Re-evaluation of PRRT2 mutations in paroxysmal disorders

Mutations in PRRT2 have recently been identified as the major cause of autosomal dominant benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis syndrome (ICCA), and paroxysmal kinesigenic dyskinesia (PKD). Other paroxysmal disorders like febrile seizures, migraine, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia have also been shown to be associated with this gene. We re-evaluated PRRT2 mutations and genetic–clinical correlations in additional cases with PKD/ICCA and other paroxysmal disorders. Two novel mutations in PRRT2 were revealed in PKD/ICCA cases, while no mutations were detected in other diseases, which suggests BFIE and PKD are still core phenotypes of PRRT2-related spectrum disorders.     

PRRT2 mutations and paroxysmal disorders

In the past year, mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. We conducted a review of the literature on PRRT2 mutation‐associated disorders. Our objectives were to describe the wide clinical spectrum associated with PRRT2 mutations, and to present the current hypotheses on the underlying pathophysiology. PRRT2 mutations are associated with a wide range of clinical syndromes: the various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, episodic ataxia and even intellectual disability in the homozygous state. The PRRT2 protein, through its interaction with SNAP‐25, could play a role in synaptic regulation in the cortex and the basal ganglia. The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability. However, this does not explain the phenotypic variability, which is likely modulated by environmental factors, modifier genes or age‐dependent expression. The clinical spectrum of PRRT2 mutations has expanded among paroxysmal disorders and beyond. Unraveling the molecular pathways linking the genetic defect to its clinical expression will be crucial for the diagnosis and treatment of these disorders.     

Phenotypic overlap among paroxysmal dyskinesia subtypes: Lesson from a family with PRRT2 gene mutation

Paroxysmal dyskinesia (PD) is a group of rare neurological conditions which was divided into paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD) and paroxysmal exercise-induced dyskinesia (PED) according to their clinical features. PRRT2 gene was initially identified as the major gene responsible for PKD followed by presence of various PRRT2 mutations discovered in families with benign familial infantile convulsions (BFIC) and infantile convulsions and choreoathetosis (ICCA). We describe a family with characteristic PD showing overlaps in clinical pictures among the three PD subgroups, and a nonsense PRRT2 mutation c.649C > T (p.Arg217X) was also detected. This broadens the phenotypic spectrum in PRRT2-related disorders. In addition, an unusual exercise trigger observed in the proband, likely representing an underestimated occurrence, together with the current clinical PD classification is also elucidated.     

Missense mutations of the proline-rich transmembrane protein 2 gene cosegregate with mild paroxysmal kinesigenic dyskinesia and infantile convulsions in a Chinese pedigree

Paroxysmal kinesigenic dyskinesia is an autosomal dominant dystonia induced by sudden voluntary movements. Recently, proline-rich transmembrane protein 2 (PRRT2) gene mutations, especially frameshift mutations, were described for PKD. In our study, we have collected a three-generation paroxysmal kinesigenic dyskinesia-infantile convulsions pedigree in Tianjin, North China. The symptoms of six patients varied; age of onset decreased in each generation. Mutations in the PRRT2 gene in nine PKD family members were screened by PCR sequencing of genomic DNA samples. Missense mutations of the PRRT2 gene were found in all four PKD patients and two children with infantile convulsions. All six individuals carried heterozygous codon 138 (Pro/Ala) and codon 306 (Ala/Asp) mutations. Missense mutations of the PRRT2 gene other than truncate and frameshift mutations were account for PKD and/or infantile convulsions. Age of onset and symptoms were not necessarily associated with PRRT2 mutations.     

PRRT2 mutation in Japanese children with benign infantile epilepsy

Mutations in PRRT2 genes have been identified as a major cause of benign infantile epilepsy and/or paroxysmal kinesigenic dyskinesia. We explored mutations in PRRT2 in Japanese patients with BIE as well as its related conditions including convulsion with mild gastroenteritis and benign early infantile epilepsy. We explored PRRT2 mutations in Japanese children who had had unprovoked infantile seizures or convulsion with mild gastroenteritis. The probands included 16 children with benign infantile epilepsy, 6 children with convulsions with mild gastroenteritis, and 2 siblings with benign early infantile epilepsy. In addition, we recruited samples from family members when PRRT2 mutation was identified in the proband. Statistical analyses were performed to identify differences in probands with benign infantile epilepsy according to the presence or absence of PRRT2 mutation. Among a total of 24 probands, PRRT2 mutations was identified only in 6 probands with benign infantile epilepsy. A common insertion mutation, c.649_650insC, was found in 5 families and a novel missense mutation, c.981C>G (I327M), in one. The family history of paroxysmal kinesigenic dyskinesia was more common in probands with PRRT2 mutations than in those without mutations. Our study revealed that PRRT2 mutations are common in Japanese patients with benign infantile epilepsy, especially in patients with a family history of paroxysmal kinesigenic dyskinesia.     

