REVIEW CME
Paroxysmal Dyskinesias Revisited: A Review of 500 Genetically Proven Cases and a New Classification Roberto Erro,1 Una-Marie Sheerin,2 and Kailash P. Bhatia1* 1
Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London, United Kingdom 2 Department of Molecular Neuroscience, University College London, Institute of Neurology, London, United Kingdom
ABSTRACT:
Paroxysmal movement disorders are a heterogeneous group of conditions manifesting as episodic dyskinesia with sudden onset and lasting a variable duration. Based on the difference of precipitating factors, three forms are clearly recognized, namely, paroxysmal kinesigenic (PKD), non-kinesigenic (PNKD), and exercise induced (PED). The elucidation of the genetic cause of various forms of paroxysmal dyskinesia has led to better clinical definitions based on genotype–phenotype correlations in the familial forms. However, it has been increasingly recognized that (1) there is a marked pleiotropy of mutations in such genes with still expanding clinical spectra; and (2) not all patients clinically presenting with either PKD, PNKD, or PED have mutations in these genes. We aimed to
Paroxysmal dyskinesias (PxDs) are a heterogeneous group of rare conditions (although the exact prevalence is uncertain) characterized by recurrent episodes of involuntary movement disorders lasting only a brief (but variable) duration.1 Paroxysmal dyskinesias can present with dystonic, choreic, ballistic, other, or a mixture of these hyperkinesias. The conditions can be inherited or acquired, and can also be a feature of more complex chronic neurological disorders.1 However, PxDs manifesting as isolated symptoms in
------------------------------------------------------------
*Correspondence to: Prof. K.P. Bhatia, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology Queen Square, London, WC1N 3BG, United Kingdom, E-mail: [email protected] Funding agencies: None
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 14 October 2013; Revised: 30 April 2014; Accepted: 13 May 2014 Published online 25 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25933
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Movement Disorders, Vol. 29, No. 9, 2014
review the clinical features of 500 genetically proven cases published to date. Based on our results, it is clear that there is not a complete phenotypic–genotypic correlation, and therefore we suggest an algorithm to lead the genetic analyses. Given the fact that the reliability of current clinical categorization is not entirely valid, we further propose a novel classification for paroxysmal dyskinesias, which takes into account the recent genetic discovC 2014 International Parkinson and eries in this field. V Movement Disorder Society
K e y W o r d s : paroxysmal dyskinesia; paroxysmal dystonia; paroxysmal choreo-athetosis; PKD; PNKD; PED; PRRT2; MR-1; GLUT-1; SLC2A1; KCNMA1
patients whose neurological examination between episodes is typically normal constitute the core of this group.1 A variety of names have been used by different authors to refer to these conditions. The term paroxysmal choreoathetosis first entered the literature in 1940, when Mount and Reback described a 23-yearold man who had episodes of ‘‘choreo-dystonia’’ that could last several hours.2 Over the years, more families with a similar disorder were described, and this disorder became known as paroxysmal dystonic choreoathetosis. In 1967, Kertesz described a new episodic disorder termed paroxysmal kinesigenic choreo-athetosis, noting that attacks were different for those previously reported in that episodes were very brief and induced by sudden movements.3 Then, Lance described in 1977 a third form, reporting a family that had attacks lasting between 5 and 30 minutes provoked by prolonged exercise.4 This was referred to as ‘‘intermediate type,’’ because the attack duration was longer than paroxysmal kinesigenic choreo-athetosis but less than typical paroxysmal dystonic
P A R O X Y S M A L
choreoathetosis. Following earlier allocations focusing on the duration of attacks, the current classification of PxDs by Demirkiran and Jankovic5 is mainly based on the difference of precipitating factors and recognizes three subtypes, comprising paroxysmal kinesigenic (PKD), non-kinesigenic (PNKD), and exercise-induced (PED) dyskinesia. These terms have been used widely in the literature over recent years. Each type was to be further classified as either primary or secondary, depending on its cause. In the idiopathic forms, which can be familial, imaging and other investigations are unremarkable, and no other signs suggest a neurodegenerative or symptomatic cause.1,5 Recently advances in this field have been driven by elucidation of the genetic cause of various forms of PxDs. The three major types of PxDs (i.e., PKD, PNKD, and PED) have been related to mutations in the proline-rich transmembrane protein 2 (PRRT2),6 Myofibrillogenesis regulator 1 (MR-1),7 and Glucose transporter 1 (SLC2A1)8 genes, respectively. However, it is increasingly recognized that: (1) there is a marked pleiotropy of mutations in such genes with still expanding clinical spectra; (2) not all patients clinically presenting with either PKD, PNKD, or PED have mutations in these genes. Therefore, we aimed to address the clinical characteristics of primary PxDs related to mutations in known genes by reviewing the literature on genetically proven PxDs cases. This review focuses on dyskinetic paroxysms and, hence, other forms of episodic disorders, including episodic ataxias and periodic paralyses, are not covered here. A fourth form of paroxysmal disorder, referred to as hypnogenic paroxysmal dyskinesia, was initially added to the PxDs classification. However, it has become clear that hypnogenic paroxysmal dyskinesia was a form of frontal lobe epilepsy and, as such, this is not discussed further in this review. Other rare variants of PxDs also have been described in the literature, but phenotype–genotype correlations are lacking, and therefore these also are not covered.
