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Spinocerebellar ataxia 46(SCA46)

MedGen UID:
1624251
•Concept ID:
C4540404
•
Disease or Syndrome
Synonym: SPINOCEREBELLAR ATAXIA, 46, AUTOSOMAL DOMINANT, WITH SENSORY AXONAL NEUROPATHY
SNOMED CT: SCA46 - spinocerebellar ataxia type 46 (1279839002); Spinocerebellar ataxia type 46 (1279839002)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
•Concept ID:
C0443147
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (Orphanet)
 
Gene (location): PLD3 (19q13.2)
 
Monarch Initiative: MONDO:0033481
OMIM®: 617770
Orphanet: ORPHA589522

Definition

A rare autosomal dominant cerebellar ataxia with characteristics of slowly progressive late-onset cerebellar ataxia variably combined with sensory axonal neuropathy. Patients may present gait and limb ataxia, dysarthria, abnormal oculomotor function and distal sensory impairment. Cerebellar atrophy is typically mild or absent. [from SNOMEDCT_US]

Clinical features

From HPO
Dysarthria
MedGen UID:
8510
•Concept ID:
C0013362
•
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
See: Feature record | Search on this feature
Dysmetria
MedGen UID:
68583
•Concept ID:
C0234162
•
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
See: Feature record | Search on this feature
Positive Romberg sign
MedGen UID:
66017
•Concept ID:
C0240914
•
Finding
The patient stands with the feet placed together and balance and is asked to close his or her eyes. A loss of balance upon eye closure is a positive Romberg sign and is interpreted as indicating a deficit in proprioception.
See: Feature record | Search on this feature
Cerebellar atrophy
MedGen UID:
196624
•Concept ID:
C0740279
•
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
See: Feature record | Search on this feature
Limb ataxia
MedGen UID:
196692
•Concept ID:
C0750937
•
Finding
A kind of ataxia that affects movements of the extremities.
See: Feature record | Search on this feature
Gait ataxia
MedGen UID:
155642
•Concept ID:
C0751837
•
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.
See: Feature record | Search on this feature
Sensory axonal neuropathy
MedGen UID:
334116
•Concept ID:
C1842587
•
Finding
An axonal neuropathy of peripheral sensory nerves.
See: Feature record | Search on this feature
Nystagmus
MedGen UID:
45166
•Concept ID:
C0028738
•
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
See: Feature record | Search on this feature
Slow saccadic eye movements
MedGen UID:
232942
•Concept ID:
C1321329
•
Finding
An abnormally slow velocity of the saccadic eye movements.
See: Feature record | Search on this feature
Jerky ocular pursuit movements
MedGen UID:
342908
•Concept ID:
C1853558
•
Finding
See: Feature record | Search on this feature
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVSpinocerebellar ataxia 46

Professional guidelines

PubMed

Genotype-Phenotype Correlations for ATX-TBP (SCA17): MDSGene Systematic Review.
Rossi M, Hamed M, Rodríguez-Antigüedad J, Cornejo-Olivas M, Breza M, Lohmann K, Klein C, Rajalingam R, Marras C, van de Warrenburg BP
Mov Disord 2023 Mar;38(3):368-377. Epub 2022 Nov 14 doi: 10.1002/mds.29278. PMID: 36374860
ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia.
Bhatt JM, Bush A, van Gerven M, Nissenkorn A, Renke M, Yarlett L, Taylor M, Tonia T, Warris A, Zielen S, Zinna S, Merkus PJ; European Respiratory Society
Eur Respir Rev 2015 Dec;24(138):565-81. doi: 10.1183/16000617.0066-2015. PMID: 26621971Free PMC Article
Machado-Joseph disease and SCA3: the genotype meets the phenotypes.
Junck L, Fink JF
Neurology 1996 Jan;46(1):4-8. doi: 10.1212/wnl.46.1.4. PMID: 8559417

