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A Family With Paroxysmal Nonkinesigenic Dyskinesia: Genetic and Treatment Issues
A Family With Paroxysmal Nonkinesigenic Dyskinesia: Genetic and Treatment Issues Krzysztof Szcza1uba, MD, PhD*, Marta Jurek, MSc*, Elz˙bieta Szczepanik, MD, PhD†, Andrzej Friedman, MD, PhD‡, Micha1 Milewski, PhD*, Jerzy Bal, PhD*, and Tadeusz Mazurczak, MD, PhD* Paroxysmal nonkinesigenic dyskinesia is a condition characterized by attacks of sudden involuntary movements triggered by caffeine or alcohol intake, stress, or fatigue. The paroxysms are usually of the generalized type and may last up to an hour. Described here is a Polish family with this disorder seen in two children and their father. Variable expressivity as well as reduced penetrance of the causative mutation were noteworthy in this kindred. Treatment options included abortive diazepam and prophylactic levetiracetam, with the latter having a more pronounced effect in this family. Favorable response to levetiracetam is probably linked to action of the drug on calcium channels in neurons, muscle cells, or both. Ó 2009 by Elsevier Inc. All rights reserved. Szcza1uba K, Jurek M, Szczepanik E, Friedman A, Milewski M, Bal J, Mazurczak T. A family with paroxysmal nonkinesigenic dyskinesia: genetic and treatment issues. Pediatr Neurol 2009;41:135-138.
From the *Departments of Medical Genetics and †Neurology, Institute of Mother and Child, and the ‡Department of Neurology, Faculty of Health Science, Medical University in Warsaw, Warsaw, Poland.
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2009.02.013 0887-8994/09/$—see front matter
Introduction Paroxysmal nonkinesigenic dyskinesia (OMIM no. 118800), also known as dystonia type 8, is a rare heritable disorder characterized by intermittent attacks of variabletype hyperkinetic involuntary movements without loss of consciousness. Typically, the attacks are not triggered by sudden movements but can occur after caffeine or alcohol intake, stress, or fatigue. In some families, the paroxysms take the form of chorea or choreoathetosis; in others, there is an additional dystonic component. Thus, historically, the disorder has been classified together with other primary dystonias [1]. Paroxysmal nonkinesigenic dyskinesia follows an autosomal dominant pattern of inheritance, with only two mutations identified in exon 1 of the paroxysmal nonkinesigenic dyskinesia gene, PNKD, which maps to 2q35 (alias myofibrillogenesis regulator 1 gene, MR1). The kindred described here included three individuals affected by paroxysmal nonkinesigenic dyskinesia, in each of whom a causative mutation was identified, substitution A9 V in exon 1 of the PNKD gene. This report compares the family with other cases from literature, provides data illustrating possible reduced penetrance as well as variable expressivity, and discusses alternative treatment options based on this family’s experience. Specifically, a beneficial role of levetiracetam in the affected individuals is noted, and a possible mechanism is proposed involving calcium channels. Case Report The proband, an 8-year-old girl (Fig 1, III-1), presented with attacks of sudden generalized rigidity, leg and hand extensions, mumbling speech, problems in opening her mouth, and facial grimacing. The paroxysms lasted approximately 40 minutes and were precipitated by relative physical fatigue, especially after school, or by both negative (i.e., unknown, crowded places) or positive (i.e., peals of laughter) stressors. Headache, hand muscle cramps, and particularly double vision were the major prodromal symptoms. Frequency of the attacks was one to two per day. They had begun in early infancy in the form of opisthotonus. The interictal neurologic examination was unremarkable. A 5-year-old sister (III-2) of the proband presented with attacks of generalized choreoathetosis starting in both upper and lower limbs, which lasted about 30 minutes and occurred twice a day, usually in the morning or afternoon hours. The attacks had probably started in her second year. The triggering factors were generally similar to her sister’s, with physical
Communications should be addressed to: Dr. Szcza1uba; Department of Medical Genetics; Institute of Mother and Child; Kasprzaka 17A St.; 01-211 Warsaw, Poland. E-mail: [email protected] Received November 17, 2008; accepted February 10, 2009.
