Familial paroxysmal nonkinesigenic dyskinesia (PNKD), first described in 1940 by Mount and Reback, was originally designated familial paroxysmal choreoathetosis [10]. In PNKD, involuntary movements comprising any combination of chorea, athetosis, and ballism occur spontaneously in recurrent episodes without a trigger such as sudden movement or physical exertion. The dyskinetic paroxysms involve the limbs, face, and trunk. Consciousness is preserved. Some patients report premonitory sensations, mainly focal limb paresthesia. Caffeine, alcohol, sleep deprivation, and emotional stress may reduce the threshold of these paroxysms. Duration of attacks is longer than in PKD and ranges from minutes to hours. Interepisodic neurological examination does not reveal any abnormalities. Most cases are familial following an autosomal dominant pattern of inheritance. While all types of PNKD share these characteristics in common, they display clinical variety with respect to age of onset, precipitating factors, paroxysmal symptoms, and response to medication as well as genetic heterogeneity.

In 1967 Kertesz was the first to describe a condition then termed paroxysmal kinesigenic choreoathetosis [18]. Later designated paroxysmal kinesigenic dyskinesia (PKD), and alternatively called episodic kinesigenic dyskinesia (EKD), this subtype has now been recognized as the most common form of PxDs. Attacks consist of choreatic, ballistic, and mixed dystonic symptoms with unilateral, bilateral, or alternating appearance. Involvement of the face may result in dysarthria or anarthria. However, consciousness is preserved, and the attacks are not painful. Mean age at onset is 10 years, with a range from 1 to 40 years [9]. PKD episodes are precipitated by sudden movements like initiation of standing, walking, or running. Attacks are short, with duration ranging from a few seconds to a minute. An aura is reported by a subset of patients. Aura symptoms comprise paresthesias, numbness, tingling sensations, or a feeling of muscular tension in the limb that immediately afterward would display the dyskinesia. Some patients learn to prevent the episode by slowing down their movement. Attacks recur frequently with most patients having up to 20 attacks daily, up to 100 episodes per day in puberty, and marked decrease in frequency after age 20 years.

In a large series of 121 patients, about two thirds had a family history of PKD [19]. Sporadic occurrence is observed more frequently in males than in females [19, 20].

Neurological examination is normal in primary PKD. Neuroimaging and laboratory studies may help in ruling out secondary PKD caused by multiple sclerosis, cerebral vascular disorder, or traumatic brain injury.

Heterozygous PRRT2 changes are found with high prevalence in familial PKD, BFIS, and ICCA and somewhat less often in sporadic patients. The detection of PRRT2 mutations in episodic neurological disorders prompted molecular analysis of this gene in similar conditions. This resulted in a remarkable unfolding of the clinical phenotypes of PRRT2 mutations, which were discovered in patients with migraine, hemiplegic migraine, episodic ataxia, febrile seizures, sporadic infantile convulsions, and paroxysmal torticollis – as sole presentation or in various combinations [36–47].

Homozygous PRRT2 mutations were detected in two families with more severe clinical features comprising intellectual disability, episodic ataxia, and infantile seizures [48, 49].

However, PRRT2 mutations are not a common cause of infantile epileptic encephalopathies (IEE). In a cohort of 220 patients with IEE, neither the frequent c.649-650insC mutation nor any other pathogenic variants in PRRT2 were found [50].

The function of the proline-rich transmembrane protein 2 is hardly understood at present. Evidence for an interaction with synaptosomal-associated protein 25 (SNAP-25) indicates an involvement in the release of neurotransmitters from synaptic vesicles at the presynaptic membrane [51]. An imbalance in the release of excitatory and inhibitory transmitters may result in episodic neurological features including seizures and PKD. Further research is needed to clarify the function of PRRT2 in detail.

While there is now evidence that mutations of the PRRT2 gene are the major cause of PKD, genetic heterogeneity in this most frequent subtype of PxDs is suggested by several studies [52, 53].

The term transient paroxysmal dystonia of infancy designates a rare condition observed in infants aged 1–7 months with brief frequently recurring episodes of opisthotonus or symmetrical or asymmetrical dyskinesia of the upper limbs [54–56]. Frequency of episodes usually decreases, and complete resolution of paroxysms is observed over the first years of life. Development is unimpaired. Paroxysms may be precipitated by certain movements or positions. Thus, this condition may present an infantile variant of PKD. The cause is unknown, and PRRT2 mutations are not yet on record.

