A Gardiner

PRRT2 gene mutations From paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine

ABSTRACT Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.

Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine

PRRT2 is the gene recently associated with paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy, and choreoathetosis infantile convulsions. We report four family members with PRRT2 mutations who had heterogeneous paroxysmal disorders. The index patient had transient infantile paroxysmal torticollis, then benign infantile epilepsy that responded to carbamazepine. The index patient’s father had PKD and migraine with aphasia, and his two brothers had hemiplegic migraine with onset in childhood. All four family members had the same PRRT2 c.649dupC mutation. We conclude that heterogeneous paroxysmal disorders are associated with PRRT2 mutations and include paroxysmal torticollis and hemiplegic migraine. We propose that PRRT2 is a new gene for hemiplegic migraine.

The clinical and genetic heterogeneity of paroxysmal dyskinesias

The contributions of different genes to inherited paroxysmal movement disorders are incompletely understood. Gardiner et al. identify mutations in 47% of 145 individuals with paroxysmal dyskinesias, with PRRT2 mutations in 35%, SLC2A1 in 10% and PNKD in 2%. New mutations expand the associated phenotypes and implicate overlapping mechanisms.

Rhabdomyolysis: a genetic perspective

Rhabdomyolysis (RM) is a clinical emergency characterized by fulminant skeletal muscle damage and release of intracellular muscle components into the blood stream leading to myoglobinuria and, in severe cases, acute renal failure. Apart from trauma, a wide range of causes have been reported including drug abuse and infections. Underlying genetic disorders are also a cause of RM and can often pose a diagnostic challenge, considering their marked heterogeneity and comparative rarity.In this paper we review the range of rare genetic defects known to be associated with RM. Each gene has been reviewed for the following: clinical phenotype, typical triggers for RM and recommended diagnostic approach. The purpose of this review is to highlight the most important features associated with specific genetic defects in order to aid the diagnosis of patients presenting with hereditary causes of recurrent RM.Abstract in PortugueseA rabdomiólise (RM) é um evento agudo e grave, caracterizado por danos do músculo esquelético com a liberação, em grande quantidade, de componentes intracelulares para a corrente sanguínea. Uma vasta gama de causas tem sido relatada, incluindo trauma, abuso de drogas e infecções. Doenças hereditárias também podem causar RM, mas muitas vezes representam um desafio diagnóstico, considerando a sua heterogeneidade e raridade. Por fim, diversas doenças neuromusculares costumam estar associadas com níveis de CK cronicamente elevados, dificultando a identificação correta dos episódios de RM.Nesse artigo, revisamos os diversos defeitos genéticos associados à RM. Cada gene foi revisado abrangendo os seguintes: fenótipo clínico, gatilhos para RM e abordagem diagnóstica. O objetivo desta revisão é destacar as características mais importantes associados a defeitos genéticos específicos, a fim de auxiliar o diagnóstico de pacientes com causas hereditárias de RM recorrente.

Clinical features of childhood‐onset paroxysmal kinesigenic dyskinesia with PRRT2 gene mutations

To define better the phenotype and genotype of familial and sporadic cases of paroxysmal kinesigenic dyskinesia (PKD) caused by mutations in the PRRT2 gene presenting in the paediatric age group.

Benefit of carbamazepine in a patient with hemiplegic migraine associated with PRRT2 mutation

SIR–Mutations in the PRRT2 gene have been proven to be a major cause of paroxysmal neurological disorders, particularly paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy, and infantile convulsions and choreoathetosis (ICCA). Examination of the spectrum of neurological disorders associated with PRRT2 mutations has shown that 1–4% of hemiplegic migraine patients have PRRT2 mutations. PRRT2 mutations can be associated with pleiotropy, and we have previously described a family with heterogeneous paroxysmal disorders with PKD, paroxysmal torticollis, infantile epilepsy, and hemiplegic migraine occurring in members with the common PRRT2 mutation, c.649dupC. Here we describe a previously undescribed child from this family with hemiplegic migraine and his beneficial response to carbamazepine. The patient is a 9-year-old male, whose father has hemiplegic migraine, as previously described. The patient had no history of epilepsy but does have dyslexia. His first hemiplegic migraine episode occurred during Christmas 2009 and he has had three to four episodes per year, totalling 10 episodes over the following 2 years and 7 months. All episodes were stereotypical, and the family have identified chocolate and excessive physical exertion as exacerbating features. His paroxysmal events are always hemiplegic migraine and affect the left side more than the right. The onset of the event is left-foot numbness described as being like a ‘dental anaesthetic’ that then migrates all over the unilateral side of his body. By the time the numbness migrates to his trunk and arm, he begins to feel nauseous and vomits, and then the numbness migrates to his face and sometimes his tongue. This sensory migration can take as long as 2 hours, but is usually much shorter. Once the sensory phenomena are fully evolved, he will start to have a headache which is bilateral, bitemporal, and throbbing, and is associated with photophobia and phonophobia but no visual phenomena. During the onset of the headache, he will evolve ipsilateral weakness, manifest by dragging of the ipsilateral foot and he loses strength in his ipsilateral hand. He will look white during an episode, will need to lie down, and sleep reduces the duration of an attack. He will remain ‘groggy’ and have a headache for between 12 hours and 2 days. He finds the attacks scary and upsetting, and was motivated to try a prophylactic medication. He was confirmed to have the familial PRRT2 mutation, c.649dupC. Paroxysmal kinesigenic dyskinesia and benign infantile epilepsy are typically highly responsive to low-dose carbamazepine, and his cousin with the same PRRT2 mutation had therapeutic benefit from carbamazepine for the infantile epilepsy. He was therefore started on 50mg twice a day increasing to 100mg twice a day after 2 weeks (4mg/kg/d). He has been taking the medication for 1 year and 7 months with diligent compliance, and has not had an attack during this time. This is the first report to describe a therapeutic benefit of carbamazepine in hemiplegic migraine associated with mutations in PRRT2. Certain antiepileptic drugs can be useful in patients with migraine, although the evidence for carbamazepine is lacking, as discussed in a recent systematic review. Although prolonged follow-up of this case and further cases are required to strengthen this finding, we believe this case provides a scientific rationale for the widespread testing of the PRRT2 gene and the use of antiepileptic drugs in hemiplegic migraine. Carbamazepine should be considered in patients with hemiplegic migraine with proven PRRT2 mutations, or in patients with hemiplegic migraine with a personal or family history of infantile epilepsy or PKD.