Acute-Onset Ataxia and Transient Cerebellar Diffusion Restriction Associated with a PRRT2 Mutation

PRRT2 gene mutations cause paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions, hemiplegic migraine, and episodic ataxia. A 21-year-old woman reported an episode of dizziness and ataxic gait occurring after swimming. Brain MRI showed a hyperintense cerebellar lesion on diffusion-weighted imaging (DWI) with decreased apparent diffusion coefficient. The clinical course was favorable. Both clinical and MRI abnormalities regressed. Her brother had presented PKD since adulthood. A C.649dupC PRRT2 truncating mutation was identified in both patients. To our knowledge, this is the first case of an acute cerebellar ataxia associated with heterozygous PRRT2 mutation and transient cerebellar hyperintensity on DWI. Among the clinical and genetic heterogeneities of familial paroxysmal disorders, PRRT2 mutation may be considered in patients with episodic cerebellar ataxia and diffusion restriction on neuroimaging.     

Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation,episodic ataxia,and absences

Heterozygous mutations of PRRT2, which encodes proline‐rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS), or familial paroxysmal kinesigenic dystonia (PKD). We report a consanguineous Italian family with BFIS/PKD phenotype that contained 14 living members with 6 affected individuals (four men, ranging in age from 6–44 years). We identified the reported c.649dupC (p.Arg217ProfsX8) mutation of PRRT2 gene that cosegregated with the disease and was not observed in 100 controls of matched ancestry. Four patients with BFIS phenotype were heterozygous for this mutation, including the consanguineous parents of the two affected brothers with more severe phenotypes of BFIS/PKD—mental retardation, episodic ataxia, and absences—who were the only individuals to carry a homozygous c.649dupC mutation. This family provides strong evidence that homozygous PRRT2 mutations give rise to more severe clinical disease of mental retardation, episodic ataxia, and absences, and, thus, enlarges the clinical spectrum related to PRRT2 mutations. Moreover, it suggests an additive effect of double dose of the genetic mutation and underscores the complexity of the phenotypic consequences of mutations in this gene.     

A new case of concurrent existence of PRRT2-associated paroxysmal movement disorders with c.649dup variant and 16p11.2 microdeletion syndrome

BackgroundThe PRRT2 gene located at 16p11.2 encodes proline-rich transmembrane protein 2. In recent reviews, clinical spectrum caused by pathogenic PRRT2 variants is designated as PRRT2-associated paroxysmal movement disorders, which include paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, and infantile convulsions with choreoathetosis, and hemiplegic migraine. The recurrent 16p11.2 microdeletion encompassing PRRT2 has also been reported to cause neurodevelopmental syndrome, associated with autism spectrum disorder. Although PRRT2 variants and 16p11.2 microdeletion cause each disease with the autosomal dominant manner, rare cases with bi-allelic PRRT2 variants or concurrent existence of PRRT2 variants and 16p11.2 microdeletion have been reported to show more severe phenotypes.Case reportA 22-year-old man presents with episodic ataxia, paroxysmal kinesigenic dyskinesia, seizure, intellectual disability and autism spectrum disorder. He also has obesity, hypertension, hyperuricemia, and mild liver dysfunction. Exome sequencing revealed a c.649dup variant in PRRT2 in one allele and a de novo 16p11.2 microdeletion in another allele.ConclusionsOur case showed combined clinical features of PRRT2-associated paroxysmal movement disorders and 16p11.2 microdeletion syndrome. We reviewed previous literatures and discussed phenotypic features of patients who completely lack the PRRT2 protein.     

Peri-ictal EEG in infants with PRRT2-related self-limited infantile epilepsy

Objective

Pathogenic PRRT2 variants cause self-limited (familial) infantile epilepsy (SeLIE), which is responsive to sodium channel blocking antiseizure medications. The interictal EEG is typically normal. We describe a cohort of infants with PRRT2-related SeLIE with striking peri-ictal EEG abnormalities.

