PRRT2: A major cause of infantile epilepsy and other paroxysmal disorders of childhood

PRRT2: A major cause of infantile epilepsy and other paroxysmal disorders of childhood

CHAPTER PRRT2: A major cause of infantile epilepsy and other paroxysmal disorders of childhood 8 Carlo Nobile*,1, Pasquale Striano{ *CNR-Neuroscien...

262KB Sizes 0 Downloads 35 Views

CHAPTER

PRRT2: A major cause of infantile epilepsy and other paroxysmal disorders of childhood

8

Carlo Nobile*,1, Pasquale Striano{ *CNR-Neuroscience Institute, Section of Padua, Viale G, Colombo, Padova, Italy Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute, Genova, Italy 1 Corresponding author: Tel.: +39-0498276072; Fax: +39-0498276040, e-mail address: [email protected]

{

Abstract In the past 2 years, mutations in the PRRT2 gene have been identified in patients and families with a variety of early-onset paroxysmal disorders, including various paroxysmal dyskinesias, benign familial infantile seizures, hemiplegic migraine, and episodic ataxia. In this chapter, we describe the wide clinical spectrum associated with PRRT2 mutations and present the current hypotheses on the underlying pathophysiology. Through its interaction with the presynaptic plasma membrane protein SNAP25, the PRRT2 protein may play a role in synaptic regulation in the cortex and basal ganglia. PRRT2 mutations likely have a loss-of-function effect and result in synaptic deregulation and neuronal hyperexcitability. The molecular bases underlying phenotypic variability are still unclear. Elucidating the molecular pathways linking the genetic defect to its clinical expression will improve treatment of these disorders.

Keywords PRRT2, mutations, pleiotropy, benign familial infantile convulsions, paroxysmal dyskinesia, migraine, hemiplegic migraine, episodic ataxia, SNAP25

1 INTRODUCTION In the past 2 years, mutations in the proline-rich transmembrane protein 2 (PRRT2) gene have been found in autosomal dominant early-onset neurological disorders such as paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis (ICCA), and benign familial infantile seizures (BFIS), and in some cases of Progress in Brain Research, Volume 213, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63326-2.00008-9 © 2014 Elsevier B.V. All rights reserved.

141

142

CHAPTER 8 Major cause of infantile epilepsy

paroxysmal exercised-induced dyskinesia (PED), paroxysmal non-kinesigenic dyskinesia (PNKD), hemiplegic migraine (HM), episodic ataxia (EA), childhoodabsence epilepsy (CAE), paroxysmal torticollis, and febrile seizures (FS) (Chen et al., 2011; Dale et al., 2012; Gardiner et al., 2012; Heron et al., 2012; Lee et al., 2012a,b; Li et al., 2012; Liu et al., 2012; Marini et al., 2012; Riant et al., 2012; Wang et al., 2011). PKD, ICCA, and BFIS have long been thought to be allelic disorders because they co-occur in some families and have been linked to the same region on chromosome 16p11.2-q12.1. Repeated attempts to identify the causative gene for PKD/ICCA/BFIS in this candidate region by positional cloning, including resequencing all the genes lying in the region (Kikuchi et al., 2007), failed to identify the causative gene. By using the whole-exome sequencing technology, Chen and collaborators (2011) first identified mutations in PRRT2, which is located on chromosome 16p11.2, in eight Chinese PKD families, opening the way to the identification of PRRT2 mutations in related clinical syndromes. In this chapter, we will describe the main clinical features of the syndromes so far associated with PRRT2 mutations, the features of these mutations, and as yet poorly studied biochemical and functional characteristics of this gene.

2 PRRT2-RELATED SYNDROMES 2.1 PKD PKD (MIM 128200), also named paroxysmal kinesigenic choreoathetosis (PKC), the most common type of paroxysmal dyskinesia, was first described 1892 by Shuzo Kure in a young Japanese patient who had frequent movement-induced paroxysmal attacks, typical of PKD. Later, families with this condition were described (Kertesz, 1967; Weber, 1967). This disorder is characterized by recurrent and brief attacks of choreoathetoid and/or dystonic movements without alteration of consciousness that are triggered by the initiation of voluntary movements and usually last less than 1 min (Bruno et al., 2004). Typically, onset is in childhood or adolescence and attacks are more frequent in puberty, whereas they are less frequent or even disappear in adulthood. Auras are frequent and allow some patients to have partial control of the attacks. Interictal neurological examination is normal. Attacks are generally well controlled by low-dose anticonvulsant medication such as carbamazepine or phenytoin. The syndrome is rare with a prevalence estimated at 1:150,000 (source: Genereviews, http://www.ncbi.nlm.nih.gov/books/NBK1460/). It is mainly a familial disorder with autosomal dominant inheritance and incomplete penetrance, but sporadic cases occur. PKD more commonly affects males, with a sex ratio of 3 or 4 to 1 in the sporadic form, but not in familial cases (Bruno et al., 2004). The origin of PKD, whether subcortical or cortical, is controversial. Magnetic resonance imaging of the brain is normal, and autopsies of two patients with PKD failed to demonstrate any significant morphological brain abnormalities (Kertesz, 1967; Lotze and Jankovic, 2010). The paroxysmal nature of PKD and its response to anticonvulsants suggest an epileptic origin. Additional findings supporting a cortical involvement include: focal interictal electroencephalography (EEG) changes

