# 128235

DYSTONIA 12; DYT12


Alternative titles; symbols

DYSTONIA-PARKINSONISM, RAPID-ONSET; RDP


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
19q13.2 Dystonia-12 128235 AD 3 ATP1A3 182350
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Face
- Facial dystonia
- Hypomimic face
Neck
- Torticollis
NEUROLOGIC
Central Nervous System
- Dystonia
- Bulbar and upper limb symptoms more severe than lower limb symptoms
- Parkinsonism
- Rapid initial onset of symptoms (hours to weeks)
- Bradykinesia
- Slow gait
- Unsteady gait
- Postural instability
- Dysphagia
- Dysarthria
- Drooling
- Mutism
- Onset may be triggered by emotional stress, fever, exercise, exposure to heat
- Symptoms stabilize within 4 weeks
- Most patients remain stable or improve in years after the abrupt onset of symptoms
- Transient mild dystonia may precede abrupt onset of disorder by several years
- Normal brain MRI or CT scan
- Cerebrospinal fluid may show decreased levels of homovanillic acid (HVA)
Behavioral Psychiatric Manifestations
- Depression
- Emotional lability
- Anxiety
MISCELLANEOUS
- Onset usually in late adolescence or early adulthood (range 15 to 45 years)
- Childhood onset rarely occurs
- Treatment with levodopa is not effective
- Reduced penetrance
MOLECULAR BASIS
- Caused by mutations in the alpha-3 subunit of the Na+/K+-ATPase gene (ATP1A3, 182350.0001)
Dystonia - PS128100 - 37 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p36.32-p36.13 Dystonia 13, torsion AD 2 607671 DYT13 607671
1p35.3 Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities AR 3 617282 MECR 608205
1p35.1 Dystonia 2, torsion, autosomal recessive AR 3 224500 HPCA 142622
1p34.2 GLUT1 deficiency syndrome 2, childhood onset AD 3 612126 SLC2A1 138140
1p34.2 Dystonia 9 AD 3 601042 SLC2A1 138140
2p22.2 Dystonia 33 AD, AR 3 619687 EIF2AK2 176871
2q14.3-q21.3 Dystonia 21 AD 2 614588 DYT21 614588
2q31 Paroxysmal nonkinesigenic dyskinesia 2 AD 2 611147 PNKD2 611147
2q31.2 Dystonia 16 AR 3 612067 PRKRA 603424
2q35 Paroxysmal nonkinesigenic dyskinesia 1 AD 3 118800 PNKD 609023
2q37.3 Dystonia 27 AR 3 616411 COL6A3 120250
3p13 ?Dystonia 35, childhood-onset AR 3 619921 SHQ1 613663
4q21.1 Dystonia 37, early-onset, with striatal lesions AR 3 620427 NUP54 607607
5q22.3 ?Dystonia 34, myoclonic AD 3 619724 KCNN2 605879
7q21.3 Dystonia-11, myoclonic AD 3 159900 SGCE 604149
8p11.21 Dystonia 6, torsion AD 3 602629 THAP1 609520
9q22.32 Dystonia 31 AR 3 619565 AOPEP 619600
9q34 Dystonia 23 AD 2 614860 DYT23 614860
9q34.11 Dystonia-1, torsion AD 3 128100 TOR1A 605204
11p14.3-p14.2 Dystonia 24 AD 3 615034 ANO3 610110
11q13.2 Episodic kinesigenic dyskinesia 3 AD 3 620245 TMEM151A 620108
11q23.3 ?Dystonia 32 AR 3 619637 VPS11 608549
14q22.2 Dystonia, DOPA-responsive AD, AR 3 128230 GCH1 600225
16p11.2 Episodic kinesigenic dyskinesia 1 AD 3 128200 PRRT2 614386
16q13-q22.1 Episodic kinesigenic dyskinesia 2 AD 2 611031 EKD2 611031
17q22 Dystonia 22, juvenile-onset AR 3 620453 TSPOAP1 610764
17q22 ?Dystonia 22, adult-onset AR 3 620456 TSPOAP1 610764
18p11 Dystonia-15, myoclonic AD 2 607488 DYT15 607488
18p Dystonia-7, torsion AD 2 602124 DYT7 602124
18p11.21 Dystonia 25 AD 3 615073 GNAL 139312
19p13.3 Dystonia 4, torsion, autosomal dominant AD 3 128101 TUBB4A 602662
19q13.12 Dystonia 28, childhood-onset AD 3 617284 KMT2B 606834
19q13.2 Dystonia-12 AD 3 128235 ATP1A3 182350
20p13 Dystonia 30 AD 3 619291 VPS16 608550
20p11.2-q13.12 Dystonia-17, primary torsion AR 2 612406 DYT17 612406
22q12.3 Dystonia 26, myoclonic AD 3 616398 KCTD17 616386
Xq13.1 Dystonia-Parkinsonism, X-linked XLR 3 314250 TAF1 313650

TEXT

A number sign (#) is used with this entry because rapid-onset dystonia-parkinsonism (DYT12) is caused by heterozygous mutation in the gene encoding the alpha-3 subunit of the N,K-ATPase (ATP1A3; 182350) on chromosome 19q13.

