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JNNP Online First, published on January 16, 2015 as 10.1136/jnnp-2014-309025 Movement disorders
SHORT REPORT
Severe phenotypic spectrum of biallelic mutations in PRRT2 gene Marion Delcourt,1 Florence Riant,2,3 Josette Mancini,4 Mathieu Milh,4,5 Vincent Navarro,6,7 Emmanuel Roze,8,9 Véronique Humbertclaude,10 Christian Korff,11 Vincent Des Portes,12,13 Pierre Szepetowski,14,15,16 Diane Doummar,17 Bernard Echenne,1 Samuel Quintin,18,19 Nicolas Leboucq,20 Rabbind Singh Amrathlal,21 Jacques Rochette,21 Agathe Roubertie1,22 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ jnnp-2014-309025). For numbered affiliations see end of article. Correspondence to Dr Agathe Roubertie, Service de Neuropédiatrie, CHU Gui de Chauliac, 80 Avenue Fliche, Montpellier 34295, France; [email protected] Received 18 July 2014 Revised 16 October 2014 Accepted 17 October 2014
ABSTRACT Background Heterozygous dominant mutations of PRRT2 have been associated with various types of paroxysmal neurological manifestations, including benign familial infantile convulsions and paroxysmal kinesigenic dyskinesia. The phenotype associated with biallelic mutations is not well understood as few cases have been reported. Methods PRRT2 screening was performed by Sanger sequencing and quantitative multiplex PCR of short fluorescent fragments. A CGH array was used to characterise the size of the deletion at the 16p11.2 locus. Results Five patients with homozygous or compound heterozygous deleterious PRRT2 gene mutations are described. These patients differ from those with a single mutation by their overall increased severity: (1) the combination of at least three different forms of paroxysmal neurological disorders within the same patient and persistence of paroxysmal attacks; (2) the occurrence of uncommon prolonged episodes of ataxia; and (3) the association of permanent neurological disorders including learning difficulties in four patients and cerebellar atrophy in 2. Conclusions Our observations expand the phenotype related to PRRT2 insufficiency, and highlight the complexity of the phenotype associated with biallelic mutations, which represents a severe neurological disease with various paroxysmal disorders and frequent developmental disabilities.
INTRODUCTION
To cite: Delcourt M, Riant F, Mancini J, et al. J Neurol Neurosurg Psychiatry Published Online First: [please include Day Month Year] doi:10.1136/jnnp2014-309025
Paroxysmal kinesigenic dyskinesia (PKD, MIM 128200) is a rare disorder characterised by the occurrence of brief episodes of dystonic or choreic movements triggered by sudden movements or change in movement velocity. Benign infantile familial convulsions (BFIC) is a self-limited form of epilepsy with partial seizures usually occurring in a cluster during the first year of life. PKD, BIFC and their coexistence, referred to as ‘infantile convulsions and paroxysmal choreoathetosis syndrome’ (ICCA, MIM 602066) have been linked to heterozygous mutations of the proline-rich transmembrane protein 2 (PRRT2) gene.1 More recently, other paroxysmal neurological manifestations have been reported in heterozygous patients: paroxysmal non-kinesigenic dyskinesia (PNKD), migraine with
or without aura, hemiplaegic migraine, various type of non-infantile seizures, torticollis and episodic ataxia (EA).2 Previous reports of three patients suggested that homozygous PRRT2 mutations may give rise to more severe clinical disease of mental retardation, with or without EA and epilepsy.3 4 Here, we describe in detail the phenotype of five patients with biallelic PRRT2 mutations.
MATERIAL AND METHODS Written informed consent was obtained from the patients when aged over 18 years and by both parents for patients younger than 18 years according to French legislation. Fifty-one patients with PKD, 27 ICCA and 124 patients with episodic abnormal movements such as ataxia or dystonia were tested for PRRT2 mutations. Genetic method is available in online supplementary material.
RESULTS Table 1 summarises the main clinical and genetic findings; a detailed description of patient 1 is provided thereafter, and in online supplementary material concerning patients 2–5. Family pedigrees are illustrated in online supplementary figure S1. Brain imaging findings are shown in online supplementary figure S2. Patient 1 was referred at 5 months for an afebrile generalised status epilepticus episode that lasted 1 h. Antiepileptic treatment was discontinued at 2 years. Between the age of 1.5 and 6 years, the patient had six paroxysmal episodes characterised by convergent bilateral strabismus, vomiting and marked ataxia. After each episode his condition gradually improved and returned to normal within 10 days to 6 weeks after onset. From age 4, he had paroxysmal episodes of generalised dyskinesia, with abnormal limb movements and truncal bending, triggered by stress, exertion or fatigue, but not by sudden movement. These attacks were partially controlled by carbamazepine; a 48 h episode of generalised dystonia occurred at age 14 years after an abrupt carbamazepine withdrawal. Now aged 15 years, the patient has exhibited weekly attacks of brief duration.
