Skip to main content
SpringerLink
Log in

X-Linked Ataxias

  • Reference work entry
  • First Online:
Handbook of the Cerebellum and Cerebellar Disorders

  • 187 Accesses

Abstract

X-linked ataxias are phenotypically and genotypically heterogeneous. Clinically, ataxia may be the sole, the dominant, or a nondominant phenotypic feature of X-linked ataxias. Ataxia is most commonly of the cerebellar type. Other manifestations in addition to ataxia may be neurological or non-neurological. X-linked ataxias, in which ataxia dominates the phenotype, include fragile X-tremor ataxia syndrome, X-linked sideroblastic anemia with ataxia, X-linked ataxia due to GJB1 mutations, X-linked ataxia due to PAMC3 mutations, X-linked adrenoleukodystrophy, and X-linked pyruvate-dehydrogenase deficiency. There are also a number of X-linked disorders with ataxia as a nondominant, collateral feature. The number of X-linked ataxias is steadily increasing and it is quite likely that their number will further increase. Therapy of X-linked ataxias is symptomatic. Genetic counseling not only depends on the X-linked trait of inheritance but also on the presence or absence of germline mosaicism or if the mutation concerns a trinucleotide expansion. Early recognition of X-linked ataxias is warranted to prevent long-term misdiagnosis and avoid application of ineffective treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Bansagi B, Lewis-Smith D, Pal E, Duff J, Griffin H, Pyle A, Müller JS, Rudas G, Aranyi Z, Lochmüller H, Chinnery PF, Horvath R (2016) Phenotypic convergence of Menkes and Wilson disease. Neurol Genet 2:e119

    Article  Google Scholar 

  • Barnerias C, Saudubray JM, Touati G, De Lonlay P, Dulac O, Ponsot G, Marsac C, Brivet M, Desguerre I (2010) Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev Med Child Neurol 52:e1–e9

    Article  Google Scholar 

  • Bekri S, D’Hooghe M, Vermeersch P (1993–2017) X-linked sideroblastic anemia and ataxia. 2006 Mar 1 [updated 2014 Apr 3]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N (eds) GeneReviews® [Internet]. University of Washington, Seattle. Available from http://www.ncbi.nlm.nih.gov/books/NBK1321/

  • Bertini E, des Portes V, Zanni G, Santorelli F, Dionisi-Vici C, Vicari S, Fariello G, Chelly J (2000) X-linked congenital ataxia: a clinical and genetic study. Am J Med Genet 92:53–56

    Article  CAS  Google Scholar 

  • Bourque DK, Hartley T, Nikkel SM, Pohl D, Tétreault M, Kernohan KD, Care4Rare Canada Consortium, Dyment DA (2017) A de novo mutation in RPL10 causes a rare X-linked ribosomopathy characterized by syndromic intellectual disability and epilepsy: a new case and review of the literature. Eur J Med Genet:pii: S1769-7212(17)30696-1. https://doi.org/10.1016/j.ejmg.2017.10.011

  • Caramins M, Colebatch JG, Bainbridge MN, Scherer SS, Abrams CK, Hackett EL, Freidin MM, Jhangiani SN, Wang M, Wu Y, Muzny DM, Lindeman R, Gibbs RA (2013a) Exome sequencing identification of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1). Hum Mol Genet 22:4329–4338

    Article  CAS  Google Scholar 

  • Caramins M, Colebatch JG, Bainbridge MN, Scherer SS, Abrams CK, Hackett EL, Freidin MM, Jhangiani SN, Wang M, Wu Y, Muzny DM, Lindeman R, Gibbs RA (2013b) Exome sequencing identification of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1). Hum Mol Genet 22:4329–4338

    Article  CAS  Google Scholar 

  • D’Hooghe M, Selleslag D, Mortier G, Van Coster R, Vermeersch P, Billiet J, Bekri S (2012) X-linked sideroblastic anemia and ataxia: a new family with identification of a fourth ABCB7 gene mutation. Eur J Paediatr Neurol 16:730–735

    Article  Google Scholar 

  • Feyma T, Ramsey K, C4RCD Research Group, Huentelman MJ, Craig DW, Padilla-Lopez S, Narayanan V, Kruer MC (2016) Dystonia in ATP2B3-associated X-linked spinocerebellar ataxia. Mov Disord 31:1752–1753

    Article  CAS  Google Scholar 

  • Hagerman RJ, Hagerman P (2016) Fragile X-associated tremor/ataxia syndrome – features, mechanisms and management. Nat Rev Neurol 12:403–412

    Article  CAS  Google Scholar 

  • Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, Grigsby J, Gage B, Hagerman PJ (2001) Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57:127–130

