Paroxysmal Nonkinesigenic Dyskinesia 1

A number sign (#) is used with this entry because of evidence that paroxysmal nonkinesigenic dyskinesia-1 (PNKD1) is caused by heterozygous mutation in the myofibrillogenesis regulator-1 gene (MR1; 609023) on chromosome 2q35.

Genetic Heterogeneity of Paroxysmal Nonkinesigenic Dyskinesia

See also PNKD2 (611147), which maps to chromosome 2q31, and PNKD3 (609446), caused by mutation in the KCNMA1 gene (600150) on chromosome 10q22.

Clinical Features

Mount and Reback (1940) described a family with many members in 5 generations affected by paroxysmal choreoathetosis which was thought to be separate from Huntington chorea. The attacks lasted only a few minutes, occurred a few times a day and were not accompanied by unconsciousness. Alcohol, coffee, hunger, fatigue, and tobacco were precipitating factors. Affected persons were said to be scattered throughout the southern U.S. from South Carolina to Oklahoma. Wagner et al. (1966) observed affected persons in 3 generations. Richards and Barnett (1968) suggested that it be called paroxysmal dystonic choreoathetosis to distinguish it from the more frequently reported movement-induced (kinetogenic) familial (or nonfamilial) paroxysmal choreoathetosis with which it is often confused. They also suggested use of the eponym Mount-Reback for the dystonic form. Muller and Kupke (1990) referred to this disorder as paroxysmal dystonic choreoathetosis. See familial paroxysmal dystonia (128200).

Walker (1981) provided follow-up on the Mount-Reback kindred. He observed a son and daughter of their proband. The movement disorder could be recognized in the first week of life. The attacks were usually preceded by an aura. The Canadian family reported by Richards and Barnett (1968) was the only one Walker (1981) considered identical to that of Mount and Reback. Walker (1981) raised the possibility that these 2 kindreds are related because of similar origin in the British Isles and commonality of some family names.

Byrne et al. (1991) presented a family with paroxysmal dystonic choreoathetosis transmitted as a dominant trait through 5 generations. The family was unusual in that several of the affected members showed interruption of the episodes by short periods of sleep. Also, age of onset was highly variable and some of the affected persons showed prominent myokymia. The overlapping features suggested a relationship between this disorder and familial paroxysmal ataxia with myokymia (160120).

Demirkiran and Jankovic (1995) studied 46 patients with paroxysmal dyskinesias. They introduced a new classification: kinesigenic, induced by movement; nonkinesigenic, exertion-induced; and hypnogenic, induced by sleep. Of their 46 patients, only 2 had a positive family history, 1 with kinesigenic, the other with hypnogenic dyskinesia. In the 23 other patients in which an etiology could be identified, this included psychogenic, cerebrovascular, multiple sclerosis, encephalitis, cerebral trauma, peripheral trauma, migraine, and kernicterus. Patients with kinesigenic dyskinesias responded more frequently to anticonvulsant medication than those with nonkinesigenic dyskinesias.

Fink et al. (1996) reported a large Polish-American family with PDC. Symptom onset occurred by age 2 years and persisted throughout life. Paroxysmal dyskinesia began as a sense of muscle tightening, typically in an extremity, followed by dystonic posturing and choreoathetoid movements of that extremity. Involuntary movements also affected the face, jaw, and tongue, resulting in dysarthria or dysphagia. The duration of spells ranged from less than 30 minutes to greater than several hours, and occurred up to several times a week, at rest, both spontaneously and following caffeine and alcohol consumption. Clonazepam and diazepam were moderately effective in preventing attacks or lessening their severity. Neurologic examinations between episodes were normal, and there was no disturbance of consciousness during episodes.

Muller et al. (1998) pointed out the close similarity between this disorder, which the authors referred to as dystonia-8, and that referred to elsewhere as episodic choreoathetosis/spasticity (CSE; 601042). Muller et al. (1998) referred to CSE, which maps to 1p, as dystonia-9. CSE has episodic ataxia as an additional feature, but the involuntary movements and dystonia are similar to those of PDC. In both disorders, episodes can be induced by alcohol, fatigue, and emotional stress; however, in CSE, physical exercise can also precipitate episodes, and some patients with CSE have spastic paraplegia both during and between episodes of dyskinesia.

