40040ournal ofNeurology, Neurosurgery, and Psychiatry 1995;59:400-405

Hereditary myokymia and paroxysmal J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.4.400 on 1 October 1995. Downloaded from linked to chromosome 12 is responsive to acetazolamide

Wiebe Jan Lubbers, Ewout R P Brunt, Hans Scheffer, Mike Litt, Rein Stulp, David L Browne, Tiemen W van Weerden

Abstract additional reports of four other families.' 6-9 In A sixth family with autosomal domi- hereditary myokymia and paroxysmal ataxia, nantly inherited myokymia and paroxys- patients experience short attacks, lasting up to mal ataxia is described. The syndrome in 15 minutes, which consist of generalised this family is linked to the recently dis- ataxia, slowing of movements, and variably covered locus for inherited myokymia pronounced trembling or shaking. Kine- and paroxysmal ataxia on the human sigenic provocation, often by an axial move- chromosome 12p, and a missense muta- ment after a period of rest, and a short sensory tion is shown in the KCNA1 gene. The warning are common. True vertigo and attacks of ataxia in this family compare nystagmus are absent, both during and well with those of previously described between attacks. families and similarly are precipitated by The myokymia or ranges kinesigenic stimuli, exertion, and startle. from minute movements found in relaxed Responsiveness of these attacks to low unsupported fingers to obvious stiffening of dose acetazolamide is confirmed, but the hands and feet. Sometimes EMG is some loss of efficacy occurs with pro- needed for its detection.8 In hereditary longed treatment, and side effects are myokymia and paroxysmal ataxia, myokymia notable. Although not all affected family has been shown to be of multifocal peripheral members showed myokymia on clinical nerve origin, possibly caused by spontaneous examination, electromyography invari- and prolonged axonal depolarisation.8 '° ably showed myokymic discharges, in one Phenytoin is variably effective in the preven- 68 patient only after a short provocation tion of ataxia.' A favourable response to with regional ischaemia. One affected carbonic anhydrase inhibiting drugs has not family member also had attacks of par- yet been confirmed, and is refuted in a recent oxysmal kinesigenic choreoathetosis, res- review.8 1' Although phenytoin and carbonic ponsive to carbamazepine. anhydrase inhibiting drugs act similarly in the prevention of ataxia, their effect on myokymia (J Neurol Neurosurg Psychiatry 1995;59:400-405) seems to be different, as phenytoin reduced myokymia in pronounced disease, but aceta- Department of Neurology, University zolamide and sulthiame caused an increase of Hospital Groningen, Keywords: ; hereditary myokymia; stiffhess in patients with less pronounced http://jnnp.bmj.com/ PO Box 30.001, acetazolamide myokymia.6 8 9700 RB Groningen, The Netherlands After localisation of the trait for episodic W J Lubbers Autosomal dominantly inherited episodic ataxia and myokymia, or hereditary myokymia E R P Brunt can be classified in two main cate- and paroxysmal ataxia, to chromosome 12p, T W van Weerden gories according to the presence or absence of different point mutations in the gene coding Department of myokymia.' Since the first paper by Parker, for the voltage dependent potassium channel Medical Genetics, familial periodic ataxia, without myokymia, KCNA1 in four unrelated families have State University of on September 26, 2021 by guest. Protected copyright. Groningen, A has been described in about 25 families.2 3 recently been reported. 12 13 Deusinglaan 4, Patients with familial periodic ataxia expe- We present the clinical, genetic, and EMG 9713 AW, Groningen, The Netherlands rience episodes of limb and gait ataxia, ver- findings of an additional family with heredi- H Scheffer tigo, nausea, and sometimes headache, tary myokymia and paroxysmal ataxia. R Stulp usually lasting for hours. The attacks are Departments of brought on by emotional stress, , exer- Biochemistry and alcohol, intake, and men- Methods Medical Genetics, cise, carbohydrate Oregon Health strual periods. Kinesigenic provocation is All affected family members were neurologi- Sciences University, uncommon, and attacks do not follow a sen- cally examined. Attacks were brought on by Portland, Oregon sory aura. As a rule, nystagmus is present both repeated knee bends or sudden rising from a 97201, USA between the attacks. chair. For EEG we used silver-silver chloride M Lit during and Progressive D L Browne ataxia, a disorder of pyruvate metabolism, or scalp electrodes placed according to the inter- Correspondence to: localised atrophy of the vermis has been found national 10-20 system. Serum lactate and Dr E R P Brunt, a cases. Carbonic pyruvate concentrations were measured dur- Department of Neurology, in few anhydrase inhibiting University Hospital drugs such as acetazolamide and sulthiame, ing standardised exercise.'4 We used Medelec Groningen, PO Box 30-001, also and various other SE20 surface electrodes to scan for the pres- 9700 RB Groningen, but phenytoin drugs The Netherlands. are effective in the prevention of attacks.' 3-5 ence of myokymic discharges before concen- Received 9 February 1995 Hereditary myokymia and paroxysmal tric needle EMG. Local ischaemia was and in revised form or ataxia and was applied by inflation of a blood pressure cuff 16 May 1995 ataxia episodic myokymia Accepted 1 June 1995 first described in 1975 by Van Dyke et al with around the upper arm to 220 mm Hg for Hereditary myokymia and paroxysmal ataxia linked to chromosome 12 is responsive to acetazolamide 401