Delcourt M, et al. J Neurol Neurosurg Psychiatry 2015;0:1–4. doi:10.1136/jnnp-2014-309025
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
2
clinical, brain MRI and genetic characteristics of our patients
Consanguinity
1
M/15
2*
Delcourt M, et al. J Neurol Neurosurg Psychiatry 2015;0:1–4. doi:10.1136/jnnp-2014-309025
IC/interictal EEG
PNKD
PKD
No
Coordination difficulties, no ataxia
Status epilepticus at 6 m/normal interictal EEG
No
18 months/6 Associated with strabismus, vomiting; Lasting 10 days to 6 weeks
HM/11 years
M/20
Yes
N
Focal seizures from 3 m to 3.5 y/normal interictal EEG
Yes
No
3
F/15
Yes
Motor tics
Status epilepticus at 3 and 12 m/normal interictal EEG
From 4 years Duration: 30 s to 2 min, in clusters of 1 h; Daily attacks in childhood; Improvement with carbamazepine but persistence at last follow-up From 25 m Duration: 10 s to 5 min; Several attacks per day in childhood despite carbamazepine and phenotoine; Persistence at last follow-up under both drugs From 18 m to 3 years Several per day in infancy; Relapse under lamotrigine treatment
No
4
F/25
No
N
Cluster of focal seizures et 3 m, then at 1 y; once a year at last follow-up/normal interictal EEG
No
5
F/5.5
Yes
N
Status epilepticus at 3 m, focal seizure at 8 and 16 m/normal interictal EEG
From 13 years– preceding visual aura Brief attacks of few seconds several times a day; Long-lasting attack of 10 min 4 times a year under oxcarbazepine; Rare attacks under lamotrigine (200 mg/ day) at last follow-up No
No
EA onset/episode number/clinical characteristic/duration
Migraine with or without aura/age of onset
Neurological examination (N: normal)
Cognition-learning abilities-behaviour (IQ evaluated using WISC-IV scale)
Brain MRI/age (N: normal)
PRRT2 mutation
Borderline IQ with ADHD; clumsiness, learning difficulties; educational support in a normal school
Severe cerebellar atrophy mainly involving the vermis (9 years, 14 years)
c.649dupC/ del (de novo)
M with aura/ 19 years
ADHD, learning difficulties, professional education programme for plumbing
N (5 years, 19 years)
c.649dupC/ c.649dupC
6 years/2 Following a febrile illness; With headache, vomiting, dysarthria, dyskinesia Lasting 2 weeks 7 years /3 Preceded by 1–2 days of vomiting; Associated with rigidity of the body, distal chorea, swallowing difficulties requiring nasogastric tube feeding; Lasting 5–6 days
No
Mild mental deficiency behavioural disturbances, specialised education in an institution for mentally disabled children
Mild vermian atrophy (10 years)
c.649dupC/ c.649dupC
M with ophthalmic aura/13 years
Normal IQ/moderate learning difficulties due to behavioural problems; professional education programme for children caregiver
N (21 years)
c.649dupC/ c.649dupC
1 year/4Associated with somnolence, vomiting, pyramidal tract signs; Lasting 2–4 weeks
No
Normal learning abilities
N (5 years)
c.913G>A/ c.913G>A
Age of the patients: m, months; y, years. *Patient previously reported by Caraballo. (Caraballo R, Pavek S, Lemainque A, et al. Linkage of benign familial infantile convulsions to chromosome 16p12-q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome. Am J Hum Genet 2001;68:788–94). PKD, paroxysmal kinesigenic dyskinesia; PNKD, paroxysmal non-kinesigenic dyskinesia; EA, episodic ataxia; IC, infantile convulsion; ADHD, attention-deficit/hyperactivity disorder; N, normal.
