A Family with Epilepsy and Dyskinesia due to Homozygous PRRT2 Gene Mutation

Abstract

Proline-rich transmembrane protein 2 (PRRT2) plays an important role in the central nervous system, and mutations in the gene are implicated in various neurological disorders. Variants in PRRT2 (OMIM*614386) can manifest as a variety of clinical phenotypes, including convulsions with paroxysmal choreoathetosis, paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile seizure, and hemiplegic migraine. Here, we report a family with a homozygous PRRT2 variant with benign familial infantile epilepsy and PKD attacks, summarize the clinical characteristics of neurological diseases related to the PRRT2 gene, and explore the therapeutic effects and urge that these patients be treated with acetazolamide during the dyskinesia attacks.

 

MissingLinkText

Keywords

proline-rich transmembrane protein 2 - benign familial infantile epilepsy - paroxysmal kinesigenic dyskinesia - self-limited infantile epilepsy - antiseizure medication

Introduction

Proline-rich transmembrane protein 2 (PRRT2) is located on chromosome 16p11.2 and consists of four exons, three of which encode a protein of 340 amino acids. The PRRT2 comprises a proline-rich, extracellular N-terminal domain and a membrane-bound C-terminal domain.[1] Mutations in the PRRT2 gene (OMIM: 614,386) have been identified as the major cause of self-limited infantile epilepsy.[2] Many PRRT2 gene mutations (nonsense, missense, or deletion) have been identified. The frameshift mutation c.649dupC (p.Arg217Profs*8) is the most common pathogenetic variant in ∼80% of cases.[3] PRRT2 is highly expressed in the central nervous system, especially in the cerebral cortex, basal ganglia, and cerebellum. At the cellular level, PRRT2 localizes at the plasma membrane at the presynaptic level and is mainly expressed in glutamatergic neurons. This protein was first described to interact with 25 kDa synaptosomal-associated protein, which is involved in Ca²⁺-mediated neurotransmitter release through its function as a t-SNARE protein.[4] Subsequent studies showed that PRRT2 interacts with other synaptic proteins, such as the vesicle-associated membrane protein 2 and the synaptotagmins Syt1 and 2, which again implicates PRRT2 in the Ca²⁺-mediated neurotransmitter release.[5] PRRT2 is an important negative modulator of Nav1.2 and Nav1.6 channels, which are major regulators of the excitability of excitatory neurons.[6] PRRT2 variants have been associated with a heterogeneous spectrum of paroxysmal disorders, including paroxysmal kinesigenic dyskinesia (PKD), PKD with infantile convulsions (PKD/IC), benign familial infantile epilepsy (BFIE), hemiplegic migraine and episodic ataxia,[4] and other associated neurological manifestations such as learning difficulties, intellectual disability, and autism.[6] Here, we report a family with homozygous PRRT2 variant, summarize the clinical characteristics of neurological diseases related to the PRRT2 gene, and explore the therapeutic effects.

BFIE is mostly presented in the first year of life (usually 4–7 months) with focal-onset motor seizures ± impaired awareness focal to bilateral tonic-clonic seizures, which occur in clusters of multiple brief seizures per day, on average up to 8 to 10 seizures per day every 2 to 3 hours. They almost have a normal neurological examination and normal magnetic resonance imaging. Usually, they respond well to antiseizure medications (ASMs) and resolve by the age of 2 years. Pathogenic variants in KCNQ2, SCN2A, and PRRT2 account for ∼80% of the self-limited familial neonatal, self-limited familial neonatal-infantile, and self-limited familial infantile epilepsies, respectively.[7]

PKD onset between ages 1 and 18 years with sudden attacks of unilateral or bilateral involuntary movements (i.e., dyskinesias that can include a combination of dystonia, chorea, ballism, or athetosis) triggered by sudden voluntary movements, intention to move, or acceleration of movement. These episodes are short in duration and can occur with high frequency (typically <1 minute, can be as frequent as 100 times per day). There was no loss of consciousness or pain, neurologic examination was normal between attacks, imaging was normal, and no electroencephalogram (EEG) changes during attacks.[8]

This report describes a family with homozygous PRRT2 variants with BFIE; later, they developed PKD attacks. Compared with previously reported cases with homozygous PRRT2 mutation, all patients have normal psychomotor development, and the dyskinesia attacks were controlled with acetazolamide (ACZ).

 

MissingLinkText

Case Description

The clinical profile and pedigree of the three patients are summarized in [Table 1] and [Fig. 1].

Table 1 Highlights of the three case reports

	Case 1 (index case)	Case 2	Case 3
Sex	Male	Male	Female
Current age[a]	9 y	6 y	2 y, 3 mo
Age at presentation	3 mo	3.5 mo	8 mo
Clinical presentation	-Repeated attacks of focal seizure -Dyskinesia	-Repeated focal seizures - Dyskinesia	Focal seizure tonic-clonic with uprolling eyes
Treatment	Acetazolamide + carbamazepine (tapering)	Acetazolamide + carbamazepine (tapering)	Carbamazepine
Outcome	Symptoms free	Symptoms free	Symptoms free

^a At the time of preparation of this case series.

