Alternative titles; symbols
SNOMEDCT: 609221008; ORPHA: 98809; DO: 0090053;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p11.2 | Episodic kinesigenic dyskinesia 1 | 128200 | Autosomal dominant | 3 | PRRT2 | 614386 |
A number sign (#) is used with this entry because episodic kinesigenic dyskinesia-1 (EKD1), also known as paroxysmal kinesigenic dyskinesia, is caused by heterozygous mutation in the PRRT2 gene (614386) on chromosome 16p11.
Paroxysmal kinesigenic choreoathetosis (PKC) is an autosomal dominant neurologic condition characterized by recurrent and brief attacks of involuntary movement triggered by sudden voluntary movement. These attacks usually have onset during childhood or early adulthood and can involve dystonic postures, chorea, or athetosis. Symptoms become less severe with age and show favorable response to anticonvulsant medications such as carbamazepine or phenytoin. It is the most common type of paroxysmal movement disorder. The condition is often misdiagnosed as an epileptic manifestation (summary by Chen et al., 2011).
PKC shares some clinical features with benign familial infantile convulsions (BFIC2; 605751) and infantile convulsions and paroxysmal choreoathetosis (ICCA; 602066), which are allelic disorders.
See also rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (608105), which maps to chromosome 16p12-p11.2.
Genetic Heterogeneity of Episodic Kinesigenic Dyskinesia
See also EKD2 (611031), which maps to chromosome 16q13-q22.1, and EKD3 (620245), caused by mutation in the TMEM151A gene (620108) on chromosome 11q13.
Familial paroxysmal dystonia was reported as a 'pure entity' in mother and 3 sons by Weber (1967). He claimed that only 1 family had previously been reported (Lance, 1963) and that the disorder is distinct from familial paroxysmal choreoathetosis (see PNKD1, 118800). It may be the same as the periodic dystonia reported by Smith and Heersema (1941) in which 3 unrelated sibships of Polish and Lithuanian extraction demonstrated episodic dystonic movements of 5 to 10 seconds duration induced by movement. Kertesz (1967) called the condition paroxysmal kinesigenic choreoathetosis.
Goodenough et al. (1978) divided familial paroxysmal dyskinesias into kinesigenic and nonkinesigenic forms according to whether or not paroxysms are precipitated by sudden movements. The kinesigenic form differs from the nonkinesigenic form by later onset in many cases, briefer duration of attacks (seconds to minutes) which usually occur daily, and good response to anticonvulsants. Goodenough et al. (1978) pointed out that there are also acquired forms of paroxysmal dyskinesias, e.g., with multiple sclerosis, cerebral palsy or idiopathic hypoparathyroidism.
The family first reported by Mount and Reback (1940) is an example of familial nonkinesigenic paroxysmal dyskinesia. In the familial nonkinesigenic form, the movements are of longer duration, occur less frequently, and rarely respond to anticonvulsants.
So-called incompletely atonic attacks of PKC appear to be especially frequent in Japanese. Fukuda et al. (1999) described this form in a woman, her brother, and their mother. The woman first presented at the age of 22 years with attacks of muscle weakness mainly in her limbs. The attacks of muscle weakness resembled the choreoathetotic attacks that occur in PKC in terms of their kinesigenicity and duration, clarity of consciousness during the attacks, good therapeutic response to low doses of phenytoin, and familial transmission. All 3 individuals reported by Fukuda et al. (1999) had hypercalcitoninemia which was unexplained. They were not thought to have multiple endocrine neoplasia type IIA (MEN2; 171400) or IIB (MEN2B; 162300), both of which are associated with hypercalcitoninemia.
Sadamatsu et al. (1999) performed video-monitoring EEG in 2 patients with PKC during attacks elicited by movements of the lower extremities. Findings strongly suggested that the etiology should be considered distinct from that of reflex epilepsy. However, the patients in this pedigree had experienced generalized convulsions in infancy; thus, Sadamatsu et al. (1999) could not rule out the possibility of an epileptogenic basis for the condition. No evidence for linkage was found with any 1 of 5 candidate regions.