Materials and Methods We searched the Medline database (via PubMed, a service of the National Library of Medicine’s National Center for Biotechnology Information; http://www. ncbi.nlm.nih.gov) for publications from 2004 (year the first gene for PxDs was identified) to July 2013, using the search terms paroxysmal dyskinesia, paroxysmal dystonia, paroxysmal choreo-athetosis, PKD, PNKD, PED, PRRT2, MR-1, GLUT-1, and SLC2A1. The bibliographies of relevant review articles9-13 were also checked. The selected articles were reviewed by two independent reviewers (R.E. and U-M.S.). Based on the full article list, we selected articles referring to
D Y S K I N E S I A S
R E V I S I T E D
clinic–genetic data. In articles in which large clinical series were reported, with genetic confirmation only in a proportion of these patients, we included only the genetically proven cases. We excluded articles if there were no clinical information on the patients. From articles in which a large clinical series was reported, and including patients with clinical phenotypes other than PxDs, we included only those cases with PxDs (therefore excluding patients with pure Benign Familial Infantile Seizure, a further phenotype that results from PRRT2 mutations). From the selected cases we noted age at onset, sex, familial history, precipitants and alleviating factors, duration, frequency, distribution and phenomenology of attacks, presence of aura, presence of additional or inter-ictal symptoms or signs, and response to treatment. When the age of the population was given only in mean 6 standard deviation, we included in the analysis the mean value only. When the above-mentioned features were not provided, we noted these data as unknown.
Results The search strategy yielded 73 results, of which many were focused on genetics of PxDs and therefore did not provide sufficient clinical information for the patients. According to the inclusion and exclusion criteria, we eventually selected 43 articles14-56 describing 500 genetically proven PxDs cases.
Proline-Rich Transmembrane Protein 2 (PRRT2)–Related PxDs Three-hundred seventy-four patients (247 males and 127 females) have been identified: 276 cases from 104 families and 98 sporadic cases.16,19-24,26-35,37,38,4143,46,47,49-51,55 Clinical features of these patients are summarized in Table 1A. Among the 276 familial cases, six patients (1.6% of the total cohort) had a family history of epilepsy, 131 patients (35.1% of the total cohort) had a family history of PxDs, and 139 (37.2% of the total cohort) had a family history for both PxDs and epilepsy. In 26.2% of patients, there was a personal history of infantile convulsions, and thus such cases have been categorized as having infantile convulsion choreo-athetosis syndrome by the original authors. Additional features including episodic ataxia and paroxysmal torticollis were occasionally reported. The mean age at onset for PxDs was 9.9 years (range, 1-40 years). Only 16 patients (4.3%) had onset after 18 years of age. Attacks were characterized by chorea in 15.2% of patients, dystonia in 17.6%, or both in 67.1%. Anatomical distribution of attacks was provided for 153 patients, and in most of them there was a tendency to generalization. Unilateral involvement was observed in 17.6% of these
Movement Disorders, Vol. 29, No. 9, 2014
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E R R O
E T
A L