Downloaded from http://jnnp.bmj.com/ on March 11, 2015 - Published by group.bmj.com
Patient
Sex/age at last follow-up (years)
Movement disorders
Table 1
Downloaded from http://jnnp.bmj.com/ on March 11, 2015 - Published by group.bmj.com
Movement disorders From age 11, the patient had five episodes of hemiplegic migraine characterised by ophthalmic aura, vomiting and hemiparesis that lasted 24 h. Coordination difficulties were reported from early childhood. Clinical examination did not disclose cerebellar sign. WISC-IV evaluation performed at 8 years of age showed borderline homogeneous level (total Intellectual Quotient: 71), and disclosed attention deficit disorder associated with visuospatial dyspraxia and dyslexia resulting in mild learning disabilities. Brain imaging performed at 9 and 14 years showed stable global cerebellar atrophy (see online supplementary figure S2). Patient 1 harboured a compound heterozygous genotype: c.649dupC/p.Arg217ProfsX8 and whole deletion of PRRT2 gene. Both mutations were absent in his parents. Sixteen polymorphic microsatellite markers were used to eliminate inaccurate maternity and paternity information or sampling error. A 44K CGH array analysis performed for the patient and his parents confirmed the de novo occurrence of the deletion. The precise size of the deletion was determined by using a 1M HRD array (see online supplementary figure S2). Patients 2, 3 and 4 were homozygous for the c.649dupC mutation ( p.Arg217ProfsX8) frequently reported in PKD.2 Patient 5 has the homozygous missense mutation c.913G>A/p. G305R previously reported in patients with PKD.2
DISCUSSION The phenotypes of these five patients clearly differ from their heterozygous family members, and from heterozygous patients reported to date, by their overall increased severity. An uncommon combination of at least three types of paroxysmal manifestations was reported in all except patient 5 who is only 5 years of age; this clinical pattern is clearly distinct from family heterozygous mutation carriers (who display a classical PRRT2 phenotype with benign course (BIFC, migraine, without PKD and EA) or are asymptomatic) and is uncommon in previously published patients with heterozygous mutations.2 The phenotype of patient 1 was very severe due to the combination of five distinct types of paroxysmal manifestations. Such complex phenotype was previously reported by Labate in two brothers with homozygous c.649dup mutation exhibiting a complex phenotype including BIFC, PKD, absence epilepsy, EA and mental deficiency. In these brothers, EA consisted of attacks of unsteadiness lasting less than 3 days.4 In heterozygous PRRT2 patients, EA is reported in less than 1% of the patients.2 The episodes of ataxia, not observed in their heterozygous family members, and reported in 4 out of 5 of our patients, are very singular due to their long duration (several days to 6 weeks vs seconds to hours for most common EAs) and their gravity. Finally, among the various forms of paroxysmal dyskinesias, kinesigenic PD is by far the most frequent form in PRRT2 heterozygous patients, while PNKD is rare;2 it is noteworthy that only patient 2 presented PKD; in all the patients, dyskinesias were severe and triggered by various non-kinesigenic factors. One of the main clinical findings here is the occurrence of cognitive and/or behavioural difficulties in patients 1–4 associated with brain imaging abnormalities in patients 1 and 3. Psychomotor retardation, mental deficiency or austistic features were found in patients harbouring the recurrent 16p11.2 deletion, which encompass the PRRT2 gene (figure 2D)5 and in three patients harbouring a homozygous PRRT2 mutation previously reported.3 4 Our report confirms the high frequency of cognitive disorder in PRRT2 homozygous patients. Learning disabilities or neuropsychiatric problems in heterozygous patients were only recently reported,6 and their description in 12/19
