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Dystonia 28, childhood-onset(DYT28)

MedGen UID:
934600
Concept ID:
C4310633
Disease or Syndrome
Synonym: DYT28
SNOMED CT: Dystonia 28 (1281844004); DYT28 - dystonia 28 (1281844004); KMT2B-related dystonia (1281844004); Lysine methyltransferase 2B-related dystonia (1281844004)
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): KMT2B (19q13.12)
 
Monarch Initiative: MONDO:0015004
OMIM®: 617284
Orphanet: ORPHA589618

Definition

KMT2B-related dystonia (DYT-KMT2B) is a complex childhood-onset (mean age 7 years) movement disorder described to date in 39 individuals. It is characterized by a progressive disease course evolving commonly from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Communication difficulties, secondary to articulation difficulties and low speech volume, are common. Bulbar dysfunction leads to impaired swallowing. Intellectual disability (ID) / developmental delay (DD) are commonly reported. Additional findings can include eye movement abnormalities, skin changes, psychiatric comorbidities (attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder), myoclonus, seizures, spasticity, and sensorineural hearing loss. Many affected individuals follow a similar disease course, though milder and atypical findings have been described. [from GeneReviews]

Additional description

From OMIM
Dystonia-28 (DYT28) is an autosomal dominant neurologic disorder characterized by onset of progressive dystonia in the first decade of life. Dystonia typically begins focally in the lower limbs, resulting in gait difficulties, with later progression to other body regions, including the upper limbs, neck, and orofacial region. The severity is variable, and some patients may become wheelchair-bound. Many patients also have an elongated face with bulbous nose, and some have abnormal eye movements. About half of patients show delayed motor and/or cognitive development with mild intellectual disability (summary by Zech et al., 2016 and Meyer et al., 2017).  http://www.omim.org/entry/617284

Clinical features

From HPO
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
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.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
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.
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).
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
Tip-toe gait
MedGen UID:
98104
Concept ID:
C0427144
Finding
An abnormal gait pattern characterized by the failure of the heel to contact the floor at the onset of stance during gait.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk. In general, this can refer to neurological diseases but also fractures or other sources of pain that is triggered upon walking. However, in the current context gait disturbance refers to difficulty walking on the basis of a neurological or muscular disease.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Laryngeal dystonia
MedGen UID:
409603
Concept ID:
C1963946
Disease or Syndrome
A form of focal dystonia that affects the vocal cords, associated with involuntary contractions of the vocal cords causing interruptions of speech and affecting the voice quality and often leading to patterned, repeated breaks in speech.
Oromandibular dystonia
MedGen UID:
473560
Concept ID:
C2242577
Sign or Symptom
A kind of focal dystonia characterized by forceful contractions of the face, jaw, and/or tongue causing difficulty in opening and closing the mouth and often affecting chewing and speech.
Retrocollis
MedGen UID:
854508
Concept ID:
C3887667
Disease or Syndrome
A form of torticollis in which the head is drawn back, either due to a permanent contractures of neck extensor muscles, or to a spasmodic contracture.
Craniofacial dystonia
MedGen UID:
868612
Concept ID:
C4023011
Disease or Syndrome
A form of focal dystonia affecting the face and especially the jaw that is induced by the act of speaking. It is an involuntary contraction of the masticatory muscles, resulting in dysarthria or dysphagia.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
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.
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
Astigmatism
MedGen UID:
2473
Concept ID:
C0004106
Disease or Syndrome
Astigmatism (from the Greek 'a' meaning absence and 'stigma' meaning point) is a condition in which the parallel rays of light entering the eye through the refractive media are not focused on a single point. Both corneal and noncorneal factors contribute to refractive astigmatism. Corneal astigmatism is mainly the result of an aspheric anterior surface of the cornea, which can be measured readily by means of a keratometer; in a small fraction of cases (approximately 1 in 10) the effect is neutralized by the back surface. The curvature of the back surface of the cornea is not considered in most studies, because it is more difficult to measure; moreover, in the case of severe corneal astigmatism, there is evidence that both surfaces have the same configuration. Noncorneal factors are errors in the curvature of the 2 surfaces of the crystalline lens, irregularity in the refractive index of the lens, and an eccentric lens position. Since the cornea is the dominant component of the eye's refracting system, a highly astigmatic cornea is likely to result in a similarly astigmatic ocular refraction (summary by Clementi et al., 1998).
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.
Abnormality of eye movement
MedGen UID:
99227
Concept ID:
C0497202
Finding
An abnormality in voluntary or involuntary eye movements or their control.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVDystonia 28, childhood-onset