TABLE 1. Overview of the clinical features in 374 patients with PRRT2 mutations (A) and in 73 patients with MR1 mutations (B) Total number of patients: 374
A)
Sex (M:F) Age at onset, mean (range) Family history, total n (%): Epilepsy, n (%) PxDs, n (%) Epilepsy and PxDs, n (%) Phenomenology: Dystonia, n (%) Chorea, n (%) Dystonia and chorea, n (%) Trigger: Kinesigesic, n (%) Nonkinesigesic, n (%) Duration of attacks: 1 minute, n (%) Frequency of attacks: Weekly/monthly, n (%) < 10/daily, n (%) 10-hundreds/daily, n (%) Sensory aura: Yes, n (%) No, n (%) Response to AEs: Improvement, n (%) Not tried, n (%)
247:127 9.9 years (1-40) 276 (73.8) 6 (1.6) 131 (35.1) 139 (37.2) 66 (17.6) 57 (15.2) 251 (67.1) 370 (98.9) 159 (42.5) 197 (95.6) 9 (4.4) 19 (5.1) 49 (13.1) 306 (81.8) 60 (48%) 65 (52%) 200 (77.5%) 58 (22.5%)
Total number of patients: 73
B)
Sex (M:F) Age at onset, mean (range) Family history, n (%) Phenomenology: Dystonia, n (%) Chorea, n (%) Dystonia and chorea, n (%) Dystonia, chorea and ballism, n (%) Trigger: Caffeine or alcohol, n (%) Stress/anxiety, n (%) Excitement/laughing, n (%) Prolonged exercise, n (%) Others (fever, tiredness, etc), n (%) Duration of attacks: 1 min, n (%) Frequency of attacks: Daily, n (%) Weekly, n (%) Monthly, n (%) Yearly, n (%)
42:31 5 years (1-35) 73 (100) 20 2 47 4
(27.4) (2.7) (65.1) (5.4)
69 60 11 5 14
(94.5) (82.2) (15.1) (6.8) (19.1)
4 (5.4) 69 (94.6) 4 (5.5) 56 (76.7) 8 (10.9) 5 (6.8)
Abbreviations: PxDs, paroxysmal dyskinesia; AEs, anti-epileptics.
patients. In a further 24.1%, the face was also affected (and there was a report of speech impairment), whereas in 55.5% of such cases attacks were bilateral. A kinesigenic precipitant was identifiable in almost all patients
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Movement Disorders, Vol. 29, No. 9, 2014
(98.9%). Further reported precipitants include anxiety/ startle (15.2%), intention to move, acceleration, coffee intake, and sleep deprivation (each accounting for approximately 5%-10% of cases). In addition to PKD, both PNKD and PED were reported in almost 2% of patients. Frequency of attacks ranged from hundreds per day to 1 to 2 per year. Approximately 80% of patients reported tens to hundreds of attacks per day, 13.1% had a frequency of fewer than 10 attacks per day, and 5.1% reported weekly or monthly attacks. Duration of attacks was clearly indicated for 206 cases. Mean maximal duration was 34.4 seconds. Attacks were longer than 1 minute in nine patients (4.4%) and exceptionally could last up to 20 minutes (1 patient). Data regarding presence of sensory aura were provided for 125 patients, of whom 60 (48%) had aura, either paresthesias or sensations of muscular tension, preceding the attacks. A minority of these patients could use the aura as warning sign to prevent the attacks by slowing down or ‘‘holding tight’’ of the affected limb. Data regarding treatment response were available for 258 patients. Fifty-eight patients did not require any treatment, and the remaining 200 cases reported a great benefit from the following medications: carbamazepine 50 to 600 mg daily (65.5%); phenytoin, 100 to 200 mg daily (9.5%); valproate 1,000 to 1,200 mg daily (4%); the remaining patients were on other antiepileptics. Although not systematically assessed, subsequent to puberty the frequency of episodes usually decreases with advancing age, in many to a complete resolution, regardless of any treatment.