three minutes. After informed consent, DNA mg/day. Paraesthesiae could be reduced by J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.4.400 on 1 October 1995. Downloaded from of affected and non-affected family members supplementation with 2 g potassium daily. was isolated from peripheral blood and typed with the markers D12S100, D12S372, Patient 2 (IV-6) D12S1088, KCNA5, and D12S99.12 13 The The 22 year old brother of the proband had effect of medication was evaluated by compar- experienced attacks of dizziness since the age ison of the number and severity of attacks in of 6 years, manifesting limb and gait incoordi- ensuing periods with and without open label nation and dysarthria. The attacks were treatment. brought on by sudden movements, lasted for about two minutes, and happened about once DESCRIPTION OF PATIENTS daily. At the age of 15, after a mild head Patient 1 (IV-7) injury, he also developed attacks of stereo- The proband, a 20 year old woman, had typed dystonic movements that lasted about attacks of "swinging legs" and dizziness dur- 10 seconds, and occurred up to 20 times a ing which she experienced involuntary jerky day. Usually, these dystonic movements limb movements, dysarthria, and gait ataxia. involved the right arm with variable inclusion Sometimes, a sudden sensation in her neck, of the face and leg, but they also happened in which within seconds spread over her body, the left arm, or involved both sides. As with marked the onset of an attack. First noticed at the dizziness, these attacks were provoked by the age of 6, the attacks occurred often three sudden rising, limping, and other quick move- or four times daily, lasting from 10 seconds to ments, but could also be provoked by volun- five minutes, with varied intensity. On one tary contraction of his right thigh muscles. occasion a prolonged attack with considerable The dystonic attacks started with paraesthe- leg jerks during a period of fever had siae in the ulnar side of the right hand. A prompted admission to hospital. Attacks hap- vague awareness, lasting many hours, indi- pened at rest but more often occurred during cated proneness for these dystonic attacks. At exercise or when the patient was startled, times, attacks of dystonia and of ataxia coin- standing up, running, slipping, or carrying a cided, brought on by the same kinesigenic heavy bag. The attacks had resulted in a pho- stimulus. Treatment with 400 mg carba- bic avoidance of public appearances for which mazepine a day effectively reduced the dys- she had been treated with clomipramine by a tonic attacks to less than one a day, but did psychiatrist. She also experienced episodes of not obviously reduce the occurrence of ataxia. stiffening of her right hand with her thumb The patient had a history of finger trembling forced inward. These episodes lasted from that diminished during treatment with fluvox- minutes to hours and occurred mainly during amine for . sustained use of her arm. Examination-Neurological examination with Examination-Neurological examination showed special attention to eye movements and co- normal eye movements without nystagmus, ordination was normal. Myokymia was not and normal coordination, muscle strength, detected clinically. sensation, and reflexes. Rippling of the skin was present in the first interosseous space of Treatment and follow up-Medication with both hands, and pendent fingers showed small only 62-5 mg acetazolamide once daily caused http://jnnp.bmj.com/ semirhythmical, lateral movements. pronounced paraesthesiae and was discontin- ued before its effect could be assessed. Witnessed attack-During an attack (provoked by five knee bends) that lasted about three minutes, she had rhythmic involuntary shak- ing of arns and legs that put her offbalance. A Results

