Clinical spectrum and genotype-phenotype correlations in PRRT2 Italian patients

Balagura, Ganna; Riva, Antonella; Marchese, Francesca; Iacomino, Michele; Madia, Francesca; Giacomini, Thea; Mancardi, Maria Margherita; Amadori, Elisabetta; Vari, Maria Stella; Salpietro, Vincenzo; Russo, Angelo; Messana, Tullio; Chiesa, Valentina; Giordano, Lucio; Accorsi, Patrizia; Caffi, Lorella; Orsini, Alessandro; Bonuccelli, Alice; Santucci, Margherita; Vecchi, Marilena; Vanadia, Francesca; Milito, Giuseppe; Fusco, Carlo; Cricchiutti, Giovanni; Carpentieri, M L; Margari, Lucia; Spalice, Alberto; Beccaria, Francesca; Benfenati, Fabio; Zara, Federico; Striano, Pasquale

doi:10.1016/j.ejpn.2020.06.005

Cited by 18 publications

(20 citation statements)

References 17 publications

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“…Nonetheless, there remain critical open questions for future investigation. For instance, genotype-phenotype correlations in humans are not strict, as suggested by the incomplete penetrance, which has been estimated to be about 75-90% for epilepsy and only 50-61% for PKD in pediatric cohorts (26,56). Data about adult patients with PKD are lacking.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond paroxysmal neurological disorders, there is preliminary evidence that heterozygous PRRT2 mutations might also cause intellectual disability and/or developmental delay (26,27,38), a suggestion supported by their invariable presence in cases with 16p11.2 deletions (39-41) and homozygous PRRT2 mutations (27,(42)(43)(44). The latter evidence, along with initial demonstrations that PRRT2 mutations can possibly cause brain structural alterations (27,44), is of crucial importance since it implicates PRRT2 in neurogenesis and brain development, as discussed below.…”

Section: Other Clinical Syndromesmentioning

confidence: 91%

“…It is an autosomal-dominant epileptic disorder in which non-febrile convulsions start in the first 12 months of life, have a good response to AED, and have a favorable prognosis with remission before age two (1). Seizure phenomenology consists of focal motor seizures starting with gaze staring, motor arrest and head deviation, hypertonia and cyanosis, which usually occur in clusters and might have secondary generalization (25)(26)(27). The ictal EEG often shows parieto-occipital epileptic activity that may eventually generalize (28).…”

Section: Epileptic Disordersmentioning

confidence: 99%

“…However, given the high prevalence of migraine in the general FIGURE 1 | The clinical spectrum of PRRT2-associated disorders by onset age. The curves on the background reflect the empirical distribution of age at onset for the two commonest phenotypes (i.e., epilepsy in blue and paroxysmal dyskinesia in red) based on references (10,26,27).…”

Section: Other Clinical Syndromesmentioning

confidence: 99%

“…The latter evidence, along with initial demonstrations that PRRT2 mutations can possibly cause brain structural alterations (27,44), is of crucial importance since it implicates PRRT2 in neurogenesis and brain development, as discussed below. However, it should be noted that, in the context of 16p11.2 deletions, phenotype severity might be owing to deletion of adjacent genes and, therefore, the association of intellectual disability and heterozygous PRRT2 mutations (26,27,38) requires additional confirmation.…”

Section: Other Clinical Syndromesmentioning

confidence: 99%

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The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology

2021

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Mutations in the PRRT2 (proline-rich transmembrane protein 2) gene have been identified as the main cause of an expanding spectrum of disorders, including paroxysmal kinesigenic dyskinesia and benign familial infantile epilepsy, which places this gene at the border between epilepsy and movement disorders. The clinical spectrum has largely expanded to include episodic ataxia, hemiplegic migraine, and complex neurodevelopmental disorders in cases with biallelic mutations. Prior to the discovery of PRRT2 as the causative gene for this spectrum of disorders, the sensitivity of paroxysmal kinesigenic dyskinesia to anticonvulsant drugs regulating ion channel function as well as the co-occurrence of epilepsy in some patients or families fostered the hypothesis this could represent a channelopathy. However, recent evidence implicates PRRT2 in synapse functioning, which disproves the “channel hypothesis” (although PRRT2 modulates ion channels at the presynaptic level), and justifies the classification of these conditions as synaptopathies, an emerging rubric of brain disorders. This review aims to provide an update of the clinical and pathophysiologic features of PRRT2-associated disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Other Clinical Syndromesmentioning

confidence: 91%

Section: Epileptic Disordersmentioning

confidence: 99%

Section: Other Clinical Syndromesmentioning

confidence: 99%

Section: Other Clinical Syndromesmentioning

confidence: 99%

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The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology

2021

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Translating Genetic Discovery into a Mechanistic Understanding of Pediatric Movement Disorders: Lessons from Genetic Dystonias and Related Disorders

Lin

2022

Advanced Genetics

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The era of next‐generation sequencing has increased the pace of gene discovery in the field of pediatric movement disorders. Following the identification of novel disease‐causing genes, several studies have aimed to link the molecular and clinical aspects of these disorders. This perspective presents the developing stories of several childhood‐onset movement disorders, including paroxysmal kinesigenic dyskinesia, myoclonus‐dystonia syndrome, and other monogenic dystonias. These stories illustrate how gene discovery helps focus the research efforts of scientists trying to understand the mechanisms of disease. The genetic diagnosis of these clinical syndromes also helps clarify the associated phenotypic spectra and aids the search for additional disease‐causing genes. Collectively, the findings of previous studies have led to increased recognition of the role of the cerebellum in the physiology and pathophysiology of motor control—a common theme in many pediatric movement disorders. To fully exploit the genetic information garnered in the clinical and research arenas, it is crucial that corresponding multi‐omics analyses and functional studies also be performed at scale. Hopefully, these integrated efforts will provide us with a more comprehensive understanding of the genetic and neurobiological bases of movement disorders in childhood.

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