The Genotype and Phenotype of Proline-Rich Transmembrane Protein 2 Associated Disorders in Chinese Children

Abstract

Objectives: To study the genetic and clinical characteristics of Chinese children with pathogenic proline-rich transmembrane protein 2 (PRRT2) gene-associated disorders.Methods: Targeted next generation sequencing (NGS) was used to identify pathogenic PRRT2 variations in Chinese children with epilepsy and/or kinesigenic dyskinesia. Patients with confirmed PRRT2-associated disorders were monitored and their clinical data were analyzed.Results: Forty-four patients with pathogenic PRRT2 variants were recruited. Thirty-five of them (79.5%) had heterozygous mutations, including 30 frameshifts, three missenses, one nonsense, and one splice site variant. The c.649dupC was the most common variant (56.8%). Eight patients (18.2%) showed whole gene deletions, and one patient (2.3%) had 16p11.2 microdeletion. Thirty-four cases (97.1%) were inherited and one case (2.9%) was de novo. Forty patients were diagnosed with benign familial infantile epilepsy (BFIE), two patients had paroxysmal kinesigenic dyskinesia (PKD) and two had infantile convulsions and choreoathetosis (ICCA). Patients with whole gene deletions had a later remission than patients with heterozygous mutations (13.9 vs. 7.1 months, P = 0.001). Forty-two patients were treated with antiseizure medications (ASMs). At last follow-up, 35 patients, including one who did not receive therapy, were asymptomatic, and one patient without ASMs died of status epilepticus at 12 months of age. One patient developed autism, and one patient showed mild developmental delay/intellectual disability.Conclusion: Our data suggested that patients with whole gene deletions could have more severe manifestations in PRRT2-associated disorders. Conventional ASMs, especially Oxcarbazepine, showed a good treatment response.

SON -Related Zhu-Tokita-Takenouchi-Kim Syndrome With Recurrent Hemiplegic Migraine

“…To date, there are 2 different models for PRRT2 topology in the literature; one model predicts that the long N-terminal portion is an intracellular domain, 19 , 20 whereas the other model predicts the N-terminal portion as an extracellular domain. 21 , 22 A recent study further characterized the PRRT2 protein topology using TMHMM (TransMembrane prediction using Hidden Markov Models), a transmembrane helix prediction program, 23 which supports the model of extracellular localization of the N-terminal region. Therefore, in this report, we adapted the gene/protein structure and the membrane topology of PRRT2 with a long N-terminal extracellular domain, 2 transmembrane domains (M1 and M2) separated by an intracellular (cytoplasmic) domain, and a short C-terminal extracellular domain ( Figure 5, A and B ).…”

Clinical and genetic analysis of benign familial infantile epilepsy caused by PRRT2 gene variant

“…Case 1 carried an unreported variant, c.397delG (p.E133Nfs*43), which was predicted to be deleterious and pathogenic by multiple software programs. Luo et al ( 3 ) reported that seven family members carrying heterozygous mutations in the PRRT2 gene had no clinical symptoms associated with PRRT2 -related disorders, suggesting incomplete penetrance of the PRRT2 mutations. In the current study, the variant in case 5 was inherited from the father who showed no clinical phenotype, also suggesting incomplete penetrance.…”

“…In humans and rodents, PRRT2 is a neuroprotein that is most abundantly expressed in the cerebellum, basal ganglia, and neocortex. Mutations in PRRT2 are associated with a variety of neurological disorders, such as BFIE, paroxysmal kinesigenic dyskinesia, and infantile convulsions and choreoathetosis, which account for more than 90% of all cases ( 3 , 23 ). Other rare phenotypes, including seizures, ictal ataxia, and hemiplegic migraine, have also been reported, suggesting significant phenotypic heterogeneity resulting from PRRT2 mutations ( 24 – 26 ).…”

“…The age of seizure onset in affected children usually ranges between 4 and 6 months old. The seizures usually occur in clusters and have a good prognosis and usually resolve by 2 years old ( 2 , 3 ).…”

“…Clinical data of seven children with benign familial infantile convulsions. Age of onset, Age of first onset;3 Video EEG, Video EEG features;4 Head MRI, Head magnetic Resonance Imaging; 5 Female; 6 GTCS, generalized tonic-clonic seizure; 7 HC, head circumference; 8 LEV, levetiracetam; 9 M, Male; 10 VPA, valproic acid; 11 PB, phcnobarbital; and 12 OXC, oxcarbazepine.…”