Recent clinical studies

Etiology

Complex Ataxia-Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia.
Nanetti L, Magri S, Fichera M, Castaldo A, Nigri A, Pinardi C, Mongelli A, Sarro L, Pareyson D, Grisoli M, Gellera C, Di Bella D, Mariotti C, Taroni F
Mov Disord 2023 Apr;38(4):665-675. Epub 2023 Feb 17 doi: 10.1002/mds.29352. PMID: 36799493
Genotype-Phenotype Correlations for ATX-TBP (SCA17): MDSGene Systematic Review.
Rossi M, Hamed M, Rodríguez-Antigüedad J, Cornejo-Olivas M, Breza M, Lohmann K, Klein C, Rajalingam R, Marras C, van de Warrenburg BP
Mov Disord 2023 Mar;38(3):368-377. Epub 2022 Nov 14 doi: 10.1002/mds.29278. PMID: 36374860
Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1.
Platonov FA, Tyryshkin K, Tikhonov DG, Neustroyeva TS, Sivtseva TM, Yakovleva NV, Nikolaev VP, Sidorova OG, Kononova SK, Goldfarb LG, Renwick NM
Neurogenetics 2016 Jul;17(3):179-85. Epub 2016 Apr 22 doi: 10.1007/s10048-016-0481-5. PMID: 27106293Free PMC Article
The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies.
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320
Characterization of ATM gene mutations in 66 ataxia telangiectasia families.
Sandoval N, Platzer M, Rosenthal A, Dörk T, Bendix R, Skawran B, Stuhrmann M, Wegner RD, Sperling K, Banin S, Shiloh Y, Baumer A, Bernthaler U, Sennefelder H, Brohm M, Weber BH, Schindler D
Hum Mol Genet 1999 Jan;8(1):69-79. doi: 10.1093/hmg/8.1.69. PMID: 9887333

Diagnosis

Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design.
Tolonen JP, Parolin Schnekenberg R, McGowan S, Sims D, McEntagart M, Elmslie F, Shears D, Stewart H, Tofaris GK, Dabir T, Morrison PJ, Johnson D, Hadjivassiliou M, Ellard S, Shaw-Smith C, Znaczko A, Dixit A, Suri M, Sarkar A, Harrison RE, Jones G, Houlden H, Ceravolo G, Jarvis J, Williams J, Shanks ME, Clouston P, Rankin J, Blumkin L, Lerman-Sagie T, Ponger P, Raskin S, Granath K, Uusimaa J, Conti H, McCann E, Joss S, Blakes AJM, Metcalfe K, Kingston H, Bertoli M, Kneen R, Lynch SA, Martínez Albaladejo I, Moore AP, Jones WD; Genomics England Research Consortium, Becker EBE, Németh AH
Mov Disord 2024 Jan;39(1):141-151. Epub 2023 Nov 14 doi: 10.1002/mds.29651. PMID: 37964426Free PMC Article
Complex Ataxia-Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia.
Nanetti L, Magri S, Fichera M, Castaldo A, Nigri A, Pinardi C, Mongelli A, Sarro L, Pareyson D, Grisoli M, Gellera C, Di Bella D, Mariotti C, Taroni F
Mov Disord 2023 Apr;38(4):665-675. Epub 2023 Feb 17 doi: 10.1002/mds.29352. PMID: 36799493
Genotype-Phenotype Correlations for ATX-TBP (SCA17): MDSGene Systematic Review.
Rossi M, Hamed M, Rodríguez-Antigüedad J, Cornejo-Olivas M, Breza M, Lohmann K, Klein C, Rajalingam R, Marras C, van de Warrenburg BP
Mov Disord 2023 Mar;38(3):368-377. Epub 2022 Nov 14 doi: 10.1002/mds.29278. PMID: 36374860
The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies.
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320
Cancer predisposition of ataxia-telangiectasia heterozygotes.
Swift M, Chase CL, Morrell D
Cancer Genet Cytogenet 1990 May;46(1):21-7. doi: 10.1016/0165-4608(90)90004-t. PMID: 2184933

