Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1–3), speech (item 4) and the limb kinetic subscore (items 5–8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose–finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.

[1]  L. Schöls,et al.  Autosomal dominant cerebellar ataxia: Phenotypic differences in genetically defined subtypes? , 1997, Annals of neurology.

[2]  Shinsuke Fujioka,et al.  Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics , 2011, Orphanet journal of rare diseases.

[3]  William B. Dobyns,et al.  Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel , 1997, Nature Genetics.

[4]  Adam Possner,et al.  Cerebellum , 2012, Neurology.

[5]  M Skalej,et al.  Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. , 1996, Brain : a journal of neurology.

[6]  Shigenobu Nakamura,et al.  CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1 , 1994, Nature Genetics.

[7]  Shirley Hansen,et al.  Dominantly inherited olivopontocerebellar atrophy from eastern Cuba Clinical, neuropathological, and biochemical findings , 1989, Journal of the Neurological Sciences.

[8]  M. Skalej,et al.  A new semiautomated, three‐dimensional technique allowing precise quantification of total and regional cerebellar volume using MRI , 1998, Magnetic resonance in medicine.

[9]  Visuomotor Cerebellum in Human and Nonhuman Primates , 2010, The Cerebellum.

[10]  Peter Bauer,et al.  Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6 , 2010, NeuroImage.

[11]  Harry T Orr,et al.  Trinucleotide repeat disorders. , 2007, Annual review of neuroscience.

[12]  X. Estivill,et al.  Clinical, neuropathologic, and genetic studies of a large spinocerebellar ataxia type 1 (SCA1) kindred , 1995, Neurology.

[13]  H. Mitoma,et al.  Gait disturbances in patients with pontine medial tegmental lesions: clinical characteristics and gait analysis. , 2000, Archives of neurology.

[14]  Yves Agid,et al.  Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats , 1996, Nature Genetics.

[15]  J. Hermsdörfer,et al.  Impairments of prehension kinematics and grasping forces in patients with cerebellar degeneration and the relationship to cerebellar atrophy , 2008, Clinical Neurophysiology.

[16]  P. Maruff,et al.  An optimized method for estimating intracranial volume from magnetic resonance images , 2000, Magnetic resonance in medicine.

[17]  J. Bogousslavsky,et al.  Thalamic Ataxia Syndrome , 1995, Neurology.

[18]  Alexandra Durr,et al.  Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond , 2010, The Lancet Neurology.

[19]  D. Zee,et al.  Spinocerebellar ataxia type 6: Gaze‐evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset , 1997, Annals of neurology.

[20]  G. Auburger,et al.  Autosomal dominant cerebellar ataxia , 1990, Neurology.

[21]  H. Diener,et al.  Chapter 17 – Coordination and Ataxia , 2007 .

[22]  Y. Agid,et al.  Analysis of the SCAI CAG repeat in a large number of families with dominant ataxia: Clinical and molecular correlations , 1995, Annals of neurology.

[23]  S. Pulst,et al.  Spinocerebellar Ataxia Type 2: Genotype and Phenotype in German Kindreds , 1997 .

[24]  Sergio Cocozza,et al.  Autosomal dominant cerebellar ataxia type I. Clinical and molecular study in 36 Italian families including a comparison between SCA1 and SCA2 phenotypes , 1996, Journal of the Neurological Sciences.

[25]  M Fetter,et al.  Compartmentalized cerebellar functions upon the stabilization of body posture. , 1993, Revue neurologique.

[26]  H. Paulson,et al.  The spinocerebellar ataxias. , 2009, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[27]  Huda Y. Zoghbi,et al.  Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1 , 1993, Nature Genetics.

[28]  Georg Auburger,et al.  Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2 , 1996, Nature Genetics.

[29]  J. Dichgans,et al.  Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3 , 1999, Journal of Neurology.

[30]  Jan B. M. Kuks,et al.  Textbook of Clinical Neurology , 2003 .

[31]  R W Baloh,et al.  Oculomotor phenotypes in autosomal dominant ataxias. , 1998, Archives of neurology.

[32]  E. Dietrichs.  Clinical manifestation of focal cerebellar disease as related to the organization of neural pathways , 2008, Acta neurologica Scandinavica. Supplementum.

[33]  L. Baliko,et al.  Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings , 2008, The Cerebellum.

[34]  K. Fukushima,et al.  Positional vertigo and macroscopic downbeat positioning nystagmus in spinocerebellar ataxia type 6 (SCA6) , 2003, Journal of Neurology.

[35]  D. Zee,et al.  Relative Atrophy of the Flocculus and Ocular Motor Dysfunction in SCA2 and SCA6 , 2005, Annals of the New York Academy of Sciences.

[36]  Peter Stoeter,et al.  Topodiagnostic implications of hemiataxia: An MRI-based brainstem mapping analysis , 2008, NeuroImage.

[37]  Markus Frings,et al.  Reliability and validity of the scale for the assessment and rating of ataxia: A study in 64 ataxia patients , 2007, Movement disorders : official journal of the Movement Disorder Society.

[38]  M Skalej,et al.  Autosomal dominant cerebellar ataxia type I. MRI-based volumetry of posterior fossa structures and basal ganglia in spinocerebellar ataxia types 1, 2 and 3. , 1998, Brain : a journal of neurology.

[39]  B. Tang,et al.  Spinocerebellar ataxia type 6: Systematic patho‐anatomical study reveals different phylogenetically defined regions of the cerebellum and neural pathways undergo different evolutions of the degenerative process , 2010, Neuropathology : official journal of the Japanese Society of Neuropathology.

[40]  Lippincott Williams Wilkins,et al.  Scale for the assessment and rating of ataxia: Development of a new clinical scale , 2006, Neurology.

[41]  Alexandra Durr,et al.  Spinocerebellar ataxia 3 and machado‐joseph disease: Clinical, molecular, and neuropathological features , 1996, Annals of neurology.

[42]  R. Krüger,et al.  Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds , 1998, Journal of neurology, neurosurgery, and psychiatry.