2 PRRT2-related syndromes

over the right frontocentral area found in a patient with PKD with paroxysmal dystonic posturing of the left leg (van Strien et al., 2012); EEG focal epileptic activity localized on the amygdala in a PKD patient who was cured by temporal lobectomy (Aybek et al., 2012); and various cortical perfusion alterations shown in three patients by ictal and interictal SPECT (van Strien et al., 2012). Yet, there is no loss of consciousness during attacks, and ictal/interictal EEGs are normal in the vast majority of patients. A different origin of PKD is suggested by the clinical characteristics of ictal movements, which are similar to those observed in basal ganglia disorders. Studies supporting a basal ganglia dysfunction in PKD include: ictal SPECT studies of patients with unilateral attacks showing an increased perfusion of the contralateral basal ganglia (Ko et al., 2001; Shirane et al., 2001), an interictal SPECT study of 16 patients showing decreased interictal perfusion of the posterior region of the caudate nuclei (Joo et al., 2005), and functional magnetic resonance imaging resting state analysis of seven patients showing that interictal spontaneous activity is increased in the right and left putamen and the left postcentral gyrus (Zhou et al., 2010). Taken together, these findings do not reveal the primary dysfunction responsible for PKD, but rather suggest a global dysfunction of the motor network. It has long been thought that PKD may be a channelopathy, mainly because of the clinical similarities with ion channel disorders, particularly EA type 1 (Bhatia et al., 2000; Fourcade et al., 2009). This latter disorder, which is caused by mutations in a potassium channel gene (KCNA1), is characterized by brief ataxia attacks that are often triggered by movement and decrease in frequency in adulthood. The channelopathy hypothesis would be in agreement with the sensitivity of PKD to anticonvulsant drugs, which modulate ion channels activity, and dysfunction of the basal ganglia might then be secondary to the ion channel disorder. However, the discovery of mutations in the PRRT2 gene has caused this hypothesis to be dismissed. PRRT2 is the major gene accounting for PKD, regardless of the population studied. In three different studies of familial and sporadic Chinese cases, PRRT2 mutations accounted for PKD in 16 out of 17 families (94%) and in 10 out of 29 sporadic cases (34%) (Chen et al., 2011; Li et al., 2012; Wang et al., 2011). In a study of European index cases, PRRT2 mutations were found in 13 out of 14 familial cases (93%) and nine out of 20 sporadic cases (45%) (Me´neret et al., 2012). Additional studies in other populations confirmed the predominance of PRRT2 mutations in patients with PKD (Cao et al., 2012; Gardiner et al., 2012; Groffen et al., 2012; Liu et al., 2012; Ono et al., 2012; Schmidt et al., 2012). However, a small number of patients with typical PKD have no mutations in PRRT2, suggesting the existence of at least another gene implicated in this disorder.

2.2 BFIS BFIS (OMIM 605751), also called benign familial infantile epilepsy or BFIE, is an autosomal dominant epilepsy disorder that occurs in infancy with onset between 3 and 12 months of age. It is characterized by brief seizures with motor arrest, cyanosis,

143

144

CHAPTER 8 Major cause of infantile epilepsy

hypertonia, and limb jerks. Seizures respond well to antiepileptic drugs and remission usually occurs before 2 years of age (Callenbach et al., 2002). Genetic linkage analyses of families affected with BFIS suggested that causative mutations occur in genes residing at three different chromosomal loci: 19q12-q13.11 (Guipponi et al., 1997), 1p36.12-p25.1 (Li et al., 2008), and 16p11.2-q12.1 (Callenbach et al., 2005; Caraballo et al., 2001; Striano et al., 2006; Weber et al., 2004, 2008). The latter linkage region, however, accounted for the vast majority of reported families with BFIS. Various attempts to identify the BFIS causative gene in the 16p11.2-q12.1 region, which contains about 150 genes, by candidate gene sequencing and other approaches, were unsuccessful. However, because this genomic region overlaps with that linked to PKD, following the identification of mutations in PRRT2 associated with PKD (Chen et al., 2011), mutations in PRRT2 were also found in BFIS families (Heron et al., 2012). Overall, PRRT2 mutations have been found in about 80% of BFIS families in various populations (de Vries et al., 2012; Heron et al., 2012; Schubert et al., 2012), proving that this gene is a major cause of BFIS.

2.3 ICCA SYNDROME The ICCA syndrome (MIM 602066), also known as PKD/infantile convulsions (PKD/IC), is clinically characterized by benign infantile seizures and paroxysmal dyskinesia, which are coinherited as a single autosomal dominant trait (Szepetowski et al., 1997). In families with ICCA, affected subjects have either infantile seizures, paroxysmal dyskinesia, or both (Schmidt et al., 2012); paroxysmal dyskinesias are mostly of the kinesigenic type, but families with PNKD or PED have also been reported (Rochette et al., 2010). More than 50 families with ICCA are reported in the literature (Espeche et al., 2011; Rochette et al., 2010). Linkage analysis showed that the ICCA locus overlapped with the locus mapped in PKD families on chromosome 16p11.2-q12.1, and therefore the two syndromes were suspected to be allelic (Bennett et al., 2000). This has recently been confirmed by studies showing that PRRT2 is indeed the major cause of ICCA as well as PKD and BFIS: PRRT2 mutations were found in the vast majority (>90%) of ICCA families of Asian, African-American, and Caucasian ethnicity (Heron et al., 2012; Lee et al., 2012a,b).

2.4 PNKD AND PED PNKD differs from PKD because attacks are precipitated by stress, fatigue or consumption of alcohol, coffee, and tobacco, whereas in PED attacks are triggered by prolonged exercise. In both disorders, attacks have longer duration and are less frequent than in PKD and usually respond poorly to anticonvulsant drugs. PNKD and PED occur in families with autosomal dominant inheritance and are mostly caused by mutations in the PNKD and SLC2A1 (GLUT-1) genes, respectively. A few Chinese studies have reported PRRT2 mutations in these syndromes: PRRT2 mutations were found in one family with PNKD and two sporadic cases with PED

4 Familial HM

(Liu et al., 2012), and in another family presenting with paroxysmal dyskinesia occurring both at rest and after prolonged exercise, though the duration of the attacks and their response to treatment were more consistent with PKD than PED (Wang et al., 2013). Further studies are needed to determine the exact prevalence of PRRT2 mutations in patients with PNKD and PED.

3 OTHER FORMS OF INFANTILE SEIZURES In a study of sporadic benign infantile seizures and families with atypical features of BFIS, de novo PRRT2 mutations were identified in two patients with infantile seizures without family history (Scheffer et al., 2012). Childhood infantile seizures co-occurred with BFIS in a single patient from another family (Marini et al., 2012) and were part of a complex phenotype in two patients with a homozygous PRRT2 mutation (Labate et al., 2012). However, no PRRT2 mutations were found in families with atypical infantile seizures such as later seizure onset or offset, more severe seizures, or multiple seizure type, suggesting that PRRT2 is associated with a specific self-limited, age-dependent epilepsy syndrome likely relating to developmental expression, and function of the PRRT2 protein.

3.1 EA EA is a rare disorder characterized by attacks of ataxia, usually caused by mutations in KCNA1 (EA type 1) or CACNA1A (EA type 2). In a screening of 182 individuals with EA without mutations in KCNA1 and CACNA1A, a PRRT2 mutation was found in a patient (Gardiner et al., 2012). In addition, EA was also part of a complex phenotype in two siblings with a homozygous PRRT2 mutation (Labate et al., 2012). These observations imply that PRRT2 mutations may rarely be causative of EA.