Szcza1uba et al: Paroxysmal Nonkinesigenic Dyskinesia 135
Figure 1. Pedigree of the family with paroxysmal nonkinesigenic dyskinesia. Solid symbols indicate affected family members. A9 V/ , mutation carrier. fatigue a much more potent stressor. Neurologic examination between the attacks was unrevealing. The 44-year-old father (II-1) of the two affected girls had a history of relatively milder hand and finger muscle spasms with or without facial twitching, two to three times a month, and lasting up to 30 minutes, not infrequently before bedtime. He suggested no clear precipitant to the paroxysms and required no treatment for his condition. His neurologic examination was unremarkable. The 64-year-old paternal grandmother (I-2) of the proband had reportedly no history of dyskinetic events whatsoever, according to family members (including her husband). Her neurologic findings were normal as well. To identify the causative mutation, exon 1 of the PNKD gene was sequenced, after polymerase chain reaction with a pair of primers: forward TGT AGG CAG GAC GGA AGG AG and reverse TGC AGA AAA GTG TGG GGA GGA ACC. The polymerase chain reaction conditions were as follows: 35 cycles of 95 C for 300 seconds, 95 C for 30 seconds, 60 C for 30 seconds, 72 C for 30 seconds, and 72 C for 600 seconds. The reaction mixture was 3 mL 10 polymerase chain reaction buffer, 3 mL deoxynucleotide triphosphates (2.5 mmol/L), 0.6 mL forward primer (10 pmol/mL), 0.6 mL reverse primer (10 pmol/mL), 0.2 mL Taq polymerase (2 units/mL), and 22.6 mL water. After analysis of all three affected individuals in this family, a 72C > T transition was identified in exon 1 of the PNKD gene, which leads to an alanine-to-valine substitution (A9V) in the encoded protein. The reportedly asymptomatic paternal grandmother also harbors the mutation (Fig 2).
Discussion More than 15 kindreds and more than 50 patients with paroxysmal nonkinesigenic dyskinesia have been described in the literature [2]. In this rare condition, attacks of
136 PEDIATRIC NEUROLOGY Vol. 41 No. 2
(dystonic) choreoathetosis last 10 minutes to 1 hour and are triggered by various stimuli. In the present pair of young female siblings, the attacks are 30-40 minutes long and occur up to two times daily. Morphologically, the paroxysms are slightly different in each girl. Overall, physical fatigue and stress seem to be main precipitating factors in both affected patients; however, neither factor triggers attacks in their father. The father has relatively mild clinical manifestations, possibly reflecting variable expressivity of the condition. Intrafamilial clinical heterogeneity is seen in many neurological disorders; nonetheless, in most PNKD families the symptoms are of similar frequency, morphology, and duration. In turn, the lack of symptoms in the paternal grandmother, who also harbors the familial mutation, probably represents reduced penetrance of the pathogenic mutation. Reduced penetrance has been seen in more than 10% of confirmed carriers and is limited to families with one particular causative mutation [3]. It was described initially by Rainier et al. [4] as likely resulting from the effects of modifying genetic background or environmental factors. Modifying genetic background can generally be divided into genes and proteins. Polymorphisms within the PNKD gene or within other interacting genes are yet to be elucidated as possible modifiers. Notably, however, three splicing variants of PNKD have been identified, one of which is devoid of the mutation-harboring first exon. This isoform, called MR-1M, is expressed in the brain and in some peripheral tissues; in the cell, it resides in the perinuclear region. Thus, potentially, subtle imbalances between systemic and intracellular concentration of all three isoforms, including MR-1M, could result in clinical nonpenetrance. Other possible modifiers are neurotransmitters, such as dopamine or g-aminobutyric acid. Their role in penetrance or expressivity could be age-dependent, as is suggested for dopamine in dystonia type 1, another primary dystonia. Recently, an age-dependent effect of estrogen has been demonstrated for paroxysmal nonkinesigenic dyskinesia [5]. Two recurrent mutations in exon 1 of PNKD gene (A7V and A9V) are responsible for clinical expression of paroxysmal nonkinesigenic dyskinesia [6]. In all the cases of paroxysmal nonkinesigenic dyskinesia in a Slavic ethnic background, the A9V mutation was present, including another Polish family [5]. The gene is expressed in many tissues, including brain and skeletal muscle. In the muscle, its product interacts with sarcomeric proteins, particularly myomesin and b-enolase. These two proteins are involved in the organization of M-bands in striated muscle, one of the steps in mature myofibril formation [7]. How the mutated PNKD gene leads to paroxysmal involuntary muscle spasms is unclear, but both mutations likely disrupt a-helical structure of N-terminal region of MR-1S and MR-1L isoforms, causing the whole protein to misfold or mislocalize (first nucleotides encode signal peptide). In most patients with paroxysmal nonkinesigenic dyskinesia, identification of a PNKD gene mutation precludes favorable response to benzodiazepines taken as abortive or preventative agents [2]. Indeed, in the proband a change
Figure 2. Sequencing analysis reveals the substitution 72C > T (A9V) (arrow, upper panel) in a carrier and the normal sequence (lower panel) in a noncarrier.