G.P.22

Recurrent rhabdomyolysis complicates a number of inherited muscle and metabolic disorders and represents a serious, potentially life-threatening condition which frequently requires critical care. Identification of the underlying genetic cause has traditionally relied upon detailed history and examination findings which subsequently guide the investigative work-up. However, in many cases the causative molecular defect remains undetermined. This study aims to investigate whether utilising next-generation sequencing (NGS) technology early in the diagnostic pathway might offer a rapid, cost-effective tool for the diagnosis of patients with recurrent attacks of rhabdomyolysis when a genetic aetiology is suspected. We have designed a “rhabdomyolysis gene panel” comprised of 48 genes known or predicted to cause rhabdomyolysis using NGS technology. Over 200 patients have been recruited. In addition, array CGH and whole exome sequencing may be used. A pilot study of 53 patients with a panel of sequenced 35 rhabdomyolysis genes using an amplicon based sequencing panel on an Illumina MiSeq was performed. 52 of the first 53 first evaluated patients have a variant in at least 1 gene. 49 patients have heterozygous variants in at least two different genes. We identified 15 cases out of 52 with probable pathogenic mutations using this approach. The pilot study showed that the rhabdomyolysis genetic panel is a potentially useful way to identify genetic alterations in patients with rhabdomyolysis. The high number of symptomatic patients with mutations identified in more than one gene associated with rhabdomyolysis suggests that gene–gene interaction(s) may play an important role. We are currently preparing a new extended panel of 48 genes.

Paroxysmal Kinesigenic Dyskinesia May Be Misdiagnosed in Co‐occurring Gilles de la Tourette Syndrome

Tics, particularly at a young age, may be difficult to distinguish from other abrupt and brief movements, such as myoclonus and chorea. Their suppressibility and association with premonitory urges serve as useful diagnostic clues. However, not all individuals with tics or Gilles de la Tourette syndrome (GTS) are able to exert conscious inhibitory tic control and not all tics are preceded by premonitory sensations. Furthermore, hyperkinesias in other paroxysmal movement disorders, such as in paroxysmal kinesigenic dyskinesia (PKD), a condition associated with several episodic neurologic disorders and for which a causative gene has been recently described,1 are commonly preceded by sensory phenomena, such as numbness of the affected body sites or epigastric area.1–3 Moreover, the presence of dystonic tics, which differ from clonic tics in phenomenology and duration, might further contribute to diagnostic confusion.4–7 On the other hand, not all sudden and repetitive movements in GTS are tics and more than one hyperkinesia may co-occur in a single patient. Their proper recognition bears significant prognostic and therapeutic implications. Here, we present the case of an adolescent with a classic history of GTS, who was referred to our clinic upon developing longer-lasting and, on occasion, disabling hyperkinetic episodes at a later age misdiagnosed as complex tics.

GYG1 causing progressive limb girdle myopathy with onset during teenage years (polyglucosan body myopathy 2)

An 84-year-old lady with slowly progressive limb and axial muscle weakness with onset in her teens was referred for genetic investigations. Targeted next generation sequencing (NGS) revealed a homozygous mutation GYG1 in exon5:c.487delG:p.D163fs, confirming the diagnosis of Polyglucosan Body Myopathy 2 (PGBM2). Retrospective review of muscle pathology revealed a florid vacuolar myopathy with histochemical and ultrastructural features consistent with a polyglucosan storage myopathy. No cardiac symptoms were reported. Our case is consistent with the core phenotype of GYG1-related PGBM2 apart from an early onset of weakness without cardiac symptoms. The presence of α-amylase resistant PAS-positive material in skeletal muscle biopsy of patients with slowly progressive limb girdle muscle weakness should prompt the search for GYG1 mutations. This case highlights the combined role of muscle pathology and NGS in the molecular resolution of patients with undiagnosed neuromuscular conditions.

P40 Episodic ataxia: screening candidate genes and genetic analysis of families

involved in the care of each patient, with a particular focus on response and tolerability to recommended therapy. Results: Our results support previous reported findings in terms of clinical features as well as the poor response to pyridostigmine. We were interested to note that although treatment with fluoxetine was beneficial, a number of our patients suffered significant adverse effects that hindered optimum dose titration or led to treatment cessation. Patients receiving quinidine seem to tolerate this treatment better. Conclusion: Slow channel CMS are a rare category of CMS with distinct clinical and neurophysiological features. Establishing the underlying genetic diagnosis is essential in selecting the correct treatment. In contrast to other published series, our study suggests that fluoxetine can be associated with significant side effects thus reducing treatment effectiveness.