4 FAMILIAL HM HM is a rare subtype of migraine with aura, in which attacks are associated with transient weakness or hemiparesis (Russell and Ducros, 2011). Typically, the attacks start in the first or second decade of life, and the weakness is associated with other aura symptoms, including persistent cerebellar dysfunction and various types of seizures. HM shows sporadic or autosomal dominant inheritance. Three HM genes have been identified: CACNA1A, ATP1A2, and SCN1A, which account for about 3/4 of familial patients and a minority of sporadic patients (Russell and Ducros, 2011). In a study of 101 index patients with HM (48 familial, 52 sporadic, and 1 unknown) without mutations in the three known HM genes, PRRT2 mutations were found in four patients (Riant et al., 2012). One of them subsequently developed paroxysmal dyskinesia and generalized epileptic seizures, whereas the others had no paroxysmal movement disorders or epilepsy. In addition, PKD, HM, and paroxysmal torticollis,

145

146

CHAPTER 8 Major cause of infantile epilepsy

which is suspected to be a migraine equivalent in infancy (Bonnet et al., 2010), were variably associated with PRRT2 mutations in different subjects from a single family (Dale et al., 2012). However, the other known HM genes were not tested in this family. Other studies confirmed that PRRT2 mutations are rarely found in HM, either isolated or in association with PKD, BFIS, or EA (Cloarec et al., 2012; Gardiner et al., 2012; Marini et al., 2012). PRRT2 mutations were also found to segregate with migraine with or without aura in the context of ICCA families (Cloarec et al., 2012; Marini et al., 2012). In some families, phenocopies without PRRT2 mutations were found, likely due to the high prevalence of migraine in the general population (Cloarec et al., 2012; van Vliet et al., 2012). However, the detection of PRRT2 mutations in families with different forms of ICCA-related migraine, the well-known links between infantile convulsions and HM, and the increased risk of migraine in PNKD patients argue in favor of a non-spurious association of typical migraine with PRRT2 mutations in the context of familial ICCA (Cloarec et al., 2012).

5 INTELLECTUAL DISABILITY A large study of 136 consanguineous families with autosomal-recessive intellectual disability (ID) performed by homozygosity mapping and next-generation sequencing uncovered 50 novel candidate genes for ID, including PRRT2 (Najmabadi et al., 2011). A homozygous PRRT2 mutation was found in five affected members of one family. Their ID was described as severe and non-syndromic, which implies there were no associated clinical signs. In another consanguineous family, ID, PKD, EA, and CAE were associated with a homozygous PRRT2 mutation, whereas heterozygous mutation carriers had BFIS or were asymptomatic (Labate et al., 2012). Several PRRT2 mutation carriers with learning or intellectual disabilities and other neuropsychiatric manifestations were found in ICCA or BFIS families (Dje´mie´ et al., 2014), suggesting that neuropsychiatric problems may be part of the phenotypic spectrum associated with PRRT2 mutations. More studies are needed to elucidate whether psychiatric symptoms are more common in patients with ICCA or BFIS and PRRT2 mutations. If this will be the case, the concept of ICCA/BFIS as a benign syndrome may be reconsidered.

6 PRRT2 MUTATIONS The PRRT2 gene lies on chromosome 16p11.2 and consists of four exons, the first and large part of the fourth being untranslated (Fig. 1). The mutations reported so far have been found in exon 2 and 3, and most of them cause protein truncation. An overview of all mutations is given in Fig. 1 and Table 1. Overall, PRRT2 mutations have been found in the vast majority (85–91%) of familial cases of BFIS, ICCA, and PKD. They were found much less commonly in the reported sporadic cases, with an overall

q23.1

q22.1

q21

q12.2

q12.1

q11.2

p11.2

p12.1

p12.3

p13.3

Chromosome 16

PD ICCA BFIS HM FS, CAE EA ID

PRRT2 c.824C>T/p.S275F c.748C>T c.879+1G>T c.649dupC

85%

c.649delC

c.879+5G>A

c.649C>T

c.980_981insT c.981C>G/p.I327M

c.629dupC c.629delC c.604_607delTCAC

c.922C>T/p.R308C c.922C>G/p.R308C

c.573dupT c.514_517delTCTG c.434delC

Exon 1

c.1011C>T c.1011_1012delCG+1_9delGTGAGTGGG

c.950G>A/p.S317N

c.1012+2dupT

c.904dupG

Exon 2

Exon 4

Exon 3 879

1

880

1012

1013 1023

c.880-2A>T c.972delA c.595G>T c.562C>T

c.859G>A/p.A287T c.841T>C/p.W281R

c.516_517insT c.487C>T c.369dupG

c.796C>T/p.R266W

c.968G>A/p.G323E c.776dupG c.964delG

c.291delC c.272delC

c.971G>A/p.G324E c.970G>A/p.G324R

c.718C>T

c.916G>A/p.A306T c.913G>A/p.G305R

3 large deletions

FIGURE 1 Representation of the reported PRRT2 mutations and their clinical expression. Forty-seven different mutations have been reported so far, including 25 frameshift or nonsense mutations (53%), 16 missense (34%), and six splice site mutations (13%). The c.649 mutation hotspot is circled in black. It comprises three truncating mutations that account for 85% of all reported symptomatic PRRT2-mutated index cases. The c.649dupC/p.Arg217ProfsX8 mutation represents 82% of them all. The remaining 15% are caused by other truncating mutations, missense mutations (underlined), and splice site mutations (in italics). Five mutations are not represented because of incomplete nomenclature. BFIS, benign familial infantile seizures; CAE, childhood-absence epilepsy; EA, episodic ataxia; FS, febrile seizures; HM, hemiplegic migraine; ICCA, infantile convulsions with choreoathetosis syndrome; ID, intellectual disability; PD, paroxysmal dyskinesia. Reproduced with permission from Me´neret et al. (2013).