Therapy

Longitudinal Changes of Clinical, Imaging, and Fluid Biomarkers in Preataxic and Early Ataxic Spinocerebellar Ataxia Type 2 and 7 Carriers.
Coarelli G, Dubec-Fleury C, Petit E, Sayah S, Fischer C, Nassisi M, Gatignol P, Dorgham K, Daghsen L, Daye P, Cunha P, Kacher R, Hilab R, Hurmic H, Lamazière A, Lamy JC, Welter ML, Chupin M, Mangin JF, Lane R, Gaymard B, Pouget P, Audo I, Brice A, Tezenas du Montcel S, Durr A
Neurology 2024 Sep 10;103(5):e209749. Epub 2024 Aug 12 doi: 10.1212/WNL.0000000000209749. PMID: 39133883Free PMC Article
Efficacy and Safety of Repetitive Transcranial Magnetic Stimulation in Spinocerebellar Ataxia Type 3: a Systematic Review and Meta‑analysis of Randomized Controlled Trials.
Qiu M, Wang R, Shen Y, Hu Z, Zhang Y
Cerebellum 2024 Aug;23(4):1604-1613. Epub 2023 Nov 17 doi: 10.1007/s12311-023-01628-z. PMID: 37975968
Genotype-Phenotype Correlations for ATX-TBP (SCA17): MDSGene Systematic Review.
Rossi M, Hamed M, Rodríguez-Antigüedad J, Cornejo-Olivas M, Breza M, Lohmann K, Klein C, Rajalingam R, Marras C, van de Warrenburg BP
Mov Disord 2023 Mar;38(3):368-377. Epub 2022 Nov 14 doi: 10.1002/mds.29278. PMID: 36374860
Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study.
Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Bishop KM, Foster R, Liu Y, Ramirez-Schrempp D, Schneider E, Bennett CF, Wong J, Farwell W
Lancet Child Adolesc Health 2021 Jul;5(7):491-500. Epub 2021 Jun 3 doi: 10.1016/S2352-4642(21)00100-0. PMID: 34089650
Natural history of most common spinocerebellar ataxia: a systematic review and meta-analysis.
Diallo A, Jacobi H, Tezenas du Montcel S, Klockgether T
J Neurol 2021 Aug;268(8):2749-2756. Epub 2020 Apr 7 doi: 10.1007/s00415-020-09815-2. PMID: 32266540

Prognosis

Complex Ataxia-Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia.
Nanetti L, Magri S, Fichera M, Castaldo A, Nigri A, Pinardi C, Mongelli A, Sarro L, Pareyson D, Grisoli M, Gellera C, Di Bella D, Mariotti C, Taroni F
Mov Disord 2023 Apr;38(4):665-675. Epub 2023 Feb 17 doi: 10.1002/mds.29352. PMID: 36799493
Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3.
Faber J, Schaprian T, Berkan K, Reetz K, França MC Jr, de Rezende TJR, Hong J, Liao W, van de Warrenburg B, van Gaalen J, Durr A, Mochel F, Giunti P, Garcia-Moreno H, Schoels L, Hengel H, Synofzik M, Bender B, Oz G, Joers J, de Vries JJ, Kang JS, Timmann-Braun D, Jacobi H, Infante J, Joules R, Romanzetti S, Diedrichsen J, Schmid M, Wolz R, Klockgether T
Mov Disord 2021 Oct;36(10):2273-2281. Epub 2021 May 5 doi: 10.1002/mds.28610. PMID: 33951232Free PMC Article
Non-ataxic manifestations of Spinocerebellar ataxia-2, their determinants and predictors.
Stezin A, Venkatesh SD, Thennarasu K, Purushottam M, Jain S, Yadav R, Pal PK
J Neurol Sci 2018 Nov 15;394:14-18. Epub 2018 Sep 1 doi: 10.1016/j.jns.2018.08.024. PMID: 30196130
Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1.
Platonov FA, Tyryshkin K, Tikhonov DG, Neustroyeva TS, Sivtseva TM, Yakovleva NV, Nikolaev VP, Sidorova OG, Kononova SK, Goldfarb LG, Renwick NM
Neurogenetics 2016 Jul;17(3):179-85. Epub 2016 Apr 22 doi: 10.1007/s10048-016-0481-5. PMID: 27106293Free PMC Article
ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia.
Bhatt JM, Bush A, van Gerven M, Nissenkorn A, Renke M, Yarlett L, Taylor M, Tonia T, Warris A, Zielen S, Zinna S, Merkus PJ; European Respiratory Society
Eur Respir Rev 2015 Dec;24(138):565-81. doi: 10.1183/16000617.0066-2015. PMID: 26621971Free PMC Article