Heterozygous mutation in the ATP1A3 gene can also cause 2 other neurologic disorders that share some clinical features: alternating hemiplegia of childhood-2 (AHC2; 614820) and CAPOS syndrome (CAPOS; 601338).


Description

Dystonia-12 (DYT12), also known as rapid-onset dystonia-parkinsonism, is an autosomal dominant disorder characterized by abrupt onset of asymmetric dystonia and parkinsonism in young adulthood, often after a trigger such as physical overexertion, trauma, heat, or fever. Affected individuals also show slowly progressive nonparoxysmal neurologic deterioration in a rostrocaudal gradient with prominent bulbar dysfunction (summary by Rosewich et al., 2014).


Clinical Features

Dobyns et al. (1993) described a large Indiana family with an apparently 'new' autosomal dominant form of dystonia-parkinsonism characterized by an unusually rapid evolution of signs and symptoms. Affected persons developed dystonia and parkinsonism between 14 and 45 years of age. The onset was acute in 6 individuals with the abrupt onset of symptoms over the course of several hours, and was subacute in 4 others who had evolution over several days or weeks. Thereafter, progression of symptoms was usually very slow. Two had intermittent focal dystonia without parkinsonism, and 1 obligate gene carrier was asymptomatic at age 68 years. Cerebrospinal fluid levels of homovanillic acid were decreased in the 2 individuals tested, but dopaminergic therapy provided only slight benefit. The family contained at least 4 instances of male-to-male transmission of the disorder. Linkage analysis with 3 markers near the gene for idiopathic torsion dystonia (DYT1; 128100) showed several obligate recombinations, thus excluding that gene as the site of the mutation in this disorder.

Brashear et al. (1996) analyzed the variable phenotype. Onset occurred during childhood, adolescence, or adulthood. In contrast to dopamine-responsive dystonia, treatment with L-DOPA was not very effective.

Brashear et al. (1997) reported a family with 4 affected members. One woman reported onset of mild cramping in the left arm and hand and mild limping at age 18 years. While walking on a warm day at age 23, she suddenly felt tremulous, hot, and confused, and developed severe dystonic spasms in the left leg. Over the next 2 days, she had unsteady gait and worsening of dystonia. Neurologic examination at that time showed dysarthria, dysphagia, bradykinesia, and dystonic posturing. Over the following 12 years, she showed slight improvement in dysarthria, with no change in dysphagia, dystonic spasms, and bradykinesia. She used a walker and wheelchair. The other affected family members had a similar clinical history.

Brashear et al. (1998) detected low levels of homovanillic acid (HVA) in the CSF of affected patients and asymptomatic gene carriers, suggesting a defect in the CNS dopaminergic system.

Pittock et al. (2000) reported a family in which 8 members were affected with RDP in an autosomal dominant pattern of inheritance. Five members developed sudden-onset (several hours to days) dystonia with postural instability, and 4 of the 5 had associated severe bulbar symptoms such as dysarthria, drooling, and orofacial dystonia. Some patients showed hypertonicity and hyperreflexia. Two patients had onset associated with a stressor and 1 individual had intermittent hemidystonia with dysarthria coming on abruptly in times of stress or anxiety. Psychiatric morbidity in the family was common, including severe depression, social anxiety, schizoid personality disorder, and mild mental retardation. In most patients, the progression was stable. Autopsy of 1 patient showed no evidence of nerve cell loss, gliosis, or Lewy body formation.

Zaremba et al. (2004) reported a family from southern Poland in which 4 sibs had DYT12. Age at onset ranged from 16 to 28 years, with all affected persons developing sudden and rapid onset of their symptoms. The main clinical features included dystonia of the face, arms, and legs, parkinsonism, and dysarthria. The proband reported abrupt onset at age 17 years of dysarthria, mutism, and drooling, followed by dysphagia and dystonic spasms in the lower face with marked distortion of the lower jaw and involuntary dystonic movements in the right upper limb. Several weeks before, she had some transient speech disturbances lasting several hours. Psychiatric consult diagnosed 'hysteric conversion.' She later experienced intermittent periods of worsening and improvement but remained independent. Physical examination at age 35 years showed parkinsonism with broad-based gait, bradykinesia, hypomimic face, and dystonia of the neck and right arm. She was emotionally labile and depressed. A sister reported transient oculogyric crisis and mutism lasting for 1 year beginning after mild head trauma. She showed improvement after the delivery of her only child, but walking disturbances persisted. A third sib had acute onset at age 28 years of dystonia, severe dysarthria, hypomimic face, and walking difficulties, with only slight improvement over 5 years. Two years earlier, she had experienced an episode of retrocollis that resolved completely within 12 hours. The fourth sib had the mildest course, with sudden onset of cramping in the left wrist and abnormal posturing of the left foot, and dysarthria. In all patients, the course was stationary with a tendency toward improvement over many years. Neither parent was affected, suggesting incomplete penetrance.