Table 1 Families and sporadic cases that have been screened for mutations in PRRT2 described in the literature, allocated to the different phenotypes of BFIS, ICCA, PKD, and others BFIS

ICCA

PKD

Others

References

Familial

Sporadic

Familial

Sporadic

Familial

Sporadic

Familial

Sporadic

Chen et al. (2011)









8 (8)







Wang et al. (2011)









5 (5)







Li et al. (2012)









4 (3)

29 (10)





Liu et al. (2012)





2 (2)



3 (2)

10 (2)

1 PNKDlike (1)

4 PED (2)

1PNKD (0)

Heron et al. (2012)

17 (14)



6 (5)











Detected mutations (familial/sporadic) c.649dupC (6/0) c.972delA (1/0) c.514_517delTCTG (1/0) c.649dupC (3/0) c.487C>T (1/0) c796C>T (1/0) c.649dupC (1/6) c.859G>A (1/0) c.369dupG (1/0) c.1011_1012delCC +1_9delGTGATGGG (0/1) c.964delG (0/1) c.841T>C (0/1) c.922C>T (0/1) c.649dupC (ICCA 1/0, PKD 2/0, PED 0/2, PNKD-like 1/0) c.904dupG (ICCA 1/0) c.1011C>T (PKD 0/1) c.913G>A (PKD 0/1) c.649dupC (BFIS 12/0, ICCA 3/0) c.879+5G>A (BFIS 1/0) c.879+1G>T (BFIS 1/0) c.629_630insC (ICCA 1/0) c.950G>A (ICCA 1/0)

Cao et al. (2012)









3 (2)

8 (1)





Ono et al. (2012) Lee et al. (2012a)

2 (2)







15 (15)











25 (24)









Schubert et al. (2012)

49 (42)

3 (1)

[78 (28)] –











Me´neret et al. (2012)





2 (2)



12 (11)

20 (9)





Groffen et al. (2012)









3 (2)

9 (3)



1 PED (0) 4 PNKD (0)

Van Vliet et al. (2012)





3 (3)



2 (2)

4 (2)





c.649dupC (1/1) c.573dupT (1/0) c.649dupC, c789C>T (BFIS 2/0, PKD 15/0) c.516_517insT (1 case) c.649_650insC (48 cases) pR240X (2 cases) c.980_981insT (1 case) c.649dupC (39/1) c.629delC (1/0) c.968G>A (1/0) c.219delC (1/0) c.649dupC (PKD 11/6, ICCA 1/0) c.649delC (PKD 1/1) c.562C>T (ICCA 1/0) c.649C>T (PKD 0/1) c.629dupC (PKD 0/1) c.649dupC (1/1) c.649C>T (1/0) c.649delC (0/1) c.3698T>C in 30 UTR (0/1) c.649dupC (ICCA 2/0, PKD 2/1) c.824C>T (ICCA 1/0) c.649C>T (PKD 0/1) Continued

Table 1 Families and sporadic cases that have been screened for mutations in PRRT2 described in the literature, allocated to the different phenotypes of BFIS, ICCA, PKD, and others—cont’d BFIS

ICCA

PKD

Others

References

Familial

Sporadic

Familial

Sporadic

Familial

Sporadic

Familial

Sporadic

Lee et al. (2012b)

-



13 (8)

15 (5)









Dale et al. (2012) Becker et al. (2013)



















1 (1) with FHM 8 (8)

1 (1)

1 (1)

12 (5)





Summary Cases

68 (58)

3 (1)

60 (53)

16 (6)

56 (51)

92 (32)

1 (1)

PED 5 (2) PNKD 5 (0)

Mutation rate

85%

33%

88%

38%

91%

35%

100%

Detected mutations (familial/sporadic) c.649dupC (4/3) c.649delC (0/1) c.272delC (1/0) c.595G>T (1/0) c.604_607delTCAC (0/1) c.718C>T (1/0) c.922C>G (1/0) c.649dupC (1) c.649dupC (PKD0/3, ICCA 6/1) c.649C>T (ICCA 1/0) c.291delC (ICCA 1/0) c.388delG (PKD 1/0) c.884G>A (PKD 0/1) c.919C>T (PKD 0/1) Overall rate of mutations Families: 88% Sporadic cases: 35% Rate of c.649dupC mutations: 233 (133) 57%

Most of the mutations reported so far are listed, showing the types of PRRT2 mutations most frequently found and their phenotypic effects. Reproduced with permission from Becker et al. (2013).

6 PRRT2 mutations

mutation rate of 34%. All mutations found in sporadic and familial cases are distributed equally with regard to the three different phenotypes (Fig. 1). The PRRT2 mutations identified so far include a considerable number of loss-offunction and missense amino acid changing mutations. The most common mutation identified in all three phenotypes is the frameshift single-nucleotide duplication c.649dupC (p.R217fsX224), which was found in 62% of PKD, ICCA, and BFIS families. It is most likely that this mutation arose independently in at least some of the families, given their diverse ethnic and geographic origins. In support of this, genotyping of three microsatellite markers closely linked to PRRT2 did not show any common haplotypes in PRRT2-mutated BFIS and ICCA families from different countries, indicating that these mutations resulted from independent mutational events (Heron et al., 2012). The PRRT2 c.649dupC mutation occurs at a mutation “hot spot.” The high frequency of this mutation is probably due to the sequence context in which it occurs. The insertion of a cytosine (C) base occurs in a homopolymer of nine C bases adjacent to four guanine bases. This DNA sequence has the potential to form a hairpin-loop structure, possibly leading to DNA-polymerase slippage and the insertion of an extra C base during DNA replication. A deletion of the same C, c.649delC, has also been reported. Most PRRT2 mutations introduce premature termination codons that are located >55 nucleotides from the last exon–exon junction on the spliced messenger RNA. These mutations, therefore, likely cause degradation of the mutated messenger RNA by the nonsense-mediated messenger RNA decay system of the cells, thereby resulting in PRRT2 haploinsufficiency (Cartegni et al., 2002). On the other hand, missense mutations are unlikely to affect expression but may occur at functionally important protein sites, such as the transmembrane (TM) protein domain (see below), thus altering protein function. Therefore, the overall pathogenesis of most PRRT2 mutations is predicted to be loss of function, though some missense mutations could be consistent with dominant-negative effect (Li et al., 2012; Wang et al., 2011). In many families, apparently unaffected individuals with a PRRT2 mutation are identified. In BFIS families, however, an accurate clinical history of the occurrence of infantile seizures cannot always be obtained for older family members, making the precise penetrance of the mutations difficult to determine. The striking pleiotropic phenotypic expression of PRRT2 mutations, although confined to neurologic paroxysmal disorders, is puzzling. It is not clear how subjects with deleterious PRRT2 mutations can present with phenotypes as different as PKD, ICCA, BFIS, HM, EA, FS, or paroxysmal torticollis. Interfamilial and intrafamilial variability is observed even in patients carrying the recurrent c.649dupC mutation. Mutations in other genes, such as CACNA1A, similarly result in pleiotropic phenotypes, but the variability is usually due to a genotype–phenotype effect (Rajakulendran et al., 2012). Instead, the location and type of mutation within PRRT2 do not appear to predict the clinical phenotype. Because age influences the clinical manifestations associated with PRRT2 mutations, age-dependent expression of PRRT2 may play a role in these phenotypic variations. For example, PRRT2 mutations are more likely to induce epilepsy in infancy and PKD in childhood or adolescence, with a tendency to remission in adulthood.

