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Torsion dystonia 4(DYT4)

MedGen UID:
342124
•Concept ID:
C1851943
•
Disease or Syndrome
Synonyms: Autosomal dominant torsion dystonia 4; Dystonia musculorum deformans 4; Hereditary whispering dysphonia
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): TUBB4A (19p13.3)
 
Monarch Initiative: MONDO:0007493
OMIM®: 128101
Orphanet: ORPHA98805

Definition

Dystonia-4 (DYT4), also known as whispering dysphonia, is an autosomal dominant neurologic disorder characterized by onset in the second to third decade of progressive laryngeal dysphonia followed by the involvement of other muscles, such as the neck or limbs. Some patients develop an ataxic gait (summary by Hersheson et al., 2013). [from OMIM]

Clinical features

From HPO
Slender build
MedGen UID:
376828
•Concept ID:
C1850573
•
Finding
Asthenic habitus refers to a slender build with long limbs, an angular profile, and prominent muscles or bones.
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Dysphagia
MedGen UID:
41440
•Concept ID:
C0011168
•
Disease or Syndrome
Difficulty in swallowing.
See: Feature record | Search on this feature
Torsion dystonia
MedGen UID:
3941
•Concept ID:
C0013423
•
Disease or Syndrome
Sustained involuntary muscle contractions that produce twisting and repetitive movements of the body.
See: Feature record | Search on this feature
Torticollis
MedGen UID:
11859
•Concept ID:
C0040485
•
Sign or Symptom
Torticollis is a twisted neck as a result of shortening of sternocleidomastoid muscle. This short and fibrotic muscle pulls the head laterally and rotates the chin and face to the opposite end. Facial asymmetry may be a manifestation (summary by Engin et al., 1997).
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Limb dystonia
MedGen UID:
152944
•Concept ID:
C0751093
•
Sign or Symptom
A type of dystonia (abnormally increased muscular tone causing fixed abnormal postures) that affects muscles of the limbs.
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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.
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Generalized dystonia
MedGen UID:
341342
•Concept ID:
C1848954
•
Finding
A type of dystonia that affects all or most of the body.
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Hemidystonia
MedGen UID:
743329
•Concept ID:
C1960561
•
Disease or Syndrome
Hemidystonia refers to dystonia which involves the ipsilateral face, arm, and leg.
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Dysphonia
MedGen UID:
282893
•Concept ID:
C1527344
•
Mental or Behavioral Dysfunction
Difficulty in speaking due to a physical disorder of the mouth, tongue, throat, or vocal cords. Associated with a known physical or neurological cause.
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Narrow face
MedGen UID:
373334
•Concept ID:
C1837463
•
Finding
Bizygomatic (upper face) and bigonial (lower face) width are both more than 2 standard deviations below the mean (objective); or, an apparent reduction in the width of the upper and lower face (subjective).
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Sunken cheeks
MedGen UID:
869726
•Concept ID:
C4024154
•
Finding
Lack or loss of the soft tissues between the zygomata and mandible.
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVTorsion dystonia 4
Follow this link to review classifications for Torsion dystonia 4 in Orphanet.

Professional guidelines

PubMed

In vivo optogenetic inhibition of striatal parvalbumin-reactive interneurons induced genotype-specific changes in neuronal activity without dystonic signs in male DYT1 knock-in mice.
Schulz A, Richter F, Richter A
J Neurosci Res 2023 Apr;101(4):448-463. Epub 2022 Dec 22 doi: 10.1002/jnr.25157. PMID: 36546658
Sporadic adult onset primary torsion dystonia is a genetic disorder by the temporal discrimination test.
Kimmich O, Bradley D, Whelan R, Mulrooney N, Reilly RB, Hutchinson S, O'Riordan S, Hutchinson M
Brain 2011 Sep;134(Pt 9):2656-63. Epub 2011 Aug 11 doi: 10.1093/brain/awr194. PMID: 21840890
Treatment of cervical dystonia: a comparison of measures for outcome assessment.
Lindeboom R, Brans JW, Aramideh M, Speelman HD, De Haan RJ
Mov Disord 1998 Jul;13(4):706-12. doi: 10.1002/mds.870130417. PMID: 9686779

