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Spastic ataxia 3(SPAX3; ARSAL)

MedGen UID:
370715
Concept ID:
C1969645
Disease or Syndrome
Synonyms: Ataxia, spastic, 3, autosomal recessive; AUTOSOMAL RECESSIVE SPASTIC ATAXIA WITH LEUKOENCEPHALOPATHY
SNOMED CT: ARSAL - autosomal recessive spastic ataxia with leukoencephalopathy (784343003); Autosomal recessive spastic ataxia type 3 (784343003); Autosomal recessive spastic ataxia with leukoencephalopathy (784343003); SPAX3 - autosomal recessive spastic ataxia type 3 (784343003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): MARS2 (2q33.1)
 
Monarch Initiative: MONDO:0012664
OMIM®: 611390
Orphanet: ORPHA314603

Definition

A rare genetic autosomal recessive spastic ataxia disease with characteristics of cerebellar ataxia, spasticity, cerebellar (and in some cases cerebral) atrophy, dystonia and leucoencephalopathy. Caused by homozygous or compound heterozygous complex genomic rearrangements involving the MARS2 gene on chromosome 2q33. [from SNOMEDCT_US]

Clinical features

From HPO
Neurogenic bladder
MedGen UID:
595
Concept ID:
C0005697
Disease or Syndrome
A type of bladder dysfunction caused by neurologic damage. Neurogenic bladder can be flaccid or spastic. Common manifestatios of neurogenic bladder are overflow incontinence, frequency, urgency, urge incontinence, and retention.
Urinary urgency
MedGen UID:
39315
Concept ID:
C0085606
Finding
Urge incontinence is the strong, sudden need to urinate.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
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.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
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.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
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.
Cerebellar vermis atrophy
MedGen UID:
149271
Concept ID:
C0742028
Disease or Syndrome
Wasting (atrophy) of the vermis of cerebellum.
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.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
Spastic ataxia
MedGen UID:
376528
Concept ID:
C1849156
Disease or Syndrome
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Horizontal nystagmus
MedGen UID:
124399
Concept ID:
C0271385
Disease or Syndrome
Nystagmus consisting of horizontal to-and-fro eye movements.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVSpastic ataxia 3
Follow this link to review classifications for Spastic ataxia 3 in Orphanet.

Professional guidelines

PubMed

van de Warrenburg BP, van Gaalen J, Boesch S, Burgunder JM, Dürr A, Giunti P, Klockgether T, Mariotti C, Pandolfo M, Riess O
Eur J Neurol 2014 Apr;21(4):552-62. Epub 2014 Jan 13 doi: 10.1111/ene.12341. PMID: 24418350

Recent clinical studies

Etiology

Indelicato E, Nachbauer W, Fauth C, Krabichler B, Schossig A, Eigentler A, Dichtl W, Wenning G, Wagner M, Fanciulli A, Janecke A, Boesch S
Parkinsonism Relat Disord 2019 May;62:210-214. Epub 2018 Dec 11 doi: 10.1016/j.parkreldis.2018.12.007. PMID: 30573412
Synofzik M, Németh AH
Handb Clin Neurol 2018;155:73-89. doi: 10.1016/B978-0-444-64189-2.00005-6. PMID: 29891078
Picher-Martel V, Dupre N
CNS Neurol Disord Drug Targets 2018;17(3):161-171. doi: 10.2174/1871527317666180419115029. PMID: 29676235
Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine CS, Mochel F, Labauge P, Ewenczyk C, Ding J, Gibbs JR, Hannequin D, Melki J, Toutain A, Laugel V, Forlani S, Charles P, Broussolle E, Thobois S, Afenjar A, Anheim M, Calvas P, Castelnovo G, de Broucker T, Vidailhet M, Moulignier A, Ghnassia RT, Tallaksen C, Mignot C, Goizet C, Le Ber I, Ollagnon-Roman E, Pouget J, Brice A, Singleton A, Durr A; Spastic Paraplegia and Ataxia Network
JAMA Neurol 2018 May 1;75(5):591-599. doi: 10.1001/jamaneurol.2017.5121. PMID: 29482223Free PMC Article
Storey E
Semin Neurol 2014 Jul;34(3):280-92. Epub 2014 Sep 5 doi: 10.1055/s-0034-1386766. PMID: 25192506