in duration of attacks was observed after oral administration of 2 mg diazepam as early as the prodromal phase (Table 1), but no such effect was observed in the proband’s sister. Also, the morphology or frequency of the paroxysms remained the same in both girls with diazepam. The limited efficacy of the drug in the proband and lack of response in her sister may have resulted from the fact that perhaps diazepam, through enhancement of g-aminobutyric-acidmediated transmission, exerts a merely modifying effect in basal ganglia, rather unrelated to the molecular defect in paroxysmal nonkinesigenic dyskinesia. The medication was therefore changed to levetiracetam, in light of a recent encouraging report from Alemdar et al. [8]. Albeit in a likely secondary dyskinesia, the authors noted antidyskinetic effects of the drug, taken at a total dose of 1000 mg/day, in a patient with idiopathic hypoparathyroidism and basal ganglia calcification. Although this effect may not have been strictly related to the hypocalcemia present in their patient, calcium channels constitute very
likely targets of levetiracetam in striatal, neocortical, hippocampal, and pyramidal neurons [9]. This calcium release inhibition by levetiracetam is also seen in ryanodineregulated channels, whose ligand is caffeine, which is known to trigger dyskinetic attacks [10]. In both affected siblings, a favorable effect on the duration of the paroxysms was observed for levetiracetam taken prophylactically twice daily (Table 1). Fewer attacks were observed in the proband; in her sister, the attacks were significantly milder. Notably, no adverse effects were observed in the two girls when given regular doses of levetiracetam. Favorable response to levetiracetam may be achieved both in the peripheral and central nervous system. In the muscle, MR-1 protein may regulate muscle contraction in a way that involves ryanodine channels. Normally, the channels open and calcium is released, which is the first signal for the contractile apparatus to work. The MR-1 protein may control the process through binding contractile proteins like myosin light chain or myomesin. When
Table 1. Pharmacotherapeutic effect of diazepam and levetiracetam in the two affected girls with mutation of the PNKD gene (alias MR1), substitution A9V in exon 1 Patient Proband (III-1 in Fig 1)
Pretreatment Characteristics 1-2 attacks per day, 40 min duration, afternoon hours. Pocket-knife dystonic posturing (upper and lower limbs extended), facial grimacing. Could not open mouth. No choreoathetosis.
Effect of Diazepam Shortened duration to 20 min. No effect on frequency. No effect on morphology.
Effect of Levetiracetam At daily dose 2 750 mg: shortened duration to 10 min. Attacks less frequent (2/week). No effect on morphology.
2 attacks No effect. At daily dose 2 500 mg: shortened duration per day, 30 min duration, to 15 minutes. No change in frequency. morning and afternoon. Morphology: only sudden sleepiness and Generalized chorea starting pain in hands and legs. in upper limbs, athetosis, back spasms, facial grimacing. Abortive dose of 2 mg of diazepam up to 2-3 doses/day during 12 weeks of therapy was used. Later on, levetiracetam 2 times daily was tried during 20 weeks of therapy.