Recent clinical studies

Etiology

X-Linked Dystonia-Parkinsonism ("Lubag") May Present with Peripheral Synucleinopathy.
Evidente VGH, Evidente DH, Ortega SC, Levine TD, Freeman R, Gibbons CH
Mov Disord 2022 Jan;37(1):130-136. Epub 2021 Sep 28 doi: 10.1002/mds.28801. PMID: 34582053
Pallidal degenerations and related disorders: an update.
Jellinger KA
J Neural Transm (Vienna) 2022 Jun;129(5-6):521-543. Epub 2021 Aug 7 doi: 10.1007/s00702-021-02392-2. PMID: 34363531
Voice and swallowing dysfunction in X-linked dystonia parkinsonism.
Song PC, Le H, Acuna P, De Guzman JKP, Sharma N, Francouer TN, Dy ME, Go CL
Laryngoscope 2020 Jan;130(1):171-177. Epub 2019 Mar 19 doi: 10.1002/lary.27897. PMID: 30889292
Long-term follow-up of deep brain stimulation for Meige syndrome.
Lyons MK, Birch BD, Hillman RA, Boucher OK, Evidente VG
Neurosurg Focus 2010 Aug;29(2):E5. doi: 10.3171/2010.4.FOCUS1067. PMID: 20672922
Genetics of primary torsion dystonia.
Brüggemann N, Klein C
Curr Neurol Neurosci Rep 2010 May;10(3):199-206. doi: 10.1007/s11910-010-0107-5. PMID: 20425035

Diagnosis

X-Linked Dystonia-Parkinsonism ("Lubag") May Present with Peripheral Synucleinopathy.
Evidente VGH, Evidente DH, Ortega SC, Levine TD, Freeman R, Gibbons CH
Mov Disord 2022 Jan;37(1):130-136. Epub 2021 Sep 28 doi: 10.1002/mds.28801. PMID: 34582053
Pallidal degenerations and related disorders: an update.
Jellinger KA
J Neural Transm (Vienna) 2022 Jun;129(5-6):521-543. Epub 2021 Aug 7 doi: 10.1007/s00702-021-02392-2. PMID: 34363531
Genetics of primary torsion dystonia.
Brüggemann N, Klein C
Curr Neurol Neurosci Rep 2010 May;10(3):199-206. doi: 10.1007/s11910-010-0107-5. PMID: 20425035
Dystonia.
Bressman SB
Curr Opin Neurol 1998 Aug;11(4):363-72. doi: 10.1097/00019052-199808000-00013. PMID: 9725083
Sleep and degenerative neurologic disorders.
Chokroverty S
Neurol Clin 1996 Nov;14(4):807-26. doi: 10.1016/s0733-8619(05)70286-3. PMID: 8923496

Therapy

A Network Imaging Biomarker of X-Linked Dystonia-Parkinsonism.
Niethammer M, Tang CC, Jamora RDG, Vo A, Nguyen N, Ma Y, Peng S, Waugh JL, Westenberger A, Eidelberg D
Ann Neurol 2023 Oct;94(4):684-695. Epub 2023 Jul 11 doi: 10.1002/ana.26732. PMID: 37376770
4-Phenylbutyrate attenuates the ER stress response and cyclic AMP accumulation in DYT1 dystonia cell models.
Cho JA, Zhang X, Miller GM, Lencer WI, Nery FC
PLoS One 2014;9(11):e110086. Epub 2014 Nov 7 doi: 10.1371/journal.pone.0110086. PMID: 25379658Free PMC Article
Dystonia.
Bressman SB
Curr Opin Neurol 1998 Aug;11(4):363-72. doi: 10.1097/00019052-199808000-00013. PMID: 9725083
Torsion dystonia.
Berardelli A, Currà A, Manfredi M
Curr Opin Neurol 1996 Aug;9(4):317-20. doi: 10.1097/00019052-199608000-00014. PMID: 8858192
Lisuride in dystonia.
Quinn NP, Lang AE, Sheehy MP, Marsden CD
Neurology 1985 May;35(5):766-9. doi: 10.1212/wnl.35.5.766. PMID: 3887215