patients is striking.7 Brain MRI from patients 1 and 3 (who exhibited the more severe phenotype) revealed definite cerebellar atrophy, which had never been reported previously in heterozygous nor homozygous patients. PRRT2 protein is a proline rich protein that interacts with the synaptosomal-associated protein (SNAP25) involved in the fusion of synaptic vesicles to the plasma membrane and calcium triggered exocytosis, suggesting a role of PRRT2 in vesicle trafficking and neurotransmitter release. Although patient 1–4 harboured stop codon mutations or deletions on both alleles, which can lead to very low levels or complete absence of protein, patient 5 carried missense mutations that might lead to a modified protein and not to its absence, which could explain her milder phenotype. PRRT2 protein is highly expressed in the cortex and in the cerebellum, which is consistent with the wide range of possible manifestations, including EA and might support our finding of cerebellar atrophy. These observations expand the phenotype related to PRRT2 insufficiency; we suggest that biallelic PRRT2 mutations should be suspected when patients present a combination of various types of attacks, especially prolonged attacks of EA or when associated with cognitive disabilities, or when consanguinity is present. The occurrence of permanent neurological troubles in PRRT2 mutation carriers encourages further evaluation and prompts consideration of PRRT2-related disease as a more widespread neurodevelopmental disorder. Author affiliations 1 Service de Neuropédiatrie, CHU Gui de Chauliac, Montpellier, France 2 Laboratoire de Génétique, AP-HP, Groupe Hospitalier Lariboisière-Fernand Widal, Paris, France 3 INSERM UMR-S740; Université Paris 7 Denis Diderot, Paris, France 4 Service de Neurologie Pédiatrique, CHU Timone Enfants, Marseille, France 5 Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France 6 AP-HP, Unité d’épilepsie, Institut du Cerveau et de la Moelle épinière, Hôpital PitiéSalpêtrière, Paris, France 7 INSERM, UMRS 975, et CNRS 7225—Institut du Cerveau et de la Moelle épinière, Hôpital Pitié-Salpêtrière,Université Pierre et Marie Curie-Paris-6, Paris, France 8 Département des Maladies du Système Nerveux, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France 9 CRICM, INSERM U1127, CNRS UMR 7225, UPMC UMR-S975, Paris, France 10 Service de Médecine Psychologique Enfants et Adolescents, CHU Saint Eloi, Montpellier, France 11 Neuropédiatrie HUG, Genève, Suisse 12 Neuropédiatrie, HFME, Hospices Civils de Lyon, Bron, France 13 Université Lyon 1, F-69008 Lyon, France 14 INSERM U901, Marseille, France 15 Institut de Neurobiologie de la Méditerranée (INMED), Marseille, France 16 UMR_S901, Université d’Aix-Marseille, Marseille, France 17 Service de Neurologie Pédiatrique, AP-HP, Hôpital Trousseau, Paris, France 18 Team Genome and Cancer, Hematology Laboratory Assistance Publique-Hopitaux de Paris, Saint-Louis Hospital, Paris, France 19 Inserm U944, Saint-Louis Hospital, Paris, France 20 Service de Neuroradiologie, CHU Gui de Chauliac, Montpellier, France 21 EA 4666, CHU d’Amiens—UPJV, Laboratoire de Génétique, Hôpital Sud, Amiens, France 22 INSERM U 1051, Institut des Neurosciences de Montpellier, Montpellier, France Funding JR received a grant from “the Conseil Régional de Picardie” and an inter-reg (EU) grant. ER is the recipient of a grant “poste d’acceuil” AP-HP/CNRS. He received research support from INSERM (COSSEC), AP-HP (DRC-PHRC), Fondation pour la Recherche sur le Cerveau (FRC), the Dystonia Coalition (Pilot project), Ipsen, and Merz-Pharma, Novartis, Teva, Lundbeck, Orkyn; served on scientific advisory boards for Orkyn, Ipsen, and Merz-Pharma; received speech honorarium from Novartis and Orkyn; received travel funding from Teva, Novartis, the Dystonia Coalition, the Movement Disorders Society, and the World Federation of Neurology Association of Parkinsonism and Related Disorders. AR received travel funding from Genzyme, Viropharma and Biomarin. Competing interests None. Ethics approval This study was approved by the regional review board.
Delcourt M, et al. J Neurol Neurosurg Psychiatry 2015;0:1–4. doi:10.1136/jnnp-2014-309025
3
Downloaded from http://jnnp.bmj.com/ on March 11, 2015 - Published by group.bmj.com
Movement disorders Provenance and peer review Not commissioned; externally peer reviewed.
4
5
REFERENCES 1 2 3
4
Chen W-J, Lin Y, Xiong Z-Q, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011;43:1252–5. Méneret A, Gaudebout C, Riant F, et al. PRRT2 mutations and paroxysmal disorders. Eur J Neurol 2013;20:872–8. Najmabadi H, Hu H, Garshasbi M, et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 2011;478:57–63.
6
7
Labate A, Tarantino P, Viri M, et al. Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences. Epilepsia 2012;53:e196–9. Shinawi M, Liu P, Kang SHL, et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet 2010;47:332–41. Guerrero-López R, Ortega-Moreno L, Giráldez BG, et al. Atypical course in individuals from Spanish families with benign familial infantile seizures and mutations in the. Epilepsy Res 2014;108:1274–8. Djemie T, Weckhuysen S, Holmgren P, et al. PRRT2 mutations: exploring the phenotypical boundaries. J Neurol Neurosurg Psychiatr 2014;85:462–5.