Fig. 1 The family pedigree.

Case 1

The index case was born at term after a spontaneous delivery with an unremarkable perinatal period ([Table 1]). He developed repeated attacks of focal seizure at the age of 3 months, which responded to phenobarbital syrup at the therapeutic dose; seizure reoccurs when trying to shift to valproate. At 1.4 years old, the seizures were controlled with carbamazepine (CBZ) 20 mg/kg/d in combination with valproate 50 mg/kg/d. At the age of 2.3 years, the child developed brief attacks of unsteady gait, which lasted for a few seconds, and he had no more seizures, so gradually, the valproate was withdrawn. At 4.5 years old, the seizure was controlled on CBZ. However, he developed repeated brief episodes of abnormal movement in the form of attacks of unsteadiness with mouth and both hands twitching for 20 seconds many times per day, as his younger brother had been developing repeated focal seizures, so an epilepsy gene panel was requested. The result was negative; at 8 years of age, the patient developed attacks of spindle movement of arms and legs without loss of consciousness. Interictal EEG was normal, and CBZ drug level was at therapeutic levels; levetiracetam was added but did not change the attacks, and the attacks have been worsening with clobazam. Whole exome sequencing (WES) was requested, and the result showed a homozygous pathogenic variant (c.649dup p.(Arg217Profs*8) identified in the PRRT2 gene. This result is consistent with a genetic diagnosis of autosomal recessive PRRT2-related disease. So, ACZ at a dose of 250 mg once daily (8 mg/kg/d) was started; a few days after initiation of ACZ, the patient became symptom-free, with the cessation of involuntary dystonic trunk and extremity movements.

 

MissingLinkText

Case 2

His symptoms started at the age of 3.5 months with repeated focal seizures, which initially responded to phenobarbital (4 mg/kg/d), later switched to valproate and then to levetiracetam, but he showed poor response to both at the age of 6 months, the seizures were relieved after starting CBZ ([Table 1]). Later, the patient developed a brief attack of unsteadiness (dyskinesia) movements for a few seconds many times per day. ACZ 250 mg once daily was started together with his brother, and the patient had a dramatic response and achieved freedom from attacks in a few days.

 

MissingLinkText

Case 3

A 2-year and 3-month-old girl began to experience convulsive seizures at 8 months of age, which manifested as focal seizure tonic-clonic with uprolling eyes lasting 2 minutes many times a day; interictal EEG showed focal discharges ([Table 1]). She did not have any seizures after starting treatment with CBZ, and to date of this report, she did not experience any dyskinetic movements.

 

MissingLinkText

 

MissingLinkText

Discussion

In 2015, Ebrahimi-Fakhari et al[4] reported ∼600 individuals with PRRT2-BFIE, 560 with PRRT2-PKD, and 210 with PRRT2-PKD/IC. They also estimated that the prevalence of PRRT2-PKD is 1:150,000 individuals. PRRT2-PKD appears to be 1.5 times more common in males than females. As it is a rare disorder, its true frequency in the general population may be underestimated. The index patient in this report had WES, but the other two siblings did not because of financial reasons.

The results identified a homozygous pathogenic c.649dup p.(Arg217Profs*8) variant in the PRRT2 gene, consistent with a genetic diagnosis of autosomal recessive PRRT2-related disease. In concomitant with Maini et al (2016), a study demonstrates that, in the majority of PRRT2-related cases with epilepsy, the seizure course is reported to be relatively benign, with resolution within the first 2 to 3 years of age,[3] the reported three siblings have been presented in the first year of life with focal-onset motor seizures respond to CBZ, and they have normal psychomotor development. However, there is variability in seizure severity. For example, in a report of five Spanish families, 36% of individuals with PRRT2 variants had an atypical course with either neonatal onset seizures, learning difficulties, or mild hemiparesis.[9] Two patients with homozygous variants in PRRT2 (c.649dupC) have been reported in the literature to have a more severe phenotype than their family members with the c.649dupC variant in the heterozygous state, with a combination of phenotypes including BFIE, PKD, episodic ataxia, and developmental delay.[10]

