J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.565 on 1 October 1998. Downloaded from J Neurol Neurosurg Psychiatry 1998;65:565–568 565

SHORT REPORT

Spinocerebellar ataxia type 6 with positional vertigo and acetazolamide responsive episodic ataxia

Joanna C Jen, Qing Yue, Juliana Karrim, Stanley F Nelson, Robert W Baloh

Abstract tions in other parts of CACNA1A. SCA6 has The SCA6 mutation, a small expansion of clinical features that overlap with those of a CAG repeat in a calcium channel gene EA-2. CACNA1A, was identified in three pedi- grees. Point mutations in other parts of Case reports the gene CACNA1A were excluded and The study was approved by our institutional new clinical features of SCA6 reported— review board and informed consent was namely, central positional nystagmus and obtained from all subjects. The pedigrees are episodic ataxia responsive to acetazola- shown in the figure. mide. The three allelic disorders, episodic ataxia type 2, familial hemiplegic mi- PEDIGREE 1 graine, and SCA6, have overlapping clini- This family was previously reported as an cal features. atypical EA-2 linked to chromosome 19p (J Neurol Neurosurg Psychiatry 1998;65:565–568) (family 4).5 The type of mutation was un- known. The proband began having episodes of Keywords: SCA6; spinocerebellar ataxia; hereditary dizziness and ataxia at the age of 42. She also ataxia; calcium channel noted positional vertigo so that she slept propped up with pillows. About a year later, she noticed mild interictal imbalance. Initial exam- Episodic ataxia type 2 (EA-2) is an autosomal ination disclosed a central type of positional dominant disorder characterised by episodes of nystagmus (conjugate downbeat nystagmus ataxia lasting hours to days with interictal nys- that did not fatigue with repeated positioning). tagmus. Precipitated by physical exertion or Tandem walking was impaired, but limb coor- emotional stress, the episodes are often dra- http://jnnp.bmj.com/ 1 dination was normal. Acetazolamide markedly matically responsive to acetazolamide. Symp- decreased the episodes of dizziness and ataxia, Department of toms typically begin before the age of 20; some but follow up examination still showed down- Neurology patients later develop a gradually progressive beat positional nystagmus and mild truncal JCJen cerebellar ataxia. QYue ataxia. She has taken 250 mg acetazolamide J Karrim In two families with EA-2 and four families twice daily for three years with continued good R W Baloh with familial hemiplegic migraine (FHM), response. point mutations were identified in CACNA1A

Four of five living aVected family members on September 26, 2021 by guest. Protected copyright. Department of (formerly known as CACNL1A4), which maps reported episodes of ataxia in addition to a Pediatrics/Hematology to chromosome 19p and codes for the human and Oncology slowly progressive ataxia. Old records docu- neuronal voltage dependent calcium channel mented that the proband’s father initially Stanley F Nelson 2 3 á1A subunit. Zhuchenko et al reported an presented at the age of 45 with positional 4 Department of association (later confirmed by others ) be- vertigo, followed by episodic and progressive Surgery (Head and tween small CAG expansions (repeat numbers ataxia. The proband’s great aunt and her Neck), UCLA School of 21–27 compared with 4–16 in controls) in daughter (II-3, III-6) reported episodes typical Medicine, Los Angeles, CACNA1A and a late onset dominantly inher- California, USA of basilar migraine beginning in their teens and R W Baloh ited ataxic syndrome, which they named spontaneously disappearing in their late 20s. spinocerebellar ataxia type 6 (SCA6). They did Correspondence to: not report episodic features or response to PEDIGREE 2 Dr Robert W Baloh, UCLA acetazolamide in their patients. In addition, Department of Neurology, The proband presented at age 56 reporting Box 951769, Los Angeles, mutations elsewhere in the gene were not positional vertigo since the age of 50, episodes CA 90095–1769, USA. excluded so that it is possible that point muta- of dizziness and ataxia since the age of 51, and Telephone 001 310 825 tions in other parts of the gene rather than the 5910; fax 001 310 206 1513; mildly progressive ataxia beginning at the age email:[email protected] expanded CAG repeats determined the clinical of 55. Examination showed slight downbeat syndrome. nystagmus on lateral gaze, prominent posi- Received 18 December 1997 We now report new clinical features in three tional downbeat nystagmus with vertigo, and and in revised form 9 March 1998 families with an expanded CAG repeat in mild truncal ataxia. Brain MRI showed moder- Accepted 19 March 1998 CACNA1A (SCA6) and exclude point muta- ate vermian atrophy. Acetazolamide (250 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.565 on 1 October 1998. Downloaded from 566 Jen, Yue,Karrim, et al