finger-to-nose test showed a kinetic Figure 1 shows the relevant data on pedigree on September 26, 2021 by guest. Protected copyright. and . A spontaneous or gaze evoked and genotype. Table 1 shows characteristics nystagmus was absent. Half an hour later of the affected family members. The attacks another attack occurred after 20 knee bends, were first noticed in childhood, showed a and showed a gradual build up with contin- maximum in the second decade, and declined ued provocation. Rising quickly after a hand with increasing age. Ataxia was often pre- clap failed to provoke an attack. ceded by a sensory warning and usually built up within 10 seconds followed by a more Treatment and follow up-During treatment gradual decline. The shaking that accompa- with acetazolamide no attacks occurred for nied the ataxia could be slight or pronounced. three days, but then reappeared once or twice Several circumstances influenced the occur- a day, at about half the original frequency. rence of attacks, and people could often sense This partial effect remained for over three a certain proneness. Attempts to provoke an months. When on acetazolamide treatment, attack by repeated knee bends or sudden performance of knee bends did not provoke rising were uncomfortable and often not an attack and she was able to engage in new successful. activities. After an interruption of the acetazo- lamide medication she had many long attacks, EXAMINATION AND WVITNESSED ATTACKS again easily provoked by exercise. Prevention Apart from the presence of myokymia, neuro- of attacks and paraesthesiae were obviously logical examination between attacks was both dose related, with an optimal dose of 187 normal in all affected members. Rippling of 402 Lubbers, Brunt, Scheffer, Litt, Stulp, Browne, van Weerden

Figure 1 Relevant part of J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.4.400 on 1 October 1995. Downloaded from the pedigree. Affected people are represented with black symbols. The genotypic data of chromosome 12p markers are shown below each symbol. Thefollowing markers are represented: A = D12S100, B = D12S372, 11 4 C = D12S1088, D = KCNA5, and A- - E = D12S99. B-- C- - D -- E - -

III 14 A2 4 A2 B3 3 B3 2 3 C4 1 C4 3 3 D 1 2 D 1 4 1 E 3 1 4 6 E 3 3 3

IV A 1 3 B 3 3 C 4 1 D2 4 E 3 3

the skin and lateral finger movements freely but without visible ataxia or tremor. indicated myokymia in three of the six In one patients. patient (III-14) the finger LACTATE AND PYRUVATE TEST movements were semirhythmic in a lateral Serum lactate and pyruvate concentrations in similar to the direction, appearance of cases III-13, IV-6, and IV-7 were within the myokymia in the family previously described normal range. by us.8 In two other patients (IV-7 and IV-8) involuntary activity was different, with inter- ELECTROENCEPHALOGRAPHY mittent, unpredictable small jerky finger An EEG of patient IV-7 before and movements that we did not during at first recognise a provoked attack was normal. An EEG as a myokymic manifestation. A minor attack registration of patient IV-6 in 1989 showed witnessed in patient III-13, consisted of an lateralised left temporal slowing, unchanged uncomfortable feeling and inability to move during provoked attacks of dystonia. http://jnnp.bmj.com/

Table 1 Data ofaffectedfamily members Patient III-11 III-13 III-14 IV-6 * IV-7 IV-8 Age (y) ri) 4i2A,, I - Ataxia: 37 22 20 18