151

152

CHAPTER 8 Major cause of infantile epilepsy

A similar phenomenon has been observed in benign familial neonatal-infantile seizures caused by mutations in the SCN2A gene, encoding the sodium channel Nav1.2, which is expressed transiently during development, thus explaining the spontaneous seizure remission with aging (Liao et al., 2010). Other genetic, epigenetic or environmental factors determining the kind of paroxysmal manifestation in a given PRRT2-mutated subject remain to be elucidated.

7 PRRT2 PROTEIN AND FUNCTION PRRT2 encodes a protein of 340 amino acids containing a central proline-rich region and two predicted TM domains in its C-terminal portion (Fig. 2). This latter region is highly conserved throughout evolution, suggesting it has an important biological function. This is also supported by the occurrence of many pathogenic nonsynonymous mutations in the two TM domains (Fig. 2). PRRT2 has a predominantly cerebral and spinal expression with a particular temporal pattern. Expression studies performed in mouse whole brain by reverse transcriptase polymerase chain reaction showed low expression in the embryonic

R217Efs R217Pfs R217X

Nonsense/frameshift PRRT2 mutations R145Gfs P91Qfs S124Vfs P45Rfs

S172Rfs E173X

R240X

E199X S202Hfs

S248Afs Q250X

Q188X A211Sfs G192Wfs

R163X

N108Tfs

D302Gfs E260X

PRD

NH2

V325Sfs I327Ifs

TM1

CYT

TM2

COOH

R229K

I327M

P138A P215R

Missense PRRT2 mutations

P216H

G323E

R266W

S317N

S275F P279S W281R A287T

A291V

G305R G305W A306D R308C

FIGURE 2 PRRT2 protein domain structure and mutation map. In the upper panel, on a pink (gray in the print version) background, the identified nonsense and frameshift mutations are reported. In the lower blue (light gray in the print version) panel, the fewer missense mutations are shown. PRD, proline-rich domain; TM, transmembrane domain; CYT, cytoplasmic region.

8 Conclusions

brain before day 16 (E16), then a marked increase during the early postnatal stages till postnatal day 14 (P14), and again relatively low expression in adulthood (Chen et al., 2011). In situ hybridization and immunohistochemistry studies showed that at P14 PRRT2 mRNA has diffuse cerebral expression, predominantly in the cerebral cortex, the hippocampus, and the cerebellum (Chen et al., 2011). Another in situ hybridization study performed at P21 and P46 found widespread expression in the cerebral cortex and the basal ganglia, which is relevant to BFIS, ICCA, and PKD pathophysiology (Heron et al., 2012). Yeast two-hybrid experiments showed that PRRT2 interacts with synaptosomalassociated protein 25 kDa (SNAP25), a presynaptic Q-SNARE protein involved in the fusion of synaptic vesicles to the neuronal plasma membrane and neurotransmitter release (Jarvis and Zamponi, 2005). The interaction with SNAP25 and the possible disruption of neurotransmitter release associated with PRRT2 mutations is consistent with the pathogenic pathways involved in PNKD, as mutations in the PNKD gene are associated with disruption of synaptic protein-regulated exocytosis and neurotransmitter release (Stelzl et al., 2005). In addition, SNAP25 is thought to modulate the kinetics of voltage-gated Ca2+ channels, including the Cav2.1 calcium channel, encoded by the CACNA1A gene, previously linked to HM. In patients with PRRT2 mutations, the interaction between PRRT2 and SNAP25 might be affected, resulting in an alteration of Cav2.1 properties with ensuing neuronal hyperexcitability. The most effective drugs in PKD are voltage-gated sodium channel blockers (carbamazepine, oxcarbazepine, phenytoin, lacosamide). Although PRRT2-linked PKD can no longer be considered a channelopathy, the transmembrane PRRT2 protein may form a complex with an ion channel or regulate key properties of ion channels, including sodium channels possibly related to PKD.

8 CONCLUSIONS PRRT2 mutations are a major cause of paroxysmal dyskinesia and infantile seizures of various types, but they have also been identified in some individuals with EA, paroxysmal torticollis, HM, and migraine with or without auras. They can even be associated, in the homozygous state, with ID. The possible role of PRRT2 in other paroxysmal disorders has yet to be investigated. As little is known about the function of PRRT2, it is difficult to hypothesize how the same mutation of this gene can cause both epilepsy and movement disorders either in the same individual or family, or in separate families. Further studies are needed to determine the possible effect of modifier genes, age-dependent expression or environmental factors on phenotypic variability. The genetic overlap between epilepsy and movement disorders has also been recognized in GLUT1 deficiency syndrome, in which both epilepsy and paroxysmal exercise-induced dyskinesia co-occur in families and individuals (Mullen et al., 2010; Suls et al., 2008). The identification of PRRT2 significantly extends our current knowledge of the molecular basis for infantile epilepsies (Heron and Mulley, 2011) and continues to

153

154

CHAPTER 8 Major cause of infantile epilepsy

expand the importance of the role of non-ion channel genes in the pathogenesis of epilepsy. Although the molecular basis of the BFIS and ICCA phenotypes has not yet been defined for approximately 20% of the families affected by these disorders, the identification of a BFIS-associated genetic mutation will assist the classification of autosomal dominant infantile seizure syndromes. Confirmation of PRRT2 mutations in patients with infantile seizures provides families and clinicians with reassurance that seizures are likely to be self-limited with an excellent outcome. Families can also be forewarned about the possibility of PKD developing later in childhood or adolescence to enable rapid diagnosis and appropriate treatment. The implications of the PRRT2 discovery for clinical practice include the possibility of a simple genetic test and genetic counseling for PRRT2-associated paroxysmal disorders and suggest the potential use of sodium channel blockers to treat patients with any PRRT2-related paroxysmal manifestation, given their remarkable efficiency in PKD.