Pedigree 1

I

2 II 3 22/11

1 2 * 3 4 ***5 6 87 III

12/13 22/13 13/11 22/13 13/13 22/13 22/13

1 * IV

22/13

Pedigree 2 Pedigree 3

I

* ** * II

22/13 22/13 13/13

* * * III 13/11 22/13 22/13

Three pedigrees identified with SCA6. *Examined; arrow=proband; CAG repeat numbers for both alleles for those tested are as indicated.

mg/day) initially stopped his episodes of ataxia. truncal ataxia, and increased muscle tone with After six months, the episodes began recurring. hyperreflexia. He tried acetazolamide for about http://jnnp.bmj.com/ Increasing the dose to 500 mg/day again a month but reported no benefit. Brain MRI stopped the attacks, but they began recurring showed mild vermian atrophy. about six months later. He is now maintained The proband’s 72 year old sister considered on 750 mg/day with only infrequent episodes. herself normal but did admit to occasional The central positional nystagmus and interictal positional dizziness so that she slept with mild ataxia are unchanged on acetazolamide. several pillows. On examination, she had slight The proband’s 63 year old sister reported an horizontal gaze evoked nystagmus, prominent almost identical history of positional vertigo downbeat positional nystagmus, and mildly on September 26, 2021 by guest. Protected copyright. and spontaneous episodes of ataxia beginning impaired tandem walking. in her early 50s, followed by progressive ataxia a few years later. She has used a cane since Genetic studies 1993. Her examination disclosed downbeat CAG repeat expansions in CACNA1A were nystagmus on lateral gaze, prominent posi- identified by 4% agarose or 10% polyacryla- tional downbeat nystagmus, slurring of speech, mide gel electrophoresis of polymerase chain and truncal and appendicular ataxia. reaction (PCR) amplified fragments using primers flanking the CAG repeat region.36The PEDIGREE 3 number of repeats for both the expanded and The proband, age 65, recalled having positional the normal alleles in IV-1 of pedigree 1 and vertigo dating back to his late teens. He had to III-1 in pedigree 2 were ascertained by electro- stop playing American football in high school phoresis in denaturing polyacrylamide gels and because he developed severe vertigo when compared with a sequencing ladder.6 Genetic pinned to the ground. He slept propped up and analysis showed CAG repeat expansion to 22 in avoided lying flat. He noticed fatiguability and a one allele, with 13 repeats in the normal allele. gradual deterioration in balance in his early 50s DNA from these two patients were used as without much fluctuation in his symptoms. positive controls for each set of PCR and gel Examination disclosed gaze evoked nystagmus electrophoresis. The repeat expansion cosegre- on lateral gaze, downbeat positional nystagmus, gated with phenotype (figure). J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.565 on 1 October 1998. Downloaded from Spinocerebellar ataxia type 6 with positional vertigo and acetazolamide responsive episodic ataxia 567