Age of onset (y) 6 6 5 6 on September 26, 2021 by guest. Protected copyright. Attenuation >20 6 4 (y) >16 >18 >17 Frequency 2-3/week 4-10/day 2/day 2-3/week 3-4/day Duration 1-5 min 1-5 min 1-5 2-3/week min 2 min-3 h 10 s-5-min 2-3 min Sensory aura + + + Subjective + + Diplopia Nausea Sweating Oscillopsia Nausea "Dizziness"+ sensations Weakness Diplopia "Dizziness" "Dizziness" "Dizziness" Stiffness Carpal Movement Gait and limb Gait and limb Gait and limb Gait coordination ataxia and limb Gait and limb Gait and limb ataxia ataxia ataxia ataxia ataxia Provocation: shaking limbs jerky movements trembling "Spontaneous" Sudden movements Exertion + Additional + Menses Menses Emotional Emotional Startle Startle influences startle illness, stress stress Examination: Smell of food Nystagmus Ataxia Myokymia + (rhythmic) + (jerky and + (jerky and rrhythmic) rhythmic) Myokymia on EMG + Treatment with + acetazolamide: + + Dose (mg) 125 63 Effectt 63 188 + + 63 31 *IV-6 also paroxysmal kinesigenic choreoathetosis. t? = effect could not be evaluated, as treatent was not tolerated; + = attacks reduced by more than half. Hereditary myokymia and paroxysmal ataxia linked to chromosome 12 is responsive to acetazolamide 403 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.4.400 on 1 October 1995. Downloaded from A .L~kJL~52ms Free quency had risen, increased in length. Volitional contraction during 10-15 seconds interrupted the myokymic activity for one or two seconds, but a short, jerk-like contraction could start myokymic activity that had not been previously present. In patient IV-6, in 20 whom we were unable to detect myokymia by EMG, three minutes of regional ischaemia brought on typical repetitive myokymic activity (fig 2B). In patients IV-7 and IV-8, with more jerky involuntary finger movements, elec- tromyography showed irregularly repeated complex bursts of about 50-100 ms with varying shape as well as the repetitive myokymic activity (fig 2C).

LINKAGE STUDIES 20._ Free 20 0 uLV Ap1 With markers closely linked to the hereditary we 20.5~~~~~~~~~~~~n Free myokymia and paroxysmal ataxia locus, 200 tLU Amp show linkage in this family to chromosome 12p (fig 1). No crossover was identified, and u Amp in patient III-14, a mutation apparently C I Free resulted in a new allele for marker D12S100. m p I1 Table 2 shows the calculated pairwise lod scores for linkage. Sequencing of the KCNA1 gene identified a Glu325Asp missense mutation, detailed findings of which will be presented else- where. 15

