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Spinocerebellar ataxia type 4(SCA4)

MedGen UID:
199815
Concept ID:
C0752122
Disease or Syndrome
Synonym: Spinocerebellar ataxia autosomal dominant with sensory axonal neuropathy
SNOMED CT: Spinocerebellar ataxia type 4 (715755008)
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.
 
Gene (location): ZFHX3 (16q22.2-22.3)
 
Monarch Initiative: MONDO:0010847
OMIM®: 600223
Orphanet: ORPHA98765

Definition

Spinocerebellar ataxia-4 (SCA4) is an autosomal dominant neurologic disorder characterized by the onset of balance disturbances and gait and limb ataxia usually in the fourth decade, although earlier onset in the teens or twenties has been reported. There is evidence of genetic anticipation within families. The disorder is slowly progressive, and most patients eventually become wheelchair-bound. Additional features include hypometric or slow saccades, sensory or sensorimotor axonal peripheral neuropathy, dysarthria, and autonomic dysfunction, including orthostatic hypotension and problems with bowel or bladder control. More severely affected individuals have dysphagia and significant unintended weight loss, which may contribute to premature death. Brain imaging shows cerebellar atrophy (Wallenius et al., 2024). For a discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400). [from OMIM]

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.
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.
Sensory neuropathy
MedGen UID:
101791
Concept ID:
C0151313
Disease or Syndrome
Peripheral neuropathy affecting the sensory nerves.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Progressive cerebellar ataxia
MedGen UID:
140727
Concept ID:
C0393525
Disease or Syndrome
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
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.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Limb dysmetria
MedGen UID:
340244
Concept ID:
C1854489
Finding
A type of dysmetria involving the limbs.
Impaired smooth pursuit
MedGen UID:
325176
Concept ID:
C1837458
Finding
An impairment of the ability to track objects with the ocular smooth pursuit system, a class of rather slow eye movements that minimizes retinal target motion.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVSpinocerebellar ataxia type 4
Follow this link to review classifications for Spinocerebellar ataxia type 4 in Orphanet.

Professional guidelines

PubMed

Niemann N, Jankovic J
Parkinsonism Relat Disord 2019 Oct;67:74-89. Epub 2019 Jun 30 doi: 10.1016/j.parkreldis.2019.06.025. PMID: 31272925
de Silva RN, Vallortigara J, Greenfield J, Hunt B, Giunti P, Hadjivassiliou M
Pract Neurol 2019 Jun;19(3):196-207. Epub 2019 May 2 doi: 10.1136/practneurol-2018-002096. PMID: 31048364Free PMC Article
van Os NJH, Haaxma CA, van der Flier M, Merkus PJFM, van Deuren M, de Groot IJM, Loeffen J, van de Warrenburg BPC, Willemsen MAAP; A-T Study Group
Dev Med Child Neurol 2017 Jul;59(7):680-689. Epub 2017 Mar 20 doi: 10.1111/dmcn.13424. PMID: 28318010

Recent clinical studies

Etiology

Hellenbroich Y, Pawlack H, Rüb U, Schwinger E, Zühlke Ch
J Neurol 2005 Dec;252(12):1472-5. Epub 2005 Jul 7 doi: 10.1007/s00415-005-0892-y. PMID: 15999233
Li M, Ishikawa K, Toru S, Tomimitsu H, Takashima M, Goto J, Takiyama Y, Sasaki H, Imoto I, Inazawa J, Toda T, Kanazawa I, Mizusawa H
J Hum Genet 2003;48(3):111-8. doi: 10.1007/s100380300017. PMID: 12624721

Diagnosis

Dalski A, Pauly MG, Hanssen H, Hagenah J, Hellenbroich Y, Schmidt C, Strohschehn J, Spielmann M, Zühlke C, Brüggemann N
J Neurol 2024 Sep;271(9):6289-6300. Epub 2024 Aug 2 doi: 10.1007/s00415-024-12600-0. PMID: 39095619Free PMC Article
Rudaks LI, Yeow D, Ng K, Deveson IW, Kennerson ML, Kumar KR
Cerebellum 2024 Oct;23(5):2152-2168. Epub 2024 May 18 doi: 10.1007/s12311-024-01703-z. PMID: 38760634Free PMC Article
Algahtani H, Shirah B, Naseer MI
Clin Neurol Neurosurg 2024 May;240:108271. Epub 2024 Mar 30 doi: 10.1016/j.clineuro.2024.108271. PMID: 38569247
Chen Z, Gustavsson EK, Macpherson H, Anderson C, Clarkson C, Rocca C, Self E, Alvarez Jerez P, Scardamaglia A, Pellerin D, Montgomery K, Lee J, Gagliardi D, Luo H; Genomics England Research Consortium, Hardy J, Polke J, Singleton AB, Blauwendraat C, Mathews KD, Tucci A, Fu YH, Houlden H, Ryten M, Ptáček LJ
Mov Disord 2024 Mar;39(3):486-497. Epub 2024 Jan 10 doi: 10.1002/mds.29704. PMID: 38197134
Hellenbroich Y, Gierga K, Reusche E, Schwinger E, Deller T, de Vos RA, Zühlke C, Rüb U
J Neural Transm (Vienna) 2006 Jul;113(7):829-43. Epub 2005 Dec 19 doi: 10.1007/s00702-005-0362-9. PMID: 16362839

Prognosis

Dalski A, Pauly MG, Hanssen H, Hagenah J, Hellenbroich Y, Schmidt C, Strohschehn J, Spielmann M, Zühlke C, Brüggemann N
J Neurol 2024 Sep;271(9):6289-6300. Epub 2024 Aug 2 doi: 10.1007/s00415-024-12600-0. PMID: 39095619Free PMC Article
Hellenbroich Y, Gierga K, Reusche E, Schwinger E, Deller T, de Vos RA, Zühlke C, Rüb U
J Neural Transm (Vienna) 2006 Jul;113(7):829-43. Epub 2005 Dec 19 doi: 10.1007/s00702-005-0362-9. PMID: 16362839

Clinical prediction guides

Dalski A, Pauly MG, Hanssen H, Hagenah J, Hellenbroich Y, Schmidt C, Strohschehn J, Spielmann M, Zühlke C, Brüggemann N
J Neurol 2024 Sep;271(9):6289-6300. Epub 2024 Aug 2 doi: 10.1007/s00415-024-12600-0. PMID: 39095619Free PMC Article
Wallenius J, Kafantari E, Jhaveri E, Gorcenco S, Ameur A, Karremo C, Dobloug S, Karrman K, de Koning T, Ilinca A, Landqvist Waldö M, Arvidsson A, Persson S, Englund E, Ehrencrona H, Puschmann A
Am J Hum Genet 2024 Jan 4;111(1):82-95. Epub 2023 Nov 29 doi: 10.1016/j.ajhg.2023.11.008. PMID: 38035881Free PMC Article
Hellenbroich Y, Gierga K, Reusche E, Schwinger E, Deller T, de Vos RA, Zühlke C, Rüb U
J Neural Transm (Vienna) 2006 Jul;113(7):829-43. Epub 2005 Dec 19 doi: 10.1007/s00702-005-0362-9. PMID: 16362839
Takashima M, Ishikawa K, Nagaoka U, Shoji S, Mizusawa H
J Hum Genet 2001;46(4):167-71. doi: 10.1007/s100380170083. PMID: 11322654

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