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Spinocerebellar ataxia 49(SCA49)

MedGen UID:
1805601
Concept ID:
C5676950
Disease or Syndrome
Synonym: SCA49
 
Gene (location): SAMD9L (7q21.2)
 
Monarch Initiative: MONDO:0030805
OMIM®: 619806

Definition

Spinocerebellar ataxia-49 (SCA49) is an autosomal dominant neurologic disorder characterized initially by gait abnormalities, gaze-evoked nystagmus, and hyperreflexia. The age at onset is highly variable, ranging from the second to seventh decades, even within the same family. The disorder is slowly progressive, and later features may include dysarthria, dysmetria, diplopia, pyramidal signs, and axonal peripheral neuropathy. Brain imaging shows cerebellar atrophy and myelination defects (Corral-Juan et al., 2022). [from OMIM]

Clinical features

From HPO
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
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.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Unsteady gait
MedGen UID:
68544
Concept ID:
C0231686
Finding
A shaky or wobbly manner of walking.
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
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.
Dysdiadochokinesis
MedGen UID:
115975
Concept ID:
C0234979
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to perform rapidly alternating movements, such as pronating and supinating his or her hand on the dorsum of the other hand as rapidly as possible.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
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.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
Sensory axonal neuropathy
MedGen UID:
334116
Concept ID:
C1842587
Finding
An axonal neuropathy of peripheral sensory nerves.
Diplopia
MedGen UID:
41600
Concept ID:
C0012569
Disease or Syndrome
Diplopia is a condition in which a single object is perceived as two images, it is also known as double vision.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Gaze-evoked nystagmus
MedGen UID:
1808161
Concept ID:
C5574666
Disease or Syndrome
Nystagmus made apparent by looking to the right or to the left.

Professional guidelines

PubMed

Evers MM, Tran HD, Zalachoras I, Pepers BA, Meijer OC, den Dunnen JT, van Ommen GJ, Aartsma-Rus A, van Roon-Mom WM
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Brain 2012 Oct;135(Pt 10):2994-3004. Epub 2012 Sep 10 doi: 10.1093/brain/aws224. PMID: 22964162
Geschwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst SM
Neurology 1997 Nov;49(5):1247-51. doi: 10.1212/wnl.49.5.1247. PMID: 9371902

Recent clinical studies

Etiology

Zhou H, Nguyen H, Enriquez A, Morsy L, Curtis M, Piser T, Kenney C, Stephen CD, Gupta AS, Schmahmann JD, Vaziri A
Neurol Sci 2022 Apr;43(4):2589-2599. Epub 2021 Oct 19 doi: 10.1007/s10072-021-05657-6. PMID: 34664180
Castelli LM, Huang WP, Lin YH, Chang KY, Hautbergue GM
Biochem Soc Trans 2021 Apr 30;49(2):775-792. doi: 10.1042/BST20200690. PMID: 33729487Free PMC Article
Ebrahimi-Fakhari D
Neuropediatrics 2018 Feb;49(1):18-25. Epub 2017 Nov 7 doi: 10.1055/s-0037-1608652. PMID: 29112993
Zambonin JL, Bellomo A, Ben-Pazi H, Everman DB, Frazer LM, Geraghty MT, Harper AD, Jones JR, Kamien B, Kernohan K, Koenig MK, Lines M, Palmer EE, Richardson R, Segel R, Tarnopolsky M, Vanstone JR, Gibbons M, Collins A, Fogel BL; Care4Rare Canada Consortium, Dudding-Byth T, Boycott KM
Orphanet J Rare Dis 2017 Jun 28;12(1):121. doi: 10.1186/s13023-017-0672-7. PMID: 28659154Free PMC Article
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

Diagnosis

Bonnet C, Pellerin D, Roth V, Clément G, Wandzel M, Lambert L, Frismand S, Douarinou M, Grosset A, Bekkour I, Weber F, Girardier F, Robin C, Cacciatore S, Bronner M, Pourié C, Dreumont N, Puisieux S, Iruzubieta P, Dicaire MJ, Evoy F, Rioux MF, Hocquel A, La Piana R, Synofzik M, Houlden H, Danzi MC, Zuchner S, Brais B, Renaud M
Sci Rep 2023 Jun 15;13(1):9737. doi: 10.1038/s41598-023-36654-8. PMID: 37322040Free PMC Article
Saito R, Tada Y, Oikawa D, Sato Y, Seto M, Satoh A, Kume K, Ueki N, Nakashima M, Hayashi S, Toyoshima Y, Tokunaga F, Kawakami H, Kakita A
Acta Neuropathol Commun 2022 Dec 7;10(1):177. doi: 10.1186/s40478-022-01486-6. PMID: 36476347Free PMC Article
Zhou H, Nguyen H, Enriquez A, Morsy L, Curtis M, Piser T, Kenney C, Stephen CD, Gupta AS, Schmahmann JD, Vaziri A
Neurol Sci 2022 Apr;43(4):2589-2599. Epub 2021 Oct 19 doi: 10.1007/s10072-021-05657-6. PMID: 34664180
Paolini Paoletti F, Prontera P, Nigro P, Simoni S, Cappelletti G, Filidei M, Calabresi P, Parnetti L, Tambasco N
Neurol Sci 2021 Oct;42(10):4309-4315. Epub 2021 May 24 doi: 10.1007/s10072-021-05313-z. PMID: 34031796
Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

