Pure PxDs (normal interepisodic findings)
Paroxysmal nonkinesigenic dyskinesia (PNKD)
Onset in early childhood
Precipitation by caffeine, alcohol
Duration of attacks 10 min to few hrs
Paroxysmal nonkinesigenic dyskinesia and generalized epilepsy (GEPD)
Onset in early childhood
One family reported
Paroxysmal nonkinesigenic dyskinesia
PNKD affecting hands and feet
One family reported
Paroxysmal kinesigenic dyskinesia (PKD)
Onset age 6–15 yrs
Allelism with BFIS, ICCA, hemiplegic migraine, others. Genetic heterogeneity
Sudden movements trigger attacks
Duration of attacks seconds to 1 min
Response to CPZ, PHT
Paroxysmal exercise-induced dyskinesia (PED)
PED without epilepsy or learning difficulties
DYT18, mild variant of GLUT1-DS
Rolandic epilepsy with PED and writer’s cramp (RE-PED-WC)
Rolandic seizures and PED peaking in childhood, writer’s cramp persisting.
One family reported. Similarity with ICCA
Infantile paroxysmal dyskinesia
Transient paroxysmal dystonia of infancy
Onset in first months of life
Infantile variant of PKD?
Opisthotonus, (a)symmetrical dyskinesia of arms, cessation within first years of life, normal development
Benign paroxysmal torticollis of infancy
Onset in first year of life
CACNA1A or PRRT2 mutations reported in few cases
Paroxysmal tilting of head, vomiting, duration hours to days, persisting during sleep, cessation by 3–5 years of age
Family history of migraine
Complicated PxDs (embedded in chronic and complex neurological conditions)
Glucose transport protein type 1 deficiency syndrome (GLUT1-DS)
Wide phenotypic variability from infantile epileptic encephalopathy to adult-onset absence seizures
Reduced CSF glucose level, reduced CSF/blood glucose ratio
PED in many patients
Paroxysmal exercise induced (PED) with or without epilepsy and/or hemolytic anemia
PED with or without epilepsy, learning difficulties
DYT18, part of GLUT1-DS
Paroxysmal choreoathetosis and progressive spastic paraplegia
PKD/PED, onset in childhood
DYT9, part of GLUT1-DS
Alternating hemiplegia of childhood (AHC)
Onset before age 18 mo
Phenotypic spectrum with RDP (DYT12)
Paroxysmal hemidystonia, hemiplegia triggered by emotional, physical stress
Baseline DD/ID, ataxia, dystonia
Monocarboxylate transporter 8 (MCT8) deficiency, Allan-Herndon-Dudley syndrome
Severe intellectual disability
Increased serum triiodothyronine (FT3)
Hypotonia, later spasticity, ataxia
Elongated face, bitemporal narrowing
PKD in some patients, triggered by passive movements
Paroxysmal hypnogenic dyskinesia (PHD), delineated as a further subtype in former classifications  and characterized by attacks of dyskinesia occurring primarily during sleep, is now generally recognized as autosomal dominant nocturnal frontal lobe epilepsy.
Paroxysmal Dyskinesia with Normal Interepisodic Findings (Pure PxDs)
Paroxysmal Nonkinesigenic Dyskinesia (PNKD)
Familial paroxysmal nonkinesigenic dyskinesia (PNKD), first described in 1940 by Mount and Reback, was originally designated familial paroxysmal choreoathetosis . 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.
Genetics of PNKD
As early as 1996, a first PNKD gene had been mapped to the long arm of chromosome 2. Almost 20 years later, the gene was identified, when in 2004 two independent research groups discovered heterozygous mutations in the myofibrillogenesis regulator gene (MR1) in several families with PNKD [11, 12]. Penetrance is reduced, as single family members carried a mutation but were free of PNKD.
The MR1 (alternatively designated PNKD) gene on chromosome 2q35 contains 12 exons and encodes for a protein with three isoforms (MR1L, MR1M, and MR1S) with different cellular distribution and presumably distinct biological functions. The CNS-specific isoform MR1L consists of 385 amino acids and is localized mainly on the cell membrane. However, details of its function are not yet known [11, 12]. Studies of the subcellular localization of both wild-type and mutant MR1 isoforms pointed to a novel disease mechanism involving the mitochondrial targeting sequence . Investigations of the stability, cellular localization, and enzymatic activity of the PNKD protein in cultured cells and transgenic animals indicated that MR1 mutations disrupt protein processing in vivo resulting in an impairment of cellular redox status due to reduced glutathione levels .
Subsequently MR1 mutations were confirmed in further kindreds with PNKD. A large study included 49 patients with PNKD from eight families carrying MR1 mutations and compared them with 22 patients from six kindreds with clinical diagnosis of PKND but without MR1 mutations . In kindreds with MR1 mutations, penetrance was calculated as 98 %. In patients with MR1 mutations, onset of attacks was in infancy or early childhood, attacks were precipitated by consumption of either alcohol or caffeine, and PNKD showed positive response to benzodiazepines or sleep. In contrast, patients with PNKD who did not carry an MR1 mutation showed a broader variation in their age of onset, triggering factors, paroxysmal features, and response to medication .