Methods

We included all infants diagnosed with PRRT2-related SeLIE during July 2020 to November 2021 at the Royal Children's Hospital, Melbourne. Clinical features and results of aetiologic investigations were collected from electronic medical records. All EEGs were reviewed independently by two epileptologists.

Results

Ten infants presented with focal seizures at a median age of 5 months (range: 3–6 months). Eight had a family history of epilepsy, paroxysmal kinesigenic dyskinesia (PKD) or hemiplegic migraine. Seven of the eight infants with an EEG performed within 24 h of the most recent seizure had epileptiform discharges. Their EEGs showed focal sharp waves, spikes, polyspikes or fast activity independently over the left and right temporo-occipital regions. Conversely, the two infants with last known seizure greater than 24 h prior to their EEG had no epileptiform discharges. Oxcarbazepine was commenced in two infants and was effective. Eight infants were initially treated with levetiracetam, and all were subsequently switched to oxcarbazepine due to ongoing seizures or side effects.

Significance

Posterior polymorphic focal epileptiform discharges on a peri-ictal EEG recording are a feature of PRRT2-related SeLIE. This finding, particularly in the presence of a family history of infantile epilepsy, PKD or hemiplegic migraine, suggests a diagnosis of PRRT2-related SeLIE and has important treatment implications.     

Mutations in PRRT2 are not a common cause of infantile epileptic encephalopathies

Heterozygous mutations in PRRT2 have recently been identified as the major cause of autosomal dominant benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis syndrome (ICCA), and paroxysmal kinesigenic dyskinesia (PKD). Homozygous mutations in PRRT2 have also been reported in two families with intellectual disability (ID) and seizures. Heterozygous mutations in the genes KCNQ2 and SCN2A cause the two other autosomal dominant seizure disorders of infancy: benign familial neonatal epilepsy and benign familial neonatal‐infantile epilepsy. Mutations in KCNQ2 and SCN2A also contribute to severe infantile epileptic encephalopathies (IEEs) in which seizures and intellectual disability co‐occur. We therefore hypothesized that PRRT2 mutations may also underlie cases of IEE. We examined PRRT2 for heterozygous, compound heterozygous or homozygous mutations to determine their frequency in causing epileptic encephalopathies (EEs). Two hundred twenty patients with EEs with onset by 2 years were phenotyped. An assay for the common PRRT2 c.649‐650insC mutation and high resolution‐melt analysis for mutations in the remaining exons of PRRT2 were performed. Neither the common mutation nor any other pathogenic variants in PRRT2 were detected in the 220 patients. Our findings suggest that mutations in PRRT2 are not a common cause of IEEs.     

Girl with a PRRT2 mutation and infantile focal epilepsy with bilateral spikes

This paper documents the case of a female Japanese patient with infantile focal epilepsy, which was different from benign infantile seizures, and a family history of infantile convulsion and paroxysmal choreoathetosis. The patient developed partial seizures (e.g., psychomotor arrest) at age 14 months. At the time of onset, interictal electroencephalography (EEG) showed bilateral parietotemporal spikes, but the results of neurologic examination and brain magnetic resonance imaging were normal. Her seizures were well controlled with carbamazepine, and she had a normal developmental outcome. EEG abnormalities, however, persisted for more than 6 years, and the spikes moved transiently to the occipital area and began to resemble the rolandic spikes recognized in benign childhood epilepsy. Her father had paroxysmal kinesigenic dyskinesia, with an onset age of 6 years, and her youngest sister had typical benign infantile seizures. Genetic analysis demonstrated that all affected members had a heterozygous mutation of c.649_650insC in the proline-rich transmembrane protein-2 (PRRT2) gene. This case indicates that the phenotypic spectrum of infantile seizures or epilepsy with PRRT2-related pathology may be larger than previously expected, and that genetic investigation of the effect of PRRT2 mutations on idiopathic seizures or epilepsy in childhood may help elucidate the pathological backgrounds of benign childhood epilepsy.     

