Dystonia 12

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 (601338).

Description

Dystonia-12, 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).

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.

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.

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.