Delcourt M, et al. J Neurol Neurosurg Psychiatry 2015;0:1–4. doi:10.1136/jnnp-2014-309025
Downloaded from http://jnnp.bmj.com/ on March 11, 2015 - Published by group.bmj.com
Severe phenotypic spectrum of biallelic mutations in PRRT2 gene Marion Delcourt, Florence Riant, Josette Mancini, Mathieu Milh, Vincent Navarro, Emmanuel Roze, Véronique Humbertclaude, Christian Korff, Vincent Des Portes, Pierre Szepetowski, Diane Doummar, Bernard Echenne, Samuel Quintin, Nicolas Leboucq, Rabbind Singh Amrathlal, Jacques Rochette and Agathe Roubertie J Neurol Neurosurg Psychiatry published online January 16, 2015
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JNNP Online First, published on January 16, 2015 as 10.1136/jnnp-2014-309025 Movement disorders
SHORT REPORT
Severe phenotypic spectrum of biallelic mutations in PRRT2 gene Marion Delcourt,1 Florence Riant,2,3 Josette Mancini,4 Mathieu Milh,4,5 Vincent Navarro,6,7 Emmanuel Roze,8,9 Véronique Humbertclaude,10 Christian Korff,11 Vincent Des Portes,12,13 Pierre Szepetowski,14,15,16 Diane Doummar,17 Bernard Echenne,1 Samuel Quintin,18,19 Nicolas Leboucq,20 Rabbind Singh Amrathlal,21 Jacques Rochette,21 Agathe Roubertie1,22 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ jnnp-2014-309025). For numbered affiliations see end of article. Correspondence to Dr Agathe Roubertie, Service de Neuropédiatrie, CHU Gui de Chauliac, 80 Avenue Fliche, Montpellier 34295, France; [email protected] Received 18 July 2014 Revised 16 October 2014 Accepted 17 October 2014
ABSTRACT Background Heterozygous dominant mutations of PRRT2 have been associated with various types of paroxysmal neurological manifestations, including benign familial infantile convulsions and paroxysmal kinesigenic dyskinesia. The phenotype associated with biallelic mutations is not well understood as few cases have been reported. Methods PRRT2 screening was performed by Sanger sequencing and quantitative multiplex PCR of short fluorescent fragments. A CGH array was used to characterise the size of the deletion at the 16p11.2 locus. Results Five patients with homozygous or compound heterozygous deleterious PRRT2 gene mutations are described. These patients differ from those with a single mutation by their overall increased severity: (1) the combination of at least three different forms of paroxysmal neurological disorders within the same patient and persistence of paroxysmal attacks; (2) the occurrence of uncommon prolonged episodes of ataxia; and (3) the association of permanent neurological disorders including learning difficulties in four patients and cerebellar atrophy in 2. Conclusions Our observations expand the phenotype related to PRRT2 insufficiency, and highlight the complexity of the phenotype associated with biallelic mutations, which represents a severe neurological disease with various paroxysmal disorders and frequent developmental disabilities.
INTRODUCTION
To cite: Delcourt M, Riant F, Mancini J, et al. J Neurol Neurosurg Psychiatry Published Online First: [please include Day Month Year] doi:10.1136/jnnp2014-309025
Paroxysmal kinesigenic dyskinesia (PKD, MIM 128200) is a rare disorder characterised by the occurrence of brief episodes of dystonic or choreic movements triggered by sudden movements or change in movement velocity. Benign infantile familial convulsions (BFIC) is a self-limited form of epilepsy with partial seizures usually occurring in a cluster during the first year of life. PKD, BIFC and their coexistence, referred to as ‘infantile convulsions and paroxysmal choreoathetosis syndrome’ (ICCA, MIM 602066) have been linked to heterozygous mutations of the proline-rich transmembrane protein 2 (PRRT2) gene.1 More recently, other paroxysmal neurological manifestations have been reported in heterozygous patients: paroxysmal non-kinesigenic dyskinesia (PNKD), migraine with
or without aura, hemiplaegic migraine, various type of non-infantile seizures, torticollis and episodic ataxia (EA).2 Previous reports of three patients suggested that homozygous PRRT2 mutations may give rise to more severe clinical disease of mental retardation, with or without EA and epilepsy.3 4 Here, we describe in detail the phenotype of five patients with biallelic PRRT2 mutations.
MATERIAL AND METHODS Written informed consent was obtained from the patients when aged over 18 years and by both parents for patients younger than 18 years according to French legislation. Fifty-one patients with PKD, 27 ICCA and 124 patients with episodic abnormal movements such as ataxia or dystonia were tested for PRRT2 mutations. Genetic method is available in online supplementary material.