REFERENCES Aybek, S., Rossetti, A.O., Maeder-Ingvar, M., Vingerhoets, F.J., 2012. Paroxysmal kinesigenic dyskinesias of epileptic origin abolished by temporal lobectomy. Mov. Disord. 27, 923–925. Becker, F., Schubert, J., Striano, P., Anttonen, A.K., Liukkonen, E., Gaily, E., Gerloff, C., Mu¨ller, S., Heußinger, N., Kellinghaus, C., Robbiano, A., Polvi, A., Zittel, S., von Oertzen, T.J., Rostasy, K., Scho¨ls, L., Warner, T., Mu¨nchau, A., Lehesjoki, A.E., Zara, F., Lerche, H., Weber, Y.G., 2013. PRRT2-related disorders: further PKD and ICCA cases and review of the literature. J. Neurol. 260, 1234–1244. Bennett, L.B., Roach, E.S., Bowcock, A.M., 2000. A locus for paroxysmal kinesigenic dyskinesia maps to human chromosome 16. Neurology 54, 125–130. Bhatia, K.P., Griggs, R.C., Ptacek, L.J., 2000. Episodic movement disorders as channelopathies. Mov. Disord. 15, 429–433. Bonnet, C., Roubertie, A., Doummar, D., Bahi-Buisson, N., Cochen de Cock, V., Roze, E., 2010. Developmental and benign movement disorders in childhood. Mov. Disord. 25, 1317–1334. Bruno, M.K., Hallett, M., Gwinn-Hardy, K., Sorensen, B., Considine, E., Tucker, S., Lynch, D.R., Mathews, K.D., Swoboda, K.J., Harris, J., Soong, B.W., Ashizawa, T., Jankovic, J., Renner, D., Fu, Y.H., Ptacek, L.J., 2004. Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. Neurology 63, 2280–2287. Callenbach, P.M., de Coo, R.F.M., Vein, A.A., Arts, W.F., Oosterwijk, J., Hageman, G., ten Houten, R., Terwindt, G.M., Lindhout, D., Frants, R.R., Brouwer, O.F., 2002. Benign familial infantile convulsions: a clinical study of seven Dutch families. Eur. J. Paediatr. Neurol. 6, 269–283. Callenbach, P.M., van den Boogerd, E.H., de Coo, R.F., ten Houten, R., Oosterwijk, J.C., Hageman, G., Frants, R.R., Brouwer, O.F., van den Maagdenberg, A.M., 2005. Refinement of the chromosome 16 locus for benign familial infantile convulsions. Clin. Genet. 67, 517–525. Cao, L., Huang, X.J., Zheng, L., Xiao, Q., Wang, X.J., Chen, S.D., 2012. Identification of a novel PRRT2 mutation in patients with paroxysmal kinesigenic dyskinesias and c.649dupC as a mutation hot-spot. Parkinsonism Relat. Disord. 18, 704–706.

References

Caraballo, R., Pavek, S., Lemainque, A., Gastaldi, M., Echenne, B., Motte, J., Genton, P., Cersosimo, R., Humbertclaude, V., Fejerman, N., Monaco, A.P., Lathrop, M.G., Rochette, J., Szepetowski, P., 2001. Linkage of benign familial infantile convulsions to chromosome 16p12-q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome. Am. J. Hum. Genet. 68, 788–794. Cartegni, L., Chew, S.L., Krainer, A.R., 2002. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat. Rev. Genet. 3, 285–298. 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., 2011. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat. Genet. 43, 1252–1255. Cloarec, R., Bruneau, N., Rudolf, G., Massacrier, A., Salmi, M., Bataillard, M., Boulay, C., Caraballo, R., Fejerman, N., Genton, P., Hirsch, E., Hunter, A., Lesca, G., Motte, J., Roubertie, A., Sanlaville, D., Wong, S.W., Fu, Y.H., Rochette, J., Pta´cek, L.J., Szepetowski, P., 2012. PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine. Neurology 79, 2097–2103. Dale, R.C., Gardiner, A., Antony, J., Houlden, H., 2012. Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine. Dev. Med. Child Neurol. 54, 958–960. de Vries, B., Callenbach, P.M., Kamphorst, J.T., Weller, C.M., Koelewijn, S.C., ten Houten, R., de Coo, I.F., Brouwer, O.F., van den Maagdenberg, A.M., 2012. PRRT2 mutation causes benign familial infantile convulsions. Neurology 79 (352), 2154–2155. Dje´mie´, T., Weckhuysen, S., Holmgren, P., Hardies, K., Van Dyck, T., Hendrickx, R., Schoonjans, A.S., Van Paesschen, W., Jansen, A.C., DeMeirleir, L., Selim, L.A., Girgis, M.Y., Buyse, G., Lagae, L., Smets, K., Smouts, I., Claeys, K.G., Van den Bergh, V., Grisar, T., Blatt, I., Shorer, Z., Roelens, F., Afawi, Z., Helbig, I., Ceulemans, B., De Jonghe, P., Suls, A., 2014. PRRT2 mutations: exploring the phenotypical boundaries. J. Neurol. Neurosurg. Psychiatry 85, 462–465. Espeche, A., Cersosimo, R., Caraballo, R.H., 2011. Benign infantile seizures and paroxysmal dyskinesia: a well-defined familial syndrome. Seizure 20, 686–691. Fourcade, G., Roubertie, A., Doummar, D., Vidailhet, M., Labauge, P., 2009. Paroxysmal kinesigenic dyskinesia: a channelopathy? Study of 19 cases. Rev. Neurol. (Paris) 165, 164–169. Gardiner, A.R., Bhatia, K.P., Stamelou, M., Dale, R.C., Kurian, M.A., Schneider, S.A., Wali, G.M., Counihan, T., Schapira, A.H., Spacey, S.D., Valente, E.M., SilveiraMoriyama, L., Teive, H.A., Raskin, S., Sander, J.W., Lees, A., Warner, T., Kullmann, D.M., Wood, N.W., Hanna, M., Houlden, H., 2012. PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine. Neurology 79, 2115–2121. Groffen, A.J., Klapwijk, T., van Rootselaar, A.F., Groen, J.L., Tijssen, M.A., 2012. Genetic and phenotypic heterogeneity in sporadic and familial forms of paroxysmal dyskinesia. J. Neurol. 260, 93–99. Guipponi, M., Rivier, F., Vigevano, F., Beck, C., Crespel, A., Echenne, B., Lucchini, P., Sebastianelli, R., Baldy-Moulinier, M., Malafosse, A., 1997. Linkage mapping of benign familial infantile convulsions (BFIC) to chromosome 19q. Hum. Mol. Genet. 6, 473–477. Heron, S.E., Mulley, J.C., 2011. The molecular genetics of benign epilepsies of infancy. In: Afawi, Z. (Ed.), Clinical and Genetic Aspects of Epilepsy. Intech Open, Rijeka, Croatia, pp. 95–112. Heron, S.E., Grinton, B.E., Kivity, S., Afawi, Z., Zuberi, S.M., Hughes, J.N., Pridmore, C., Hodgson, B.L., Iona, X., Sadleir, L.G., Pelekanos, J., Herlenius, E., Goldberg-Stern, H.,