Sister (III-2 in Fig 1)
Szcza1uba et al: Paroxysmal Nonkinesigenic Dyskinesia 137
mutated, the MR-1 is inactive (probably mislocalized), and ryanodine channel activators cause exaggerated uncontrollable response. Although binding sites of levetiracetam have so far been restricted to neuronal cells only, the drug may influence calcium flow at the neuromuscular junction level through one or more other proteins. So far, no clear role of the MR-1 protein within the central nervous system has emerged from the literature. We hypothesize that MR-1 may be sensitive to intraneuronal calcium stores, which in turn are modified by levetiracetam through its action on calcium channels. Defective MR-1 protein action within the central nervous system may cause destabilization of actin cytoskeleton (i.e., via myomesin) and in this way lead to paroxysms. Antidyskinetic activity of levetiracetam or other pyrrolidone derivatives may also be linked with its synaptic transport modification by binding synaptic vesicle protein SV2A [11,12]. In conclusion, as seen in the present kindred, the clinical picture of paroxysmal nonkinesigenic dyskinesia can be variable up to the point of nonpenetrance. Therapeutic options include the well-proved abortive effect of diazepam; alternatively, another benzodiazepine may be tried in paroxysmal nonkinesigenic dyskinesia patients, either after onset of an attack or preventatively [13]. Further research is needed regarding the possible beneficial prophylactic role of regular doses of levetiracetam in paroxysmal nonkinesigenic dyskinesia, as it may suppress or alleviate the paroxysms through calcium-channel-modifying effects. The antidyskinetic effect may still be transient, as seen in other antiepileptic drugs (i.e., valproate) [2], but more pronounced and more effective than that of benzodiazepines. The authors thank Sandra Peacock (Baylor College of Medicine) for her useful comments. This work was sponsored by the Polish Scientific Committee under grant number PBZ-KBN-122 P05/01-11.
138 PEDIATRIC NEUROLOGY Vol. 41 No. 2
References [1] Bhidayasiri R, Pulst SM. Dystonia (DYT) genetic loci. Eur J Pediatr Neurol 2005;9:367-70. [2] Bruno MK, Lee HY, Auburger GW, et al. Genotype–phenotype correlation of paroxysmal nonkinesigenic dyskinesia. Neurology 2007; 68:1782-9. [3] Stefanova E, Djarmati A, Momcilovic´ D, et al. Clinical characteristics of paroxysmal nonkinesigenic dyskinesia in Serbian family with myofibrillogenesis regulator 1 gene mutation. Mov Disord 2006;21: 2010-5. [4] Rainier S, Thomas D, Tokarz D, et al. Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch Neurol 2004;61:1025-9. [5] Friedman A, Zakrzewska-Pniewska B, Domitrz I, Lee HY, Ptacek L, Kwiecinski H. Paroxysmal non-kinesigenic dyskinesia caused by the mutation of MR-1 in a large Polish kindred. Eur Neurol 2009;61: 39-41. [6] Lee HY, Xu Y, Huang Y, et al. The gene for paroxysmal nonkinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum Mol Genet 2004;13:3161-70. [7] Li TB, Liu XH, Feng S, et al. Characterization of MR-1, a novel myofibrillogenesis regulator in human muscle. Acta Biochim Biophys Sin (Shanghai) 2004;36:412-8. [8] Alemdar M, Iseri P, Selekler M, Komsuog˘lu SS. Levetiracetamresponding paroxysmal nonkinesigenic dyskinesia. Clin Neuropharmacol 2007;30:241-4. [9] Surges R, Volynski KE, Walker MC. Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited [Erratum at http://tan.sagepub.com/ content/vol1/issue1/]. Ther Adv Neurol Disord 2008;1:13-24. [10] Angehagen M, Margineanu DG, Ben-Menachem E, Ronnback L, Hansson E, Klitgaard H. Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials In hippocampal neurons. Neuroreport 2003;14:471-5. [11] Hamann M, Sander SE, Richter A. Brivaracetam and seletracetam, two new SV2A ligands, improve paroxysmal dystonia in the dtsz mutant hamster. Eur J Pharmacol 2008;601:99-102. [12] Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004;101:9861-6. [13] Dooley JM, Brna PM. Sublingual lorazepam in the treatment of familial paroxysmal nonkinesigenic dyskinesia. Pediatr Neurol 2004;30: 365-6.
From the *Departments of Medical Genetics and †Neurology, Institute of Mother and Child, and the ‡Department of Neurology, Faculty of Health Science, Medical University in Warsaw, Warsaw, Poland.