RESULTS Table 1 summarises the main clinical and genetic findings; a detailed description of patient 1 is provided thereafter, and in online supplementary material concerning patients 2–5. Family pedigrees are illustrated in online supplementary figure S1. Brain imaging findings are shown in online supplementary figure S2. Patient 1 was referred at 5 months for an afebrile generalised status epilepticus episode that lasted 1 h. Antiepileptic treatment was discontinued at 2 years. Between the age of 1.5 and 6 years, the patient had six paroxysmal episodes characterised by convergent bilateral strabismus, vomiting and marked ataxia. After each episode his condition gradually improved and returned to normal within 10 days to 6 weeks after onset. From age 4, he had paroxysmal episodes of generalised dyskinesia, with abnormal limb movements and truncal bending, triggered by stress, exertion or fatigue, but not by sudden movement. These attacks were partially controlled by carbamazepine; a 48 h episode of generalised dystonia occurred at age 14 years after an abrupt carbamazepine withdrawal. Now aged 15 years, the patient has exhibited weekly attacks of brief duration.
Delcourt M, et al. J Neurol Neurosurg Psychiatry 2015;0:1–4. doi:10.1136/jnnp-2014-309025
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
2
clinical, brain MRI and genetic characteristics of our patients
Consanguinity
1
M/15
2*
Delcourt M, et al. J Neurol Neurosurg Psychiatry 2015;0:1–4. doi:10.1136/jnnp-2014-309025
IC/interictal EEG
PNKD
PKD
No
Coordination difficulties, no ataxia
Status epilepticus at 6 m/normal interictal EEG
No
18 months/6 Associated with strabismus, vomiting; Lasting 10 days to 6 weeks
HM/11 years
M/20
Yes
N
Focal seizures from 3 m to 3.5 y/normal interictal EEG
Yes
No
3
F/15
Yes
Motor tics
Status epilepticus at 3 and 12 m/normal interictal EEG
From 4 years Duration: 30 s to 2 min, in clusters of 1 h; Daily attacks in childhood; Improvement with carbamazepine but persistence at last follow-up From 25 m Duration: 10 s to 5 min; Several attacks per day in childhood despite carbamazepine and phenotoine; Persistence at last follow-up under both drugs From 18 m to 3 years Several per day in infancy; Relapse under lamotrigine treatment
No
4
F/25
No
N
Cluster of focal seizures et 3 m, then at 1 y; once a year at last follow-up/normal interictal EEG
No
5
F/5.5
Yes
N
Status epilepticus at 3 m, focal seizure at 8 and 16 m/normal interictal EEG
From 13 years– preceding visual aura Brief attacks of few seconds several times a day; Long-lasting attack of 10 min 4 times a year under oxcarbazepine; Rare attacks under lamotrigine (200 mg/ day) at last follow-up No
No
EA onset/episode number/clinical characteristic/duration
Migraine with or without aura/age of onset
Neurological examination (N: normal)
Cognition-learning abilities-behaviour (IQ evaluated using WISC-IV scale)
Brain MRI/age (N: normal)
PRRT2 mutation
Borderline IQ with ADHD; clumsiness, learning difficulties; educational support in a normal school
Severe cerebellar atrophy mainly involving the vermis (9 years, 14 years)
c.649dupC/ del (de novo)
M with aura/ 19 years
ADHD, learning difficulties, professional education programme for plumbing
N (5 years, 19 years)
c.649dupC/ c.649dupC
6 years/2 Following a febrile illness; With headache, vomiting, dysarthria, dyskinesia Lasting 2 weeks 7 years /3 Preceded by 1–2 days of vomiting; Associated with rigidity of the body, distal chorea, swallowing difficulties requiring nasogastric tube feeding; Lasting 5–6 days
No
Mild mental deficiency behavioural disturbances, specialised education in an institution for mentally disabled children
Mild vermian atrophy (10 years)
c.649dupC/ c.649dupC
M with ophthalmic aura/13 years
Normal IQ/moderate learning difficulties due to behavioural problems; professional education programme for children caregiver
N (21 years)
c.649dupC/ c.649dupC
1 year/4Associated with somnolence, vomiting, pyramidal tract signs; Lasting 2–4 weeks
No
Normal learning abilities
N (5 years)
c.913G>A/ c.913G>A
Age of the patients: m, months; y, years. *Patient previously reported by Caraballo. (Caraballo R, Pavek S, Lemainque A, et al. Linkage of benign familial infantile convulsions to chromosome 16p12-q12 suggests allelism to the infantile convulsions and choreoathetosis syndrome. Am J Hum Genet 2001;68:788–94). PKD, paroxysmal kinesigenic dyskinesia; PNKD, paroxysmal non-kinesigenic dyskinesia; EA, episodic ataxia; IC, infantile convulsion; ADHD, attention-deficit/hyperactivity disorder; N, normal.