Brashear et al. (2007) reviewed the clinical features of 36 individuals from 10 families with DYT12 confirmed by genetic analysis. Seven of the families had previously been reported by de Carvalho Aguiar et al. (2004). The disorder was characterized by abrupt onset of bulbar and limb dystonia with features of parkinsonism. The onset was sometimes preceded by vague antecedent symptoms, such as dystonia or cramping of the hands or distal leg. The age at onset ranged from 8 to 55 years and was always abrupt, usually following a physical or psychologic trigger. Bulbar symptoms were striking, with dysarthria, hypophonia, and dysphagia appearing in a rostrocaudal gradient. Involuntary parkinsonian movements included bradykinesia and postural instability, but usually not tremor. Nonmotor features, such as depression and social phobia, were present in some individuals.

Anselm et al. (2009) reported a boy, born of a Caucasian father and Chinese mother, who had early-onset of severe DYT12 confirmed by genetic analysis (D923N; 182350.0007). Hypotonia and in-toeing of the left foot were noted at age 3 years. On the day of onset at age 4, he sustained mild head trauma followed by sudden onset of mutism, eye convergence, and inability to walk. Over several hours, he developed prominent hypotonia that later evolved into severe dystonia. Mutism evolved into severe dysarthria and drooling. His condition stabilized over several months, and he showed mild improvement over the next 8 years. Early brain PET scan showed hypermetabolism in the striatum involving the caudate nuclei and putamen bilaterally, whereas later scans showed mildly decreased metabolic activity in both thalami and the left putamen. About a year after onset, he developed unusual episodes of flaccidity lasting for hours, later replaced by shorter episodes of stiffness. Treatment with L-DOPA was not effective. At the time of the report, he had bulbar symptoms, striking oromotor dystonia with inability to speak or swallow well, and apraxia.

Tarsy et al. (2010) reported a 29-year-old woman of African Caribbean descent with DYT12. She had onset at age 26 years of weakness and flexion of the left hand and ankle, which progressed rapidly over the next few years to become frank dystonia of the left arm and bulbar symptoms, including dysphagia, laryngeal dysfunction with task-specific dysphonia, and oropharyngeal dysmotility. She also had mild parkinsonism, with hypomimia and wide-based gait. Treatment with oral trihexyphenidyl and botulinum injection into selected laryngeal muscles resulted in clinical improvement. Molecular testing identified a heterozygous mutation in the ATP1A3 gene (E277K; 182350.0003).

Balestrini et al. (2020) evaluated the cardiac phenotype in 110 patients with ATP1A3-related disorders, including 98 with AHC2, 9 with DYT12, and 3 with CAPOS; 22 of the AHC2 patients were previously reported, whereas all of the DYT12 and CAPOS patients were newly reported. Seizures were reported in 58 patients, status epilepticus in 21, and autonomic dysfunction in 60. Syncope, which was the only reported symptom related to cardiac function, was seen in 3 patients. Resting electrocardiogram abnormalities were seen in 6 of the 9 patients with DYT12. Repolarization abnormalities were seen in Holter monitoring in 1 of 2 patients with DYT12 tested. There was no difference in prevalence of 12-lead ECG abnormalities between patients with AHC2, DYT12, or CAPOS.

Clinical Variability

Sweadner et al. (2016) reported a 26-year-old man with an unusual DYT12 phenotype. He presented at age 19 years with rapidly progressive ataxia, dysarthria, and tremor, resulting in the loss of independent ambulation, but with minimal dystonia. Brain imaging showed progressive and severe cerebellar atrophy. Exome sequencing identified a de novo heterozygous missense mutation in the ATP1A3 gene (G316S; 182350.0018), and in vitro functional studies showed that the mutation resulted in a cellular growth defect. Exome sequencing showed that the patient also carried a de novo heterozygous missense E482K variant in the UBQLN4 gene (605440), which may have played a role in the prominent cerebellar ataxia and cerebellar atrophy observed in this patient; functional studies of the UBQLN4 variant were not performed.


