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Paroxysmal non-kinesigenic dyskinesia due to a PNKD recurrent mutation: Report of two Southern European families
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 8 6 e8 9
Official Journal of the European Paediatric Neurology Society
Case study
Paroxysmal non-kinesigenic dyskinesia due to a PNKD recurrent mutation: Report of two Southern European families Roser Pons a, Ester Cuenca-Leo´n b, Elena Miravet c, Montse Pons c, Athina Xaidara a, Sotiris Youroukos a, Alfons Macaya b,* a
First Department of Pediatrics, Agia Sofia Hospital, University of Athens, Greece Grup de Recerca en Neurologia Infantil, Hospital Universitari Vall d’Hebron, Barcelona, Spain c Servei de Neuropediatria, Hospital Universitari Son Dureta, Mallorca, Spain b
article info
abstract
Article history:
Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal dominant disorder char-
Received 5 May 2010
acterized by attacks of dystonic or choreathetotic movements precipitated by stress,
Received in revised form
fatigue, coffee, alcohol or menstruation. In this report we present two families with PNKD
8 September 2010
of Southern European origin carrying a PNKD recurrent mutation. Incomplete penetrance
Accepted 27 September 2010
and intrafamilial variability was detected in both families. Treatment with valproic acid and levetiracetam provided favorable response.
Keywords:
ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
Dystonia
reserved.
Choreoathetosis Valproic acid Levetiracetam Autosomal dominant Southern Europe
1.
Introduction
PNKD is an autosomal dominant disorder characterized by attacks of dystonic or choreathetotic movements lasting from minutes to hours without change in level of alertness. The attacks can be precipitated by stress, fatigue, coffee, alcohol and menstruation. Mutations in PNKD on chromosome 2q35, encoding the PNKD protein (formerly named myofibrillogenesis regulator 1 protein, MR-1) have been indentified in
several families with PNKD.1e8 The analysis of these families has shown a rather uniform phenotype.6 Two common mutations in the first exon of PNKD (p.Ala7Val and p.Ala9Val) have been detected in different population groups1e8 with no evidence of a common ancestor.3 More recently a third mutation (p.Ala33Pro) has been reported in one patient.9 In this report we present 2 families of Southern European origin with the p.Ala7Val mutation.
* Corresponding author. Servei de Neurologia Infantil, Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron 119-129, 09035-Barcelona, Spain. Tel.: þ34 934893890; fax: þ34 932746837. E-mail address: [email protected] (A. Macaya). 1090-3798/$ e see front matter ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2011.09.008
87
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 8 6 e8 9
2.2.
2.
Patients
2.1.
Family 1 (Fig. 1), index patient (1.32)
This 3 year old Greek boy started having weekly episodes of rapid breathing of 1e2 min duration at the age of 3 months. Two-to-three months later the episodes began to be associated with drooling and limb posturing. The events increased gradually in frequency and peaked at 2 years of age when he suffered 1e2 episodes per day. By 2 ½ years of age the events began to decrease in frequency. His father (1.22) and two relatives in the paternal side (1.23, 1.34) suffer from similar paroxysmal events. A summary of their available clinical presentation is depicted in Table 1. At 3 years of age the attacks occur once per month mainly late in the day. They are preceded by a feeling of intense fatigue followed by dystonic posturing of one or both upper limbs. During the episodes he drools and his speech becomes slurred. At times he also has dystonic posturing of one or both legs. The duration is generally 4e5 min and occasionally up to 20 min. During the events he remains alert and usually asks for water to shorten the attacks. Distraction can also shorten the attacks. Between the events his neurologic examination is normal. He has not received any treatment for his attacks.