155

156

CHAPTER 8 Major cause of infantile epilepsy

Bassan, H., Haan, E., Korczyn, A.D., Gardner, A.E., Corbett, M.A., Ge´cz, J., Thomas, P.Q., Mulley, J.C., Berkovic, S.F., Scheffer, I.E., Dibbens, L.M., 2012. PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am. J. Hum. Genet. 90, 152–160. Jarvis, S.E., Zamponi, G.W., 2005. Masters or slaves? Vesicle release machinery and the regulation of presynaptic calcium channels. Cell Calcium 37, 483–488. Joo, E.Y., Hong, S.B., Tae, W.S., Kim, J.H., Han, S.J., Seo, D.W., Lee, K.H., Kim, M.H., Kim, S., Lee, M.H., Kim, B.T., 2005. Perfusion abnormality of the caudate nucleus in patients with paroxysmal kinesigenic choreoathetosis. Eur. J. Nucl. Med. Mol. Imaging 32, 1205–1209. Kertesz, A., 1967. Paroxysmal kinesigenic choreoathetosis: an entity within the paroxysmal choreoathetosis syndrome: description of 10 cases, including 1 autopsied. Neurology 17, 680–690. Kikuchi, T., Nomura, M., Tomita, H., Harada, N., Kanai, K., Konishi, T., Yasuda, A., Matsuura, M., Kato, N., Yoshiura, K., Niikawa, N., 2007. Paroxysmal kinesigenic choreoathetosis (PKC): confirmation of linkage to 16p11-q21, but unsuccessful detection of mutations among 157 genes at the PKC-critical region in seven PKC families. J. Hum. Genet. 52, 334–341. Ko, C.H., Kong, C.K., Ngai, W.T., Ma, K.M., 2001. Ictal (99m)Tc ECD SPECT in paroxysmal kinesigenic choreoathetosis. Pediatr. Neurol. (24), 225–227. Kure, S., 1892. Atypical Thomsen’s disease. Tokyo Igakukai Zasshi 6, 505–514. Labate, A., Tarantino, P., Viri, M., Mumoli, L., Gagliardi, M., Romeo, A., Zara, F., Annesi, G., Gambardella, A., 2012. Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences. Epilepsia 53, 196–199. Lee, H.Y., Huang, Y., Bruneau, N., Roll, P., Roberson, E.D., Hermann, M., Quinn, E., Maas, J., Edwards, R., Ashizawa, T., Baykan, B., Bhatia, K., Bressman, S., Bruno, M.K., Brunt, E.R., Caraballo, R., Echenne, B., Fejerman, N., Frucht, S., Gurnett, C.A., Hirsch, E., Houlden, H., Jankovic, J., Lee, W.L., Lynch, D.R., Mohammed, S., Mu¨ller, U., Nespeca, M.P., Renner, D., Rochette, J., Rudolf, G., Saiki, S., Soong, B.W., Swoboda, K.J., Tucker, S., Wood, N., Hanna, M., Bowcock, A.M., Szepetowski, P., Fu, Y.H., Pta´cˇek, L.J., 2012a. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep. 1, 2–12. Lee, Y.C., Lee, M.J., Yu, H.Y., Chen, C., Hsu, C.H., Lin, K.P., Liao, K.K., Chang, M.H., Liao, Y.C., Soong, B.W., 2012b. PRRT2 mutations in paroxysmal kinesigenic dyskinesia with infantile convulsions in a Taiwanese cohort. PLoS One 7, e38543. Li, H.Y., Li, N., Jiang, H., Shen, L., Guo, J.F., Zhang, R.X., Xia, K., Pan, Q., Zi, X.H., Tang, B.S., 2008. A novel genetic locus for benign familial infantile seizures maps to chromosome 1p36.12-p35.1. Clin. Genet. 74, 490–492. Li, J., Zhu, X., Wang, X., Sun, W., Feng, B., Du, T., Sun, B., Niu, F., Wei, H., Wu, X., Dong, L., Li, L., Cai, X., Wang, Y., Liu, Y., 2012. Targeted genomic sequencing identifies PRRT2 mutations as a cause of paroxysmal kinesigenic choreoathetosis. J. Med. Genet. 49, 76–78. Liao, Y., Deprez, L., Maljevic, S., Pitsch, J., Claes, L., Hristova, D., Jordanova, A., Ala-Mello, S., Bellan-Koch, A., Blazevic, D., Schubert, S., Thomas, E.A., Petrou, S., Becker, A.J., De Jonghe, P., Lerche, H., 2010. Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain 133, 1403–1414. Liu, Q., Qi, Z., Wan, X.H., Li, J.Y., Shi, L., Lu, Q., Zhou, X.Q., Qiao, L., Wu, L.W., Liu, X.Q., Yang, W., Liu, Y., Cui, L.Y., Zhang, X., 2012. Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression. J. Med. Genet. 49, 79–82.