TREATMENT AND FOLLOW UP Treatment with acetazolamide was initiated in all affected family members. Paraesthesiae occurred in all patients, even at a low dose, and caused the medication to be stopped in three patients with relatively few attacks. The Figure 2 EMG recording ofspontaneous muscle activity. (A) Different independendy paraesthesiae appeared about 15 minutes after occurring multiplets. Surface recordingfrom muscle abductor poUlicis brevis, patient IV-7. the ingestion of acetazolamide and lasted for (B) Single rhythmically occurring duplet, brought on by three minutes oflocal ischaemia. Concentric needle recordingfrom muscle abductor digiti quinti, patient IV-6. (C) several hours. They could be diminished by Irregularly occurring bursts causing small jerkyfinger movements. Spontaneous myokymic oral potassium. Parallel to the occurrence of activity marked by A Surface recordingfrom first dorsal interosseous muscle, patient IV-8. paraesthesiae, two patients noticed increased low doses of muscle stiffness. Relatively http://jnnp.bmj.com/ 63-188 mg acetazolamide a day were accepted by three patients (IV-7, III-13, and ELECTROMYOGRAPHY III-14), reducing both the number and the All but one (IV-6) of the affected members severity of attacks. This effect was obvious showed resting EMG activity in the hand and from the first day and lasted for about one day lower arm muscles. In three patients (III-11, after the treatment ended. After one or two III-13, III-14) myokymic activity consisted of weeks of treatment about half of its initial effi- rhythmically repeated, independently occur- cacy was gradually lost. Stabilisation followed on September 26, 2021 by guest. Protected copyright. ring singlets and multiplets of relatively low thereafter. amplitude (up to 600 uV), with a frequency of 2-5/s and a spike interval of 5-10 ms (fig 2A). During three minutes of ischaemia, some Discussion myokymic discharges showed a gradual two to The syndrome of hereditary myokymia and threefold rise in frequency, which returned to paroxysmal ataxia in this family compares well baseline after deflation. After ischaemia addi- with the five families described previously.' 69 tional myokymic discharges were recruited, Table 3 summarises the data. Obviously, the and myokymic discharges, in which the fre- attacks in childhood may initially pass unrecognised. A kinesigenic provocation, occurring in five out of six families with Table 2 Lod scoresfor the 12p markers hereditary myokymia and paroxysmal ataxia, 8 value may serve to differentiate within the episodic ataxias, although this is not mentioned in 0-001 0-01 0-05 0-10 0-20 0-30 0-40 recent reviews.3"' Diminished physical activity D12S1088 0 60 0-59 0-56 0-51 0-41 0-29 0-16 and kinesigenic provocation may well play a KCNA5 2-10 2-07 1-93 1-74 1-33 0-87 0-39 D12S99 0 90 0-86 0-81 0-72 0-51 0 30 0 09 part in the reduced occurrence of attacks after the teenage years. The presence of a sensory No Lod score was calculated for D12S100 due to the occurrence of a new allele in patient E11-14. Marker D12S372 was not informative. The map distances for the markers used are D12S100- warning, mentioned in two other families with 4cM-Dl2S372-3cM-Dl2Sl088-lcM-KCNA5-lcM-Dl2S99.'2 hereditary myokymia and paroxysmal ataxia, 404 Lubbers, Brunt, Scheffer, Litt, Stulp, Browne, van Weerden J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.4.400 on 1 October 1995. Downloaded from Table 3 Familial paroxysmal ataxia with continuous myokymia Authors Van Dyke Hanson Gancher Brunt and Vaamonde Lubbers etal6 etal7 and Nutt Van Weerden' etal9 etal (1975) (1977) (1986) (1990) (1991) (1995) Inheritance AD AD Number: AD AD AD AD Reported 3 3 3 22 3 6 Examined 7 3 7 22 1 Affected 1 1 4 6 Ataxia: 15 28 3 9 Age of onset (y) 2-12 4-8 6-15 2-15 Attenuation ? 6 4-6 (y) ? >20 20-50 >20 Frequency 0-10/day 0-1/day 0-2/day 0-15/day 0-3/week Duration ±3 min 10-15 min +2 min In A 0-10/day 111111 Iv S-iU ;0tew min 10 s-5/d min to 6mm Sensory aura +? (up h) (up to 3 h) Subjective + sensations Vertigo, Eyes drawn Weightlessness, Limb stiffnesss, Blurred vision Dizziness diplopia, backward, sensation of heavy feeling, weakness, blurred vision weakness legs falling visio)n Movements, Generalised Generalised ±blurred stiffhess coordination Generalised Generalised Generalised Generalised ataxia, ataxia, ataxia, ataxia, ataxia?, ataxia, jerking, nodding shaking, tremor? postural of head and tremcor jerking shaking arms staggering of head and arrmss trembling Stiffening Generalised Stiffening, Limb muscles Few: stiffening.g Spasm hand Stiffening myokymia, in body, twitching, hands and foot hands, carpal spasm arms and hands puckering mouth carpal spasm Provocation Kinesigenic + Kinesigenic + ? caloric Kinesigenic Kinesigenic + Kinesigenic + Kinesigenic + caloric exercise exercise stimulation + stimulation - Additional Hunger, fatigue Perimenstrual Stress, fatigue, Startle, Stress, fatigue, influences excitement, illness excitement Startle, anxiety anxiousness, hyperventilation, perimenstrual Interval examination: illness illness illness Nystagmus Ataxia Myokymia ?+: few, >50y Face, hands, Resting tremor Face Face, hands, Skin rippling Face, fingers, moving fingers, in body, hands distal limbs, pending finger face, hands carpal spasm, (contractures) regular/jerky calf moving fingers movements movements EMG hypertrophy (thumb adduction) CMUA CMUA, Neuromyotonia Irregular/regular High frequency irregular/regular Neuromyotonia repetitive grouped repetitive singlets irregular singlets repetitive singlets, discharges multiplets multiplets multiplets Treatment: (postischaemic) Phenytoin Ataxial Ataxial Ataxia-+ Ataxia-+ Ataxia ? Acetazolamide Myokymia-i Myokymia-+ Myokymial Myokymia? Myokymia? Ataxia - Ataxial Ataxia - Ataxial Myokymia? MyokymiaT Myokymia? Mvokvmiat AD = autosomal = dominant; CMUA continuous motor unit activity; - = absent; ? = -+ = = I = decrease. unknown; no change; t increase;

