212 Journal ofNeurology, Neurosurgery, and Psychiatry 1992;55:212-213

SHORT REPORT J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.3.212 on 1 March 1992. Downloaded from

Familial paroxysmal : report of a family

C H Hawkes

Abstract type reactions. There was no vestibulo-ocular Three cases from one kindred who suffer reflex suppression. Pure tone audiograms and from dominant paroxysmal ataxia are caloric tests were absent from the right ear. The described. This is a rare benign non- left audiogram was normal but caloric tests progressive disorder of childhood onset, showed large amplitude responses. Brainstem characterised by bouts of ataxia with auditory evoked responses were normal on the abrupt onset lasting minutes or hours. left and absent on the right. No abnormalities Cases may be identified on the basis of a were seen on EEG or visual evoked response. A suggestive history, persisting provisional diagnosis of basilar migraine was between episodes, and dominant inheri- made. At a further assessment one year ago, she tance. Treatment with acetazolamide is was screened for the possibility of mitochon- often dramaticallyeffective. Thisfamilyis drial disease because of slight elevation of thought to be the first described in the UK creatine kinase (150 units, normal < 120), but a but many more probably exist, mis- muscle biopsy specimen was normal, and the labelled as epilepsy or migraine. diagnosis of familial paroxysmal ataxia was made. An MRI scan showed distinct atrophy of the superior cerebellar vermis. Institution of Inherited episodic motor disturbances of the acetazolamide 250 mg twice daily in January central nervous system are all rare and com- 1990 resulted in a dramatic reduction ofattacks prise three main varieties: periodic paralysis, over the first eight months' observation. paroxysmal choreoathetosis, and paroxysmal ataxia. I report here the last mentioned, as it has Case 2 developed attacks at 1 year identical to not been described in the British literature, is his mother (case 1). They were initially suspec- often unrecognised, and may respond dra- ted to be epileptic, and there seemed to be some matically to acetazolamide. response to carbamazepine. Some episodes were induced by physical exercise. He showed minor mental retardation with difficulty in Case reports articulation in early life. Neurological examina- Case 1 was found to have mild concomitant tion at 6 years showed numerous caf&-au-lait

squint at 3 years old but no nystagmus. She spots and slight clumsiness of the left arm but http://jnnp.bmj.com/ developed recurrent right otitis media at 5 no evidence of neurofibromatosis. There was years and became totally deaf on that side. mild concomitant strabismus with nystagmus Corrective eye surgery was performed at 6 and jerky saccades on horizontal gaze. An EEG years and just before this, nystagmus was noted showed increased slow wave activity but a CT for the first time. Subsequently four vessel scan of the brain was normal. A provisional arteriography and air encephalography were diagnosis of epilepsy was made once more, undertaken with negative results, and a pro- followed by treatment with sodium valproate visional diagnosis of congenital nystagmus was without obvious benefit. The attacks continued on October 2, 2021 by guest. Protected copyright. made. Since then she had experienced fort- about once every six weeks. When the diagnosis nightly episodes of , ataxia, and ver- was made in his mother, acetazolamide treat- tigo often accompanied by nausea and vomiting ment was started and completely abolished followed by headache with drowsiness. Onset attacks over the first three months of observa- was abrupt over the course of a few seconds. tion. MRI scan showed striking atrophy of the There were no obvious trigger factors except particularly in the superior vermis. for exercise, and the attack duration varied from 2-24 hours. She was reassessed when 26 Case 3 is another son of case 1. His episodes years old because the attacks were recurring up began when aged 6 weeks. According to his to five times a week. Pronounced spontaneous mother his head would flop and he would shake. nystagmus was seen in all directions. Electro- When crawling at age 7 months he would Ipswich Hospital, nystagmography confirmed normal saccades inexplicably wobble. Subsequently episodes of Neurological Centre, with distinct second degree gaze paretic nys- imbalance, similar to his mother and older Heath Road, Ipswich, Suffolk IP4 5PD tagmus which was abolished in the absence of brother, recurred on a daily basis. Examination C H Hawkes fixation. Rebound nystagmus occurred on at 6 years revealed a mild convergent squint recentering from both right and left. Pursuit with nystagmus on horizontal gaze and jerky Received 4 February 1991 was severely deranged in the horizontal plane. saccades. There were two very small cafe-au- and in revised form 21 June 1991. Optokinetic responses were disturbed and lait spots. No lack of limb coordination was Accepted 9 July 1991 rotation responses revealed short cerebellar- detectable. An EEG and CT brain scan showed Familial paroxysmal ataxia: report of a family 213