Clinical prediction guides

Complex Ataxia-Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia.
Nanetti L, Magri S, Fichera M, Castaldo A, Nigri A, Pinardi C, Mongelli A, Sarro L, Pareyson D, Grisoli M, Gellera C, Di Bella D, Mariotti C, Taroni F
Mov Disord 2023 Apr;38(4):665-675. Epub 2023 Feb 17 doi: 10.1002/mds.29352. PMID: 36799493
Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study.
Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Bishop KM, Foster R, Liu Y, Ramirez-Schrempp D, Schneider E, Bennett CF, Wong J, Farwell W
Lancet Child Adolesc Health 2021 Jul;5(7):491-500. Epub 2021 Jun 3 doi: 10.1016/S2352-4642(21)00100-0. PMID: 34089650
Clinical Presentation of Ataxia-Telangiectasia.
Alyasin S, Esmaeilzadeh H, Ebrahimi N, Nabavizadeh SH, Nemati H
Arch Iran Med 2019 Dec 1;22(12):682-686. PMID: 31823618
Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways.
Gunawardena S, Goldstein LS
Arch Neurol 2005 Jan;62(1):46-51. doi: 10.1001/archneur.62.1.46. PMID: 15642849
Characterization of ATM gene mutations in 66 ataxia telangiectasia families.
Sandoval N, Platzer M, Rosenthal A, Dörk T, Bendix R, Skawran B, Stuhrmann M, Wegner RD, Sperling K, Banin S, Shiloh Y, Baumer A, Bernthaler U, Sennefelder H, Brohm M, Weber BH, Schindler D
Hum Mol Genet 1999 Jan;8(1):69-79. doi: 10.1093/hmg/8.1.69. PMID: 9887333

Recent systematic reviews

Diagnostic Yield of NGS Tests for Hereditary Ataxia: a Systematic Review.
Tenorio RB, Camargo CHF, Donis KC, Almeida CCB, Teive HAG
Cerebellum 2024 Aug;23(4):1552-1565. Epub 2023 Nov 11 doi: 10.1007/s12311-023-01629-y. PMID: 37950147
Genotype-Phenotype Correlations for ATX-TBP (SCA17): MDSGene Systematic Review.
Rossi M, Hamed M, Rodríguez-Antigüedad J, Cornejo-Olivas M, Breza M, Lohmann K, Klein C, Rajalingam R, Marras C, van de Warrenburg BP
Mov Disord 2023 Mar;38(3):368-377. Epub 2022 Nov 14 doi: 10.1002/mds.29278. PMID: 36374860
Effects of therapeutic exercise on disease severity, balance, and functional Independence among individuals with cerebellar ataxia: A systematic review with meta-analysis.
Winser S, Chan HK, Chen WK, Hau CY, Leung SH, Leung YH, Bello UM
Physiother Theory Pract 2023 Jul 3;39(7):1355-1375. Epub 2022 Feb 25 doi: 10.1080/09593985.2022.2037115. PMID: 35212247
Natural history of most common spinocerebellar ataxia: a systematic review and meta-analysis.
Diallo A, Jacobi H, Tezenas du Montcel S, Klockgether T
J Neurol 2021 Aug;268(8):2749-2756. Epub 2020 Apr 7 doi: 10.1007/s00415-020-09815-2. PMID: 32266540
The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies.
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

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    Reviews

    Related information

    • ClinVar
      Related medical variations
    • Gene
      Related information in NCBI Gene
    • GTR
      Related information in GTR
    • GTR(Clinical)
      Clinical tests in GTR
    • OMIM
      Related records in OMIM
    • OMIM(Genes)
      OMIM records containing genes associated with phenotypes registered in MedGen
    • PMC Articles
      Related information in PubMed Central Links
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