Downloaded from http://jnnp.bmj.com/ on March 11, 2015 - Published by group.bmj.com
Patient
Sex/age at last follow-up (years)
Movement disorders
Table 1
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Movement disorders From age 11, the patient had five episodes of hemiplegic migraine characterised by ophthalmic aura, vomiting and hemiparesis that lasted 24 h. Coordination difficulties were reported from early childhood. Clinical examination did not disclose cerebellar sign. WISC-IV evaluation performed at 8 years of age showed borderline homogeneous level (total Intellectual Quotient: 71), and disclosed attention deficit disorder associated with visuospatial dyspraxia and dyslexia resulting in mild learning disabilities. Brain imaging performed at 9 and 14 years showed stable global cerebellar atrophy (see online supplementary figure S2). Patient 1 harboured a compound heterozygous genotype: c.649dupC/p.Arg217ProfsX8 and whole deletion of PRRT2 gene. Both mutations were absent in his parents. Sixteen polymorphic microsatellite markers were used to eliminate inaccurate maternity and paternity information or sampling error. A 44K CGH array analysis performed for the patient and his parents confirmed the de novo occurrence of the deletion. The precise size of the deletion was determined by using a 1M HRD array (see online supplementary figure S2). Patients 2, 3 and 4 were homozygous for the c.649dupC mutation ( p.Arg217ProfsX8) frequently reported in PKD.2 Patient 5 has the homozygous missense mutation c.913G>A/p. G305R previously reported in patients with PKD.2
DISCUSSION The phenotypes of these five patients clearly differ from their heterozygous family members, and from heterozygous patients reported to date, by their overall increased severity. An uncommon combination of at least three types of paroxysmal manifestations was reported in all except patient 5 who is only 5 years of age; this clinical pattern is clearly distinct from family heterozygous mutation carriers (who display a classical PRRT2 phenotype with benign course (BIFC, migraine, without PKD and EA) or are asymptomatic) and is uncommon in previously published patients with heterozygous mutations.2 The phenotype of patient 1 was very severe due to the combination of five distinct types of paroxysmal manifestations. Such complex phenotype was previously reported by Labate in two brothers with homozygous c.649dup mutation exhibiting a complex phenotype including BIFC, PKD, absence epilepsy, EA and mental deficiency. In these brothers, EA consisted of attacks of unsteadiness lasting less than 3 days.4 In heterozygous PRRT2 patients, EA is reported in less than 1% of the patients.2 The episodes of ataxia, not observed in their heterozygous family members, and reported in 4 out of 5 of our patients, are very singular due to their long duration (several days to 6 weeks vs seconds to hours for most common EAs) and their gravity. Finally, among the various forms of paroxysmal dyskinesias, kinesigenic PD is by far the most frequent form in PRRT2 heterozygous patients, while PNKD is rare;2 it is noteworthy that only patient 2 presented PKD; in all the patients, dyskinesias were severe and triggered by various non-kinesigenic factors. One of the main clinical findings here is the occurrence of cognitive and/or behavioural difficulties in patients 1–4 associated with brain imaging abnormalities in patients 1 and 3. Psychomotor retardation, mental deficiency or austistic features were found in patients harbouring the recurrent 16p11.2 deletion, which encompass the PRRT2 gene (figure 2D)5 and in three patients harbouring a homozygous PRRT2 mutation previously reported.3 4 Our report confirms the high frequency of cognitive disorder in PRRT2 homozygous patients. Learning disabilities or neuropsychiatric problems in heterozygous patients were only recently reported,6 and their description in 12/19
patients is striking.7 Brain MRI from patients 1 and 3 (who exhibited the more severe phenotype) revealed definite cerebellar atrophy, which had never been reported previously in heterozygous nor homozygous patients. PRRT2 protein is a proline rich protein that interacts with the synaptosomal-associated protein (SNAP25) involved in the fusion of synaptic vesicles to the plasma membrane and calcium triggered exocytosis, suggesting a role of PRRT2 in vesicle trafficking and neurotransmitter release. Although patient 1–4 harboured stop codon mutations or deletions on both alleles, which can lead to very low levels or complete absence of protein, patient 5 carried missense mutations that might lead to a modified protein and not