Diagnosis

Brashear et al. (1997) developed diagnostic criteria for rapid-onset dystonia-parkinsonism. The disorder shows autosomal dominant inheritance, sudden onset of combined dystonia and parkinsonism with stabilization in less than 4 weeks, bulbar symptoms such as dysarthria and dysphagia, bulbar and arm involvement often more severe than leg involvement, moderate or no response to dopamine agonists, and normal brain MRI.

Brashear et al. (2007) reported updated diagnostic criteria for DYT12. The minimal criteria should include abrupt onset of dystonia with parkinsonism over a few minutes to 30 days, a clear rostrocaudal (face, arm, leg) gradient of involvement, and prominent bulbar findings. Suggestive features include lack of tremor, occasional mild dystonia before abrupt onset, triggers associated with onset, rare abrupt secondary worsening later in life, and stabilization of symptoms within a month of onset. There seems to be minimal improvement overall, but some have limited improvement in gait. Importantly, a family history of the disorder is not required for diagnosis.


Clinical Management

Balestrini et al. (2020) recommended that all individuals with the ATP1A3-related disorders DYT12, AHC2, and CAPOS undergo a baseline ECG, cardiac ultrasound, and Holter monitoring. They further recommended annual 12-lead ECGs for all patients, and additional studies (e.g., Holter monitoring) as needed based on patient symptoms.


Mapping

Kramer et al. (1999) studied 81 members of 2 midwestern U.S. families with rapid-onset dystonia-parkinsonism, 16 of whom exhibited classic features. Kramer et al. (1999) found significant evidence for linkage in these 2 families to markers on chromosome 19q13, with the highest multipoint lod score of 5.77 at D19S198 (theta = 0.0). The flanking markers D19S587 and D19S900 defined a candidate region of approximately 8 cM. Genetic analysis of the affected family reported by Pittock et al. (2000) suggested linkage to the RDP locus on chromosome 19q13 (lod score = 2.1).

Zaremba et al. (2004) found linkage to chromosome 19 in a family from southern Poland with RDP.


Inheritance

The transmission pattern of dystonia-12 in the family reported by Dobyns et al. (1993) was consistent with autosomal dominant inheritance.


Molecular Genetics

In affected members of 7 unrelated families with rapid-onset dystonia parkinsonism, de Carvalho Aguiar et al. (2004) identified 6 different heterozygous mutations in the ATP1A3 gene (182350.0001-182350.0006). Three of the families had previously been reported by Dobyns et al. (1993), Brashear et al. (1997), and Zaremba et al. (2004).

Brashear et al. (2007) identified mutations in the ATP1A3 gene in 3 (21%) of 14 probands referred for testing, including the T613M mutation (182350.0001) in affected members of the family reported by Pittock et al. (2000). One of the patients had a de novo mutation, and another was believed to have a de novo mutation.

Blanco-Arias et al. (2009) reported a de novo 3-bp insertion in the ATP1A3 gene (182350.0008) in a 16-year-old female patient with sudden-onset dystonia-12.


REFERENCES

  1. Anselm, I. A., Sweadner, K. J., Gollamudi, S., Ozelius, L. J., Darras, B. T. Rapid-onset dystonia-parkinsonism in a child with a novel ATP1A3 gene mutation. Neurology 73: 400-401, 2009. [PubMed: 19652145, related citations] [Full Text]

  2. Balestrini, S., Mikati, M. A., Alvarez-Garcia-Roves, R., Carboni, M. Hunanyan, A. S., Kherallah, B., McLean, M., Prange, L., De Grandis, E., Gagliardi, A., Pisciotta, L., Stagnaro, M., and 42 others. Cardiac phenotype in ATP1A3-related syndromes: a multicenter study. Neurology 95: e2866-e2879, 2020. [PubMed: 32913013, related citations] [Full Text]

  3. Blanco-Arias, P., Einholm, A. P., Mamsa, H., Concheiro, C., Gutierrez-de-Teran, H., Romero, J., Toustrup-Jensen, M. S., Carracedo, A., Jen, J. C., Vilsen, B., Sobrido, M.-J. A C-terminal mutation of ATP1A3 underscores the crucial role of sodium affinity in the pathophysiology of rapid-onset dystonia-parkinsonism. Hum. Molec. Genet. 18: 2370-2377, 2009. [PubMed: 19351654, related citations] [Full Text]

  4. Brashear, A., Butler, I. J., Ozelius, L. J., Kramer, P. L., Farlow, M. R., Breakefield, X. O., Dobyns, W. B. Rapid-onset dystonia-parkinsonism: a report of clinical, biochemical, and genetic studies in two families. Adv. Neurol. 78: 335-339, 1998. [PubMed: 9750930, related citations]

  5. Brashear, A., DeLeon, D., Bressman, S. B., Thyagarajan, D., Farlow, M. R., Dobyns, W. B. Rapid-onset dystonia-parkinsonism in a second family. Neurology 48: 1066-1069, 1997. [PubMed: 9109901, related citations] [Full Text]