Professional guidelines

PubMed

Balagura G, Riva A, Marchese F, Iacomino M, Madia F, Giacomini T, Mancardi MM, Amadori E, Vari MS, Salpietro V, Russo A, Messana T, Vignoli A, Chiesa V, Giordano L, Accorsi P, Caffi L, Orsini A, Bonuccelli A, Santucci M, Vecchi M, Vanadia F, Milito G, Fusco C, Cricchiutti G, Carpentieri M, Margari L, Spalice A, Beccaria F, Benfenati F, Zara F, Striano P
Eur J Paediatr Neurol 2020 Sep;28:193-197. Epub 2020 Jun 23 doi: 10.1016/j.ejpn.2020.06.005. PMID: 32651081
Bhidayasiri R, Tarsy D
Expert Rev Neurother 2006 Jun;6(6):863-86. doi: 10.1586/14737175.6.6.863. PMID: 16784410

Recent clinical studies

Etiology

Mandarano R, Danieli A, Petacchi E, Di Pede C, Mondani M, Armellin MT, Facchin D, Martinuzzi A
Eur J Paediatr Neurol 2022 Mar;37:62-67. Epub 2022 Feb 1 doi: 10.1016/j.ejpn.2022.01.014. PMID: 35124541
Coffey B, Jankovic J, Claassen DO, Jimenez-Shahed J, Gertz BJ, Garofalo EA, Stamler DA, Wieman M, Savola JM, Gordon MF, Alexander JK, Barkay H, Harary E
JAMA Netw Open 2021 Oct 1;4(10):e2129397. doi: 10.1001/jamanetworkopen.2021.29397. PMID: 34661664Free PMC Article
Jankovic J, Coffey B, Claassen DO, Jimenez-Shahed J, Gertz BJ, Garofalo EA, Stamler DA, Wieman M, Savola JM, Gordon MF, Alexander J, Barkay H, Harary E
JAMA Netw Open 2021 Oct 1;4(10):e2128204. doi: 10.1001/jamanetworkopen.2021.28204. PMID: 34609495Free PMC Article
Ciolfi A, Foroutan A, Capuano A, Pedace L, Travaglini L, Pizzi S, Andreani M, Miele E, Invernizzi F, Reale C, Panteghini C, Iascone M, Niceta M, Gavrilova RH, Schultz-Rogers L, Agolini E, Bedeschi MF, Prontera P, Garibaldi M, Galosi S, Leuzzi V, Soliveri P, Olson RJ, Zorzi GS, Garavaglia BM, Tartaglia M, Sadikovic B
Clin Epigenetics 2021 Aug 11;13(1):157. doi: 10.1186/s13148-021-01145-y. PMID: 34380541Free PMC Article
Balagura G, Riva A, Marchese F, Iacomino M, Madia F, Giacomini T, Mancardi MM, Amadori E, Vari MS, Salpietro V, Russo A, Messana T, Vignoli A, Chiesa V, Giordano L, Accorsi P, Caffi L, Orsini A, Bonuccelli A, Santucci M, Vecchi M, Vanadia F, Milito G, Fusco C, Cricchiutti G, Carpentieri M, Margari L, Spalice A, Beccaria F, Benfenati F, Zara F, Striano P
Eur J Paediatr Neurol 2020 Sep;28:193-197. Epub 2020 Jun 23 doi: 10.1016/j.ejpn.2020.06.005. PMID: 32651081

Diagnosis

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
Coffey B, Jankovic J, Claassen DO, Jimenez-Shahed J, Gertz BJ, Garofalo EA, Stamler DA, Wieman M, Savola JM, Gordon MF, Alexander JK, Barkay H, Harary E
JAMA Netw Open 2021 Oct 1;4(10):e2129397. doi: 10.1001/jamanetworkopen.2021.29397. PMID: 34661664Free PMC Article
Ciolfi A, Foroutan A, Capuano A, Pedace L, Travaglini L, Pizzi S, Andreani M, Miele E, Invernizzi F, Reale C, Panteghini C, Iascone M, Niceta M, Gavrilova RH, Schultz-Rogers L, Agolini E, Bedeschi MF, Prontera P, Garibaldi M, Galosi S, Leuzzi V, Soliveri P, Olson RJ, Zorzi GS, Garavaglia BM, Tartaglia M, Sadikovic B
Clin Epigenetics 2021 Aug 11;13(1):157. doi: 10.1186/s13148-021-01145-y. PMID: 34380541Free PMC Article
Jankovic J, Madisetty J, Vuong KD
Pediatrics 2004 Nov;114(5):1203-5. doi: 10.1542/peds.2004-0031. PMID: 15520096
Saint Hilaire MH, Burke RE, Bressman SB, Brin MF, Fahn S
Neurology 1991 Feb;41(2 ( Pt 1)):216-22. doi: 10.1212/wnl.41.2_part_1.216. PMID: 1992364

