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Paroxysmal kinesigenic choreoathetosis (PKC), characterised by brief attacks of abnormal involuntary movements induced by sudden voluntary movements, is either idiopathic (familial or sporadic) or symptomatic. A total of about 20 families with PKC have been reported, with autosomal dominant inheritance in most of them. No genetic study has been reported in familial PKC up to now.
We report two unrelated families with autosomal dominant PKC, in which we performed linkage analyses with loci involved in other paroxysmal movement disorders: (1) the locus for paroxysmal dystonic choreoathetosis (PDC), also known as paroxysmal nonkinesigenic dyskinesia, on chromosome 2q33–35,1 (2) the locus for AD paroxysmal choreoathetosis/spasticity (CSE), classified as “complicated” PDC, on chromosome 1p,2 and (3) the locus for episodic ataxia/myokymia (EA-1) on chromosome 12p13.3
Family A was Portuguese and family B was French. They contained a total of 10 affected and nine unaffected family members, who were all interviewed and examined by the same physician. There was no family history of epilepsy. In one family, three of the five affected members also had migraine with visual aura. Except for one patient, who had had a parkinsonian resting tremor since the age of 52, neurological examination was normal. The phenotypes of the 10 patients were very homogeneous. Age at onset of PKC attacks ranged from 1.5 to 13 years (median 6.5 years). Attacks occurred five to 20 times daily in nine patients and once a year in the other. Attacks were always triggered by a sudden movement of a lower limb (rising from a sitting position, running) that often occurred in response to an unexpected stimulus after sustained immobility. Embarrassment and stress were precipitating factors. In a few patients, fatigue, cold, or menstruation also favoured attacks. The latency between the triggering factor and dyskinesia was 0–2 seconds. Dyskinesias were usually preceded by a short aura (paraesthesias, n=4; muscular tension, n=5) in the affected hemibody. Duration of attacks was 3 to 40 seconds. Involuntary movements involved one side of the body, but sometimes extended rapidly to the whole body, with preservation of consciousness. During attacks, the intensity of the dyskinesias increased and decreased progressively. In addition to frequent dysarthria (n=7) related to orofacial dyskinesia, breathing problems (n=1) and falls (n=5) sometimes occurred during violent attacks. One patient wore a helmet during early childhood because of frequent falls. Four out of 10 patients were treated with very low doses of carbamazepine (50–200 mg/day), which completely suppressed the attacks . In six patients who were not treated, however, the frequency of the attacks decreased progressively with age, usually between the ages of 18 and 30, and completely disappeared in five of them between the ages of 11 and 37. Three attacks (lasting 5–20 seconds) were recorded by video-EEG in one patient after carbamazepine withdrawal. No EEG abnormalities were found. Neuroimaging, performed in only four patients (two brain CT and two MRI), was normal.
Because of clinical similarities between PKC and some other paroxysmal movement disorders, we hypothesised that PKC may be allelic to them. Indeed, PDC is also characterised by attacks of mixed involuntary movements (dystonic, and often choreoathetotic), that typically begin as hemidystonia but progressively affect all limbs, trunk, and neck muscles, as well as speech, with preservation of consciousness. Attacks are often preceded by an aura and their frequency decreases with age. However, by contrast with PKC, PDC attacks occur at rest, are precipitated by caffeine and alcohol, not by sudden movements, and last for minutes to hours. In CSE, attacks are similar to those in PDC, except that physical exercise is a precipitating factor, and that some patients exhibit constant spastic paraplegia.2 Finally, although EA-1 consists of continuous myokymia and attacks of generalised ataxia, often prevented by acetazolamide, some features are shared with PKC—namely, the frequent kinesigenic origin of the attacks, the presence of a sensory aura, the short duration of the attacks (several seconds to 5 minutes), and the early onset.4 Moreover, an EA-1 family in which attacks of kinesigenic episodic ataxia and PKC occurred separately in some members, and jointly in one, has been reported.4
After isolation of DNA from peripheral blood, a series of microsatellite markers were typed on: (1) chromosome 2q (D2S164)-2cM-D2S173–2cM-D2S163–2cM-D2S377–1cM-D2S126 (the PDC locus is contained in a 7 cM region flanked by D2S164 and D2S126)1; (2) chromosome 1p, with D1S197 (the CSE locus is situated in the 2 cM interval between D1S443 and D1S197)2; (3) chromosome 12p, with the 2 markers (D12S372)-4cM-D12S99–1cM-(D12S93)-7cM-D12S77 (the EA-1 locus maps to the 5 cM interval between D12S372 and D12S93).3Inheritance of PKC was dominant in both families, with two male to male transmissions in one family, excluding X linked and mitochondrial transmission. There were no asymptomatic obligate gene carriers, suggesting complete penetrance. We assumed autosomal dominant inheritance with a gene frequency of 0.0002 and complete clinical penetrance by the age of 17 years. Allele frequencies for a white population were determined according to the genome database. Two point and multipoint lod scores were calculated using the MLINK program of the Fastlink package.5
Results of the two point linkage analysis in both families are shown in the table. All markers tested generated negative lod scores at θ=0.00 except for marker D2S377 in family B. Lod scores below the threshold of −2 were obtained for all candidate regions except for the PDC locus in family B. Multipoint linkage analyses excluded the following intervals including candidate loci in families A and B respectively: 26.5 and 25 cM on chromosome 2q including the PDC locus; 26.5 and 30 cM on chromosome 12p, including the interval containing the voltage dependent potassium channel (KCNA1) gene responsible for EA-1. In conclusion, despite some clinical similarities, AD PKC is genetically distinct from both forms of PDC and from EA-1.
We thank Dr Alexandra Dürr for helpful comments and Giovanni Stevanin, Christiane Penet, Agnès Camuzat, Yolaine Pothin, and Jacky Bou for technical support. We thank both families for their participation in this study, Dr P. Chaine who referred one of the families, and Dr Merle Ruberg for critical reading of the manuscript.