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Spastic ataxia 5(SPAX5)

MedGen UID:
482607
Concept ID:
C3280977
Disease or Syndrome
Synonym: Spastic ataxia 5, autosomal recessive
SNOMED CT: AFG3L2 (AFG3 like matrix AAA peptidase subunit 2) related spastic ataxia, myoclonic epilepsy, neuropathy syndrome (771469002); Early-onset spastic ataxia, myoclonic epilepsy, neuropathy syndrome (771469002); Autosomal recessive spastic ataxia type 5 (771469002); AFG3L2-related spastic ataxia, myoclonic epilepsy, neuropathy syndrome (771469002)
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): AFG3L2 (18p11.21)
 
Monarch Initiative: MONDO:0013776
OMIM®: 614487
Orphanet: ORPHA313772

Definition

Spastic ataxia-5 (SPAX5) is an autosomal recessive neurodegenerative disorder characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy (summary by Pierson et al., 2011). For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (108600). [from OMIM]

Clinical features

From HPO
Lower limb muscle weakness
MedGen UID:
324478
Concept ID:
C1836296
Finding
Weakness of the muscles of the legs.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
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.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Spastic paraparesis
MedGen UID:
52432
Concept ID:
C0037771
Sign or Symptom
Mild or moderate loss of motor function accompanied by spasticity in the lower extremities. This condition is a manifestation of CENTRAL NERVOUS SYSTEM DISEASES that cause injury to the motor cortex or descending motor pathways.
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.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
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.
Sensorimotor neuropathy
MedGen UID:
207266
Concept ID:
C1112256
Disease or Syndrome
Onion bulb formation
MedGen UID:
376237
Concept ID:
C1847906
Finding
Repeated episodes of segmental demyelination and remyelination lead to the accumulation of supernumerary Schwann cells around axons, which is referred to as onion bulb formation. This finding affects peripheral nerves.
Spastic ataxia
MedGen UID:
376528
Concept ID:
C1849156
Disease or Syndrome
Oculomotor apraxia
MedGen UID:
483686
Concept ID:
C3489733
Disease or Syndrome
Ocular motor apraxia is a deficiency in voluntary, horizontal, lateral, fast eye movements (saccades) with retention of slow pursuit movements. The inability to follow objects visually is often compensated by head movements. There may be decreased smooth pursuit, and cancelation of the vestibulo-ocular reflex.
Generalized myoclonic seizure
MedGen UID:
892704
Concept ID:
C4021759
Disease or Syndrome
A generalized myoclonic seizure is a type of generalized motor seizure characterized by bilateral, sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Increased intramyocellular lipid droplets
MedGen UID:
866481
Concept ID:
C4020730
Finding
An abnormal increase in intracellular lipid droplets In a muscle. The number and size of these drops can increase with somd disorders of lipid metabolism affecting muscle. See PMID 20691590 for histological images.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVSpastic ataxia 5
Follow this link to review classifications for Spastic ataxia 5 in Orphanet.

Professional guidelines

PubMed

Vogel AP, Stoll LH, Oettinger A, Rommel N, Kraus EM, Timmann D, Scott D, Atay C, Storey E, Schöls L, Synofzik M
J Neurol 2019 May;266(5):1260-1266. Epub 2019 Mar 6 doi: 10.1007/s00415-019-09258-4. PMID: 30840144

Recent clinical studies

Etiology

Rezk M, Pittock SJ, Kapadia RK, Knight AM, Guo Y, Gupta P, LaFrance-Corey RG, Zekeridou A, McKeon A, Dasari S, Mills JR, Dubey D
Front Immunol 2023;14:1243946. Epub 2023 Sep 18 doi: 10.3389/fimmu.2023.1243946. PMID: 37795104Free PMC Article
Colucci F, Neri M, Fortunato F, Ferlini A, Carrozzo R, Torraco A, Lamantea E, Legati A, Tecilla G, Pugliatti M, Sensi M
Cerebellum 2023 Dec;22(6):1313-1319. Epub 2022 Nov 30 doi: 10.1007/s12311-022-01497-y. PMID: 36447112
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
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

Diagnosis

Ghosh Dastidar R, Banerjee S, Lal PB, Ghosh Dastidar S
Mol Neurobiol 2024 Jul;61(7):3788-3808. Epub 2023 Nov 28 doi: 10.1007/s12035-023-03768-z. PMID: 38012514Free PMC Article
Franchino CA, Brughera M, Baderna V, De Ritis D, Rocco A, Seneca S, Regal L, Podini P, D'Antonio M, Toro C, Quattrini A, Scalais E, Maltecca F
Brain 2024 Mar 1;147(3):1043-1056. doi: 10.1093/brain/awad340. PMID: 37804316Free PMC Article
Rezk M, Pittock SJ, Kapadia RK, Knight AM, Guo Y, Gupta P, LaFrance-Corey RG, Zekeridou A, McKeon A, Dasari S, Mills JR, Dubey D
Front Immunol 2023;14:1243946. Epub 2023 Sep 18 doi: 10.3389/fimmu.2023.1243946. PMID: 37795104Free 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
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

Therapy

Lessard I, Côté I, St-Gelais R, Hébert LJ, Brais B, Mathieu J, Rodrigue X, Gagnon C
Cerebellum 2024 Apr;23(2):489-501. Epub 2023 Apr 27 doi: 10.1007/s12311-023-01558-w. PMID: 37101017
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

Prognosis

Ghosh Dastidar R, Banerjee S, Lal PB, Ghosh Dastidar S
Mol Neurobiol 2024 Jul;61(7):3788-3808. Epub 2023 Nov 28 doi: 10.1007/s12035-023-03768-z. PMID: 38012514Free PMC Article
Rezk M, Pittock SJ, Kapadia RK, Knight AM, Guo Y, Gupta P, LaFrance-Corey RG, Zekeridou A, McKeon A, Dasari S, Mills JR, Dubey D
Front Immunol 2023;14:1243946. Epub 2023 Sep 18 doi: 10.3389/fimmu.2023.1243946. PMID: 37795104Free PMC Article
Chen J, Zhao Z, Shen H, Bing Q, Li N, Guo X, Hu J
BMC Neurol 2022 May 16;22(1):180. doi: 10.1186/s12883-022-02708-z. PMID: 35578252Free PMC Article
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

Clinical prediction guides

Hosseini Bereshneh A, Hosseipour S, Rasoulinezhad MS, Pak N, Garshasbi M, Tavasoli AR
Eur J Med Genet 2020 May;63(5):103868. Epub 2020 Jan 28 doi: 10.1016/j.ejmg.2020.103868. PMID: 32004679
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
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
Criscuolo C, Procaccini C, Meschini MC, Cianflone A, Carbone R, Doccini S, Devos D, Nesti C, Vuillaume I, Pellegrino M, Filla A, De Michele G, Matarese G, Santorelli FM
J Neurol 2015 Dec;262(12):2755-63. Epub 2015 Nov 3 doi: 10.1007/s00415-015-7911-4. PMID: 26530509

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