To date, a total of 73 patients from 13 families with MR1 mutations have been reported (reviewed in ). In a small number of patients, PxDs were triggered by prolonged exercise, thus linking MR1 mutations with PED.
In a large kindred with 16 individuals (10 males, 6 females) who were affected by PNKD (n = 7), generalized epileptic seizures (absence, generalized tonic-clonic) (n = 4), or both (n = 5), the locus was mapped to chromosome 10q22 (generalized epilepsy and paroxysmal dyskinesia, GEPD, OMIM #609446). The region identified by linkage analysis contained two genes encoding ion channels, and a missense mutation was detected in one of them, the KCNMA1 gene. This gene encodes for the pore-forming α-subunit of the BK channel, a calcium-sensitive potassium channel . To date, no further patients with this disorder were reported.
Autosomal dominantly inherited PNKD was observed in a Canadian family with 10 affected members (8 females, 2 males) over three generations . PNKD involved the hands and feet symmetrically, with a duration ranging between 2 and 10 min. The attacks were not triggered by movement, exercise, alcohol, caffeine, or excitement. Onset was variable, ranging from 1 to 77 years. Genetic analysis of the MR1 gene was normal in these patients. A locus was identified on chromosome 2q31  and termed PNKD2 (OMIM %611147), although its report dated slightly later than the discovery of KCNMA1-associated PNKD.
PRRT2 and SLC2A1
Few patients with mutations of the PRRT2 or the SLC2A1 gene experience PNKD. They are discussed in more details below.
Paroxysmal Kinesigenic Dyskinesia (PKD)
In 1967 Kertesz was the first to describe a condition then termed paroxysmal kinesigenic choreoathetosis . 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 . 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 . 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.
Genetics of PKD
The combination of familial PKD with benign familial infantile convulsions (BFIS) in the same family or even the same patient had been recognized for a long time . Linkage studies in kindreds with the infantile convulsions and choreoathetosis (ICCA) syndrome and in families with PKD mapped the locus for both disorders to the pericentric region of chromosome 16 [22–24]. Thus, allelism of these conditions was suggested. Further studies narrowed down the critical region for PKD/ICCA. However, conventional genetic methods including linkage and haplotype analysis as well as Sanger sequencing of more than 150 genes located around the critical region in chromosome 16 were not able to identify the associated gene . Only with the advent of whole-exome sequencing it was possible to demonstrate heterozygous mutations in PRRT2 as a cause of PKD [26–29]. The PRRT2 gene consists of four exons and encodes the proline-rich transmembrane protein 2. This protein comprises 340 amino acids and two putative transmembrane domains. Numerous reports subsequently confirmed that PRRT2 mutations are the major cause of both, PKD and BFIS [30–35]. Most of these mutations are truncating and are predicted to result in haploinsufficiency. A recent review analyzed clinical features of 374 patients with PRRT2 mutations reported in the literature .
Phenotypic Spectrum of PRRT2-Related Disorders
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 .
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 . 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.
Paroxysmal Dystonia of Infancy
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
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 . 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 . In addition, a PRRT2 mutation was found in a patient with transient infantile paroxysmal torticollis . Further studies will clarify whether CACNA1A and PRRT2 mutations significantly account for infantile paroxysmal torticollis or paroxysmal dystonia.
Paroxysmal Exercise-Induced Dyskinesia (PED)
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. .
PED may constitute the only clinical symptom without any accompanying clinical features between the attacks . 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)  and with migraine . 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.
Genetics of PED
At present, mutations in the SLC2A1 gene encoding for glucose transport protein type 1 (GLUT1) are considered the major cause of PED in both sporadic patients and affected families (DYT18, OMIM #612126) [62, 69, 70]. PED has been recognized to be part of the phenotypic spectrum of GLUT1 deficiency syndrome (GLUT1-DS) and in fact had been mentioned in this context earlier . Most patients with PED due to SLC2A1 mutations present with complex interepisodic neurological features. A recent review of 41 mostly sporadic patients with SLC2A1-related PxDs attributed exercise as precipitating factor in 95.2 % and reported concomitant disturbances in 65.8 % . Therefore, this condition is addressed in more detail in the next chapter. Possibly, particularly the mono- or oligosymptomatic GLUT1-DS patients with PED as the prominent feature will go undiagnosed in many cases.
Paroxysmal Dyskinesia Embedded in Chronic Neurological Conditions (Complicated PxDs)
PxDs are occasionally incorporated in a chronic and complex neurological disease. Only for a few of these conditions detailed phenotypic description and elucidation of the genetic basis has been achieved to date.
Glucose Transport Protein Type 1 Deficiency Syndrome (GLUT1-DS)
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 .
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 .