Myofibrillogenesis Regulator 1 (MR-1) Related PxDs Seventy-three patients (42 males and 31 females) from 13 families have been identified, whereas no sporadic case has been yet reported.18,39,44,45,54 Clinical features of these cases are detailed in Table 1B. Mean age at onset was 5 years (range: 6 mo to 35 y), with 24.6% of patients having attacks starting before the age of 1 year, and only 2.8% of patients having onset after age 18 years. Attacks were characterized by dystonia (27.4%), chorea (2.7%), both (65.1%), or by a mixture of dystonia, chorea, and ballism (5.4%). However, in a number of patients episodes became heterogeneous during the course of the disease, being more dystonic in the early phase, with more choreic components being observed thereafter. Clear description of the body regions affected by the dyskinesias was available for only 19 patients, of whom 52.6% presented with generalized dyskinesias and 47.4% with unilateral/focal dyskinesias. Approximately one third of the latter reported that attacks could start in one limb to spread over the body and become generalized. Speech impairment was reported in 35.6% of patients, most likely because of involvement of the
P A R O X Y S M A L
face (oral dyskinesia or tongue dystonia). Additional features reported during the attacks were less commonly seen (
Paroxysmal Dyskinesias Revisited: A Review of 500 Genetically Proven Cases and a New Classification Roberto Erro,1 Una-Marie Sheerin,2 and Kailash P. Bhatia1* 1
Sobell Department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London, United Kingdom 2 Department of Molecular Neuroscience, University College London, Institute of Neurology, London, United Kingdom
ABSTRACT:
Paroxysmal movement disorders are a heterogeneous group of conditions manifesting as episodic dyskinesia with sudden onset and lasting a variable duration. Based on the difference of precipitating factors, three forms are clearly recognized, namely, paroxysmal kinesigenic (PKD), non-kinesigenic (PNKD), and exercise induced (PED). The elucidation of the genetic cause of various forms of paroxysmal dyskinesia has led to better clinical definitions based on genotype–phenotype correlations in the familial forms. However, it has been increasingly recognized that (1) there is a marked pleiotropy of mutations in such genes with still expanding clinical spectra; and (2) not all patients clinically presenting with either PKD, PNKD, or PED have mutations in these genes. We aimed to
Paroxysmal dyskinesias (PxDs) are a heterogeneous group of rare conditions (although the exact prevalence is uncertain) characterized by recurrent episodes of involuntary movement disorders lasting only a brief (but variable) duration.1 Paroxysmal dyskinesias can present with dystonic, choreic, ballistic, other, or a mixture of these hyperkinesias. The conditions can be inherited or acquired, and can also be a feature of more complex chronic neurological disorders.1 However, PxDs manifesting as isolated symptoms in
------------------------------------------------------------
*Correspondence to: Prof. K.P. Bhatia, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology Queen Square, London, WC1N 3BG, United Kingdom, E-mail: [email protected] Funding agencies: None
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 14 October 2013; Revised: 30 April 2014; Accepted: 13 May 2014 Published online 25 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25933
1108
Movement Disorders, Vol. 29, No. 9, 2014
review the clinical features of 500 genetically proven cases published to date. Based on our results, it is clear that there is not a complete phenotypic–genotypic correlation, and therefore we suggest an algorithm to lead the genetic analyses. Given the fact that the reliability of current clinical categorization is not entirely valid, we further propose a novel classification for paroxysmal dyskinesias, which takes into account the recent genetic discovC 2014 International Parkinson and eries in this field. V Movement Disorder Society
K e y W o r d s : paroxysmal dyskinesia; paroxysmal dystonia; paroxysmal choreo-athetosis; PKD; PNKD; PED; PRRT2; MR-1; GLUT-1; SLC2A1; KCNMA1
patients whose neurological examination between episodes is typically normal constitute the core of this group.1 A variety of names have been used by different authors to refer to these conditions. The term paroxysmal choreoathetosis first entered the literature in 1940, when Mount and Reback described a 23-yearold man who had episodes of ‘‘choreo-dystonia’’ that could last several hours.2 Over the years, more families with a similar disorder were described, and this disorder became known as paroxysmal dystonic choreoathetosis. In 1967, Kertesz described a new episodic disorder termed paroxysmal kinesigenic choreo-athetosis, noting that attacks were different for those previously reported in that episodes were very brief and induced by sudden movements.3 Then, Lance described in 1977 a third form, reporting a family that had attacks lasting between 5 and 30 minutes provoked by prolonged exercise.4 This was referred to as ‘‘intermediate type,’’ because the attack duration was longer than paroxysmal kinesigenic choreo-athetosis but less than typical paroxysmal dystonic
P A R O X Y S M A L
choreoathetosis. Following earlier allocations focusing on the duration of attacks, the current classification of PxDs by Demirkiran and Jankovic5 is mainly based on the difference of precipitating factors and recognizes three subtypes, comprising paroxysmal kinesigenic (PKD), non-kinesigenic (PNKD), and exercise-induced (PED) dyskinesia. These terms have been used widely in the literature over recent years. Each type was to be further classified as either primary or secondary, depending on its cause. In the idiopathic forms, which can be familial, imaging and other investigations are unremarkable, and no other signs suggest a neurodegenerative or symptomatic cause.1,5 Recently advances in this field have been driven by elucidation of the genetic cause of various forms of PxDs. The three major types of PxDs (i.e., PKD, PNKD, and PED) have been related to mutations in the proline-rich transmembrane protein 2 (PRRT2),6 Myofibrillogenesis regulator 1 (MR-1),7 and Glucose transporter 1 (SLC2A1)8 genes, respectively. However, it is increasingly recognized that: (1) there is a marked pleiotropy of mutations in such genes with still expanding clinical spectra; (2) not all patients clinically presenting with either PKD, PNKD, or PED have mutations in these genes. Therefore, we aimed to address the clinical characteristics of primary PxDs related to mutations in known genes by reviewing the literature on genetically proven PxDs cases. This review focuses on dyskinetic paroxysms and, hence, other forms of episodic disorders, including episodic ataxias and periodic paralyses, are not covered here. A fourth form of paroxysmal disorder, referred to as hypnogenic paroxysmal dyskinesia, was initially added to the PxDs classification. However, it has become clear that hypnogenic paroxysmal dyskinesia was a form of frontal lobe epilepsy and, as such, this is not discussed further in this review. Other rare variants of PxDs also have been described in the literature, but phenotype–genotype correlations are lacking, and therefore these also are not covered.