  6. Brashear, A., Dobyns, W. B., de Carvalho Aguiar, P., Borg, M., Frijns, C. J. M., Gollamudi, S., Green, A., Guimaraes, J., Haake, B. C., Klein, C., Linazasoro, G., Munchau, A., Raymond, D., Riley, D., Saunders-Pullman, R., Tijssen, M. A. J., Webb, D., Zaremba, J., Bressman, S. B., Ozelius, L. J. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain 130: 828-835, 2007. [PubMed: 17282997, related citations] [Full Text]

  7. Brashear, A., Farlow, M. R., Butler, I. J., Kasarskis, E. J., Dobyns, W. B. Variable phenotype of rapid-onset dystonia-parkinsonism. Mov. Disord. 11: 151-156, 1996. [PubMed: 8684384, related citations] [Full Text]

  8. de Carvalho Aguiar, P., Sweadner, K. J., Penniston, J. T., Zaremba, J., Liu, L., Caton, M., Linazasoro, G., Borg, M., Tijssen, M. A. J., Bressman, S. B., Dobyns, W. B., Brashear, A., Ozelius, L. J. Mutations in the Na(+)/K(+)-ATPase alpha-3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron 43: 169-175, 2004. [PubMed: 15260953, related citations] [Full Text]

  9. Dobyns, W. B., Ozelius, L. J., Kramer, P. L., Brashear, A., Farlow, M. R., Perry, T. R., Walsh, L. E., Kasarskis, E. J., Butler, I. J., Breakefield, X. O. Rapid-onset dystonia-parkinsonism. Neurology 43: 2596-2602, 1993. [PubMed: 8255463, related citations] [Full Text]

  10. Kramer, P. L., Mineta, M., Klein, C., Schilling, K., de Leon, D., Farlow, M. R., Breakefield, X. O., Bressman, S. B., Dobyns, W. B., Ozelius, L. J., Brashear, A. Rapid-onset dystonia-parkinsonism: linkage to chromosome 19q13. Ann. Neurol. 46: 176-182, 1999. [PubMed: 10443882, related citations] [Full Text]

  11. Pittock, S. J., Joyce, C., O'Keane, V., Hugle, B., Hardiman, O., Brett, F., Green, A. J., Barton, D. E., King, M. D., Webb, D. W. Rapid-onset dystonia-parkinsonism: a clinical and genetic analysis of a new kindred. Neurology 55: 991-995, 2000. [PubMed: 11061257, related citations] [Full Text]

  12. Rosewich, H., Ohlenbusch, A., Huppke, P., Schlotawa, L., Baethmann, M., Carrilho, I., Fiori, S., Lourenco, C. M., Sawyer, S., Steinfeld, R., Gartner, J., Brockmann, K. The expanding clinical and genetic spectrum of ATP1A3-related disorders. Neurology 82: 945-955, 2014. [PubMed: 24523486, related citations] [Full Text]

  13. Sweadner, K. J., Toro, C., Whitlow, C. T., Snively, B. M., Cook, J. F., Ozelius, L. J., Markello, T. C., Brashear, A. ATP1A3 mutation in adult rapid-onset ataxia. PLoS One 11: e0151429, 2016. Note: Electronic Article. [PubMed: 26990090, related citations] [Full Text]

  14. Tarsy, D., Sweadner, K. J., Song, P. C. Case 17-2010: a 29-year-old woman with flexion of the left hand and foot and difficulty speaking. New Eng. J. Med. 362: 2213-2219, 2010. [PubMed: 20558373, related citations] [Full Text]

  15. Zaremba, J., Mierzewska, H., Lysiak, Z., Kramer, P., Ozelius, L. J., Brashear, A. Rapid-onset dystonia-parkinsonism: a fourth family consistent with linkage to chromosome 19q13. Mov. Disord. 19: 1506-1510, 2004. [PubMed: 15390049, related citations] [Full Text]