Family 2 (Fig. 1), index patient (2.41)
This is an 8 year old Spanish girl with learning difficulties and attention deficit disorder who at the age of 2 years started having paroxysmal episodes of stiffening of the right arm and leg and oral dyskinesias. The events occurred 4-to-6 times per month and lasted 30 min-to-2 hours. She was treated with valproic acid with a period of improvement in the frequency and severity of her attacks. Introduction of topiramate was unsuccessful. She is currently on valproic acid having one episode every 5e6 months. Between the events her neurologic examination is normal. Her brother (2.42), father (2.31), and several members in the paternal side (2.22, 2.33, 2.35, 2.45) (Fig. 1) suffer from paroxysmal events (Table 1).
3.
Methods
Genomic DNA from 17 subjects of the two unrelated families was isolated. Each subject provided written informed consent for DNA analysis and the local ethics committee approved the study following the guidelines of the Helsinki Declaration. The first exon of PNKD and its flanking intronic junctions including splice sites were PCR amplified in a single product. Purification and sequencing with forward and reverse primers
Table 1 e Clinical characteristics of index cases and family members with PNKD mutations. Sex Family 1 1.11 M 1.22 M
1.23 F 1.32 M
1.34 F Family 2 2.22 M
Age at onset
Attack phenomenology
NA (deceased) Asymptomatic Early childhood Dystonia, dysarthria Oculogyric crisis and generalized dystonia during severe episodes NA Dystonia, dysarthria 3 mo Early infancy: Hyperventilation Later infancy: dystonia, dysarthria, drooling NA Dystonia, dysarthria NA
2.31 M
Teenager
2.33 M 2.35 M 2.41 F
Young adult Young adult 2 years
2.42 M
18 mo
2.44 M 2.45 M
6 mo
Triggering Duration of Alleviating Treatment factor events factors
Frequency of events and course
S, F, A, C
min-to-1 h
To drink water Relaxation
None
Highest frequency during childhood 0e2/year in adulthood
NA S, F
NA 4-to-20 min
NA To drink water Distraction
NA None
NA 1e2/day during infancy 1/month at age 3 years
NA
NA
NA
NA
NA
Arm and leg stiffening Occasionally tremor Right arm dystonia
NA
NA
NA
Levetiracetam
None on levetiracetam
T, A
30min-to-3 h NR
Levetiracetam
Right arm dystonia Right arm dystonia Stiffening of right arm and leg, oral dyskinesias Cervical rigidity, stiffening of one or two legs Occasional inability to move ipsilateral arm Asymptomatic Inability to move arm Oral dyskinesias
NR NR NR
NR NR NR NR 30min-to-2 h NR
NR
10-to-20 min
NR
NR NR Valproic acid Topiramate Valproic acid
Off alcohol 0e3/month None on levetiracetam NR NR 4e6/month 2e3/year on valproic acid 2e3/week None on valproic acid
NR
Minutes
NR
Valproic acid
None on valproic acid
NA ¼ Information not available, NR ¼ not reported, S ¼ stress (anxiety, excitement, intercurrent illnesses), F ¼ fatigue, A ¼ alcohol, C ¼ coffee.
88
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 8 6 e8 9
of independent PCR products were performed. The missense change identified was named according to Human Genome Variation Society guidelines using RefSeq accession number NM_015488 as cDNA reference sequence, with nucleotide 145, the A of the ATG initiation codon, corresponding to þ1, and NP_056303 as the protein reference sequence.
4.
Results
Both index patients (1.32 and 2.41) were found to harbor the previously reported,1,2 recurrent p.Ala7Val variant in the PNKD (MR-1) protein. This was brought about by a C to T transition at nucleotide 20 in PNKD, exon 1. The presence of the p.Ala7Val PNKD missense mutation was tested in 6 relatives of index patient 1.32 and in 9 relatives of index patient 2.41 (Fig. 1).The p.Ala7Val mutation was shared by all the affected members in both families. Two unaffected members carried the mutation (1.11 and 2.44). Individual 2.24, suffering from unprovoked nocturnal episodes of oromandibular hypertonia, did not carry the p.Ala7Val mutation.
5.
