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Short Report
Severe phenotypic spectrum of biallelic mutations in PRRT2 gene
  1. Marion Delcourt1,
  2. Florence Riant2,3,
  3. Josette Mancini4,
  4. Mathieu Milh4,5,
  5. Vincent Navarro6,7,
  6. Emmanuel Roze8,9,
  7. Véronique Humbertclaude10,
  8. Christian Korff11,
  9. Vincent Des Portes12,13,
  10. Pierre Szepetowski14,15,16,
  11. Diane Doummar17,
  12. Bernard Echenne1,
  13. Samuel Quintin18,19,
  14. Nicolas Leboucq20,
  15. Rabbind Singh Amrathlal21,
  16. Jacques Rochette21,
  17. Agathe Roubertie1,22
  1. 1Service de Neuropédiatrie, CHU Gui de Chauliac, Montpellier, France
  2. 2Laboratoire de Génétique, AP-HP, Groupe Hospitalier Lariboisière-Fernand Widal, Paris, France
  3. 3INSERM UMR-S740; Université Paris 7 Denis Diderot, Paris, France
  4. 4Service de Neurologie Pédiatrique, CHU Timone Enfants, Marseille, France
  5. 5Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France
  6. 6AP-HP, Unité d’épilepsie, Institut du Cerveau et de la Moelle épinière, Hôpital Pitié-Salpêtrière, Paris, France
  7. 7INSERM, 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. 8Département des Maladies du Système Nerveux, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
  9. 9CRICM, INSERM U1127, CNRS UMR 7225, UPMC UMR-S975, Paris, France
  10. 10Service de Médecine Psychologique Enfants et Adolescents, CHU Saint Eloi, Montpellier, France
  11. 11Neuropédiatrie HUG, Genève, Suisse
  12. 12Neuropédiatrie, HFME, Hospices Civils de Lyon, Bron, France
  13. 13Université Lyon 1, F-69008 Lyon, France
  14. 14INSERM U901, Marseille, France
  15. 15Institut de Neurobiologie de la Méditerranée (INMED), Marseille, France
  16. 16UMR_S901, Université d'Aix-Marseille, Marseille, France
  17. 17Service de Neurologie Pédiatrique, AP-HP, Hôpital Trousseau, Paris, France
  18. 18Team Genome and Cancer, Hematology Laboratory Assistance Publique-Hopitaux de Paris, Saint-Louis Hospital, Paris, France
  19. 19Inserm U944, Saint-Louis Hospital, Paris, France
  20. 20Service de Neuroradiologie, CHU Gui de Chauliac, Montpellier, France
  21. 21EA 4666, CHU d'Amiens—UPJV, Laboratoire de Génétique, Hôpital Sud, Amiens, France
  22. 22INSERM U 1051, Institut des Neurosciences de Montpellier, Montpellier, France
  1. Correspondence to Dr Agathe Roubertie, Service de Neuropédiatrie, CHU Gui de Chauliac, 80 Avenue Fliche, Montpellier 34295, France; A-roubertie{at}


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.


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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.


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.

Table 1

clinical, brain MRI and genetic characteristics of our patients

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.

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


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.



  • 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.

  • Provenance and peer review Not commissioned; externally peer reviewed.