Hilary J. Vernon - updated : 02/01/2021
Cassandra L. Kniffin - updated : 4/13/2016
Cassandra L. Kniffin - updated : 9/29/2014
Cassandra L. Kniffin - updated : 6/10/2010
George E. Tiller - updated : 3/30/2010
Cassandra L. Kniffin - updated : 12/17/2009
Cassandra L. Kniffin - updated : 3/21/2005
Cassandra L. Kniffin - updated : 3/10/2005
Cassandra L. Kniffin - updated : 9/30/2003
Ada Hamosh - updated : 10/24/2000
Victor A. McKusick - updated : 5/6/1998
Creation Date:
Victor A. McKusick : 5/11/1992
carol : 12/15/2022
carol : 01/07/2022
carol : 02/02/2021
carol : 02/01/2021
carol : 04/14/2016
ckniffin : 4/13/2016
alopez : 9/29/2014
ckniffin : 9/29/2014
mcolton : 2/21/2014
wwang : 6/11/2010
ckniffin : 6/10/2010
wwang : 3/31/2010
terry : 3/30/2010
wwang : 1/8/2010
ckniffin : 12/17/2009
ckniffin : 4/5/2005
ckniffin : 3/21/2005
wwang : 3/16/2005
wwang : 3/10/2005
ckniffin : 3/10/2005
ckniffin : 3/10/2005
carol : 10/2/2003
ckniffin : 9/30/2003
alopez : 10/25/2000
terry : 10/24/2000
carol : 10/2/2000
carol : 9/29/1999
carol : 5/13/1998
terry : 5/6/1998
carol : 4/1/1994
carol : 10/26/1993
carol : 10/18/1993
carol : 10/4/1993
carol : 9/30/1993
carol : 9/16/1993

# 128235

DYSTONIA 12; DYT12


Alternative titles; symbols

DYSTONIA-PARKINSONISM, RAPID-ONSET; RDP


SNOMEDCT: 702323008;   ORPHA: 71517;   DO: 0090056;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
19q13.2 Dystonia-12 128235 Autosomal dominant 3 ATP1A3 182350

TEXT

A number sign (#) is used with this entry because rapid-onset dystonia-parkinsonism (DYT12) is caused by heterozygous mutation in the gene encoding the alpha-3 subunit of the N,K-ATPase (ATP1A3; 182350) on chromosome 19q13.

Heterozygous mutation in the ATP1A3 gene can also cause 2 other neurologic disorders that share some clinical features: alternating hemiplegia of childhood-2 (AHC2; 614820) and CAPOS syndrome (CAPOS; 601338).


Description

Dystonia-12 (DYT12), also known as rapid-onset dystonia-parkinsonism, is an autosomal dominant disorder characterized by abrupt onset of asymmetric dystonia and parkinsonism in young adulthood, often after a trigger such as physical overexertion, trauma, heat, or fever. Affected individuals also show slowly progressive nonparoxysmal neurologic deterioration in a rostrocaudal gradient with prominent bulbar dysfunction (summary by Rosewich et al., 2014).


Clinical Features

Dobyns et al. (1993) described a large Indiana family with an apparently 'new' autosomal dominant form of dystonia-parkinsonism characterized by an unusually rapid evolution of signs and symptoms. Affected persons developed dystonia and parkinsonism between 14 and 45 years of age. The onset was acute in 6 individuals with the abrupt onset of symptoms over the course of several hours, and was subacute in 4 others who had evolution over several days or weeks. Thereafter, progression of symptoms was usually very slow. Two had intermittent focal dystonia without parkinsonism, and 1 obligate gene carrier was asymptomatic at age 68 years. Cerebrospinal fluid levels of homovanillic acid were decreased in the 2 individuals tested, but dopaminergic therapy provided only slight benefit. The family contained at least 4 instances of male-to-male transmission of the disorder. Linkage analysis with 3 markers near the gene for idiopathic torsion dystonia (DYT1; 128100) showed several obligate recombinations, thus excluding that gene as the site of the mutation in this disorder.

Brashear et al. (1996) analyzed the variable phenotype. Onset occurred during childhood, adolescence, or adulthood. In contrast to dopamine-responsive dystonia, treatment with L-DOPA was not very effective.

Brashear et al. (1997) reported a family with 4 affected members. One woman reported onset of mild cramping in the left arm and hand and mild limping at age 18 years. While walking on a warm day at age 23, she suddenly felt tremulous, hot, and confused, and developed severe dystonic spasms in the left leg. Over the next 2 days, she had unsteady gait and worsening of dystonia. Neurologic examination at that time showed dysarthria, dysphagia, bradykinesia, and dystonic posturing. Over the following 12 years, she showed slight improvement in dysarthria, with no change in dysphagia, dystonic spasms, and bradykinesia. She used a walker and wheelchair. The other affected family members had a similar clinical history.

Brashear et al. (1998) detected low levels of homovanillic acid (HVA) in the CSF of affected patients and asymptomatic gene carriers, suggesting a defect in the CNS dopaminergic system.

Pittock et al. (2000) reported a family in which 8 members were affected with RDP in an autosomal dominant pattern of inheritance. Five members developed sudden-onset (several hours to days) dystonia with postural instability, and 4 of the 5 had associated severe bulbar symptoms such as dysarthria, drooling, and orofacial dystonia. Some patients showed hypertonicity and hyperreflexia. Two patients had onset associated with a stressor and 1 individual had intermittent hemidystonia with dysarthria coming on abruptly in times of stress or anxiety. Psychiatric morbidity in the family was common, including severe depression, social anxiety, schizoid personality disorder, and mild mental retardation. In most patients, the progression was stable. Autopsy of 1 patient showed no evidence of nerve cell loss, gliosis, or Lewy body formation.