Fig. 1 e Top: Pedigrees of families 1 and 2. Solid symbols indicate affected family members with PNKD. Bottom: Chromatograms showing the c.20C > T (p.Ala7Val) heterozygous mutation in a patient and the WT sequence in a control individual.
Discussion
In this report, we describe two Southern European families with PNKD and mutations in PNKD. In keeping with the known limited spectrum of mutations of this condition,1e8 both families carried the alanine to valine mutation at amino acid 7 of the PNKD/MR-1 protein (p.Ala7Val). Despite the phenotypic and genotypic homogeneity of patients with PNKD mutations,6 a number of issues are still insufficiently characterized including penetrance and variability in the age at onset and clinical course. While a penetrance of 98% has been calculated in a series of 8 families with proven PNKD mutations,6 incomplete and age-dependent penetrance has been noted in other kindreds.3,5,8,10 In our experience, the lack of symptoms of subject 1.11 and putatively of subject 2.44 (Table 1), further supports the incomplete penetrance of this condition. Generally, patients with PNKD present in infancy or early childhood,6 but onset in early adulthood is not rare.2 Intrafamilial variability also exists,3,8 and this is also the case in our families, both displaying clinical anticipation (Table 1). Given the uniformity in the genetic basis of this disorder, variable expressivity might be related to age-related factors, genetic modifiers or environmental factors. This is further supported by the wide range of tolerance to precipitating factors between individuals and within the same individual.10 Similar to a genetic animal model of primary paroxysmal dystonia (dt[sz] mutant hamster), where age-dependent remission of dystonia is characteristic,11 61% of patients with PNKD show a tendency to decrease the frequency of their attacks with age4,6; however, in some patients, episodes may remain unchanged or worsen with age.4,6,7 Furthermore, an incremental-decremental pattern in frequency and severity of the attacks, with a peak in adolescence,3 and reduction or disappearance of attacks during pregnancy have also been
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 8 6 e8 9
described,6,7 perhaps reflecting a hormonal influence in the natural history of PNKD. Evolving symptomatology has been reported.6,8 Episodes of dystonia in the first moths of life that incorporated choreic components with increasing age were reported in one patient6 and opisthotonus in early infancy that evolved into generalized dystonia was reported in another.8 In our series, patient 1.32 presented with brief episodes of hyperventilation early in life that gradually incorporated a motor component and evolved into classic dystonic events. It is possible that the evolving nature of the attacks is the expression of developmental factors, either related to the expression of PNKD or to the function and organization of motor control areas. It is debated whether the pathophysiological mechanism of PNKD is related to a defective detoxification mechanism during times of stress2 or to a deleterious effect of the mutated mitochondrial targeting sequence of the MR-1 protein.9 It has also been postulated that MR-1 plays an important role in maintaining excitability of essential parts of the motor system given its expression in cerebellum, spinal cord and basal ganglia.2 In this regard, a role for dopamine dysfunction in the origin of PNKD is conceivable. This is supported by the precipitation of attacks by alcohol and caffeine which can stimulate dopamine release and by similarities with inherited disorders of dopamine metabolism, such as preferential occurrence of dyskinetic attacks latter in the day3,12 and the beneficial effect of sleep in stopping the attacks.3,6,10,12 We believe that the presence of tremor in patient 2.22 and the oculogyric crises in patient 1.22 (Table 1) are additional clinical features that support the role of dopamine imbalance at the time of the PNKD attacks. Furthermore, several PET studies12e14 pointed to alterations in dopamine release or postsynaptic function. On the other hand, although some patients with PNKD have shown some response to L-dopa,6,10 a consistent response is lacking. In contrast with paroxysmal kinesigenic dyskinesias, patients with PNKD generally respond poorly to antiepileptic drugs.6,7,10 In patients with PNKD with proven PNKD mutations benzodiazepines are the most effective prophylactic as well as abortive treatment, with a reported 97% of responders.6 Two of our patients (2.41 and 2.42) showed incomplete response to valproic acid therapy (Table 1). Similarly, four out of six reported patients showed beneficial response to valproic acid but lost responsiveness over the years.6 Prophylactic treatment with levetiracetam was beneficial in a Polish PNKD family.8 Our patients 2.22 and 2.31 showed a favorable response to levetiracetam (Table 1), although it is also possible that the resolution of their events reflects the natural history of PNKD.6 In summary: In this report we present two Southern European families with PNKD and confirm recurrence of the p.Ala7Val PNKD mutation also in this population group. Incomplete penetrance and intrafamilial variability was noted. Valproic acid reduced the frequency of the events and
89
levetiracetam completely prevented the attacks in one pedigree.