Prognosis

Basal ganglia and cerebellar pathology in X-linked dystonia-parkinsonism.
Hanssen H, Heldmann M, Prasuhn J, Tronnier V, Rasche D, Diesta CC, Domingo A, Rosales RL, Jamora RD, Klein C, Münte TF, Brüggemann N
Brain 2018 Oct 1;141(10):2995-3008. doi: 10.1093/brain/awy222. PMID: 30169601
Long-term follow-up of deep brain stimulation for Meige syndrome.
Lyons MK, Birch BD, Hillman RA, Boucher OK, Evidente VG
Neurosurg Focus 2010 Aug;29(2):E5. doi: 10.3171/2010.4.FOCUS1067. PMID: 20672922
Genetics of primary torsion dystonia.
Brüggemann N, Klein C
Curr Neurol Neurosci Rep 2010 May;10(3):199-206. doi: 10.1007/s11910-010-0107-5. PMID: 20425035
The relationship between trauma and idiopathic torsion dystonia.
Fletcher NA, Harding AE, Marsden CD
J Neurol Neurosurg Psychiatry 1991 Aug;54(8):713-7. doi: 10.1136/jnnp.54.8.713. PMID: 1940944Free PMC Article
Idiopathic torsion dystonia (dystonia musculorum deformans). A review of forty-two patients.
Marsden CD, Harrison MJ
Brain 1974 Dec;97(4):793-810. doi: 10.1093/brain/97.1.793. PMID: 4474046

Clinical prediction guides

A Network Imaging Biomarker of X-Linked Dystonia-Parkinsonism.
Niethammer M, Tang CC, Jamora RDG, Vo A, Nguyen N, Ma Y, Peng S, Waugh JL, Westenberger A, Eidelberg D
Ann Neurol 2023 Oct;94(4):684-695. Epub 2023 Jul 11 doi: 10.1002/ana.26732. PMID: 37376770
X-Linked Dystonia-Parkinsonism ("Lubag") May Present with Peripheral Synucleinopathy.
Evidente VGH, Evidente DH, Ortega SC, Levine TD, Freeman R, Gibbons CH
Mov Disord 2022 Jan;37(1):130-136. Epub 2021 Sep 28 doi: 10.1002/mds.28801. PMID: 34582053
DYT-TUBB4A (DYT4 Dystonia): New Clinical and Genetic Observations.
Bally JF, Camargos S, Oliveira Dos Santos C, Kern DS, Lee T, Pereira da Silva-Junior F, Puga RD, Cardoso F, Barbosa ER, Yadav R, Ozelius LJ, de Carvalho Aguiar P, Lang AE
Neurology 2021 Apr 6;96(14):e1887-e1897. Epub 2020 Sep 17 doi: 10.1212/WNL.0000000000010882. PMID: 32943487Free PMC Article
Voice and swallowing dysfunction in X-linked dystonia parkinsonism.
Song PC, Le H, Acuna P, De Guzman JKP, Sharma N, Francouer TN, Dy ME, Go CL
Laryngoscope 2020 Jan;130(1):171-177. Epub 2019 Mar 19 doi: 10.1002/lary.27897. PMID: 30889292
Dystonia-4 (DYT4)-associated TUBB4A mutants exhibit disorganized microtubule networks and inhibit neuronal process growth.
Watanabe N, Itakaoka M, Seki Y, Morimoto T, Homma K, Miyamoto Y, Yamauchi J
Biochem Biophys Res Commun 2018 Jan 1;495(1):346-352. Epub 2017 Nov 7 doi: 10.1016/j.bbrc.2017.11.038. PMID: 29127012

Recent systematic reviews

Understanding Psychiatric Disorders in Idiopathic and Inherited (Monogenic) Forms of Isolated and Combined Dystonia: A Systematic Review.
Lane V, Lane M, Sturrock A, Rickards H
J Neuropsychiatry Clin Neurosci 2021 Fall;33(4):295-306. Epub 2021 Jul 19 doi: 10.1176/appi.neuropsych.20110293. PMID: 34280321

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