PRRT2 Mutations Cause Benign Familial Infantile Epilepsy and Infantile Convulsions with Choreoathetosis Syndrome

Heron, Sarah E.; Grinton, Bronwyn E.; Kivity, Sara; Afawi, Zaid; Zuberi, Sameer M.; Hughes, James; Pridmore, Clair; Hodgson, Bree; Iona, Xenia; Sadleir, Lynette G.; Pelekanos, James T.; Herlenius, Eric; Goldberg‐Stern, Hadassa; Bassan, Haim; Haan, Eric; Korczyn, Amos D.; Gardner, Alison; Corbett, Mark; Gécz, Jozef; Thomas, Paul Q.; Mulley, John C.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Dibbens, Leanne M.

doi:10.1016/j.ajhg.2011.12.003

Cited by 237 publications

(265 citation statements)

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“…The p.Arg217-Profs*8 is a recurrent frameshift, loss of function mutation 13 that has also been identified in families and in sporadic patients with paroxysmal kinesigenic dyskinesias with or without infantile convulsions and benign familial infantile epilepsy. [9][10][11][12][13][14] The analysis of additional BFIS families led us to identify the c.649dupC in 3 additional familial cases and in the 2 sporadic cases (table, figure 2). In one of the 2 sporadic patients, the mutation occurred de novo.…”

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confidence: 99%

PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine

et al. 2012

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Objective: To perform a clinical and genetic study of a family with benign familial infantile seizures (BFIS) and, upon finding a PRRT2 gene mutation, to study a cohort of probands with a similar phenotype. We extended the study to all available family members to find out whether PRRT2 mutations cosegregated with additional symptoms. Methods:We carried out a clinical and genealogic study of a 3-generation family and of 32 additional probands with BFIS (11 families), infantile convulsions and paroxysmal choreoathetosis (ICCA) (9 families), BFIS/generalized epilepsy with febrile seizures plus (5 families), and sporadic benign neonatal or infantile seizures (7 probands/families). We performed a genetic study consisting of linkage analysis and PRRT2 screening of the 33 probands/families. Results:We obtained a positive linkage in the 16p11.3-q23.1 chromosomal region in the large BFIS family. Mutation analysis of PRRT2 gene revealed a c.649dupC (p.Arg217Profs*8) in all affected individuals. PRRT2 analysis of the 32 additional probands showed mutations in 10, 8 familial and 2 sporadic, probands. Overall we found PRRT2 mutations in 11 probands with a mutation rate of 11 out of 33 (33%). BFIS co-occurred with migraine and febrile seizures in 2 families, with childhood absence epilepsy in one family and with hemiplegic migraine in one family. Conclusion:Our results confirm the predominant role of PRRT2 mutations in BFIS and expand the spectrum of PRRT2-associated phenotypes to include febrile seizures, childhood absence seizures, migraine, and hemiplegic migraine.

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PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine

et al. 2012

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“…Recently, missense mutations in the gene PRRT2 (proline-rich transmembrane protein 2) were described for both paroxysmal kinesigenic dyskinesia and BFIS, and the combination of both called infantile convulsions and choreoathetois (ICCA) [18][19][20][21][22]. The resulting protein might be functionally relevant in the vesicle synaptic metabolism of neurons as it interacts with SNAP25, which is a member of the SNARE complex responsible for the vesicle exocytosis into the synaptic cleft [18].…”

Section: Good Prognosismentioning

confidence: 99%

Genetic Biomarkers in Epilepsy

et al. 2014

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The identification of valid biomarkers for outcome prediction of diseases and improvement of drug response, as well as avoidance of side effects is an emerging field of interest in medicine. The concept of individualized therapy is becoming increasingly important in the treatment of patients with epilepsy, as predictive markers for disease prognosis and treatment outcome are still limited. Currently, the clinical decision process for selection of an antiepileptic drug (AED) is predominately based on the patient's epileptic syndrome and side effect profiles of the AEDs, but not on effectiveness data. Although standard dosages of AEDs are used, supplemented, in part, by therapeutic monitoring, the response of an individual patient to a specific AED is generally unpredictable, and the standard care of patients in antiepileptic treatment is more or less based on trial and error. Therefore, there is an urgent need for valid predictive biomarkers to guide patient-tailored individualized treatment strategies in epilepsy, a research area that is still in its infancy. This review focuses on genomic factors as part of an individual concept for AED therapy summarizing examples that influence the prognosis of the disease and the response to AEDs, including side effects.

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“…The clinical spectrum of PRRT2 mutations includes cases of ICCA, BFIE, some "PNKD-like" syndromes, and PED. [1][2][3] Not all patients with classic carbamazepine-responsive PKD harbor mutations in coding regions of PRRT2. Genetic testing for PRRT2 mutations should be considered in patients with clinical features of PKD, ICCA, and BFIE in order to establish a definitive etiology and avert unnecessary searches for secondary causes.…”

Section: Paroxysmal Kinesigenic Dyskinesiamentioning

confidence: 99%

Non-Parkinson movement disorders

LeDoux

2013

Neur Clin Pract

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SummarySolutions to the major riddles in movement disorders are appearing at a breathtaking pace: 1) loss-offunction mutations in PRRT2, which encodes a cell surface protein expressed in neurons, have been found in many patients with paroxysmal kinesigenic dyskinesias; 2) mutations in CIZ1, which encodes a protein involved in cell-cycle control at the G1-S checkpoint, have been identified in a small percentage of patients with cervical dystonia; and 3) finally, after many years of genetics and identification of more than 25 disease-associated genes, cellular studies related to the pathobiology of hereditary spastic paraplegia are converging on defects in modeling the endoplasmic reticulum and membrane trafficking. On the treatment front, the distinctive syndromes of faciobrachial dystonic seizures with anti-LRI1 antibodies and anti-N-methyl-D-aspartic acid encephalitis with orobuccolingual dyskinesias are becoming increasingly recognized by clinicians as imminently treatable conditions. Also on the treatment front, the first phase I trial of MRI-guided high-intensity focused ultrasound for essential tremor has been completed and intraoperative MRI is currently being used to place electrodes in the brains of patients with medically intractable dystonia. Definitive etiologies and efficacious treatments for non-Parkinson disease movement disorders are no longer wishful thinking.H istorically, neurologists have been fascinated by the phenomenology and pathogenesis of non-Parkinson disease (PD) movement disorders such as the dystonias, paroxysmal dyskinesias, and hereditary spastic paraplegias. Technology drives change. With recent advances in "new-generation" massively parallel sequencing of DNA, molecular neuroimmunology, and cell biology, the mysteries of non-PD movement disorders are falling like a deck of cards. On the therapeutic front, intraoperative MRI is being used to guide targeted ultrasound for noninvasive creation of lesions

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PRRT2 Mutations Cause Benign Familial Infantile Epilepsy and Infantile Convulsions with Choreoathetosis Syndrome

Cited by 237 publications

References 26 publications

PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine

PRRT2 mutations in familial infantile seizures, paroxysmal dyskinesia, and hemiplegic migraine

Genetic Biomarkers in Epilepsy

Non-Parkinson movement disorders

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