Therapy

Coarelli G, Heinzmann A, Ewenczyk C, Fischer C, Chupin M, Monin ML, Hurmic H, Calvas F, Calvas P, Goizet C, Thobois S, Anheim M, Nguyen K, Devos D, Verny C, Ricigliano VAG, Mangin JF, Brice A, Tezenas du Montcel S, Durr A
Lancet Neurol 2022 Mar;21(3):225-233. Epub 2022 Jan 18 doi: 10.1016/S1474-4422(21)00457-9. PMID: 35063116
Donath H, Woelke S, Schubert R, Kieslich M, Theis M, Auburger G, Duecker RP, Zielen S
Cerebellum 2022 Feb;21(1):39-47. Epub 2021 Apr 24 doi: 10.1007/s12311-021-01257-4. PMID: 33893614Free PMC Article
Nanri K, Mitoma H, Ihara M, Tanaka N, Taguchi T, Takeguchi M, Ishiko T, Mizusawa H
Cerebellum 2014 Oct;13(5):623-7. doi: 10.1007/s12311-014-0582-3. PMID: 24997752
Evers MM, Toonen LJ, van Roon-Mom WM
Mol Neurobiol 2014 Jun;49(3):1513-31. Epub 2013 Nov 29 doi: 10.1007/s12035-013-8596-2. PMID: 24293103Free PMC Article
McGrath-Morrow SA, Lederman HM, Aherrera AD, Lefton-Greif MA, Crawford TO, Ryan T, Wright J, Collaco JM
Pediatr Pulmonol 2014 Jan;49(1):84-90. Epub 2013 Feb 8 doi: 10.1002/ppul.22760. PMID: 23401357Free PMC Article

Prognosis

Bueno-Martínez E, Sanoguera-Miralles L, Valenzuela-Palomo A, Esteban-Sánchez A, Lorca V, Llinares-Burguet I, Allen J, García-Álvarez A, Pérez-Segura P, Durán M, Easton DF, Devilee P, Vreeswijk MP, de la Hoya M, Velasco-Sampedro EA
J Pathol 2022 Sep;258(1):83-101. Epub 2022 Jul 15 doi: 10.1002/path.5979. PMID: 35716007Free PMC Article
Tokushige SI, Matsuda S, Inomata-Terada S, Hamada M, Ugawa Y, Tsuji S, Terao Y
Clin Neurophysiol 2021 Jan;132(1):63-76. Epub 2020 Oct 22 doi: 10.1016/j.clinph.2020.09.026. PMID: 33254099
Zambonin JL, Bellomo A, Ben-Pazi H, Everman DB, Frazer LM, Geraghty MT, Harper AD, Jones JR, Kamien B, Kernohan K, Koenig MK, Lines M, Palmer EE, Richardson R, Segel R, Tarnopolsky M, Vanstone JR, Gibbons M, Collins A, Fogel BL; Care4Rare Canada Consortium, Dudding-Byth T, Boycott KM
Orphanet J Rare Dis 2017 Jun 28;12(1):121. doi: 10.1186/s13023-017-0672-7. PMID: 28659154Free PMC Article
Monte TL, Reckziegel ER, Augustin MC, Silva ASP, Locks-Coelho LD, Barsottini O, Pedroso JL, Vargas FR, Saraiva-Pereira ML, Leotti VB, Jardim LB; Rede Neurogenética
Cerebellum 2017 Aug;16(4):852-858. doi: 10.1007/s12311-017-0855-8. PMID: 28456900
Faryniuk JH, Zeigelboim BS, Teive HAG, Fo VR, Liberalesso PBN, Marques JM
Int Tinnitus J 2017 Apr 19;20(2):93-101. doi: 10.5935/0946-5448.20160018. PMID: 28422031

Clinical prediction guides

Bueno-Martínez E, Sanoguera-Miralles L, Valenzuela-Palomo A, Esteban-Sánchez A, Lorca V, Llinares-Burguet I, Allen J, García-Álvarez A, Pérez-Segura P, Durán M, Easton DF, Devilee P, Vreeswijk MP, de la Hoya M, Velasco-Sampedro EA
J Pathol 2022 Sep;258(1):83-101. Epub 2022 Jul 15 doi: 10.1002/path.5979. PMID: 35716007Free PMC Article
Zhou H, Nguyen H, Enriquez A, Morsy L, Curtis M, Piser T, Kenney C, Stephen CD, Gupta AS, Schmahmann JD, Vaziri A
Neurol Sci 2022 Apr;43(4):2589-2599. Epub 2021 Oct 19 doi: 10.1007/s10072-021-05657-6. PMID: 34664180
Stezin A, Bhardwaj S, Hegde S, Jain S, Bharath RD, Saini J, Pal PK
Parkinsonism Relat Disord 2021 Apr;85:78-83. Epub 2021 Mar 13 doi: 10.1016/j.parkreldis.2021.02.028. PMID: 33756405Free PMC Article
Lemos J, Novo A, Duque C, Cunha I, Ribeiro J, Castelhano J, Januário C
Cerebellum 2021 Jun;20(3):402-409. Epub 2020 Nov 19 doi: 10.1007/s12311-020-01217-4. PMID: 33215370
Zambonin JL, Bellomo A, Ben-Pazi H, Everman DB, Frazer LM, Geraghty MT, Harper AD, Jones JR, Kamien B, Kernohan K, Koenig MK, Lines M, Palmer EE, Richardson R, Segel R, Tarnopolsky M, Vanstone JR, Gibbons M, Collins A, Fogel BL; Care4Rare Canada Consortium, Dudding-Byth T, Boycott KM
Orphanet J Rare Dis 2017 Jun 28;12(1):121. doi: 10.1186/s13023-017-0672-7. PMID: 28659154Free PMC Article

Recent systematic reviews

Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320
Shaw C, Abrams K, Marteau TM
Soc Sci Med 1999 Dec;49(12):1571-98. doi: 10.1016/s0277-9536(99)00244-0. PMID: 10574231

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