    Article  CAS  Google Scholar 

  • Heimer G, Eyal E, Zhu X, Ruzzo EK, Marek-Yagel D, Sagiv D, Anikster Y, Reznik-Wolf H, Pras E, Oz Levi D, Lancet D, Ben-Zeev B, Nissenkorn A (2017) Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin. Eur J Paediatr Neurol:pii: S1090-3798(17)31647-1. https://doi.org/10.1016/j.ejpn.2017.09.004

  • Hobson GM, Kamholz J (1993–2017) PLP1-related disorders. 1999 Jun 15 [updated 2013 Feb 28]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N (eds) GeneReviews® [Internet]. University of Washington, Seattle. Available from http://www.ncbi.nlm.nih.gov/books/NBK1182/

  • Isidor B, Pichon O, Baron S, David A, Le Caignec C (2010) Deletion of the CUL4B gene in a boy with mental retardation, minor facial anomalies, short stature, hypogonadism, and ataxia. Am J Med Genet A 152A:175–180

    Article  Google Scholar 

  • Kang JW, Lee SM, Koo KY, Lee YM, Nam HS, Quan Z, Kang HC (2014a) Isolated cerebellar variant of adrenoleukodystrophy with a de novo adenosine triphosphate-binding cassette D1 (ABCD1) gene mutation. Yonsei Med J:1157–1160

    Google Scholar 

  • Kang JW, Lee SM, Koo KY, Lee YM, Nam HS, Quan Z, Kang HC (2014b) Isolated cerebellar variant of adrenoleukodystrophy with a de novo adenosine triphosphate-binding cassette D1 (ABCD1) gene mutation. Yonsei Med J 55:1157–1160

    Article  Google Scholar 

  • Kesserwani H (2020) Chronic progressive spastic paraparesis: think of peroxisomal disorders – a case report of X-linked adult onset adrenoleukodystrophy with an update on the latest treatment strategies. Cureus 12:e9626. https://doi.org/10.7759/cureus.9626

    Article  PubMed  PubMed Central  Google Scholar 

  • Khalifa M, Naffaa L (2015) Exome sequencing reveals a novel WDR45 frameshift mutation and inherited POLR3A heterozygous variants in a female with a complex phenotype and mixed brain MRI findings. Eur J Med Genet 58:381–386

    Article  Google Scholar 

  • Kong HE, Zhao J, Xu S, Jin P, Jin Y (2017) Fragile X-associated tremor/ataxia syndrome: from molecular pathogenesis to development of therapeutics. Front Cell Neurosci 11:128. https://doi.org/10.3389/fncel.2017.00128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuehlewein L, Schöls L, Llavona P, Grimm A, Biskup S, Zrenner E, Kohl S (2019) Phenotypic spectrum of autosomal recessive retinitis pigmentosa without posterior column ataxia caused by mutations in the FLVCR1 gene. Graefes Arch Clin Exp Ophthalmol 257:629–638. https://doi.org/10.1007/s00417-018-04233-7

    Article  CAS  PubMed  Google Scholar 

  • Leonard H, Cobb S, Downs J (2017) Clinical and biological progress over 50 years in Rett syndrome. Nat Rev Neurol 13:37–51

    Article  CAS  Google Scholar 

  • Liu X, Zhou K, Yu D, Cai X, Hua Y, Zhou H, Wang C (2017) A delayed diagnosis of X-linked hyper IgM syndrome complicated with toxoplasmic encephalitis in a child: a case report and literature review. Medicine (Baltimore) 96:e8989. https://doi.org/10.1097/MD.0000000000008989

    Article  Google Scholar 

  • Margari L, Lamanna AL, Buttiglione M, Craig F, Petruzzelli MG, Terenzio V (2013) Long-term follow-up of neurological manifestations in a boy with incontinentia pigmenti. Eur J Pediatr 172:1259–1262

    Article  Google Scholar 

  • Maruyama K, Ogaya S, Kurahashi N, Umemura A, Yamada K, Hashiguchi A, Takashima H, Torres RJ, Aso K (2016) Arts syndrome with a novel missense mutation in the PRPS1 gene: a case report. Brain Dev 38:954–958

    Article  Google Scholar 

  • Masurel-Paulet A, Piton A, Chancenotte S, Redin C, Thauvin-Robinet C, Henrenger Y, Minot D, Creppy A, Ruffier-Bourdet M, Thevenon J, Kuentz P, Lehalle D, Curie A, Blanchard G, Ghosn E, Bonnet M, Archimbaud-Devilliers M, Huet F, Perret O, Philip N, Mandel JL, Faivre L (2016) A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome. Am J Med Genet A 170:2103–2110

    Article  CAS  Google Scholar 

  • Owczarek-Lipska M, Mulahasanovic L, Obermaier CD, Hörtnagel K, Neubauer BA, Korenke GC, Biskup S, Neidhardt J (2019) Novel mutations in the GJC2 gene associated with Pelizaeus-Merzbacher-like disease. Mol Biol Rep 46:4507–4516. https://doi.org/10.1007/s11033-019-04906-4

