The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood

Abstract

Pathogenic variants in PRRT2, encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2. The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

“…The clinical phenotype with self-limiting infantile-onset seizures in this boy is partially overlapping with the mild end of KCNA2 -related epilepsy. Therefore, a role of the specific KCNA2 variant p.Tyr417Cys in benign infantile epilepsy (BFIS) appears possible, with a reduced penetrance, similar to other known genetic causes of infantile seizures such as PRRT2 [ 49 ], SCN2A [ 50 ], and SCN8A [ 51 ]. The novel variant p.(Pro407Ala) was found in a three-year-old girl (#2) with neonatal-onset developmental and epileptic encephalopathy and profound intellectual disability (ID).…”

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

“…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.…”

“…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).…”

“…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).…”

“…The ictal EEG often shows parieto-occipital epileptic activity that may eventually generalize ( 28 ). Bilateral tonic-clonic or absence seizures and benign myoclonus of infancy have been rarely described ( 27 , 29 , 30 ). Conversely, PRRT2 mutations are not found in families with atypical infantile seizures such as later seizure onset or offset, more severe seizures, or multiple seizure type ( 29 ).…”