Zaremba et al. (2004) reported a family from southern Poland in which 4 sibs had DYT12. Age at onset ranged from 16 to 28 years, with all affected persons developing sudden and rapid onset of their symptoms. The main clinical features included dystonia of the face, arms, and legs, parkinsonism, and dysarthria. The proband reported abrupt onset at age 17 years of dysarthria, mutism, and drooling, followed by dysphagia and dystonic spasms in the lower face with marked distortion of the lower jaw and involuntary dystonic movements in the right upper limb. Several weeks before, she had some transient speech disturbances lasting several hours. Psychiatric consult diagnosed 'hysteric conversion.' She later experienced intermittent periods of worsening and improvement but remained independent. Physical examination at age 35 years showed parkinsonism with broad-based gait, bradykinesia, hypomimic face, and dystonia of the neck and right arm. She was emotionally labile and depressed. A sister reported transient oculogyric crisis and mutism lasting for 1 year beginning after mild head trauma. She showed improvement after the delivery of her only child, but walking disturbances persisted. A third sib had acute onset at age 28 years of dystonia, severe dysarthria, hypomimic face, and walking difficulties, with only slight improvement over 5 years. Two years earlier, she had experienced an episode of retrocollis that resolved completely within 12 hours. The fourth sib had the mildest course, with sudden onset of cramping in the left wrist and abnormal posturing of the left foot, and dysarthria. In all patients, the course was stationary with a tendency toward improvement over many years. Neither parent was affected, suggesting incomplete penetrance.

Brashear et al. (2007) reviewed the clinical features of 36 individuals from 10 families with DYT12 confirmed by genetic analysis. Seven of the families had previously been reported by de Carvalho Aguiar et al. (2004). The disorder was characterized by abrupt onset of bulbar and limb dystonia with features of parkinsonism. The onset was sometimes preceded by vague antecedent symptoms, such as dystonia or cramping of the hands or distal leg. The age at onset ranged from 8 to 55 years and was always abrupt, usually following a physical or psychologic trigger. Bulbar symptoms were striking, with dysarthria, hypophonia, and dysphagia appearing in a rostrocaudal gradient. Involuntary parkinsonian movements included bradykinesia and postural instability, but usually not tremor. Nonmotor features, such as depression and social phobia, were present in some individuals.

Anselm et al. (2009) reported a boy, born of a Caucasian father and Chinese mother, who had early-onset of severe DYT12 confirmed by genetic analysis (D923N; 182350.0007). Hypotonia and in-toeing of the left foot were noted at age 3 years. On the day of onset at age 4, he sustained mild head trauma followed by sudden onset of mutism, eye convergence, and inability to walk. Over several hours, he developed prominent hypotonia that later evolved into severe dystonia. Mutism evolved into severe dysarthria and drooling. His condition stabilized over several months, and he showed mild improvement over the next 8 years. Early brain PET scan showed hypermetabolism in the striatum involving the caudate nuclei and putamen bilaterally, whereas later scans showed mildly decreased metabolic activity in both thalami and the left putamen. About a year after onset, he developed unusual episodes of flaccidity lasting for hours, later replaced by shorter episodes of stiffness. Treatment with L-DOPA was not effective. At the time of the report, he had bulbar symptoms, striking oromotor dystonia with inability to speak or swallow well, and apraxia.

Tarsy et al. (2010) reported a 29-year-old woman of African Caribbean descent with DYT12. She had onset at age 26 years of weakness and flexion of the left hand and ankle, which progressed rapidly over the next few years to become frank dystonia of the left arm and bulbar symptoms, including dysphagia, laryngeal dysfunction with task-specific dysphonia, and oropharyngeal dysmotility. She also had mild parkinsonism, with hypomimia and wide-based gait. Treatment with oral trihexyphenidyl and botulinum injection into selected laryngeal muscles resulted in clinical improvement. Molecular testing identified a heterozygous mutation in the ATP1A3 gene (E277K; 182350.0003).

Balestrini et al. (2020) evaluated the cardiac phenotype in 110 patients with ATP1A3-related disorders, including 98 with AHC2, 9 with DYT12, and 3 with CAPOS; 22 of the AHC2 patients were previously reported, whereas all of the DYT12 and CAPOS patients were newly reported. Seizures were reported in 58 patients, status epilepticus in 21, and autonomic dysfunction in 60. Syncope, which was the only reported symptom related to cardiac function, was seen in 3 patients. Resting electrocardiogram abnormalities were seen in 6 of the 9 patients with DYT12. Repolarization abnormalities were seen in Holter monitoring in 1 of 2 patients with DYT12 tested. There was no difference in prevalence of 12-lead ECG abnormalities between patients with AHC2, DYT12, or CAPOS.