发作性运动诱发性运动障碍一家系临床与遗传学特点

目的探讨家族性发作性运动诱发性运动障碍(paroxysmal kinesigenic dyskinesia,PKD)临床及遗传学特点。方法对1个PKD家系共14名成员进行PRRT2基因检测及调查随访,其中患病2例(1例住院治疗,另1例未治疗),总结分析其临床表现、遗传特点、药物治疗效果及预后。结果该家系2例患者均为男性,患病率14.3%,其中1例不治自愈,1例用卡马西平疗效显著,用拉莫三嗪也有效。该家系为单纯性PKD家系,PRRT2基因检测结果显示该家系中3例存在突变c.797GA(p.266RQ),其中1例无临床症状,符合常染色体显性遗传,伴不全外显,存在遗传早现;该家系合并存在多囊肾家族史。结论单纯家族性PKD抗癫痫药物疗效与突变类型及临床特征有关;治疗方案选择应以临床特点及突变类型为依据。     

PRRT2-related disorders: further PKD and ICCA cases and review of the literature

Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307*, c.388delG/p.Ala130Profs*46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80–100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.     

Lacosamide for children with paroxysmal kinesigenic dyskinesia

ObjectivesThis study was performed to evaluate the efficacy and tolerability of lacosamide (LCM) for paroxysmal kinesigenic dyskinesia (PKD) in children.MethodsWe retrospectively reviewed the medical charts of pediatric PKD patients (aged <16 years) treated with LCM. Data regarding demographic characteristics, proline-rich transmembrane protein 2 (PRRT2) gene variant, clinical features of PKD, dose of LCM, efficacy, and adverse events were recorded.ResultsFour eligible patients (3 males, 1 female) were identified, with an age of onset ranging from 8.3 to 14.7 years. PRRT2 variant was evaluated in three children and a c.649dupC variant was identified in one child with a positive family history. Attacks were bilateral in three children and left-sided in one. Two children had a family history of PKD and one child had a family history of benign infantile epilepsy. Treatment with carbamazepine failed in two children due to drowsiness and auditory disturbance. The initial dose of LCM was 50 mg/day in three children and 100 mg/day in one. All patients were attack-free within a few days. The maintenance dose was mostly similar to the initial dose. No adverse events related to LCM were reported during follow-up.ConclusionsLCM is an effective and well-tolerated treatment for PKD in children, and low-dose treatment may be viable.     

A new family with paroxysmal exercise induced dystonia and migraine: a clinical and genetic study

OBJECTIVE: To characterise the phenotype of a family with paroxysmal exercise induced dystonia (PED) and migraine and establish whether it is linked to the paroxysmal non-kinesigenic dyskinesia (PNKD) locus on chromosome 2q33-35, the familial hemiplegic migraine (FHM) locus on chromosome 19p, or the familial infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome) locus on chromosome 16. METHODS: A family, comprising 30 members, was investigated. Fourteen family members in two generations including three spouses were examined. Haplotypes were reconstructed for all the available family members by typing several microsatellite markers spanning the PNKD, FHM, and ICCA loci. Additionally, the four exons containing the known FHM mutations were sequenced. RESULTS: Of 14 members examined four were definitely affected and one member was affected by history. The transmission pattern in this family was autosomal dominant with reduced penetrance. Mean age of onset in affected members was 12 (range 9-15 years). Male to female ratio was 3:1. Attacks of PED in affected members were predominantly dystonic and lasted between 15 and 30 minutes. They were consistently precipitated by walking but could also occur after other exercise. Generalisation did not occur. Three of the affected members in the family also had migraine without aura. Linkage of the disease to the PNKD, FHM, or ICCA loci was excluded as no common haplotype was shared by all the affected members for each locus. In addition, direct DNA sequential analysis of the FHM gene (CACNL1A4) ruled out all known FHM point mutations. CONCLUSIONS: This family presented with the classic phenotype of PED and is not linked to the PNKD, FHM, or ICCA loci. A new gene, possibly coding for an ion channel, is likely to be the underlying cause of the disease.     

Partial Cosegregation of Familial Hemiplegic Migraine and a Benign Familial Infantile Epileptic Syndrome