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2009.02.013 0887-8994/09/$—see front matter
Introduction Paroxysmal nonkinesigenic dyskinesia (OMIM no. 118800), also known as dystonia type 8, is a rare heritable disorder characterized by intermittent attacks of variabletype hyperkinetic involuntary movements without loss of consciousness. Typically, the attacks are not triggered by sudden movements but can occur after caffeine or alcohol intake, stress, or fatigue. In some families, the paroxysms take the form of chorea or choreoathetosis; in others, there is an additional dystonic component. Thus, historically, the disorder has been classified together with other primary dystonias [1]. Paroxysmal nonkinesigenic dyskinesia follows an autosomal dominant pattern of inheritance, with only two mutations identified in exon 1 of the paroxysmal nonkinesigenic dyskinesia gene, PNKD, which maps to 2q35 (alias myofibrillogenesis regulator 1 gene, MR1). The kindred described here included three individuals affected by paroxysmal nonkinesigenic dyskinesia, in each of whom a causative mutation was identified, substitution A9 V in exon 1 of the PNKD gene. This report compares the family with other cases from literature, provides data illustrating possible reduced penetrance as well as variable expressivity, and discusses alternative treatment options based on this family’s experience. Specifically, a beneficial role of levetiracetam in the affected individuals is noted, and a possible mechanism is proposed involving calcium channels. Case Report The proband, an 8-year-old girl (Fig 1, III-1), presented with attacks of sudden generalized rigidity, leg and hand extensions, mumbling speech, problems in opening her mouth, and facial grimacing. The paroxysms lasted approximately 40 minutes and were precipitated by relative physical fatigue, especially after school, or by both negative (i.e., unknown, crowded places) or positive (i.e., peals of laughter) stressors. Headache, hand muscle cramps, and particularly double vision were the major prodromal symptoms. Frequency of the attacks was one to two per day. They had begun in early infancy in the form of opisthotonus. The interictal neurologic examination was unremarkable. A 5-year-old sister (III-2) of the proband presented with attacks of generalized choreoathetosis starting in both upper and lower limbs, which lasted about 30 minutes and occurred twice a day, usually in the morning or afternoon hours. The attacks had probably started in her second year. The triggering factors were generally similar to her sister’s, with physical
Communications should be addressed to: Dr. Szcza1uba; Department of Medical Genetics; Institute of Mother and Child; Kasprzaka 17A St.; 01-211 Warsaw, Poland. E-mail: [email protected] Received November 17, 2008; accepted February 10, 2009.
Szcza1uba et al: Paroxysmal Nonkinesigenic Dyskinesia 135
Figure 1. Pedigree of the family with paroxysmal nonkinesigenic dyskinesia. Solid symbols indicate affected family members. A9 V/ , mutation carrier. fatigue a much more potent stressor. Neurologic examination between the attacks was unrevealing. The 44-year-old father (II-1) of the two affected girls had a history of relatively milder hand and finger muscle spasms with or without facial twitching, two to three times a month, and lasting up to 30 minutes, not infrequently before bedtime. He suggested no clear precipitant to the paroxysms and required no treatment for his condition. His neurologic examination was unremarkable. The 64-year-old paternal grandmother (I-2) of the proband had reportedly no history of dyskinetic events whatsoever, according to family members (including her husband). Her neurologic findings were normal as well. To identify the causative mutation, exon 1 of the PNKD gene was sequenced, after polymerase chain reaction with a pair of primers: forward TGT AGG CAG GAC GGA AGG AG and reverse TGC AGA AAA GTG TGG GGA GGA ACC. The polymerase chain reaction conditions were as follows: 35 cycles of 95 C for 300 seconds, 95 C for 30 seconds, 60 C for 30 seconds, 72 C for 30 seconds, and 72 C for 600 seconds. The reaction mixture was 3 mL 10 polymerase chain reaction buffer, 3 mL deoxynucleotide triphosphates (2.5 mmol/L), 0.6 mL forward primer (10 pmol/mL), 0.6 mL reverse primer (10 pmol/mL), 0.2 mL Taq polymerase (2 units/mL), and 22.6 mL water. After analysis of all three affected individuals in this family, a 72C > T transition was identified in exon 1 of the PNKD gene, which leads to an alanine-to-valine substitution (A9V) in the encoded protein. The reportedly asymptomatic paternal grandmother also harbors the mutation (Fig 2).
