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Autosomal dominant cerebellar ataxias (ADCA) are characterised by clinical and genetic heterogeneity with a substantial overlap of clinical features and a variable degree of adherence to three distinct phenotypes according to Harding’s clinical classification: ADCA type I, II, and III.1 The availability of molecular genetic testing has provided increasing appreciation of a wider clinical spectrum than previously thought for each ADCA subgroup. In addition there is an increasing list of genes harbouring disease causing mutations which, to date, include spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, 8, 10, 12, and 17.2 SCA 6 is caused by unstable CAG expansion in the α-1A calcium channel gene (CACNA1A).4 We present a confirmed case of SCA 6 presenting with a task specific focal dystonia (writer’s cramp) predated the onset of progressive gait ataxia by five years, which further widens the clinical spectrum of SCA 6.
A 57 year old female pharmacist first presented at the age of 42 with a two month history of progressive difficulty in writing prescriptions as a result of writing induced cramp affecting the right hand. This task specific focal dystonia was aggravated by stress and fatigue. Her father was reported to have had Parkinson’s disease on the basis of developing tremor and gait disturbance at age 40.
On examination, the patient’s gait was normal and no focal neurological deficits were identified. Her writing, after a normal start, was interrupted by a semiflexed posture of the fingers to maintain the grasp of the pen, with the index finger and thumb appeared hyperextended and the wrist hyperflexed. This was accompanied by an ache in the hand. A working diagnosis of writer’s cramp with a suspicion of familial dystonic disorders was made and she was started on the anticholinergic drug, trihexyphenidyl.
On annual follow up, she reported a satisfactory improvement in her symptoms. During this period and on more than one occasion, no cerebellar signs were identified.
Five years after the onset of focal dystonia, she developed an intention tremor in her right hand and upper limb ataxia but with a normal gait. A diagnosis of autoimmune hypothyroidism was made following a confirmatory test results and thyroxine was started concurrently with propranolol to control the tremor. Two years later, at the age of 49, she began to experience difficulties with maintaining her balance when walking downhill, which later progressed to an increasing tendency to sway or trip. The writer’s cramp had persisted with progressive tremor and clumsiness in both arms, forcing her to swap hands when writing (fig 1). A more detailed family history revealed additional information about paternal relatives who had a history of tremor and gait disturbance; however, none had developed writer’s cramp.
Neurological examination now showed evidence of gait and limb ataxia, mild intention tremor, and horizontal gaze-evoked nystagmus, with mild dysarthria and no other neurological deficit. Ancillary tests to exclude acquired ataxias were also done, and brain magnetic resonance imaging revealed evidence of marked cerebellar atrophy with sparing of cortical and brain stem structures.
With informed consent, genomic DNA was extracted from peripheral blood leucocytes. Screening for trinucleotide repeat expansions for SCA 1, 2, 3, and 6 was done using polymerase chain reaction (PCR) amplifications of the genomic sequences containing each trinucleotide repeat expansion site. The PCR products were size fractionated by electrophoresis in a 6% polyacrylamide gel, which was then dry blotted. After hybridisation with a gamma-32P labelled (CAG)n oligonucleotide probe, allele sizes were visualised by autoradiography. Estimations of trinucleotide repeat size for each gene was made using well characterised positive control samples. A pathological 22 repeat expansion in the CACNA1A gene3 and another allele of 12 repeats were detected (fig 2). Alleles within normal range were detected in the SCA 1, 2, and 3 genes.
We describe a case of SCA 6 with a focal dystonia preceding the onset of gait or limb ataxia by a period of at least five years. Recently, there has been a report of similar SCA 6 presentation but with a more progressive, disabling, and treatment resistant shoulder girdle and upper limb dystonia.3 In the original description of SCA 6, the most common presenting feature was a progressive cerebellar syndrome, accompanied by involuntary movements, dystonic posturing, sensory loss, and changes in the deep tendon reflexes.4 Other presenting features have been reported as a result of direct molecular testing, including episodic ataxia and positional vertigo associated with downbeat nystagmus.5 Our report provides further evidence of a wider clinical presentation of SCA 6, but may also be relevant to other ADCAs, which were previously considered to be relatively “pure” cerebellar ataxias.
This case also shows that, in the absence of a suggestive family history or presenting cerebellar features, it is unusual for clinicians to include ADCA in the differential diagnosis. Dystonia or extrapyramidal motor signs have often been associated with SCA 3, but are not specific, as overlap exists, though less frequently, with other subtypes in ADCA I.6 With disease progression, the focal dystonia in our patient has partially resolved and has been predominantly replaced by a mild pancerebellar ataxia with very few extracerebellar signs and absence of other extrapyramidal features. The evolution of these signs and the partial resolution of the writer’s cramp persuade us that the dystonia and ataxia are part of the same pathological process rather than separate disease entities.
Ten years after the onset of gait disturbance, the patient is walking using only one stick and remains employed, consistent with the mild disease course previously reported for SCA 6 phenotype. Increasingly, the availability of molecular investigations is indicating a need to revise the phenotype according to the underlying genotype. It is apparent that the majority of the inherited ataxias have a broader clinical spectrum than has previously been appreciated, particularly with ADCA.6 Our experience highlights the wide range of syndromic presentations as well as advocating the clinical value of testing SCA 6 alongside SCA 1, 2, and 3 which constitute ADCA I. In addition, it may be useful to screen SCA loci in the ADCA I subgroup in cases of idiopathic focal dystonia who develop features of cerebellar dysfunction or who have a relevant family history.
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