Clinical Variability

Sweadner et al. (2016) reported a 26-year-old man with an unusual DYT12 phenotype. He presented at age 19 years with rapidly progressive ataxia, dysarthria, and tremor, resulting in the loss of independent ambulation, but with minimal dystonia. Brain imaging showed progressive and severe cerebellar atrophy. Exome sequencing identified a de novo heterozygous missense mutation in the ATP1A3 gene (G316S; 182350.0018), and in vitro functional studies showed that the mutation resulted in a cellular growth defect. Exome sequencing showed that the patient also carried a de novo heterozygous missense E482K variant in the UBQLN4 gene (605440), which may have played a role in the prominent cerebellar ataxia and cerebellar atrophy observed in this patient; functional studies of the UBQLN4 variant were not performed.


Diagnosis

Brashear et al. (1997) developed diagnostic criteria for rapid-onset dystonia-parkinsonism. The disorder shows autosomal dominant inheritance, sudden onset of combined dystonia and parkinsonism with stabilization in less than 4 weeks, bulbar symptoms such as dysarthria and dysphagia, bulbar and arm involvement often more severe than leg involvement, moderate or no response to dopamine agonists, and normal brain MRI.

Brashear et al. (2007) reported updated diagnostic criteria for DYT12. The minimal criteria should include abrupt onset of dystonia with parkinsonism over a few minutes to 30 days, a clear rostrocaudal (face, arm, leg) gradient of involvement, and prominent bulbar findings. Suggestive features include lack of tremor, occasional mild dystonia before abrupt onset, triggers associated with onset, rare abrupt secondary worsening later in life, and stabilization of symptoms within a month of onset. There seems to be minimal improvement overall, but some have limited improvement in gait. Importantly, a family history of the disorder is not required for diagnosis.


Clinical Management

Balestrini et al. (2020) recommended that all individuals with the ATP1A3-related disorders DYT12, AHC2, and CAPOS undergo a baseline ECG, cardiac ultrasound, and Holter monitoring. They further recommended annual 12-lead ECGs for all patients, and additional studies (e.g., Holter monitoring) as needed based on patient symptoms.


Mapping

Kramer et al. (1999) studied 81 members of 2 midwestern U.S. families with rapid-onset dystonia-parkinsonism, 16 of whom exhibited classic features. Kramer et al. (1999) found significant evidence for linkage in these 2 families to markers on chromosome 19q13, with the highest multipoint lod score of 5.77 at D19S198 (theta = 0.0). The flanking markers D19S587 and D19S900 defined a candidate region of approximately 8 cM. Genetic analysis of the affected family reported by Pittock et al. (2000) suggested linkage to the RDP locus on chromosome 19q13 (lod score = 2.1).

Zaremba et al. (2004) found linkage to chromosome 19 in a family from southern Poland with RDP.


Inheritance

The transmission pattern of dystonia-12 in the family reported by Dobyns et al. (1993) was consistent with autosomal dominant inheritance.


Molecular Genetics

In affected members of 7 unrelated families with rapid-onset dystonia parkinsonism, de Carvalho Aguiar et al. (2004) identified 6 different heterozygous mutations in the ATP1A3 gene (182350.0001-182350.0006). Three of the families had previously been reported by Dobyns et al. (1993), Brashear et al. (1997), and Zaremba et al. (2004).

Brashear et al. (2007) identified mutations in the ATP1A3 gene in 3 (21%) of 14 probands referred for testing, including the T613M mutation (182350.0001) in affected members of the family reported by Pittock et al. (2000). One of the patients had a de novo mutation, and another was believed to have a de novo mutation.

Blanco-Arias et al. (2009) reported a de novo 3-bp insertion in the ATP1A3 gene (182350.0008) in a 16-year-old female patient with sudden-onset dystonia-12.


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Contributors:
Hilary J. Vernon - updated : 02/01/2021
Cassandra L. Kniffin - updated : 4/13/2016
Cassandra L. Kniffin - updated : 9/29/2014
Cassandra L. Kniffin - updated : 6/10/2010
George E. Tiller - updated : 3/30/2010
Cassandra L. Kniffin - updated : 12/17/2009
Cassandra L. Kniffin - updated : 3/21/2005
Cassandra L. Kniffin - updated : 3/10/2005
Cassandra L. Kniffin - updated : 9/30/2003
Ada Hamosh - updated : 10/24/2000
Victor A. McKusick - updated : 5/6/1998

Creation Date:
Victor A. McKusick : 5/11/1992

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