14:1101–8.
pubmed: 26377379
doi: 10.1016/S1474-4422(15)00202-1
Zoghbi HY, Pollack MS, Lyons LA, Ferrell RE, Daiger SP, Beaudet AL. Spinocerebellar ataxia: variable age of onset and linkage to human leukocyte antigen in a large kindred. Ann Neurol. 1988;23:580–4.
pubmed: 3165612
doi: 10.1002/ana.410230609
Tezenas Du Montcel S, Durr A, Rakowicz M, Nanetti L, Charles P, Sulek A, et al. Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet. 2014;51:479–86.
pubmed: 24780882
doi: 10.1136/jmedgenet-2013-102200
Kacher R, Lejeune F-X, David I, Boluda S, Coarelli G, Leclere-Turbant S, et al. CAG repeat mosaicism is gene specific in spinocerebellar ataxias. Am J Hum Genet. 2024;111:913–26.
pubmed: 38626762
pmcid: 11080609
doi: 10.1016/j.ajhg.2024.03.015