Acknowledgments Supported by AGAUR (2009 SGR-078).
references
1. Rainier S, Thomas D, Tokarz D, et al. Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch Neurol 2004;61:1025e9. 2. Lee HY, Xu Y, Huang Y, et al. The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum Mol Genet 2004;13:3161e70. D, et al. Clinical 3. Stefanova E, Djarmati A, Momcilovic characteristics of paroxysmal nonkinesigenic dyskinesia in Serbian family with Myofibrillogenesis regulator 1 gene mutation. Mov Disord 2006;21:2010e5. 4. Chen DH, Matsushita M, Rainier S, et al. Presence of alanineto-valine substitutions in myofibrillogenesis regulator 1 in paroxysmal nonkinesigenic dyskinesia: confirmation in 2 kindreds. Arch Neurol 2005;62:597e600. 5. Hempelmann A, Kumar S, Muralitharan S, Sander T. Myofibrillogenesis regulator 1 gene (MR-1) mutation in an Omani family with paroxysmal nonkinesigenic dyskinesia. Neurosci Lett 2006;402:118e20. 6. Bruno MK, Lee HY, Auburger GW, et al. Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia. Neurology 2007;68:1782e9. 7. 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;61:39e41. 8. Szczałuba K, Jurek M, Szczepanik E, et al. A family with paroxysmal nonkinesigenic dyskinesia: genetic and treatment issues. Pediatr Neurol 2009;41:135e8. 9. Ghezzi D, Viscomi C, Ferlini A, et al. Paroxysmal nonkinesigenic dyskinesia is caused by mutations of the MR-1 mitochondrial targeting sequence. Hum Mol Genet 2009;18: 1058e64. 10. Fink JK, Hedera P, Mathay JG, Albin RL. Paroxysmal dystonic choreoathetosis linked to chromosome 2q: clinical analysis and proposed pathophysiology. Neurology 1997;49:177e83. 11. Hamann M, Sander SE, Richter A. Age-dependent alterations of striatal calretinin interneuron density in a genetic animal model of primary paroxysmal dystonia. J Neuropathol Exp Neurol 2005;64:776e81. 12. Jarman PR, Bhatia KP, Davie C, et al. Paroxysmal dystonic choreoathetosis: clinical features and investigation of pathophysiology in a large family. Mov Disord 2000;15:648e57. 13. Lombroso CT, Fischman A. Paroxysmal non-kinesigenic dyskinesia: pathophysiological investigations. Epileptic Disord 1999;1:187e93. 14. Bohnen NI, Albin RL, Frey KA. Fink JK. (þ)-alpha-[11C] Dihydrotetrabenazine PET imaging in familial paroxysmal dystonic choreoathetosis. Neurology 1999;52:1067e9.