    Article  CAS  PubMed  Google Scholar 

  • Parisi M, Glass I (1993–2017) Joubert syndrome. 2003 Jul 9 [updated 2017 Jun 29]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N (eds) GeneReviews® [Internet]. University of Washington, Seattle. Available from http://www.ncbi.nlm.nih.gov/books/NBK132

  • Pehlke JR, Venkataramani V, Emmert S, Mohr A, Zoll B, Nau R (2013) X-linked recessive ichthyosis (XRI), cerebellar ataxia and neuropsychiatric symptoms. Fortschr Neurol Psychiatr 81:40–43

    Article  CAS  Google Scholar 

  • Rattay TW, Rautenberg M, Söhn AS, Hengel H, Traschütz A, Röben B, Hayer SN, Schüle R, Wiethoff S, Zeltner L, Haack TB, Cegan A, Schöls L, Schleicher E, Peter A (2020) Defining diagnostic cutoffs in neurological patients for serum very long chain fatty acids (VLCFA) in genetically confirmed X-Adrenoleukodystrophy. Sci Rep 10:15093. https://doi.org/10.1038/s41598-020-71248-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sandford E, Burmeister M (2014) Genes and genetic testing in hereditary ataxias. Genes (Basel) 5:586–603

    Article  Google Scholar 

  • Siskind C, Feely SM, Bernes S, Shy ME, Garbern JY (2009) Persistent CNS dysfunction in a boy with CMT1X. J Neurol Sci 279:109–113

    Article  Google Scholar 

  • Tonduti D, Vanderver A, Berardinelli A, Schmidt JL, Collins CD, Novara F, Genni AD, Mita A, Triulzi F, Brunstrom-Hernandez JE, Zuffardi O, Balottin U, Orcesi S (2013) MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features. J Child Neurol 28:795–800

    Article  Google Scholar 

  • Vicario M, Calì T, Cieri D, Vallese F, Bortolotto R, Lopreiato R, Zonta F, Nardella M, Micalizzi A, Lefeber DJ, Valente EM, Bertini E, Zanotti G, Zanni G, Brini M, Carafoli E (2017) A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations: biochemical characterization of the pump defect. Biochim Biophys Acta 1863:3303–3312

    Article  CAS  Google Scholar 

  • Vicario M, Zanni G, Vallese F, Santorelli F, Grinzato A, Cieri D, Berto P, Frizzarin M, Lopreiato R, Zonta F, Ferro S, Sandre M, Marin O, Ruzzene M, Bertini E, Zanotti G, Brini M, Calì T, Carafoli E (2018) A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia. Neurobiol Dis 115:157–166. https://doi.org/10.1016/j.nbd.2018.04.009

    Article  CAS  PubMed  Google Scholar 

  • Zanni G, Bertini ES (2011) X-linked disorders with cerebellar dysgenesis. Orphanet J Rare Dis 6:24. https://doi.org/10.1186/1750-1172-6-24

    Article  PubMed  PubMed Central  Google Scholar 

  • Zanni G, Calì T, Kalscheuer VM, Ottolini D, Barresi S, Lebrun N, Montecchi-Palazzi L, Hu H, Chelly J, Bertini E, Brini M, Carafoli E (2012) Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. Proc Natl Acad Sci U S A 109:14514–14519

    Article  CAS  Google Scholar 

  • Zhao C, Liu Y, Wang Y, Li H, Zhang B, Yue Y, Zhang J (2020) A Chinese case of fragile X-associated tremor/ataxia syndrome (FXTAS) with orthostatic tremor: case report and literature review on tremor in FXTAS. BMC Neurol 20(1):145. https://doi.org/10.1186/s12883-020-01726-z

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik Landstrasse, Messerli Institute, Vienna, Austria

    Josef Finsterer

Authors
  1. Josef Finsterer
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. CHU-Charleroi, University of Mons, Charleroi, Belgium

    Mario U. Manto

  2. Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA

    Donna L. Gruol

  3. Ataxia Center, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Jeremy D. Schmahmann

  4. Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan

    Noriyuki Koibuchi

  5. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

    Roy V. Sillitoe

Section Editor information

  1. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jeremy D. Schmahmann

  2. CHU-Charleroi, University of Mons, UMons, Charleroi, Belgium

    Mario U. Manto

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Finsterer, J. (2022). X-Linked Ataxias. In: Manto, M.U., Gruol, D.L., Schmahmann, J.D., Koibuchi, N., Sillitoe, R.V. (eds) Handbook of the Cerebellum and Cerebellar Disorders. Springer, Cham. https://doi.org/10.1007/978-3-030-23810-0_103

Download citation

Publish with us

Policies and ethics

Search

Navigation