Therapy

Mandarano R, Danieli A, Petacchi E, Di Pede C, Mondani M, Armellin MT, Facchin D, Martinuzzi A
Eur J Paediatr Neurol 2022 Mar;37:62-67. Epub 2022 Feb 1 doi: 10.1016/j.ejpn.2022.01.014. PMID: 35124541
Coffey B, Jankovic J, Claassen DO, Jimenez-Shahed J, Gertz BJ, Garofalo EA, Stamler DA, Wieman M, Savola JM, Gordon MF, Alexander JK, Barkay H, Harary E
JAMA Netw Open 2021 Oct 1;4(10):e2129397. doi: 10.1001/jamanetworkopen.2021.29397. PMID: 34661664Free PMC Article
Jankovic J, Coffey B, Claassen DO, Jimenez-Shahed J, Gertz BJ, Garofalo EA, Stamler DA, Wieman M, Savola JM, Gordon MF, Alexander J, Barkay H, Harary E
JAMA Netw Open 2021 Oct 1;4(10):e2128204. doi: 10.1001/jamanetworkopen.2021.28204. PMID: 34609495Free PMC Article
Ciolfi A, Foroutan A, Capuano A, Pedace L, Travaglini L, Pizzi S, Andreani M, Miele E, Invernizzi F, Reale C, Panteghini C, Iascone M, Niceta M, Gavrilova RH, Schultz-Rogers L, Agolini E, Bedeschi MF, Prontera P, Garibaldi M, Galosi S, Leuzzi V, Soliveri P, Olson RJ, Zorzi GS, Garavaglia BM, Tartaglia M, Sadikovic B
Clin Epigenetics 2021 Aug 11;13(1):157. doi: 10.1186/s13148-021-01145-y. PMID: 34380541Free PMC Article
Bhidayasiri R, Tarsy D
Expert Rev Neurother 2006 Jun;6(6):863-86. doi: 10.1586/14737175.6.6.863. PMID: 16784410

Prognosis

Öz Yıldız S, Yalnızoğlu D, Şimsek Kiper PÖ, Göçmen R, Soğukpınar M, Utine GE, Haliloğlu G
Neuropediatrics 2024 Jun;55(3):156-165. Epub 2024 Feb 16 doi: 10.1055/s-0044-1779618. PMID: 38365196
Rangel YA, Espinosa E
Biomedica 2022 Sep 2;42(3):429-434. doi: 10.7705/biomedica.6296. PMID: 36122281Free PMC Article
Ramezani Ghamsari M, Ghourchian S, Emamikhah M, Safdarian M, Shahidi G, Parvaresh M, Moghaddasi M, Habibi SAH, Munhoz RP, Rohani M
Clin Neurol Neurosurg 2021 Feb;201:106449. Epub 2020 Dec 28 doi: 10.1016/j.clineuro.2020.106449. PMID: 33395620
Jankovic J, Madisetty J, Vuong KD
Pediatrics 2004 Nov;114(5):1203-5. doi: 10.1542/peds.2004-0031. PMID: 15520096
Saint Hilaire MH, Burke RE, Bressman SB, Brin MF, Fahn S
Neurology 1991 Feb;41(2 ( Pt 1)):216-22. doi: 10.1212/wnl.41.2_part_1.216. PMID: 1992364

Clinical prediction guides

Mandarano R, Danieli A, Petacchi E, Di Pede C, Mondani M, Armellin MT, Facchin D, Martinuzzi A
Eur J Paediatr Neurol 2022 Mar;37:62-67. Epub 2022 Feb 1 doi: 10.1016/j.ejpn.2022.01.014. PMID: 35124541
Coffey B, Jankovic J, Claassen DO, Jimenez-Shahed J, Gertz BJ, Garofalo EA, Stamler DA, Wieman M, Savola JM, Gordon MF, Alexander JK, Barkay H, Harary E
JAMA Netw Open 2021 Oct 1;4(10):e2129397. doi: 10.1001/jamanetworkopen.2021.29397. PMID: 34661664Free PMC Article
Jankovic J, Coffey B, Claassen DO, Jimenez-Shahed J, Gertz BJ, Garofalo EA, Stamler DA, Wieman M, Savola JM, Gordon MF, Alexander J, Barkay H, Harary E
JAMA Netw Open 2021 Oct 1;4(10):e2128204. doi: 10.1001/jamanetworkopen.2021.28204. PMID: 34609495Free PMC Article
Ramezani Ghamsari M, Ghourchian S, Emamikhah M, Safdarian M, Shahidi G, Parvaresh M, Moghaddasi M, Habibi SAH, Munhoz RP, Rohani M
Clin Neurol Neurosurg 2021 Feb;201:106449. Epub 2020 Dec 28 doi: 10.1016/j.clineuro.2020.106449. PMID: 33395620
Horisawa S, Azuma K, Akagawa H, Nonaka T, Kawamata T, Taira T
Ann Clin Transl Neurol 2020 Oct;7(10):2047-2051. Epub 2020 Sep 4 doi: 10.1002/acn3.51170. PMID: 32886413Free PMC Article

Recent systematic reviews

Öz Yıldız S, Yalnızoğlu D, Şimsek Kiper PÖ, Göçmen R, Soğukpınar M, Utine GE, Haliloğlu G
Neuropediatrics 2024 Jun;55(3):156-165. Epub 2024 Feb 16 doi: 10.1055/s-0044-1779618. PMID: 38365196

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