Official Journal of the European Paediatric Neurology Society
Case study
Paroxysmal non-kinesigenic dyskinesia due to a PNKD recurrent mutation: Report of two Southern European families Roser Pons a, Ester Cuenca-Leo´n b, Elena Miravet c, Montse Pons c, Athina Xaidara a, Sotiris Youroukos a, Alfons Macaya b,* a
First Department of Pediatrics, Agia Sofia Hospital, University of Athens, Greece Grup de Recerca en Neurologia Infantil, Hospital Universitari Vall d’Hebron, Barcelona, Spain c Servei de Neuropediatria, Hospital Universitari Son Dureta, Mallorca, Spain b
article info
abstract
Article history:
Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal dominant disorder char-
Received 5 May 2010
acterized by attacks of dystonic or choreathetotic movements precipitated by stress,
Received in revised form
fatigue, coffee, alcohol or menstruation. In this report we present two families with PNKD
8 September 2010
of Southern European origin carrying a PNKD recurrent mutation. Incomplete penetrance
Accepted 27 September 2010
and intrafamilial variability was detected in both families. Treatment with valproic acid and levetiracetam provided favorable response.
Keywords:
ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
Dystonia
reserved.
Choreoathetosis Valproic acid Levetiracetam Autosomal dominant Southern Europe
1.
Introduction
PNKD is an autosomal dominant disorder characterized by attacks of dystonic or choreathetotic movements lasting from minutes to hours without change in level of alertness. The attacks can be precipitated by stress, fatigue, coffee, alcohol and menstruation. Mutations in PNKD on chromosome 2q35, encoding the PNKD protein (formerly named myofibrillogenesis regulator 1 protein, MR-1) have been indentified in
several families with PNKD.1e8 The analysis of these families has shown a rather uniform phenotype.6 Two common mutations in the first exon of PNKD (p.Ala7Val and p.Ala9Val) have been detected in different population groups1e8 with no evidence of a common ancestor.3 More recently a third mutation (p.Ala33Pro) has been reported in one patient.9 In this report we present 2 families of Southern European origin with the p.Ala7Val mutation.
* Corresponding author. Servei de Neurologia Infantil, Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron 119-129, 09035-Barcelona, Spain. Tel.: þ34 934893890; fax: þ34 932746837. E-mail address: [email protected] (A. Macaya). 1090-3798/$ e see front matter ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2011.09.008
87
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 8 6 e8 9
2.2.
2.
Patients
2.1.
Family 1 (Fig. 1), index patient (1.32)
This 3 year old Greek boy started having weekly episodes of rapid breathing of 1e2 min duration at the age of 3 months. Two-to-three months later the episodes began to be associated with drooling and limb posturing. The events increased gradually in frequency and peaked at 2 years of age when he suffered 1e2 episodes per day. By 2 ½ years of age the events began to decrease in frequency. His father (1.22) and two relatives in the paternal side (1.23, 1.34) suffer from similar paroxysmal events. A summary of their available clinical presentation is depicted in Table 1. At 3 years of age the attacks occur once per month mainly late in the day. They are preceded by a feeling of intense fatigue followed by dystonic posturing of one or both upper limbs. During the episodes he drools and his speech becomes slurred. At times he also has dystonic posturing of one or both legs. The duration is generally 4e5 min and occasionally up to 20 min. During the events he remains alert and usually asks for water to shorten the attacks. Distraction can also shorten the attacks. Between the events his neurologic examination is normal. He has not received any treatment for his attacks.
Family 2 (Fig. 1), index patient (2.41)
This is an 8 year old Spanish girl with learning difficulties and attention deficit disorder who at the age of 2 years started having paroxysmal episodes of stiffening of the right arm and leg and oral dyskinesias. The events occurred 4-to-6 times per month and lasted 30 min-to-2 hours. She was treated with valproic acid with a period of improvement in the frequency and severity of her attacks. Introduction of topiramate was unsuccessful. She is currently on valproic acid having one episode every 5e6 months. Between the events her neurologic examination is normal. Her brother (2.42), father (2.31), and several members in the paternal side (2.22, 2.33, 2.35, 2.45) (Fig. 1) suffer from paroxysmal events (Table 1).
3.