no abnormality. Acetazolamide was started in pyruvate dysmetabolism and, at necropsy, one May 1990 and again over the first three months subject displayed features consistent with J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.3.212 on 1 March 1992. Downloaded from of monitoring no more attacks were witnessed. Leigh's disease." MRI often shows atrophy (as A urinary screen for abnormal amino acids in in case 1 and 2) ofthe superior vermis. 2 This is the mother and both sons was within normal of considerable interest as the puruvate limits. A further sibling aged 10 years (female) dehydrogenase activity relative to the rate of is quite healthy. A brother of the index case pyruvate oxidation is lowest in the superior (aged 42) is educationally subnormal. Three vermis, hence defects ofthis enzyme too mild to other brothers and her sister are healthy. The impair carbohydrate catabolism in other parts father ofthe index case was initially ataxic then of the brain may selectively cause dysfunction chairbound for 13 years and died aged 67. Her here." 4 The presence of pyruvate disorder in maternal grandmother died from "creeping an X-linked family and not in the dominant paralysis", but no further particulars are form, implies a spectrum of pyruvate dysfunc- obtainable. tion which is genetically determined. The first line oftreatment is acetazolamide,"5 which is effective in at least half of cases. If acetazolamide fails, phenytoin may be helpful Discussion but sometimes worsens symptoms.' This is Familial paroxysmal ataxia is an autosomal thought to be the first family with the typical, dominant disorder first described in 1946.' dominant form of disease to be described in Since then some 17 families have been des- UK but many other families must exist undiag- cribed, mostly from the United States, Canada, nosed-mislabelled as epilepsy or migraine. and France.2' The basic cause is unknown. Accurate diagnosis in one individual will Onset is usually in early childhood, and the usually reveal similarly affected family mem- attacks of imbalance, which are frequent and bers, all of whom could benefit from effective disabling, do not seem to be associated with treatment. progressive neurological dysfunction, although exceptions are found.26 Between attacks, many I thank Professor A E Harding, Institute of Neurology, Queen patients have spontaneous in Square, for recognising the disorder in case 1 and for helpful nystagmus (often comments on the text. Drs J Gould and C Verity, Ipswich the vertical as well as horizontal plane) but little Hospital, kindly gave permission to document cases 2 and 3. I am or no limb ataxia. Inconstant also grateful to Dr C Freer, Addenbrookes Hospital, precipitating Cambridge, who organised the MRI scan on case 2 and to Mrs M factors are described such as fatigue, emotion, Mortimer for secretarial support. exercise, change of position, or . Episodes typically consist oflimb ataxia, dysar- thria, nausea, vomiting, and oscillopsia 1 Parker HL. Periodic Ataxia. Mayo Clinic Proc 1946;38: occasionally with and blurred vision. 642-5. The duration is characteristically a few min- 2 Donat JR, Auger R. Familial periodic ataxia. Arch Neurol but 1979;36:568-9. utes, episodes lasting seconds or days are 3 Gancher ST, Nutt JG. Autosomal dominant episodic ataxia: documented.5 There is one report of paroxys- a heterogeneous syndrome. Movement Disorders mal ataxia 1986;1(4):239-53. associated with episodic choreoath- 4 Friedman JH, Hollmann PA. Acetazolamide responsive etosis;' another family member showed ataxia hereditary paroxysmal ataxia. Movement Disorders and 1987;2:67-82. interictal . A further patient 5 Bouchard JP, Roberge C, van Gelder NM, et al. Familial

with associated neuromyotonia has been recen- periodic ataxia responsive to acetazolamide. Can J Neurol http://jnnp.bmj.com/ The Sci 1984;11:550-3. tly reported.'0 neuromyotonia variety does 6 Farmer TW, Mustian VM. Vestibulocerebellar ataxia. Arch not seem to respond. to acetazolamide. The Neurol 1963;4:471-80. 7 White JC. Familial periodic nystagmus, and ataxia. disorder is readily confused with other dis- Arch Neurol 1969;20:276-80. eases, particularly epilepsy, especially (as in 8 Trillet M, Gouttard M, Schott B. Ataxie paroxystique familiale sensible a l'acetazolamide. Rev Neurol case 2) when the EEG is abnormal. Benign 1985;141:203-6. episodic vertigo ofchildhood is not familial and 9 Aimard G, Vighetto A, Trillet M, et al. Ataxie paroxystique is self limiting. Basilar migraine is a seductive familiale sensible a l'acetazolamide. Rev Neurol

1983;139:251-7. on October 2, 2021 by guest. Protected copyright. alternative diagnosis, especially in those com- 10 Vaamonde J, Artieda J, Obeso JA. Hereditary paroxysmal ataxia with neuromyotonia. Movement Disorders plaining of headache after an attack, and was a 1991;6(2):180-2. provisional diagnosis in case 1. Some amino- 11 Livingstone IR, Gardner-Medwin D, Pennington RJT. Familial intermnittent ataxia with possible X-linked reces- acidurias may be episodic (for example, Hart- sive inheritance. Two patients with abnormal pyruvate nup or maple syrup urine disease), but these are metabolism and a response to acetazolamide. J Neurol Sci 1984;64:89-97. readily identified by urinary examination and 12 Vighetto A, Froment JC, Trillet M, Aimard G. Magnetic the presence of progressive mental deteriora- resonance imaging in familial paroxysmal ataxia. Arch Neurol 1988;45:547-9. tion. 13 Reynolds SF, Blass JP. A possible mechanism for selective The underlying cause ofparoxysmal ataxia is cerebellar damage in partial pyruvate dehydrogenase deficiency. Neurology 1976;26:625-8. presumably biochemical, and there are 14 Zasorin NL, Baloh RW, Myers LB. Acetazolamide-respon- provisional reports of disordered pyruvate sive episodicataxia syndrome. Neurology 1983;33:1212-4. 15 Griggs RC, Moxley RT, Lafrance RA, et al. Hereditary metabolism.89 In a pedigree displaying prob- paroxysmal ataxia: response to acetazolamide. Neurology able X-index inheritance there was evidence of 1978;28:1259-64.