Discussion More than 15 kindreds and more than 50 patients with paroxysmal nonkinesigenic dyskinesia have been described in the literature [2]. In this rare condition, attacks of
136 PEDIATRIC NEUROLOGY Vol. 41 No. 2
(dystonic) choreoathetosis last 10 minutes to 1 hour and are triggered by various stimuli. In the present pair of young female siblings, the attacks are 30-40 minutes long and occur up to two times daily. Morphologically, the paroxysms are slightly different in each girl. Overall, physical fatigue and stress seem to be main precipitating factors in both affected patients; however, neither factor triggers attacks in their father. The father has relatively mild clinical manifestations, possibly reflecting variable expressivity of the condition. Intrafamilial clinical heterogeneity is seen in many neurological disorders; nonetheless, in most PNKD families the symptoms are of similar frequency, morphology, and duration. In turn, the lack of symptoms in the paternal grandmother, who also harbors the familial mutation, probably represents reduced penetrance of the pathogenic mutation. Reduced penetrance has been seen in more than 10% of confirmed carriers and is limited to families with one particular causative mutation [3]. It was described initially by Rainier et al. [4] as likely resulting from the effects of modifying genetic background or environmental factors. Modifying genetic background can generally be divided into genes and proteins. Polymorphisms within the PNKD gene or within other interacting genes are yet to be elucidated as possible modifiers. Notably, however, three splicing variants of PNKD have been identified, one of which is devoid of the mutation-harboring first exon. This isoform, called MR-1M, is expressed in the brain and in some peripheral tissues; in the cell, it resides in the perinuclear region. Thus, potentially, subtle imbalances between systemic and intracellular concentration of all three isoforms, including MR-1M, could result in clinical nonpenetrance. Other possible modifiers are neurotransmitters, such as dopamine or g-aminobutyric acid. Their role in penetrance or expressivity could be age-dependent, as is suggested for dopamine in dystonia type 1, another primary dystonia. Recently, an age-dependent effect of estrogen has been demonstrated for paroxysmal nonkinesigenic dyskinesia [5]. Two recurrent mutations in exon 1 of PNKD gene (A7V and A9V) are responsible for clinical expression of paroxysmal nonkinesigenic dyskinesia [6]. In all the cases of paroxysmal nonkinesigenic dyskinesia in a Slavic ethnic background, the A9V mutation was present, including another Polish family [5]. The gene is expressed in many tissues, including brain and skeletal muscle. In the muscle, its product interacts with sarcomeric proteins, particularly myomesin and b-enolase. These two proteins are involved in the organization of M-bands in striated muscle, one of the steps in mature myofibril formation [7]. How the mutated PNKD gene leads to paroxysmal involuntary muscle spasms is unclear, but both mutations likely disrupt a-helical structure of N-terminal region of MR-1S and MR-1L isoforms, causing the whole protein to misfold or mislocalize (first nucleotides encode signal peptide). In most patients with paroxysmal nonkinesigenic dyskinesia, identification of a PNKD gene mutation precludes favorable response to benzodiazepines taken as abortive or preventative agents [2]. Indeed, in the proband a change
Figure 2. Sequencing analysis reveals the substitution 72C > T (A9V) (arrow, upper panel) in a carrier and the normal sequence (lower panel) in a noncarrier.