In a comprehensive review of clinical and molecular genetics of primary dystonias, Muller et al. (1998) referred to this disorder as dystonia-10 and pointed to the reports of Kertesz (1967) and Walker (1981) as examples.
In an extensive linkage study of patients with PKC, Tomita et al. (1999) reported that 42% of their patients had afebrile, general convulsions in infancy (see, e.g., BFIC2, 605751).
Spacey et al. (2002) reported a Caucasian English family in which 8 members had either PKC or seizure. Four family members with PKC had attacks that were choreic and lasted less than a minute, and four family members had generalized and/or partial seizures without PKC, including 2 with infantile seizures. There was suggestive linkage to chromosome 16 if the phenotype considered was PKC plus seizures.
Chen et al. (2011) reported 8 unrelated Han Chinese families with EKD1 confirmed by genetic analysis (614386.0001-614386.0003). The transmission pattern in each family was consistent with autosomal dominant inheritance. The proband of 1 family was described in detail. He had onset at age 6 years of dystonic posturing of the head and arm, usually triggered by standing up quickly. This occurred up to 10 times per day, and lasted about 5 to 10 minutes. Brain MRI and EEG were normal at age 9 years. Treatment with carbamazepine resulted in complete symptom resolution.
In a 2-stage study, Li et al. (2013) found that all (100%) of 25 patients with EKD1 due to mutations in the PRRT2 gene responded favorably to treatment with carbamazepine, whereas 31 (94%) of 33 patients with a similar phenotype who did not carry PRRT2 mutations had no or only partial response to this medication. The study provided Class IV evidence of a correlation between genotype and phenotype in patients with EKD1 due to a PRRT2 mutation and response to carbamazepine.
Both autosomal dominant and autosomal recessive modes of inheritance of the kinesigenic form were proposed by Goodenough et al. (1978). The cases interpreted as autosomal recessive may have been instances of reduced penetrance in an affected parent or new mutation. Autosomal dominant inheritance is well established in the familial nonkinesigenic form.
Sadamatsu et al. (1999) studied a pedigree in which 5 members in 3 generations had PKC; 1 individual in the second generation was not affected.
Tomita et al. (1999) performed genomewide linkage analysis on 8 Japanese families with PKC. Two-point linkage analysis provided a maximum lod score of 10.27 (recombination fraction of 0.00; penetrance of 0.7) at marker D16S3081, and a maximum multipoint lod score for a subset of markers was calculated to be 11.51 (penetrance of 0.8) at D16S3080. Haplotype analysis defined the disease locus within a region of approximately 12.4 cM between D16S3093 and D16S416. P1-derived artificial chromosome clones containing D16S3093 and D16S416 were mapped by FISH to 16p11.2 and 16q12.1, respectively. Thus, in the 8 families studied, the chromosomal location of the PKC critical region (PKCCR) is 16p11.2-q12.1. The same region was implicated in a study of an African American family with PKC in which linkage analysis localized the gene to an 18-cM interval between D16S3100 and D16S771 (Bennett et al., 2000).
Tomita et al. (2002) showed that wet ear wax (117800) cosegregated with PKC in 8 Japanese families and indeed maps to the same region of chromosome 16.
Kikuchi et al. (2007) reported 4 new families in which a total of 16 members had autosomal dominant PKC. Haplotype analysis showed that affected individuals shared a 24-cM segment between D16S3131 and D16S408. Molecular analysis of coding regions of 157 genes within the PKCCR in these 4 families and 3 additional PKC families did not show any clear pathogenic mutations.
Genetic Heterogeneity
Spacey et al. (2002) reported a 3-generation Caucasian English family in which 4 individuals had PKC inherited in an autosomal dominant pattern. Age of onset ranged from 6 to 13 years, and dystonic episodes lasted only 5 to 20 seconds. None had epilepsy or migraine. Three patients showed remission of PKC at ages 28 to 31 years. Linkage analysis excluded the pericentromeric region of chromosome 16, indicating genetic heterogeneity.