and at times experienced all by members of absence of myokymic activity, we the present seems to be although family another feature found a wide variation http://jnnp.bmj.com/ that between patients and differentiates attacks in hereditary over time. Myokymic activity brought about myokymia and paroxysmal ataxia from those ischaemia also in familial by widens this range. periodic ataxia. Obviously the amount of myokymic activity The shaking of legs and trunk during an also varies between families. attack shown by one of the members of the Genetic linkage of episodic ataxia and present family was more pronounced than myokymia (hereditary myokymia and previously found by us, but has also been paroxysmal ataxia) to loci D1 2S9

1, on September 26, 2021 by guest. Protected copyright. described in two other families with hereditary D12S100, CACNLIA1, D12S372, pY21-1 myokymia and paroxysmal ataxia.6-8 The nor- (=D12S1088), KCNA5, D12S93, and mal, unaltered EEG during one of the pro- DI 2S99 on chromosome was voked 12p shown pre- attacks and the normal pyruvate and viously.12 The to the ataxia lactate are linkage episodic in line with previous findings.6 The and myokymia locus and the finding of clinical and EMG manifestation and the reac- another missense mutation in the KCNA1 tivity of myokymia in this family compare well gene groups this family with those previously with our previously described family, with the described. 1213 exception of the irregular, choreiform jerky The prevention of attacks of ataxia movements and by finger non-repetitive long acetazolamide in this family confirms our pre- bursts on EMG in two affected members.8 vious findings in hereditary myokymia and The provocation of myokymia by local paroxysmal ataxia.5 A reduced efficacy after ischaemia during three minutes extends the some weeks has also been reported found in some enhancement of myokymia after patients of the first family that we studied. and seems to be a ischaemia, simple test to The early decline followed by a prolonged support the diagnosis in patients suspected to have remaining efficacy suggests a metabolic adap- hereditary myokymia and paroxysmal tation rather than a placebo effect, but we ataxia who have no spontaneous myokymic have not found changes in laboratory values. activity. In the EMG examination with sur- The effect of face suppressive acetazolamide may electrodes on more than 25 affected peo- not occur in all families with hereditary ple we have not previously encountered myokymia and paroxysmal ataxia, but clearly Hereditary myokymia andparoxysmal ataxia linked to chromosome 12 is responsive to acetazolamide 405