All 47 exons and flanking introns were with normal modulatory interactions with subjected to single strand conformational kinases, G proteins, complex formation, and polymorphism analysis (SSCP)78 of PCR cytoskeletal elements. amplified genomic DNA from IV-1 and III-2 in The clinical benefit of acetazolamide is pre- pedigree 1, III-1, and III-2 in pedigree 2. No sumably mediated by increasing the extracellu- aberrantly migrating fragments compared with lar concentration of free protons in the unaVected relatives or 15 unrelated controls cerebellum.11 Calcium channels are sensitive to were identified.26 changes in pH: protons reduce the unitary conductance and channel open probability.12 The molecular mechanism of proton block of Discussion voltage gated calcium channels was recently We confirmed in three pedigrees an association shown to involve a protonation site within the between a small CAG repeat expansion in pore that is critical for calcium ion CACNA1A and late onset slowly progressive permeability.13 Acetazolamide likely stabilises ataxia SCA6.3 CAG repeat expansion to 22 the transient dysfunction of mutant calcium cosegregated with aVected persons in these channels by acidification. pedigrees. No other mutation was identified in Although many clinical features were com- the coding sequence of CACNA1A by SSCP, a mon in the three pedigrees, clinical heterogen- method that has been successfully applied to eity was found. Episodic features were promi- screen for mutations in various hereditary dis- nent in pedigrees 1 and 2 but not in pedigree 3. orders including familial hemiplegic migraine Members of pedigree 1 experienced basilar and episodic ataxia.26 Therefore, CAG repeat migraine-like attacks, which are common in expansion in CACNA1A likely caused ataxia in pedigrees with FHM.14 Members of pedigrees these patients. 1 and 3 exhibited interictal hyperreflexia and Furthermore, we identified two new clinical spasticity, extracerebellar signs commonly seen features in patients with SCA6: positional ver- with other SCA syndromes. Additional genetic tigo with central positional nystagmus and epi- or environmental factors must account for the sodic ataxia responsive to acetazolamide. In clinical variability within pedigrees and among several of these patients; the onset of positional diVerent pedigrees with the same genetic vertigo and nystagmus preceded the onset of defects. gait diYculty by many years. We think that this That the stable CAG repeat expansion in is the first report of a genetic cause for central CACNA1A is associated with a phenotype positional nystagmus. The early manifestation similar to that in patients with point mutations of downbeat nystagmus would suggest rela- in the same gene suggests that the incorpora- tively selective involvement of the flocculus.9 tion of additional glutamines alters the channel

Indeed, despite uniform expression of the á1A function as would a missense mutation leading gene in the cerebellum, a restricted pattern of to an amino acid substitution. Indeed, a point cerebellar degeneration has been found in tot- mutation in CACNA1A with a predicted tering and leaner mice, which are mutant mice change in a highly conserved amino acid with ataxia and epilepsy recently found to have residue in the critical pore region results in a mutations in the mouse analogue of severe progressive ataxia syndrome.6 We antici- 10

CACNA1A. Detailed anatomical definition pate identification of other phenotypes associ- http://jnnp.bmj.com/ may clarify whether there is region specific or ated with novel mutations in CACNA1A. Fur- age specific alternative splicing favouring the thermore, analysis of the mutant calcium longer splice variants containing the CAG channels will undoubtedly disclose new func- repeats, thus rendering the cells in the flocculus tional domains within the channel. particularly susceptible to pathological changes associated with the inclusion of expanded This work was supported by NIH grants AG9063, P01 DC02952, and DC00008–21. polyglutamine tracts in the calcium channel á1A

subunit. DiVerential expression of the auxiliary on September 26, 2021 by guest. Protected copyright. 1 Griggs RC, Moxley RT, Lafrance RA, et al. Hereditary par- subunits may aVect the calcium channel activ- oxysmal ataxia: response to acetazolamide. Neurology ity. Cell specific modulators, such as kinases 1978;28:1259–64. 2 OphoV RA, Terwindt GS, Vergouwe MN, et al. Familial and phosphatases, of the calcium channel hemiplegic migraine and episodic ataxia type-2 are caused could also contribute to the restricted expres- by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87:543–52. sion of this genetic mutation. 3 Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal Similar to patients with EA-2, our patients dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the á1A-voltage-dependent reported episodes of dizziness and ataxia calcium channel. Nat Genet 1997;15:62–9. precipitated by stress and fatigue. These 4 Zoghbi HY. CAG repeats in SCA6: anticipating new clues. Neurology 1997;49:1196–9. episodes were superimposed on a slowly 5 Baloh RW, Yue Q, Furman JM, et al. Familial episodic progressive decline in baseline function. Such ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol 1997;41:8–16. episodes may result from transient impairment 6 Yue Q, Jen JC, Nelson SF, et al. Progressive ataxia due to a of channel function triggered by environmental missense mutation in a calcium channel gene. Am J Hum factors. The progressive neuronal degeneration Genet 1997;61:1078–87. 7 Orita M, Iwahana H, Kanazawa H, et al. Detection of poly- is likely due to chronic excess calcium entry morphisms of human DNA by gel electrophoresis as leading to an increase in intracellular calcium single-strand conformation polymorphisms. Proc Natl Acad Sci USA 1989;86:2766–70. ultimately leading to cell death. Polyglutamines 8 Ravnik-Glavak M, Glavac D, Dean M. Sensitivity of single- strand conformation polymorphism and heteroduplex in the C-terminus of the calcium channel á1A method for mutation detection in the cystic fibrosis gene. subunit may aVect normal voltage dependent Hum Molec Genet 1994;3:801–7. 9 Zee DS, Yamazaki A, Butler PH, et al.EVects of ablation of or calcium dependent inactivation of the chan- flocculus and paraflocculus on eye movements in primate. nel complex. Furthermore, they could interfere J Neurophysiol 1981;46:878–99. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.4.565 on 1 October 1998. Downloaded from 568 Jen, Yue,Karrim, et al