Diagnosis

Pauly MG, Brüggemann N, Efthymiou S, Grözinger A, Diaw SH, Chelban V, Turchetti V, Vona B, Tadic V, Houlden H, Münchau A, Lohmann K
Int J Mol Sci 2023 Jan 18;24(3) doi: 10.3390/ijms24031874. PMID: 36768210Free PMC Article
Synofzik M, Németh AH
Handb Clin Neurol 2018;155:73-89. doi: 10.1016/B978-0-444-64189-2.00005-6. PMID: 29891078
Picher-Martel V, Dupre N
CNS Neurol Disord Drug Targets 2018;17(3):161-171. doi: 10.2174/1871527317666180419115029. PMID: 29676235
Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine CS, Mochel F, Labauge P, Ewenczyk C, Ding J, Gibbs JR, Hannequin D, Melki J, Toutain A, Laugel V, Forlani S, Charles P, Broussolle E, Thobois S, Afenjar A, Anheim M, Calvas P, Castelnovo G, de Broucker T, Vidailhet M, Moulignier A, Ghnassia RT, Tallaksen C, Mignot C, Goizet C, Le Ber I, Ollagnon-Roman E, Pouget J, Brice A, Singleton A, Durr A; Spastic Paraplegia and Ataxia Network
JAMA Neurol 2018 May 1;75(5):591-599. doi: 10.1001/jamaneurol.2017.5121. PMID: 29482223Free PMC Article
Storey E
Semin Neurol 2014 Jul;34(3):280-92. Epub 2014 Sep 5 doi: 10.1055/s-0034-1386766. PMID: 25192506

Therapy

Beichert L, Seemann J, Kessler C, Traschütz A, Müller D, Dillmann-Jehn K, Ricca I, Satolli S, Basak NA, Coarelli G, Timmann D, Gagnon C, van de Warrenburg BPC; PROSPAX Consortium, Ilg W, Synofzik M, Schüle R
Neurology 2024 Dec 24;103(12):e209887. Epub 2024 Dec 2 doi: 10.1212/WNL.0000000000209887. PMID: 39621946Free PMC Article
Traschütz A, Adarmes-Gómez AD, Anheim M, Baets J, Brais B, Gagnon C, Gburek-Augustat J, Doss S, Hanağası HA, Kamm C, Klivenyi P, Klockgether T, Klopstock T, Minnerop M, Münchau A, Renaud M, Santorelli FM, Schöls L, Thieme A, Vielhaber S, van de Warrenburg BP, Zanni G, Hilgers RD; PREPARE Consortium, Synofzik M
Ann Neurol 2023 Sep;94(3):470-485. Epub 2023 Jun 12 doi: 10.1002/ana.26712. PMID: 37243847
Bourcier D, Bélanger M, Côté I, Brais B, Synofzik M, Brisson JD, Rodrigue X, Gagnon MM, Mathieu J, Gagnon C
J Neurol Sci 2020 Oct 15;417:117050. Epub 2020 Jul 18 doi: 10.1016/j.jns.2020.117050. PMID: 32736199
Picher-Martel V, Dupre N
CNS Neurol Disord Drug Targets 2018;17(3):161-171. doi: 10.2174/1871527317666180419115029. PMID: 29676235
Gradie MI, Jorde LB, Bouchard G
Am J Phys Anthropol 1988 Nov;77(3):321-33. doi: 10.1002/ajpa.1330770305. PMID: 3067584