References

Lotze, T., Jankovic, J., 2010. Paroxysmal kinesigenic dyskinesias. Semin. Pediatr. Neurol. 10, 68–79. Marini, C., Conti, V., Mei, D., Battaglia, D., Lettori, D., Losito, E., Bruccini, G., Tortorella, G., Guerrini, R., 2012. PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine. Neurology 79, 2109–2114. Me´neret, A., Grabli, D., Depienne, C., Gaudebout, C., Picard, F., Du¨rr, A., Lagroua, I., Bouteiller, D., Mignot, C., Doummar, D., Anheim, M., Tranchant, C., Burbaud, P., Jedynak, C.P., Gras, D., Steschenko, D., Devos, D., Billette de Villemeur, T., Vidailhet, M., Brice, A., Roze, E., 2012. PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 79, 170–174. Me´neret, A., Gaudebout, C., Riant, F., Vidailhet, M., Depienne, C., Roze, E., 2013. PRRT2 mutations and paroxysmal disorders. Eur. J. Neurol. 20, 872–878. Mullen, S.A., Suls, A., De Jonghe, P., Berkovic, S.F., Scheffer, I.E., 2010. Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology 75, 432–440. Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S.S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., Pu¨ttmann, L., Vahid, L.N., Jensen, C., Moheb, L.A., Bienek, M., Larti, F., Mueller, I., Weissmann, R., Darvish, H., et al., 2011. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478, 57–63. Ono, S., Yoshiura, K., Kinoshita, A., 2012. Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions. J. Hum. Genet. 57, 338–341. Rajakulendran, S., Kaski, D., Hanna, M.G., 2012. Neuronal P/Qtype calcium channel dysfunction in inherited disorders of the CNS. Nat. Rev. Neurol. 8, 86–96. Riant, F., Roze, E., Barbance, C., Me´neret, A., Guyant-Mare´chal, L., Lucas, C., Sabouraud, P., Tre´buchon, A., Depienne, C., Tournier-Lasserve, E., 2012. PRRT2 mutations cause hemiplegic migraine. Neurology 79, 2122–2124. Rochette, J., Roll, P., Fu, Y.H., Lemoing, A.G., Royer, B., Roubertie, A., Berquin, P., Motte, J., Wong, S.W., Hunter, A., Robaglia-Schlupp, A., Ptacek, L.J., Szepetowski, P., 2010. Novel familial cases of ICCA (infantile convulsions with paroxysmal choreoathetosis) syndrome. Epileptic Disord. 12, 199–204. Russell, M.B., Ducros, A., 2011. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. Lancet Neurol. 10, 457–470. Scheffer, I.E., Grinton, B.E., Heron, S.E., Kivity, S., Afawi, Z., Iona, X., Goldberg-Stern, H., Kinali, M., Andrews, I., Guerrini, R., Marini, C., Sadleir, L.G., Berkovic, S.F., Dibbens, L.M., 2012. PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures. Neurology 79, 2104–2108. Schmidt, A., Kumar, K.R., Redyk, K., Gru¨newald, A., Leben, M., Mu¨nchau, A., Sue, C.M., Hagenah, J., Hartmann, H., Lohmann, K., Christen, H.J., Klein, C., 2012. Two faces of the same coin: benign familial infantile seizures and paroxysmal kinesigenic dyskinesia caused by PRRT2 mutations. Arch. Neurol. 69, 668–670. Schubert, J., Paravidino, R., Becker, F., Berger, A., Bebek, N., Bianchi, A., Brockmann, K., Capovilla, G., Dalla Bernardina, B., Fukuyama, Y., Hoffmann, G.F., Jurkat-Rott, K., Anttonen, A.K., Kurlemann, G., Lehesjoki, A.E., Lehmann-Horn, F., Mastrangelo, M., Mause, U., Mu¨ller, S., Neubauer, B., et al., 2012. PRRT2 mutations are the major cause of benign familial infantile seizures. Hum. Mutat. 33, 1439–1443.

157

158

CHAPTER 8 Major cause of infantile epilepsy

Shirane, S., Sasaki, M., Kogure, D., Matsuda, H., Hashimoto, T., 2001. Increased ictal perfusion of the thalamus in paroxysmal kinesigenic dyskinesia. J. Neurol. Neurosurg. Psychiatry 71, 408–410. Stelzl, U., Worm, U., Lalowski, M., et al., 2005. A human protein–protein interaction network: a resource for annotating the proteome. Cell 122, 957–968. Striano, P., Lispi, M.L., Gennaro, E., Madia, F., Traverso, M., Bordo, L., Aridon, P., Boneschi, F.M., Barone, B., Dalla Bernardina, B., Bianchi, A., Capovilla, G., De Marco, P., Dulac, O., Gaggero, R., Gambardella, A., Nabbout, R., Prudhomme, J.F., Day, R., Vanadia, F., Vecchi, M., Veggiotti, P., Vigevano, F., Viri, M., Minetti, C., Zara, F., 2006. Linkage analysis and disease models in benign familial infantile seizures: a study of 16 families. Epilepsia 47, 1029–1034. Suls, A., Dedeken, P., Goffin, K., Van Esch, H., Dupont, P., Cassiman, D., Kempfle, J., Wuttke, T.V., Weber, Y., Lerche, H., Afawi, Z., Vandenberghe, W., Korczyn, A.D., Berkovic, S.F., Ekstein, D., Kivity, S., Ryvlin, P., Claes, L.R., Deprez, L., Maljevic, S., Vargas, A., Van Dyck, T., Goossens, D., Del-Favero, J., Van Laere, K., De Jonghe, P., Van Paesschen, W., 2008. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain 131, 1831–1844. Szepetowski, P., Rochette, J., Berquin, P., Piussan, C., Lathrop, G.M., Monaco, A.P., 1997. Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromeric region of human chromosome 16. Am. J. Hum. Genet. 61, 889–898. van Strien, T.W., van Rootselaar, A.F., Hilgevoord, A.A., Linssen, W.H., Groffen, A.J., Tijssen, M.A., 2012. Paroxysmal kinesigenic dyskinesia: cortical or non-cortical origin. Parkinsonism Relat. Disord. 18, 645–648. van Vliet, R., Breedveld, G., de Rijk-van Andel, J., Brilstra, E., Verbeek, N., VerschuurenBemelmans, C., Boon, M., Samijn, J., Diderich, K., van de Laar, I., Oostra, B., Bonifati, V., Maat-Kievit, A., 2012. PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Neurology 79, 777–784. Wang, J.L., Cao, L., Li, X.H., Hu, Z.M., Li, J.D., Zhang, J.G., Liang, Y., San, A., Li, N., Chen, S.Q., Guo, J.F., Jiang, H., Shen, L., Zheng, L., Mao, X., Yan, W.Q., Zhou, Y., Shi, Y.T., Ai, S.X., Dai, M.Z., Zhang, P., Xia, K., Chen, S.D., Tang, B.S., 2011. Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain 134, 3493–3501. Wang, K., Zhao, X., Du, Y., He, F., Peng, G., Luo, B., 2013. Phenotypic overlap among paroxysmal dyskinesia subtypes: lesson from a family with PRRT2 gene mutation. Brain Dev. 35, 664–666. Weber, M.B., 1967. Familial paroxysmal dystonia. J. Nerv. Ment. Dis. 145, 221–226. Weber, Y.G., Berger, A., Bebek, N., Maier, S., Karafyllakes, S., Meyer, N., Fukuyama, Y., Halbach, A., Hikel, C., Kurlemann, G., Neubauer, B., Osawa, M., Pu¨st, B., Rating, D., Saito, K., Stephani, U., Tauer, U., Lehmann-Horn, F., Jurkat-Rott, K., Lerche, H., 2004. Benign familial infantile convulsions: linkage to chromosome 16p12-q12 in 14 families. Epilepsia 45, 601–609. Weber, Y.G., Jacob, M., Weber, G., Lerche, H., 2008. A BFIS-like syndrome with late onset and febrile seizures: suggestive linkage to chromosome 16p11.2-16q12.1. Epilepsia 49, 1959–1964. Zhou, B., Chen, Q., Gong, Q., Tang, H., Zhou, D., 2010. The thalamic ultrastructural abnormalities in paroxysmal kinesigenic choreoathetosis: a diffusion tensor imaging study. J. Neurol. 257, 405–409.