Methods
Genomic DNA from 17 subjects of the two unrelated families was isolated. Each subject provided written informed consent for DNA analysis and the local ethics committee approved the study following the guidelines of the Helsinki Declaration. The first exon of PNKD and its flanking intronic junctions including splice sites were PCR amplified in a single product. Purification and sequencing with forward and reverse primers
Table 1 e Clinical characteristics of index cases and family members with PNKD mutations. Sex Family 1 1.11 M 1.22 M
1.23 F 1.32 M
1.34 F Family 2 2.22 M
Age at onset
Attack phenomenology
NA (deceased) Asymptomatic Early childhood Dystonia, dysarthria Oculogyric crisis and generalized dystonia during severe episodes NA Dystonia, dysarthria 3 mo Early infancy: Hyperventilation Later infancy: dystonia, dysarthria, drooling NA Dystonia, dysarthria NA
2.31 M
Teenager
2.33 M 2.35 M 2.41 F
Young adult Young adult 2 years
2.42 M
18 mo
2.44 M 2.45 M
6 mo
Triggering Duration of Alleviating Treatment factor events factors
Frequency of events and course
S, F, A, C
min-to-1 h
To drink water Relaxation
None
Highest frequency during childhood 0e2/year in adulthood
NA S, F
NA 4-to-20 min
NA To drink water Distraction
NA None
NA 1e2/day during infancy 1/month at age 3 years
NA
NA
NA
NA
NA
Arm and leg stiffening Occasionally tremor Right arm dystonia
NA
NA
NA
Levetiracetam
None on levetiracetam
T, A
30min-to-3 h NR
Levetiracetam
Right arm dystonia Right arm dystonia Stiffening of right arm and leg, oral dyskinesias Cervical rigidity, stiffening of one or two legs Occasional inability to move ipsilateral arm Asymptomatic Inability to move arm Oral dyskinesias
NR NR NR
NR NR NR NR 30min-to-2 h NR
NR
10-to-20 min
NR
NR NR Valproic acid Topiramate Valproic acid
Off alcohol 0e3/month None on levetiracetam NR NR 4e6/month 2e3/year on valproic acid 2e3/week None on valproic acid
NR
Minutes
NR
Valproic acid
None on valproic acid
NA ¼ Information not available, NR ¼ not reported, S ¼ stress (anxiety, excitement, intercurrent illnesses), F ¼ fatigue, A ¼ alcohol, C ¼ coffee.
88
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 8 6 e8 9
of independent PCR products were performed. The missense change identified was named according to Human Genome Variation Society guidelines using RefSeq accession number NM_015488 as cDNA reference sequence, with nucleotide 145, the A of the ATG initiation codon, corresponding to þ1, and NP_056303 as the protein reference sequence.
4.
Results
Both index patients (1.32 and 2.41) were found to harbor the previously reported,1,2 recurrent p.Ala7Val variant in the PNKD (MR-1) protein. This was brought about by a C to T transition at nucleotide 20 in PNKD, exon 1. The presence of the p.Ala7Val PNKD missense mutation was tested in 6 relatives of index patient 1.32 and in 9 relatives of index patient 2.41 (Fig. 1).The p.Ala7Val mutation was shared by all the affected members in both families. Two unaffected members carried the mutation (1.11 and 2.44). Individual 2.24, suffering from unprovoked nocturnal episodes of oromandibular hypertonia, did not carry the p.Ala7Val mutation.
5.
Fig. 1 e Top: Pedigrees of families 1 and 2. Solid symbols indicate affected family members with PNKD. Bottom: Chromatograms showing the c.20C > T (p.Ala7Val) heterozygous mutation in a patient and the WT sequence in a control individual.