to its absence, which could explain her milder phenotype. PRRT2 protein is highly expressed in the cortex and in the cerebellum, which is consistent with the wide range of possible manifestations, including EA and might support our finding of cerebellar atrophy. These observations expand the phenotype related to PRRT2 insufficiency; we suggest that biallelic PRRT2 mutations should be suspected when patients present a combination of various types of attacks, especially prolonged attacks of EA or when associated with cognitive disabilities, or when consanguinity is present. The occurrence of permanent neurological troubles in PRRT2 mutation carriers encourages further evaluation and prompts consideration of PRRT2-related disease as a more widespread neurodevelopmental disorder. Author affiliations 1 Service de Neuropédiatrie, CHU Gui de Chauliac, Montpellier, France 2 Laboratoire de Génétique, AP-HP, Groupe Hospitalier Lariboisière-Fernand Widal, Paris, France 3 INSERM UMR-S740; Université Paris 7 Denis Diderot, Paris, France 4 Service de Neurologie Pédiatrique, CHU Timone Enfants, Marseille, France 5 Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France 6 AP-HP, Unité d’épilepsie, Institut du Cerveau et de la Moelle épinière, Hôpital PitiéSalpêtrière, Paris, France 7 INSERM, UMRS 975, et CNRS 7225—Institut du Cerveau et de la Moelle épinière, Hôpital Pitié-Salpêtrière,Université Pierre et Marie Curie-Paris-6, Paris, France 8 Département des Maladies du Système Nerveux, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France 9 CRICM, INSERM U1127, CNRS UMR 7225, UPMC UMR-S975, Paris, France 10 Service de Médecine Psychologique Enfants et Adolescents, CHU Saint Eloi, Montpellier, France 11 Neuropédiatrie HUG, Genève, Suisse 12 Neuropédiatrie, HFME, Hospices Civils de Lyon, Bron, France 13 Université Lyon 1, F-69008 Lyon, France 14 INSERM U901, Marseille, France 15 Institut de Neurobiologie de la Méditerranée (INMED), Marseille, France 16 UMR_S901, Université d’Aix-Marseille, Marseille, France 17 Service de Neurologie Pédiatrique, AP-HP, Hôpital Trousseau, Paris, France 18 Team Genome and Cancer, Hematology Laboratory Assistance Publique-Hopitaux de Paris, Saint-Louis Hospital, Paris, France 19 Inserm U944, Saint-Louis Hospital, Paris, France 20 Service de Neuroradiologie, CHU Gui de Chauliac, Montpellier, France 21 EA 4666, CHU d’Amiens—UPJV, Laboratoire de Génétique, Hôpital Sud, Amiens, France 22 INSERM U 1051, Institut des Neurosciences de Montpellier, Montpellier, France Funding JR received a grant from “the Conseil Régional de Picardie” and an inter-reg (EU) grant. ER is the recipient of a grant “poste d’acceuil” AP-HP/CNRS. He received research support from INSERM (COSSEC), AP-HP (DRC-PHRC), Fondation pour la Recherche sur le Cerveau (FRC), the Dystonia Coalition (Pilot project), Ipsen, and Merz-Pharma, Novartis, Teva, Lundbeck, Orkyn; served on scientific advisory boards for Orkyn, Ipsen, and Merz-Pharma; received speech honorarium from Novartis and Orkyn; received travel funding from Teva, Novartis, the Dystonia Coalition, the Movement Disorders Society, and the World Federation of Neurology Association of Parkinsonism and Related Disorders. AR received travel funding from Genzyme, Viropharma and Biomarin. Competing interests None. Ethics approval This study was approved by the regional review board.
Delcourt M, et al. J Neurol Neurosurg Psychiatry 2015;0:1–4. doi:10.1136/jnnp-2014-309025
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Movement disorders Provenance and peer review Not commissioned; externally peer reviewed.
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Chen W-J, Lin Y, Xiong Z-Q, et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011;43:1252–5. Méneret A, Gaudebout C, Riant F, et al. PRRT2 mutations and paroxysmal disorders. Eur J Neurol 2013;20:872–8. Najmabadi H, Hu H, Garshasbi M, et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 2011;478:57–63.
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Delcourt M, et al. J Neurol Neurosurg Psychiatry 2015;0:1–4. doi:10.1136/jnnp-2014-309025
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Severe phenotypic spectrum of biallelic mutations in PRRT2 gene Marion Delcourt, Florence Riant, Josette Mancini, Mathieu Milh, Vincent Navarro, Emmanuel Roze, Véronique Humbertclaude, Christian Korff, Vincent Des Portes, Pierre Szepetowski, Diane Doummar, Bernard Echenne, Samuel Quintin, Nicolas Leboucq, Rabbind Singh Amrathlal, Jacques Rochette and Agathe Roubertie J Neurol Neurosurg Psychiatry published online January 16, 2015
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