Prognosis

Gagnon C, Brais B, Lessard I, Lavoie C, Côté I, Mathieu J
Neurology 2019 Oct 15;93(16):e1543-e1549. Epub 2019 Sep 18 doi: 10.1212/WNL.0000000000008313. PMID: 31534027Free PMC Article
Indelicato E, Nachbauer W, Fauth C, Krabichler B, Schossig A, Eigentler A, Dichtl W, Wenning G, Wagner M, Fanciulli A, Janecke A, Boesch S
Parkinsonism Relat Disord 2019 May;62:210-214. Epub 2018 Dec 11 doi: 10.1016/j.parkreldis.2018.12.007. PMID: 30573412
Mancini C, Giorgio E, Rubegni A, Pradotto L, Bagnoli S, Rubino E, Prontera P, Cavalieri S, Di Gregorio E, Ferrero M, Pozzi E, Riberi E, Ferrero P, Nigro P, Mauro A, Zibetti M, Tessa A, Barghigiani M, Antenora A, Sirchia F, Piacentini S, Silvestri G, De Michele G, Filla A, Orsi L, Santorelli FM, Brusco A
Eur J Neurol 2019 Jan;26(1):80-86. Epub 2018 Sep 3 doi: 10.1111/ene.13768. PMID: 30098094
Gagnon C, Desrosiers J, Mathieu J
Int J Rehabil Res 2004 Sep;27(3):253-6. doi: 10.1097/00004356-200409000-00013. PMID: 15319698
Di Donato S, Gellera C, Mariotti C
Neurol Sci 2001 Jun;22(3):219-28. doi: 10.1007/s100720100017. PMID: 11731874

Clinical prediction guides

Divya KP, Cherian A, Dhing HK, Kumar S, Thomas B, Faruq M
Acta Neurol Belg 2024 Apr;124(2):475-484. Epub 2023 Oct 29 doi: 10.1007/s13760-023-02400-0. PMID: 37898963
Kanzler CM, Lessard I, Gassert R, Brais B, Gagnon C, Lambercy O
J Neurol Sci 2023 May 15;448:120621. Epub 2023 Mar 26 doi: 10.1016/j.jns.2023.120621. PMID: 37004405
Nanetti L, Sarto E, Castaldo A, Magri S, Mongelli A, Rossi Sebastiano D, Canafoglia L, Grisoli M, Malaguti C, Rivieri F, D'Amico MC, Di Bella D, Franceschetti S, Mariotti C, Taroni F
J Neurol 2019 Feb;266(2):378-385. Epub 2018 Dec 4 doi: 10.1007/s00415-018-9141-z. PMID: 30515630
Minnerop M, Kurzwelly D, Wagner H, Soehn AS, Reichbauer J, Tao F, Rattay TW, Peitz M, Rehbach K, Giorgetti A, Pyle A, Thiele H, Altmüller J, Timmann D, Karaca I, Lennarz M, Baets J, Hengel H, Synofzik M, Atasu B, Feely S, Kennerson M, Stendel C, Lindig T, Gonzalez MA, Stirnberg R, Sturm M, Roeske S, Jung J, Bauer P, Lohmann E, Herms S, Heilmann-Heimbach S, Nicholson G, Mahanjah M, Sharkia R, Carloni P, Brüstle O, Klopstock T, Mathews KD, Shy ME, de Jonghe P, Chinnery PF, Horvath R, Kohlhase J, Schmitt I, Wolf M, Greschus S, Amunts K, Maier W, Schöls L, Nürnberg P, Zuchner S, Klockgether T, Ramirez A, Schüle R
Brain 2017 Jun 1;140(6):1561-1578. doi: 10.1093/brain/awx095. PMID: 28459997Free PMC Article
Pedroso JL, de Souza PV, Pinto WB, Braga-Neto P, Albuquerque MV, Saraiva-Pereira ML, Jardim LB, Barsottini OG
Parkinsonism Relat Disord 2015 Oct;21(10):1243-6. Epub 2015 Jul 22 doi: 10.1016/j.parkreldis.2015.07.015. PMID: 26231471

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