Delcourt et al reported five additional patients: three with homozygous c.649dupC, one with a homozygous missense variant (c.913GNA), and one with concurrent c.649dupC and whole gene deletion of PRRT2.[11] All these patients had relatively severe neurological manifestations, including at least three forms of paroxysmal neurological disorders within the same patient, longer than usual episodes of ataxia, or permanent neurological disorders, including learning difficulties (four patients) and cerebellar atrophy (two patients). In the present report, the older two siblings who developed PKD and did not respond to usual ASM such as CBZ, levetiracetam, valproate or clobazam showed a dramatic response and became free of symptoms of dyskinesia, shortly after starting ACZ, which also had been reported by Martorell et al as improvement of episodic ataxia in PRRT2 mutation patients when treated with ACZ.[12] ACZ is a noncompetitive inhibitor of carbonic anhydrase containing a sulpha ring moiety that plays a vital role in the mechanism of action.[13] Velísek et al demonstrated that carbonic anhydrase knockout mice are less likely to have provoked seizures due to low plasma bicarbonate; therefore, they hypothesized that the antiseizure action of ACZ is due to a process of acidification, thereby reducing the release of acetylcholine.[14] It also reduces inflammation by reducing cytokine expression, further contributing to its antiepileptic effect.[15] The exact mechanism of ACZ for paroxysmal dystonia is unclear; it could alter the efflux of intracellular bicarbonate through γ-aminobutyric acid (GABA)-activated channels. An animal study showed that ACZ exerts antidystonic effects in the mutant hamster by inhibiting bicarbonate regeneration and reducing GABA-mediated excitation without affecting GABA-mediated inhibition. So, the neuronal hyperexcitability might be reduced, and the paroxysmal dystonia improved consequently.[16]

 

MissingLinkText

Conclusion

Identifying PRRT2 variants in patients who have epilepsy may help achieve a more personalized treatment approach. PRRT2 mutation can be associated with a variety of epileptic phenotypes, which can range from benign ASM-responsive forms to more severe epileptic encephalopathies. The three patients presented here have homozygous PRRT2 variants with BFIE and PKD attacks, and all have normal psychomotor development. The authors urge that these patients be treated with ACZ during the dyskinesia attacks.

 

MissingLinkText

 

MissingLinkText

Conflict of Interest

None declared.

Authors' Contributions

Both authors contributed to the study's conceptualization and data collection, as well as to the drafting, development, and finalization of the manuscript. They both approved the final version of the manuscript.

Patient Consent

The authors confirm that they obtained the appropriate consent from the parents of the reported cases to report anonymously. All efforts were made to avoid possible identification of the reported individuals.

Compliance with Ethical Principles

No prior ethical approval is required for single-case reports or small case series, provided that consent was obtained from the patients or guardians.

• References

• 1 Landolfi A, Barone P, Erro R. The spectrum of PRRT2-associated disorders: update on clinical features and pathophysiology. Front Neurol 2021; 12: 629747
• 2 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
• 3 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
• 4 Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C. The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain 2015; 138 (Pt 12): 3476-3495
• 5 Valente P, Castroflorio E, Rossi P. et al. PRRT2 is a key component of the Ca(2+)-dependent neurotransmitter release machinery. Cell Rep 2016; 15 (01) 117-131
• 6 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
• 7 Millevert C, Weckhuysen S. ILAE Genetics Commission. ILAE genetic literacy series: self-limited familial epilepsy syndromes with onset in neonatal age and infancy. Epileptic Disord 2023; 25 (04) 445-453
• 8 Bruno MK, Hallett M, Gwinn-Hardy K. et al. Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. Neurology 2004; 63 (12) 2280-2287
• 9 Guerrero-López R, Ortega-Moreno L, Giráldez BG. et al. Atypical course in individuals from Spanish families with benign familial infantile seizures and mutations in the PRRT2 gene. Epilepsy Res 2014; 108 (08) 1274-1278
• 10 Labate A, Tarantino P, Viri M. et al. Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation, episodic ataxia, and absences. Epilepsia 2012; 53 (12) e196-e199
• 11 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
• 12 Martorell L, Macaya A, Pérez-Dueñas B, Ortigoza-Escobar JD. Acetazolamide improves episodic ataxia in a patient with non-verbal autism and paroxysmal dyskinesia due to PRRT2 biallelic variants. Mov Disord Clin Pract 2022; 9 (07) 979-982
• 13 Masereel B, Rolin S, Abbate F, Scozzafava A, Supuran CT. Carbonic anhydrase inhibitors: anticonvulsant sulfonamides incorporating valproyl and other lipophilic moieties. J Med Chem 2002; 45 (02) 312-320
• 14 Velísek L, Moshé SL, Xu SG, Cammer W. Reduced susceptibility to seizures in carbonic anhydrase II deficient mutant mice. Epilepsy Res 1993; 14 (02) 115-121
• 15 Cai L, Chen WN, Li R, Hu CM, Lei C, Li CM. Therapeutic effect of acetazolamide, an aquaporin 1 inhibitor, on adjuvant-induced arthritis in rats by inhibiting NF-κB signal pathway. Immunopharmacol Immunotoxicol 2018; 40 (02) 117-125
• 16 Richter A, Hamann M. The carbonic anhydrase inhibitor acetazolamide exerts antidystonic effects in the dt(sz) mutant hamster. Eur J Pharmacol 2004; 502 (1-2): 105-108

Publication History

Article published online:
16 July 2025