Benign paroxysmal torticollis of infancy is characterized by recurrent episodes of cervical dystonia. A recent report concerned 10 patients and reviewed 103 cases described in the literature [57]. Onset is during the 1st year of life. Paroxysmal tilting of the head may be accompanied by vomiting, signs of discomfort, pallor, ataxia, limb dystonia, tortipelvis, and gaze abnormalities. Torticollis may concern the same side or alternate sides with successive episodes. Attacks last from several hours to a few days and typically persist during sleep. Paroxysms usually dissolve by age 3–5 years. Search for triggering factors was largely negative. Many patients show early gross and fine motor delay of mild to moderate severity, which may persist in a few cases. A family history of migraine is frequent, and there is obviously a relationship to benign paroxysmal vertigo as well as to paroxysmal dystonia of infancy [57, 58]. In a few patients with benign paroxysmal torticollis mutations of the CACNA1A gene encoding for a neuronal calcium channel were detected [59]. In addition, a PRRT2 mutation was found in a patient with transient infantile paroxysmal torticollis [41]. Further studies will clarify whether CACNA1A and PRRT2 mutations significantly account for infantile paroxysmal torticollis or paroxysmal dystonia.

The term paroxysmal exercise-induced dyskinesia (PED) designates a rare subtype of PxDs with phenotypical and genetic heterogeneity. In PED, episodes of dyskinesia are by definition triggered by prolonged exercise. Additional precipitating factors were reported in some patients comprising passive movements, exposure to cold, or electric nerve stimulation [60, 61].

Duration of episodes ranges from a few minutes to several hours, largely shorter than in PNKD, but clearly longer than in PKD. Frequency of episodes depends on the extent of sustained physical exercise and the individual threshold for a PED. A compilation of reports of approximately nine families and 20 sporadic patients with PED was provided by Suls et al. [62].

PED may constitute the only clinical symptom without any accompanying clinical features between the attacks [61]. On the other hand, PED may occur together with epilepsy, as reported in several patients and families [60, 63, 64]. PED was observed in association with rolandic epilepsy and writer’s cramp (RE-PED-WC, OMIM %608105) [65] and with migraine [66]. Moreover, PED may be embedded in a more complex chronic neurological condition. PED was reported as a presenting symptom of young-onset Parkinson’s disease [67, 68]. The genes associated with these disorders are not yet identified.

A continuous maintenance of glucose provides the main energy supply for the mammalian brain. Transfer of hydrophilic glucose across the lipophilic blood-brain barrier is facilitated by the glucose transport protein type 1 (GLUT1). Heterozygous mutations of the SLC2A1 gene encoding GLUT1 impair glucose transport into the brain. Most reported mutations occurred de novo; in familial cases, the disorder is inherited following an autosomal dominant trait. The classic phenotype was designated GLUT1 deficiency syndrome (GLUT1-DS, OMIM #606777) and comprises marked motor and mental developmental delay, epilepsy with onset in the 1st year of life, deceleration of head growth resulting in secondary microcephaly, and a mixed movement disorder with spasticity, dystonia, and ataxia. Lowered glucose levels in CSF (hypoglycorrhachia) and a reduced ratio of the glucose concentrations in CSF and serum are the clinical laboratory hallmarks. Therapy with ketogenic diet provides ketone bodies as alternative energy source for the brain and results in marked improvement of seizures and movement disorder. The effect on cognitive impairment is less impressive.

Marked variability of the clinical phenotype of GLUT1-DS has been recognized over the last years. A carbohydrate-responsive phenotype with clinical features aggravated by fasting and improving after carbohydrate intake and movement disorders such as intermittent ataxia with mild learning difficulties or predominant dystonia, but without epilepsy, were observed [72, 73]. In a study of 57 patients with GLUT1-DS, nonepileptic paroxysmal events were found in 28 % of cases. These attacks included episodes of ataxia, parkinsonian features, weakness, and nonkinesigenic dyskinesias [74].

The present expansion of the phenotypic spectrum of GLUT1-DS includes recognition of familial and sporadic PED caused by SLC2A1 mutations. Whereas a subset of patients displayed PED as the sole neurological feature or showed just mild clumsiness or dysdiadochokinesis as interepisodic findings, many patients had additional epilepsy or cognitive impairment (ranging from learning difficulties to moderate intellectual disability) or both (DYT18, OMIM #612126) [62, 69, 70]. Attacks may present with choreoathetotic movements or stiffening and cramps. In our experience, many patients with GLUT1-DS are affected by PED triggered by walking or running, but not all patients complain spontaneously about this symptom, as they learned to alleviate the dyskinesias by taking a rest or eating sweets. Apart from sustained exertion, precipitating factors include stress, fasting, anxiety, and sleep deprivation. Duration of attacks ranges from 5 min to several hours, but most PED last for about 30 min. Frequency ranges from several times a day to occasional episodes over a year [9, 62]. Ketogenic diet proved effective in many patients, if they adhere to the diet. Some patients rely on eating sweets or sugar to ease the paroxysms. Good response of PED to medication with acetazolamide was observed in a single patient with GLUT1-DS [75].