prevents its use to differentiate hereditary We thank Dr Nigel Jack for correction of the language, and J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.4.400 on 1 October 1995. Downloaded from myokymia and paroxysmal ataxia from famil- Eveline Eimers for secretarial support. ial periodic ataxia as recently suggested.'91' Although not separating episodic ataxias with and without myokymia, Ptacek, commenting on the discovery of the KCNA1 channel mutation in hereditary myokymia and parox- ysmal ataxia, drew attention to the shared favourable reaction to acetazolamide of dis- 1 Gancher ST, Nutt JG. Autosomal dominant episodic eases caused by mutations in cation chan- ataxia: a heterogeneous syndrome. Mov Disord 1986;1: 239-53. nels.16 The early occurrence of paraesthesiae 2 Parker HL. Periodic ataxia. Collected papers from the Mayo and increase in muscle stiffness after the use Clinic 1946;38:642-5. 3 Moon SL, Koller WC. Hereditary periodic ataxias. In: De of acetazolamide confirm earlier findings, and Jong JMBV, ed. Handbook of dinical neurology. Vol suggest an abnormal sensitivity to acetazo- 16(60). Hereditary neuropathies and spinocerebeUar atro- phies. Amsterdam: Elsevier, 1991:433-43. lamide as part of the hereditary myokymia 4 Griggs RC, Moxley RT, Lafrance RA, McQuillen J. and paroxysmal ataxia syndrome.8 We did not Hereditary paroxysmal ataxia: response to acetazo- lamide. Neurology 1978;28:1259-64. use phenytoin, which proved effective in two 5 Wolf P. Familiare episodische Ataxia. Nervenarzt 1980;51: of the other families with hereditary 355-8. 6 Van Dyke DH, Griggs RC, Murphy MJ, Goldstein MN. myokymia and paroxysmal ataxia, in the pre- Hereditary myokymia and periodic ataxia. J Neurol Sci sent family.67 The occurrence of attacks of 1975;25:109-18. 7 Hanson PA, Martinez LB, Cassidy R. Contractures, con- paroxysmal kinesigenic choreoathetosis in one tinuous muscle discharges and titubation. Ann Neurol affected member (IV-6) is remarkable. The 1977;1:120-4. 8 Brunt ERP, Van Weerden TW. Familial paroxysmal ataxia rarity of both conditions and the shared and continuous myokymia. Brain 1990;113:1361-82. provocation suggest a relation, but the occur- 9 Vaamonde J, Artieda J, Obeso JA. Hereditary paroxysmal ataxia with neuromyokymia. Mov Disord 199 1;6:180-2. rence after a head trauma and different reac- 10 Brunt ERP, Van Weerden TW. Distal axonal origin and tion to carbamazepine may argue for a motor unit involvement in myokymia [abstract]. Neurology 1994;44(suppl 2):A411. different aetiology.17 1819 Gancher and Nutt 11 Fahn S. The paroxysmal . In: Marsden CD, have described one family (kindred V) in Fahn S, eds. Movement disorders 3. Oxford: Butterworth- Heinemann, 1994:319-20. whom attacks of kinesigenic episodic ataxias 12 Litt M, Browne D, Kramer P, Gancher S, Brunt ERP, and ofparoxysmal kinesigenic choreoathetosis Root D, et al. A gene for episodic ataxia/myokymia maps to chromosome 12pl3. Am J Hum Genet 1994;55: occurred separately in some members, and 702-9. jointly in one': in this person, the early mani- 13 Browne DL, Gancher ST, Nutt JG, Brunt ERP, Smith EA, Kramer P, Litt M. Episodic ataxia/myokymia syn- festation of attacks of episodic ataxia at the drome is associated with point mutations in the human age of 6 years, followed by the occurrence of potassium channel gene KCNA1. Nature Genetics 1994;8:136-40. attacks of paroxysmal kinesigenic choreoa- 14 Zierz S, Meessen S, Jerusalem F. Lactat- und thetosis at the age of 15 years, closely parallel Pyruvatspiegel in der Diagnostik mitochondrialer Myopathien. Nervenartzt 1989;60:545-8. the temporal sequence in our case IV-7. The 15 Browne DL, Brunt ERP, Griggs RC, Nutt JG, Gancher presence of myokymia in this family was not ST, Smith EA, Litt M. Identification of two new KCNA1 mutations in episodic ataxia/myokymia obvious at the time of this report, but was families. Hum Mol Genet 1995 (in press). found later in some affected members (J Nutt, 16 PtkceklU. Ion channel shake-down. Nature Genetics 1994;8:111-2. personal communication). 17 Robin JJ. Paroxysmal choreoathetosis following head of a second who Ann The observation patient injury. Neurol 1977;2:447-8. http://jnnp.bmj.com/ 18 Drake ME, Jackson RD, Miller CA. Paroxysmal choreo- had combined attacks ofhereditary myokymia after head injury [letter]. J Neurol Neurosurg and paroxysmal ataxia and of paroxysmal Psychiatry 1986;49:837-8. 19 Richardson JC, Howes JL, Celinski MJ, Allman RG. kinesigenic choreoathetosis strengthens the Kinesiogenic choreoathetosis due to brain injury. Can J suggestion that occurrence of these two types Neurol Sci 1987;14:626-8. 20 Mayeux R, Fahn S. Paroxysmal dystonic choreoathetosis of attacks is not mere coincidence. Also, previ- in a patient with familial ataxia. Neurologv 1982;32: ous reports on episodic dystonia occurring in 1184-6. two families with progressive ataxia suggest a 21 Graff-Radford NR. A recessively inherited ataxia with episodes of dystonia. J Neurol Neurosurg Psychiatry 1986; possible relation.202' 49:591-4. on September 26, 2021 by guest. Protected copyright.