Materials and Methods We searched the Medline database (via PubMed, a service of the National Library of Medicine’s National Center for Biotechnology Information; http://www. ncbi.nlm.nih.gov) for publications from 2004 (year the first gene for PxDs was identified) to July 2013, using the search terms paroxysmal dyskinesia, paroxysmal dystonia, paroxysmal choreo-athetosis, PKD, PNKD, PED, PRRT2, MR-1, GLUT-1, and SLC2A1. The bibliographies of relevant review articles9-13 were also checked. The selected articles were reviewed by two independent reviewers (R.E. and U-M.S.). Based on the full article list, we selected articles referring to
D Y S K I N E S I A S
R E V I S I T E D
clinic–genetic data. In articles in which large clinical series were reported, with genetic confirmation only in a proportion of these patients, we included only the genetically proven cases. We excluded articles if there were no clinical information on the patients. From articles in which a large clinical series was reported, and including patients with clinical phenotypes other than PxDs, we included only those cases with PxDs (therefore excluding patients with pure Benign Familial Infantile Seizure, a further phenotype that results from PRRT2 mutations). From the selected cases we noted age at onset, sex, familial history, precipitants and alleviating factors, duration, frequency, distribution and phenomenology of attacks, presence of aura, presence of additional or inter-ictal symptoms or signs, and response to treatment. When the age of the population was given only in mean 6 standard deviation, we included in the analysis the mean value only. When the above-mentioned features were not provided, we noted these data as unknown.
Results The search strategy yielded 73 results, of which many were focused on genetics of PxDs and therefore did not provide sufficient clinical information for the patients. According to the inclusion and exclusion criteria, we eventually selected 43 articles14-56 describing 500 genetically proven PxDs cases.
Proline-Rich Transmembrane Protein 2 (PRRT2)–Related PxDs Three-hundred seventy-four patients (247 males and 127 females) have been identified: 276 cases from 104 families and 98 sporadic cases.16,19-24,26-35,37,38,4143,46,47,49-51,55 Clinical features of these patients are summarized in Table 1A. Among the 276 familial cases, six patients (1.6% of the total cohort) had a family history of epilepsy, 131 patients (35.1% of the total cohort) had a family history of PxDs, and 139 (37.2% of the total cohort) had a family history for both PxDs and epilepsy. In 26.2% of patients, there was a personal history of infantile convulsions, and thus such cases have been categorized as having infantile convulsion choreo-athetosis syndrome by the original authors. Additional features including episodic ataxia and paroxysmal torticollis were occasionally reported. The mean age at onset for PxDs was 9.9 years (range, 1-40 years). Only 16 patients (4.3%) had onset after 18 years of age. Attacks were characterized by chorea in 15.2% of patients, dystonia in 17.6%, or both in 67.1%. Anatomical distribution of attacks was provided for 153 patients, and in most of them there was a tendency to generalization. Unilateral involvement was observed in 17.6% of these
Movement Disorders, Vol. 29, No. 9, 2014
1109
E R R O
E T
A L
TABLE 1. Overview of the clinical features in 374 patients with PRRT2 mutations (A) and in 73 patients with MR1 mutations (B) Total number of patients: 374
A)
Sex (M:F) Age at onset, mean (range) Family history, total n (%): Epilepsy, n (%) PxDs, n (%) Epilepsy and PxDs, n (%) Phenomenology: Dystonia, n (%) Chorea, n (%) Dystonia and chorea, n (%) Trigger: Kinesigesic, n (%) Nonkinesigesic, n (%) Duration of attacks: 1 minute, n (%) Frequency of attacks: Weekly/monthly, n (%) < 10/daily, n (%) 10-hundreds/daily, n (%) Sensory aura: Yes, n (%) No, n (%) Response to AEs: Improvement, n (%) Not tried, n (%)