in duration of attacks was observed after oral administration of 2 mg diazepam as early as the prodromal phase (Table 1), but no such effect was observed in the proband’s sister. Also, the morphology or frequency of the paroxysms remained the same in both girls with diazepam. The limited efficacy of the drug in the proband and lack of response in her sister may have resulted from the fact that perhaps diazepam, through enhancement of g-aminobutyric-acidmediated transmission, exerts a merely modifying effect in basal ganglia, rather unrelated to the molecular defect in paroxysmal nonkinesigenic dyskinesia. The medication was therefore changed to levetiracetam, in light of a recent encouraging report from Alemdar et al. [8]. Albeit in a likely secondary dyskinesia, the authors noted antidyskinetic effects of the drug, taken at a total dose of 1000 mg/day, in a patient with idiopathic hypoparathyroidism and basal ganglia calcification. Although this effect may not have been strictly related to the hypocalcemia present in their patient, calcium channels constitute very
likely targets of levetiracetam in striatal, neocortical, hippocampal, and pyramidal neurons [9]. This calcium release inhibition by levetiracetam is also seen in ryanodineregulated channels, whose ligand is caffeine, which is known to trigger dyskinetic attacks [10]. In both affected siblings, a favorable effect on the duration of the paroxysms was observed for levetiracetam taken prophylactically twice daily (Table 1). Fewer attacks were observed in the proband; in her sister, the attacks were significantly milder. Notably, no adverse effects were observed in the two girls when given regular doses of levetiracetam. Favorable response to levetiracetam may be achieved both in the peripheral and central nervous system. In the muscle, MR-1 protein may regulate muscle contraction in a way that involves ryanodine channels. Normally, the channels open and calcium is released, which is the first signal for the contractile apparatus to work. The MR-1 protein may control the process through binding contractile proteins like myosin light chain or myomesin. When
Table 1. Pharmacotherapeutic effect of diazepam and levetiracetam in the two affected girls with mutation of the PNKD gene (alias MR1), substitution A9V in exon 1 Patient Proband (III-1 in Fig 1)
Pretreatment Characteristics 1-2 attacks per day, 40 min duration, afternoon hours. Pocket-knife dystonic posturing (upper and lower limbs extended), facial grimacing. Could not open mouth. No choreoathetosis.
Effect of Diazepam Shortened duration to 20 min. No effect on frequency. No effect on morphology.
Effect of Levetiracetam At daily dose 2 750 mg: shortened duration to 10 min. Attacks less frequent (2/week). No effect on morphology.
2 attacks No effect. At daily dose 2 500 mg: shortened duration per day, 30 min duration, to 15 minutes. No change in frequency. morning and afternoon. Morphology: only sudden sleepiness and Generalized chorea starting pain in hands and legs. in upper limbs, athetosis, back spasms, facial grimacing. Abortive dose of 2 mg of diazepam up to 2-3 doses/day during 12 weeks of therapy was used. Later on, levetiracetam 2 times daily was tried during 20 weeks of therapy.
Sister (III-2 in Fig 1)
Szcza1uba et al: Paroxysmal Nonkinesigenic Dyskinesia 137
mutated, the MR-1 is inactive (probably mislocalized), and ryanodine channel activators cause exaggerated uncontrollable response. Although binding sites of levetiracetam have so far been restricted to neuronal cells only, the drug may influence calcium flow at the neuromuscular junction level through one or more other proteins. So far, no clear role of the MR-1 protein within the central nervous system has emerged from the literature. We hypothesize that MR-1 may be sensitive to intraneuronal calcium stores, which in turn are modified by levetiracetam through its action on calcium channels. Defective MR-1 protein action within the central nervous system may cause destabilization of actin cytoskeleton (i.e., via myomesin) and in this way lead to paroxysms. Antidyskinetic activity of levetiracetam or other pyrrolidone derivatives may also be linked with its synaptic transport modification by binding synaptic vesicle protein SV2A [11,12]. In conclusion, as seen in the present kindred, the clinical picture of paroxysmal nonkinesigenic dyskinesia can be variable up to the point of nonpenetrance. Therapeutic options include the well-proved abortive effect of diazepam; alternatively, another benzodiazepine may be tried in paroxysmal nonkinesigenic dyskinesia patients, either after onset of an attack or preventatively [13]. Further research is needed regarding the possible beneficial prophylactic role of regular doses of levetiracetam in paroxysmal nonkinesigenic dyskinesia, as it may suppress or alleviate the paroxysms through calcium-channel-modifying effects. The antidyskinetic effect may still be transient, as seen in other antiepileptic drugs (i.e., valproate) [2], but more pronounced and more effective than that of benzodiazepines. The authors thank Sandra Peacock (Baylor College of Medicine) for her useful comments. This work was sponsored by the Polish Scientific Committee under grant number PBZ-KBN-122 P05/01-11.
138 PEDIATRIC NEUROLOGY Vol. 41 No. 2
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