Dear Sirs,

Paroxysmal kinesigenic dyskinesia (PKD) is characterized by paroxysms of dystonic, choreic, ballistic, or athetoid movements. Attacks usually commence during childhood or early adulthood, typically lasting a few seconds to a few minutes, and they can occur up to 100 times daily. Attacks usually respond to low-dose carbamazepine [1]. Mutations in PRRT2 have been identified as a cause of autosomal dominant PKD [2] and replicated in other studies [3–7]. It remains important to report the clinical characteristics of genetically defined families in order to fully describe the clinical syndrome, including the presence of additional associated features beyond the movement disorder.

In a large Caucasian family with PKD (Fig. 1), a detailed neurological history and clinical examination were undertaken. Sanger sequencing of PRRT2 was performed. Three individuals have PKD alone, and three individuals have PKD and infantile convulsions (IC). Two individuals had isolated IC, whilst two other individuals had at least one adolescent seizure but no movement disorder. The age of onset for the movement disorder ranged between 3 and 30 years. Infantile convulsions occurred between the age of 6 and 12 months. In all cases, PKD attacks were choreic or dystonic in nature, lasting less than a minute, and responded well to carbamazepine. Attacks were provoked by sudden movements in all, with stress in II:10 and III:9. Four individuals were treated with low-dose carbamazepine and/or phenytoin for PKD/IC, which abolished symptoms of the movement disorder. Neurological examination was normal (Table 1).

Fig. 1
figure 1

Pedigree of Family 1. All individuals with symptoms of PKD, PKD and IC, or isolated IC were found to have a frameshift mutation in PRRT2 (c.649_650InsC p.P217fsX7) indicated by a plus symbol; individuals found not to have the mutation are indicated by a minus symbol. Deceased members are marked with a diagonal bar. The phenotype key indicates manifestation of each individual. Individuals who were unavailable for genetic testing are marked NT

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Sanger sequencing of PRRT2 revealed the recognized pathogenic (c.649_650InsC p.P217fsX7) heterozygous mutation [2–7] in all eight clinically affected individuals as well as in three of the seven clinically unaffected individuals (Fig. 1). PRRT2 mutations are unlikely to be the cause of adolescent-onset seizures in this family, as individual III:12 did not carry the mutation. Non-penetrance was observed in three individuals. Migraine with aura, as classified using the International Headache Society diagnostic criteria [8], co-segregated in all but one individual with the p.P217fsX7 mutation, including in three individuals who do not have symptoms of IC/PKD, but was not observed in individuals who did not carry the p.P217fsX7 mutation. Visual aura (positive visual phenomena) was most frequently reported, other types of aura including expressive dysphasia, alexia and alien hand syndrome were also described. Migraine frequency ranged from twice a year to three times a month. Reported triggers included stress, sleep deprivation and exercise. Two individuals were treated with low-dose propranolol for several months, which reduced the frequency and severity of migraine attacks, but did not improve symptoms of the movement disorder.

Table 1 Clinical descriptions and genotyping results for family members
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Previously reported linkage studies for this kindred (family 3, Spacey et al.) [9] generated LOD scores that were not significant for the analysis of PKD alone or PKD ± IC. We repeated linkage analysis using Merlin [10], assuming an autosomal dominant mode of inheritance with 80 % penetrance. LOD scores for the PRRT2 mutation and PKD/IC and the PRRT2 mutation and migraine with aura are 1.65 and 2.7, respectively. Several kindreds with hemiplegic migraine and PRRT2 mutations have recently been reported [11]. Migraine (with and without aura) is over-represented in individuals with PRRT2 mutations and clustering of migraine has been identified in small kindred’s harboring PRRT2 mutations [12] In this large family, migraine with aura segregates in a Mendelian fashion in nine of 10 individuals with the PRRT2 mutation, the remaining individual is still in adolescence and could still go onto develop migraine. Furthermore, it highlights that in some families, migraine with aura may be the predominant phenotype associated with PRRT2 mutations, which is important to bear in mind when determining whether a patient with PKD/IC has a positive family history, to enable appropriate genetic counseling and testing. The association of migraine with PRRT2 mutations raises the question of whether genetic variation in PRRT2 might play a role in susceptibility to ‘common’ migraine with aura.