Bruno et al. (2007) compared the clinical features of 8 kindreds with PNKD due to MR1 mutations to those of 6 kindreds with a similar phenotype, but lacking MR1 mutations. Patients with MR1 mutations had a homogeneous phenotype with earlier onset (3 months to 12 years) of attacks consisting of a mixture of chorea and dystonia in the limbs, face, and trunk usually lasting from 10 to 60 minutes. Premonitory sensations, mainly focal limb sensation, were reported by 41% of mutation carriers. Most (86%) patients reported at least 1 attack per week at some point in their lives. Migraine headaches were present in 47%; no patients had seizures. Attacks were precipitated by caffeine, alcohol, and stress, and there was good response to benzodiazepines. Five (71%) of 7 women reported fewer or no attacks during pregnancy. Patients without MR1 mutations were more variable in age at onset, clinical features, precipitants, and response to medications. Major differences from the mutation-positive group included exercise as a precipitating factor (68%), alcohol not being a precipitating factor, ballism (18%), and seizures (23%). Bruno et al. (2007) proposed clinical criteria for PNKD based on the data.

Mapping

Fouad et al. (1996) performed linkage studies in a large 5-generation Italian family with 20 affected members, using 99 markers uniformly distributed throughout the autosomes. Positive lod scores were found with marker D2S102 at 2q31-q36; maximum lod = 4.64 at theta = 0. Additional markers were used to refine the location of the PDC locus to a 10-cM region between markers D2S128 (proximal) and D2S126 (distal). In a large Polish-American family with PDC, Fink et al. (1996) found tight linkage between the disease locus and microsatellite markers on distal 2q (2q33-q35); a maximum 2-point lod score of 4.77 at theta = 0 was found with marker D2S173. Fouad et al. (1996) and Fink et al. (1996) noted that other forms of paroxysmal neurologic disorders (e.g., hypo- and hyperkalemic periodic paralysis; 170400 and 170500, respectively) are due to mutation in ion channel genes and that a cluster of sodium channel genes is located on distal chromosome 2. Fouad et al. (1996) suggested AE3 (SLC4A3; 106195), which maps near the PDC locus, as a candidate gene.

Raskind et al. (1998) reported a family with PDC linked to chromosome 2q31-q36; a maximum 2-point lod score of 4.20 at theta = 0 was obtained for marker D2S120. The authors suggested the anion exchanger SLC4A3 as a candidate gene; however, this family was poorly informative for polymorphic markers within and flanking that gene.

Molecular Genetics

By sequence analysis, Grunder et al. (2001) excluded the acid-sensing ion channel 4 gene (ASIC4; 606715) as causative for PDC.

In affected members of 2 unrelated families with PDC, Rainier et al. (2004) identified 2 different heterozygous mutations in the MR1 gene (A9V, 609023.0001; A7V, 609023.0002). One of the families had been reported by Fink et al. (1996). In that family, 2 unaffected members had the mutation, indicating reduced penetrance.

Lee et al. (2004) identified the A9V mutation in affected members of 3 unrelated families with PNKD1 and the A7V mutation in affected members of 5 unrelated families with PNKD1. They noted that MR1 long isoform (MR1L) is likely to have similar enzymatic activity to HAGH (138760), which functions in a pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic beverages and produced as a byproduct of oxidative stress. Lee et al. (2004) suggested a mechanism whereby alcohol, coffee and stress may act as precipitants of attacks in PNKD.

In affected members of 2 unrelated families with PDC, one of which had previously been reported by Raskind et al. (1998), Chen et al. (2005) found the same MR1 mutations as those identified by Rainier et al. (2004). Haplotype analysis suggested that the mutations arose independently in all 4 families.

Djarmati et al. (2005) identified the A9V mutation in the MR1 gene (609023.0001) in a 15-year-old Serbian boy with PNKD1. The patient belonged to a large family with 12 additional affected members in 5 successive generations. Three obligate mutation carriers were unaffected, suggesting incomplete penetrance.

Ghezzi et al. (2009) reported a 3-generation PNKD family in which the proband was heterozygous for a mutation in the N-terminal mitochondrial targeting sequence (MTS) of the MR1 gene (A33P; 609023.0003). Their results differed from those reported by Lee et al. (2004) with regard to localization of the MR1 isoforms and suggested a novel disease mechanism based on a deleterious action of the MTS.