Lipton and Rivkin (2009) reported a 17-year-old boy with a history of carbamazepine-responsive paroxysmal kinesigenic dyskinesia, possible infantile-onset convulsions, and verbal learning disabilities, who presented with acute-onset gait ataxia. Motor development was normal prior to onset. Neurologic examination showed features of parkinsonism, including masked facies, monotonous prosody, and decreased spontaneous movement in all 4 limbs with poor initiation. There was also mild extrapyramidal rigidity, cogwheeling in the upper extremities, and truncal instability. Brain MRI showed mild cerebellar atrophy. Chromosomal microarray analysis detected a de novo 544-kb deletion on chromosome 16p11.2. Treatment with L-DOPA resulted in rapid resolution of parkinsonism. Lipton and Rivkin (2009) noted that parkinsonism is usually not described in this condition, and suggested that a disturbance in dopaminergic neurotransmission may underlie the disorder.
In affected members of 8 unrelated Han Chinese families with episodic kinesigenic dyskinesia-1, Chen et al. (2011) identified 3 different heterozygous truncating mutations in the PRRT2 gene (614386.0001-614386.0003). The first mutation was found by exome sequencing of a large 4-generation family with 17 affected individuals. The protein was found to be highly expressed in various regions of the mouse developing central nervous system. Expression of a truncated form of PRRT2 in COS-7 cells showed loss of membrane targeting and localization of the truncated protein in the cytoplasm, suggesting interruption of protein function.
Using a combination of exome sequencing and linkage analysis in 2 large Han Chinese families with EKD1, Wang et al. (2011) independently and simultaneously identified 2 different heterozygous truncating mutations in the PRRT2 gene (649dupC; 614386.0001 and 614386.0009, respectively) that completely segregated with the phenotype in each family. Two patients in each family also had infantile convulsion and choreoathetosis syndrome (ICCA; 602066), indicating intrafamilial variability. Analysis of 3 additional Han Chinese families with EKD1 revealed that 2 carried the 649dupC mutation and 1 had a different PRRT2 mutation (614386.0010).
Meneret et al. (2012) identified heterozygous mutations in the PRRT2 gene (see, e.g., 614386.0001; 614386.0011-614386.0012) in 22 (65%) of 34 patients of European descent with EKD1 (20 patients) or ICCA (2 patients). Mutations were found in 13 (93%) of 14 familial cases and in 9 (45%) of 20 sporadic cases. There was evidence for incomplete penetrance. The most common mutation was 649dupC, which was found in 17 of the 22 patients with PRRT2 mutations, although this was not due to a founder effect. Compared to patients without PRRT2 mutations, those with mutations had a slightly earlier age at onset (median age of 15 years and 9 years, respectively), but otherwise there were no phenotypic differences between the 2 groups. Most of the mutations caused premature termination, leading Meneret et al. (2012) to suggest that the disorders result from PRRT2 haploinsufficiency.
Ono et al. (2012) identified the 649dupC mutation in 14 of 15 Japanese families with EKD1, some of whom also had ICCA, and in 2 Japanese families with BFIS2. The mutation was shown to occur de novo in at least 1 family, suggesting that it is a mutational hotspot. EKD1, ICCA, and BFIS2 segregated with the mutation even within the same family. The findings indicated that all 3 disorders are allelic and are likely caused by a similar mechanism. In 1 family, a Japanese mother and daughter both carried a heterozygous mutation (Q250X; 614386.0015). The mother had EKD1 and her daughter had BFIS2.
Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal movement disorder, with a prevalence of 1 in 150,000 individuals (Chen et al., 2011).
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Chen, W.-J., Lin, Y., Xiong, Z.-Q., Wei, W., Ni, W., Tan, G.-H., Guo, S.-L., He, J., Chen, Y.-F., Zhang, Q.-J., Li, H.-F., Lin, Y., Murong, S.-X., Xu, J., Wang, N., Wu, Z.-Y. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nature Genet. 43: 1252-1255, 2011. [PubMed: 22101681] [Full Text: https://doi.org/10.1038/ng.1008]
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Meneret, A., Grabli, D., Depienne, C., Gaudebout, C., Picard, F., Durr, A., Lagroua, I., Bouteiller, D., Mignot, C., Doummar, D., Anheim, M., Tranchant, C., and 9 others. PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 79: 170-174, 2012. [PubMed: 22744660] [Full Text: https://doi.org/10.1212/WNL.0b013e31825f06c3]
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