247:127 9.9 years (1-40) 276 (73.8) 6 (1.6) 131 (35.1) 139 (37.2) 66 (17.6) 57 (15.2) 251 (67.1) 370 (98.9) 159 (42.5) 197 (95.6) 9 (4.4) 19 (5.1) 49 (13.1) 306 (81.8) 60 (48%) 65 (52%) 200 (77.5%) 58 (22.5%)
Total number of patients: 73
B)
Sex (M:F) Age at onset, mean (range) Family history, n (%) Phenomenology: Dystonia, n (%) Chorea, n (%) Dystonia and chorea, n (%) Dystonia, chorea and ballism, n (%) Trigger: Caffeine or alcohol, n (%) Stress/anxiety, n (%) Excitement/laughing, n (%) Prolonged exercise, n (%) Others (fever, tiredness, etc), n (%) Duration of attacks: 1 min, n (%) Frequency of attacks: Daily, n (%) Weekly, n (%) Monthly, n (%) Yearly, n (%)
42:31 5 years (1-35) 73 (100) 20 2 47 4
(27.4) (2.7) (65.1) (5.4)
69 60 11 5 14
(94.5) (82.2) (15.1) (6.8) (19.1)
4 (5.4) 69 (94.6) 4 (5.5) 56 (76.7) 8 (10.9) 5 (6.8)
Abbreviations: PxDs, paroxysmal dyskinesia; AEs, anti-epileptics.
patients. In a further 24.1%, the face was also affected (and there was a report of speech impairment), whereas in 55.5% of such cases attacks were bilateral. A kinesigenic precipitant was identifiable in almost all patients
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Movement Disorders, Vol. 29, No. 9, 2014
(98.9%). Further reported precipitants include anxiety/ startle (15.2%), intention to move, acceleration, coffee intake, and sleep deprivation (each accounting for approximately 5%-10% of cases). In addition to PKD, both PNKD and PED were reported in almost 2% of patients. Frequency of attacks ranged from hundreds per day to 1 to 2 per year. Approximately 80% of patients reported tens to hundreds of attacks per day, 13.1% had a frequency of fewer than 10 attacks per day, and 5.1% reported weekly or monthly attacks. Duration of attacks was clearly indicated for 206 cases. Mean maximal duration was 34.4 seconds. Attacks were longer than 1 minute in nine patients (4.4%) and exceptionally could last up to 20 minutes (1 patient). Data regarding presence of sensory aura were provided for 125 patients, of whom 60 (48%) had aura, either paresthesias or sensations of muscular tension, preceding the attacks. A minority of these patients could use the aura as warning sign to prevent the attacks by slowing down or ‘‘holding tight’’ of the affected limb. Data regarding treatment response were available for 258 patients. Fifty-eight patients did not require any treatment, and the remaining 200 cases reported a great benefit from the following medications: carbamazepine 50 to 600 mg daily (65.5%); phenytoin, 100 to 200 mg daily (9.5%); valproate 1,000 to 1,200 mg daily (4%); the remaining patients were on other antiepileptics. Although not systematically assessed, subsequent to puberty the frequency of episodes usually decreases with advancing age, in many to a complete resolution, regardless of any treatment.
Myofibrillogenesis Regulator 1 (MR-1) Related PxDs Seventy-three patients (42 males and 31 females) from 13 families have been identified, whereas no sporadic case has been yet reported.18,39,44,45,54 Clinical features of these cases are detailed in Table 1B. Mean age at onset was 5 years (range: 6 mo to 35 y), with 24.6% of patients having attacks starting before the age of 1 year, and only 2.8% of patients having onset after age 18 years. Attacks were characterized by dystonia (27.4%), chorea (2.7%), both (65.1%), or by a mixture of dystonia, chorea, and ballism (5.4%). However, in a number of patients episodes became heterogeneous during the course of the disease, being more dystonic in the early phase, with more choreic components being observed thereafter. Clear description of the body regions affected by the dyskinesias was available for only 19 patients, of whom 52.6% presented with generalized dyskinesias and 47.4% with unilateral/focal dyskinesias. Approximately one third of the latter reported that attacks could start in one limb to spread over the body and become generalized. Speech impairment was reported in 35.6% of patients, most likely because of involvement of the
P A R O X Y S M A L
face (oral dyskinesia or tongue dystonia). Additional features reported during the attacks were less commonly seen (
