Variable Phenotypes in the Same Patient with PRRT2-Associated Disorders

Abstract

Mutations in the PRRT2 gene lead to a spectrum of diseases with a common pathophysiology including self-limited (familial) infantile epilepsy and paroxysmal kinesigenic dyskinesia as well as other paroxysmal diseases involving movement and headache disorders. Atypical phenotypes, associated with episodic ataxia, epilepsy, hemiplegic migraine, developmental delay, and intellectual disability, have been reported in approximately 5% of the patients, which is probably an underestimation. Here, we present three patients with variable PRRT2 phenotypes in each patient. In the first two patients, the manifestations were characterized by episodes of nonepileptic paroxysms and focal seizures starting in the first years of life with good response to carbamazepine. One of them had no family history either of epilepsy or nonepileptic motor manifestations. The other patient simultaneously developed epileptic spasms. Neurodevelopment was normal in both. The third patient presented with early-onset focal epilepsy that was resistant to antiseizure medications and evolved to spike-wave activation in sleep associated with cognitive impairment and ataxia. In this patient, in addition to the mutation in the PRRT2 gene, a novel pathogenic SCN1A variant was identified. The distinct clinical presentations in the same patient observed in our cases confirm the broad spectrum of PRRT2-associated diseases.

Keywords

antiseizure medications - carbamazepine - epileptic encephalopathy - focal seizures - movement disorders - PRRT2

Publication History

Received: 05 January 2024

Accepted: 31 March 2024

Article published online:
15 May 2024

• References

• 1 Cloarec R, Bruneau N, Rudolf G. et al. PRRT2 links infantile convulsions and paroxysmal dyskinesia with migraine. Neurology 2012; 79 (21) 2097-2103
• 2 Massimino CR, Portale L, Sapuppo A. et al. PRRT2 related epilepsies: a gene review. J Pediatr Neurol 2023; 21: 264-272
• 3 Labate A, Tarantino P, Palamara G. et al. Mutations in PRRT2 result in familial infantile seizures with heterogeneous phenotypes including febrile convulsions and probable SUDEP. Epilepsy Res 2013; 104 (03) 280-284
• 4 Delcourt M, Riant F, Mancini J. et al. Severe phenotypic spectrum of biallelic mutations in PRRT2 gene. J Neurol Neurosurg Psychiatry 2015; 86 (07) 782-785
• 5 Landolfi A, Barone P, Erro R. The Spectrum of PRRT2-associated disorders: update on clinical features and pathophysiology. Front Neurol 2021; 12: 629747
• 6 Maini I, Iodice A, Spagnoli C. et al. Expanding phenotype of PRRT2 gene mutations: A new case with epilepsy and benign myoclonus of early infancy. Eur J Paediatr Neurol 2016; 20 (03) 454-456
• 7 Pavone P, Corsello G, Cho SY. et al. PRRT2 gene variant in a child with dysmorphic features, congenital microcephaly, and severe epileptic seizures: genotype-phenotype correlation?. Ital J Pediatr 2019; 45 (01) 159
• 8 Igarashi A, Okumura A, Shimojima K. et al. Focal seizures and epileptic spasms in a child with Down syndrome from a family with a PRRT2 mutation. Brain Dev 2016; 38 (06) 597-600
• 9 Fruscione F, Valente P, Sterlini B. et al. PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity. Brain 2018; 141 (04) 1000-1016
• 10 Lu B, Lou SS, Xu RS. et al. Cerebellar spreading depolarization mediates paroxysmal movement disorder. Cell Rep 2021; 36 (12) 109743
• 11 Vilas D, Marcé-Grau A, Macaya A, Valls-Solé J, Tolosa E. Galloping tongue syndrome in a PRRT2 mutation carrier. Neurol Genet 2019; 5 (06) e377
• 12 Caraballo RH, Capovilla G, Vigevano F, Beccaria F, Specchio N, Fejerman N. The spectrum of benign myoclonus of early infancy: clinical and neurophysiologic features in 102 patients. Epilepsia 2009; 50 (05) 1176-1183
• 13 Cossu A, Santos JL, Galati G. et al. PRRT2 benign familial infantile seizures (BFIS) with atypical evolution to encephalopathy related to status epilepticus during sleep (ESES). Neurol Sci 2023; 44 (06) 2173-2176
• 14 Sterlini B, Franchi F, Morinelli L. et al. Missense mutations in the membrane domain of PRRT2 affect its interaction with Nav1.2 voltage-gated sodium channels. Neurobiol Dis 2023; 183: 106177
• 15 Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C. The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain 2015; 138 (Pt 12): 3476-3495
• 16 Döring JH, Saffari A, Bast T. et al. The phenotypic spectrum of PRRT2-associated paroxysmal neurologic disorders in childhood. Biomedicines 2020; 8 (11) 456
• 17 Scheffer IE, Nabbout R. SCN1A-related phenotypes: epilepsy and beyond. Epilepsia 2019; 60 (Suppl. 03) S17-S24
• 18 Zhou P, He N, Zhang JW. et al. Novel mutations and phenotypes of epilepsy-associated genes in epileptic encephalopathies. Genes Brain Behav 2018; 17 (08) e12456
• 19 Chen WJ, Lin Y, Xiong ZQ. et al. Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011; 43 (12) 1252-1255
• 20 Heighway J, Sedo A, Garg A. et al. Sodium channel expression and transcript variation in the developing brain of human, Rhesus monkey, and mouse. Neurobiol Dis 2022; 164: 105622
• 21 Balagura G, Riva A, Marchese F. et al. Clinical spectrum and genotype-phenotype correlations in PRRT2 Italian patients. Eur J Paediatr Neurol 2020; 28: 193-197