10 Fletcher CF, Lutz CM, O’Sullivan TN, et al. Absence dihydropyridine-sensitive Ca2+ channel. Nature 1987;329: epilepsy in tottering mutant mice is associated with calcium 243–6. channel defects. Cell 1996;87:607–17. 13 Chen X-h, Bezprozvanny I, Tsien RW. Molecular basis of 11 Bain PG, O’Brien MD, Keevil F, et al. Familial periodic cer- proton block of L-type Ca2+ channels. J Gen Physiol 1996; ebellar ataxia: a problem of cerebellar intracellular pH 108:363–74. homeostasis. Ann Neurol 1992;31:147–54. 14 Haan J, Terwindt GM, OphoV RA, et al. Is familial hemiple- 12 Prod’hom B, Pietrobon D, Hess P. Direct measurement of gic migraine a form of basilar migraine? Cephalgia 1995;15: proton transfer rates to a group controlling the 477–81.

NEUROLOGICAL PICTURE

A “scar” and epilepsy: coup de sabre

B http://jnnp.bmj.com/

sabre, a rare form of localised scleroderma. This is often associated with neurological symptoms, especially epilepsy. Intracranial cal- cifications or white matter abnormalities can occur. Because the pathogenesis is still un- known, it remains a matter of debate whether

A on September 26, 2021 by guest. Protected copyright. A 28 year old man of Turkish descent had a five cerebral involvement in linear scleroderma en year history of monthly nocturnal epileptic coup de sabre is a consequence of an attacks. Physical examination disclosed a lin- inflammatory process or constitutes a neurocu- ear, atrophic, brownish skin area on the left taneous syndrome.12 forehead just lateral to the midline. The lesion R F DUYFF extended from the left superior orbital ridge JVOS into the scalp and was associated with hair loss. Department of Neurology, St Lucas Andreas Ziekenhuis, There was no facial hemiatrophy (figure A) Jan Tooropstraat 164, 1061 AE Amsterdam, Neurological examination disclosed no abnor- The Netherlands malities. EEG was normal. Brain CT showed Correspondence to: Dr R F DuyV, Department of Neurology, small intracranial calcifications in the left tem- St Lucas Andreas Ziekenhuis, Jan Tooropstraat 164, 1061 AE Amsterdam, The Netherlands. Telephone 0031 20 5108320; poral lobe and loss of subcutaneous tissue at fax 0031 20 6837024. the site of the lesion (arrows) without involve- ment of skull bone (figure B). Brain MRI was 1 Chung MH, Sum J, Morrell MJ, et al. Intracerebral involve- normal. ment in scleroderma en coup de sabre: report of a case with If, as in our patient, the history is unclear, neuropathologic findings. Ann Neurol 1995;37:679–81. 2 Pupillo G, Andermann F, Dubeau F. Linear scleroderma this lesion can be mistaken for a scar. However, and intractable epilepsy: neuropathologic evidence for a it is typical of linear scleroderma en coup de chronic inflammatory process. Ann Neurol 1996;39:277–8.