Discussion
In this report, we describe two Southern European families with PNKD and mutations in PNKD. In keeping with the known limited spectrum of mutations of this condition,1e8 both families carried the alanine to valine mutation at amino acid 7 of the PNKD/MR-1 protein (p.Ala7Val). Despite the phenotypic and genotypic homogeneity of patients with PNKD mutations,6 a number of issues are still insufficiently characterized including penetrance and variability in the age at onset and clinical course. While a penetrance of 98% has been calculated in a series of 8 families with proven PNKD mutations,6 incomplete and age-dependent penetrance has been noted in other kindreds.3,5,8,10 In our experience, the lack of symptoms of subject 1.11 and putatively of subject 2.44 (Table 1), further supports the incomplete penetrance of this condition. Generally, patients with PNKD present in infancy or early childhood,6 but onset in early adulthood is not rare.2 Intrafamilial variability also exists,3,8 and this is also the case in our families, both displaying clinical anticipation (Table 1). Given the uniformity in the genetic basis of this disorder, variable expressivity might be related to age-related factors, genetic modifiers or environmental factors. This is further supported by the wide range of tolerance to precipitating factors between individuals and within the same individual.10 Similar to a genetic animal model of primary paroxysmal dystonia (dt[sz] mutant hamster), where age-dependent remission of dystonia is characteristic,11 61% of patients with PNKD show a tendency to decrease the frequency of their attacks with age4,6; however, in some patients, episodes may remain unchanged or worsen with age.4,6,7 Furthermore, an incremental-decremental pattern in frequency and severity of the attacks, with a peak in adolescence,3 and reduction or disappearance of attacks during pregnancy have also been
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 8 6 e8 9
described,6,7 perhaps reflecting a hormonal influence in the natural history of PNKD. Evolving symptomatology has been reported.6,8 Episodes of dystonia in the first moths of life that incorporated choreic components with increasing age were reported in one patient6 and opisthotonus in early infancy that evolved into generalized dystonia was reported in another.8 In our series, patient 1.32 presented with brief episodes of hyperventilation early in life that gradually incorporated a motor component and evolved into classic dystonic events. It is possible that the evolving nature of the attacks is the expression of developmental factors, either related to the expression of PNKD or to the function and organization of motor control areas. It is debated whether the pathophysiological mechanism of PNKD is related to a defective detoxification mechanism during times of stress2 or to a deleterious effect of the mutated mitochondrial targeting sequence of the MR-1 protein.9 It has also been postulated that MR-1 plays an important role in maintaining excitability of essential parts of the motor system given its expression in cerebellum, spinal cord and basal ganglia.2 In this regard, a role for dopamine dysfunction in the origin of PNKD is conceivable. This is supported by the precipitation of attacks by alcohol and caffeine which can stimulate dopamine release and by similarities with inherited disorders of dopamine metabolism, such as preferential occurrence of dyskinetic attacks latter in the day3,12 and the beneficial effect of sleep in stopping the attacks.3,6,10,12 We believe that the presence of tremor in patient 2.22 and the oculogyric crises in patient 1.22 (Table 1) are additional clinical features that support the role of dopamine imbalance at the time of the PNKD attacks. Furthermore, several PET studies12e14 pointed to alterations in dopamine release or postsynaptic function. On the other hand, although some patients with PNKD have shown some response to L-dopa,6,10 a consistent response is lacking. In contrast with paroxysmal kinesigenic dyskinesias, patients with PNKD generally respond poorly to antiepileptic drugs.6,7,10 In patients with PNKD with proven PNKD mutations benzodiazepines are the most effective prophylactic as well as abortive treatment, with a reported 97% of responders.6 Two of our patients (2.41 and 2.42) showed incomplete response to valproic acid therapy (Table 1). Similarly, four out of six reported patients showed beneficial response to valproic acid but lost responsiveness over the years.6 Prophylactic treatment with levetiracetam was beneficial in a Polish PNKD family.8 Our patients 2.22 and 2.31 showed a favorable response to levetiracetam (Table 1), although it is also possible that the resolution of their events reflects the natural history of PNKD.6 In summary: In this report we present two Southern European families with PNKD and confirm recurrence of the p.Ala7Val PNKD mutation also in this population group. Incomplete penetrance and intrafamilial variability was noted. Valproic acid reduced the frequency of the events and
89
levetiracetam completely prevented the attacks in one pedigree.
Acknowledgments Supported by AGAUR (2009 SGR-078).
references
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