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Spinocerebellar Ataxia Type 6 with Positional Vertigo and Acetazolamide Responsive Episodic Ataxia

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Spinocerebellar Ataxia Type 6 with Positional Vertigo and Acetazolamide Responsive Episodic Ataxia 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.
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