: Purpose: We studied a large Dutch-Canadian family, in which two very rare hereditary paroxysmal neurologic disorders, familial hemiplegic migraine (FHM) and a “benign familial infantile epileptic syndrome” concur and partially cosegregate. FHM is a dominantly inherited subtype of migraine with attacks of hemiparesis, linked to chromosome 19p13 in 50% of the families tested. Recently mutations in a brain-specific P/Q-type Ca²⁺ channel α1 subunit gene (CACNLlA4) were identified in families with chromosome 19-linked FHM. The infantile epileptic syndrome resembles to two other dominantly inherited benign epilepsies occurring in the first year of life, benign familial neonatal convulsions (BFNC), assigned to chromosomes 20q13.2 and 8q, and benign infantile familial convulsions (BIFC), as yet unlinked. Methods: Linkage analysis was performed for the known locations of FHM and BFNC. The question whether the two conditions in this family can be caused by a single gene defect was addressed by additional linkage analysis. Results: We excluded linkage of the infantile convulsions to markers on chromosome 20q13.2, Sq, or 19p13. This indicates the existence of a third locus for benign familial convulsions in the first year of life. Linkage of FHM to these markers was not formally excluded but seems very unlikely. Statistical analysis of whether, in this family, both conditions are caused by a single gene defect was inconclusive. Conclusions: We describe a “benign familial infantile epileptic syndrome“ with attacks of FHM at a later age. Further genetic studies in this family may help to unravel the genetic basis of epilepsy or migraine or both.     

The PRRT2 mutation c.649dupC is the so far most frequent cause of benign familial infantile convulsions

PurposeMutations in the PRRT2 gene have been recently described as a cause of paroxysmal kinesigenic dyskinesia, infantile convulsions with choreoathetosis syndrome and, less often, infantile convulsions. We have analysed the frequency of PRRT2 mutations in families with benign familial infantile convulsions without paroxysmal kinesigenic dyskinesia.Methods and resultsDirect sequencing of the coding region identified the PRRT2 mutation c.649dupC in 5/5 families with infantile convulsions. The mutation was present in 23 family members, of which 18 were clinically affected and 2 were obligate carriers. The affected carriers of this mutation presented with different types of epileptic seizures during early childhood but did not develop additional neurological symptoms later in life.ConclusionOur data demonstrate that the PRRT2 mutation c.649dupC is a frequent cause of benign familial infantile convulsions.     

Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions

Familial hemiplegic migraine (FHM) is a rare, severe, autosomal dominant subtype of migraine with aura. Up to 75% of FHM families have a mutation in the P/Q-type calcium channel Ca(v)2.1 subunit CACNA1A gene on chromosome 19p13. Some CACNA1A mutations also may cause epilepsy. Here, we describe novel missense mutations in the ATP1A2 Na(+),K(+)-ATPase pump gene on chromosome 1q23 in two families with FHM. The M731T mutation was found in a family with pure FHM. The R689Q mutation was identified in a family in which FHM and benign familial infantile convulsions partially cosegregate. In this family, all available affected family members with FHM, benign familial infantile convulsions, or both, carry the ATP1A2 mutation. Like FHM linked to 19p13, FHM linked to 1q23 also involves dysfunction of ion transportation and epilepsy is part of its phenotypic spectrum.     

Genetic and phenotypic heterogeneity in sporadic and familial forms of paroxysmal dyskinesia

Paroxysmal dyskinesia (PxD) is a group of movement disorders characterized by recurrent episodes of involuntary movements. Familial paroxysmal kinesigenic dyskinesia (PKD) is caused by PRRT2 mutations, but a distinct etiology has been suggested for sporadic PKD. Here we describe a cohort of patients collected from our movement disorders outpatient clinic in the period 1996–2011. Fifteen patients with sporadic PxD and 23 subjects from three pedigrees with familial PKD were screened for mutations in candidate genes. PRRT2 mutations co-segregated with PKD in two families and occurred in two sporadic cases of PKD. No mutations were detected in patients with non-kinesigenic or exertion-induced dyskinesia, and none in other candidate genes including PNKD1 (MR-1) and SLC2A1 (GLUT1). Thus, PRRT2 mutations also cause sporadic PKD as might be expected given the variable expressivity and reduced penetrance observed in familial PKD. Further genetic heterogeneity is suggested by the absence of candidate gene mutations in both sporadic and familial PKD suggesting a contribution of other genes or non-coding regions.     

New family with paroxysmal exercise-induced dystonia and epilepsy.

To date, there are few reports of paroxysmal exercise-induced dystonia associated with familial epilepsy. We describe a family with 4 affected members spanning 3 generations, suggestive of autosomal-dominant inheritance, who exhibited typical exercise-induced dystonia, different types of epilepsy (absence and primary generalized seizures), developmental delay, and migraine in variable combinations. Linkage of the disease to loci on chromosome 2 (paroxysmal nonkinesigenic dyskinesia) and chromosome 16 (paroxysmal kinesigenic choreoathetosis, infantile convulsions with choreoathetosis) was excluded, suggesting an as yet unidentified underlying genetic basis.