A new autosomal dominant pure cerebellar ataxia.

A kindred is described with a dominantly inherited "pure" cerebellar ataxia in which the currently known spinocerebellar ataxias have been excluded. In the eight subjects studied, a notable clinical feature is slow progression, with the three least affected having only a mild degree of gait ataxia after three or more decades of disease duration. Pending an actual chromosomal locus discovery, the name spinocerebellar ataxia (SCA)15 is expectantly applied.     

A case of Machado-Joseph disease presenting pure cerebellar ataxia]

We report a 61-year-old woman with Machado-Joseph disease (MJD) presenting with pure cerebellar ataxia. The patient exhibited an unsteady gait at the age of 51 years. She was admitted to our hospital at the age of 61 years. Her older brother had been diagnosed as having spinocerebellar degeneration (SCD). Our patient showed gaze-evoked nystagmus, wide-based gait, slight lack of coordination of the four extremities, mildly ataxic speech and slight decrease in the bilateral Achilles tendon reflexes. Babinski's sign was absent. Sensory impairments were not present and muscle tone and muscle strength were normal. There was no autonomic dysfunctions. MRI revealed moderate atrophy of the cerebellum and pons. We performed gene analysis of SCD using white blood cells from the patient, and the analysis showed 70 CAG repeats in the MJD1 gene, which is an abnormally high number of repeats. Compared with three reported cases of MJD presenting pure cerebellar ataxia, only our patient showed a nasal voice. The number of CAG repeats in the MJD1 gene of our patients was the most prolonged of the four cases. MJD should be considered in patients with familial SCD even if their neurological signs and symptoms outside the cerebellum are not obvious.     

Radial diffusivity in the cerebellar peduncles correlates with clinical severity in Friedreich ataxia

Friedreich ataxia (FRDA) is a common inherited ataxia, caused by an expanded GAA repeat sequence in the Frataxin (FXN) gene. The proprioceptive system, which enters the cerebellum through the cerebellar peduncles, is a primary focus of pathology. In this study, we investigate the relationship of clinical and genetic data with diffusion-tensor imaging (DTI) indices reflecting white matter integrity of the cerebellar peduncles. Nine FRDA patients underwent DTI. After between-subject registration using tract-based spatial statistics, a white matter atlas was used for computing average values of DTI indices in the regions of interest. These were the inferior, middle and superior cerebellar peduncles (ICP, MCP, SCP). For Bonferroni correction, significance threshold was set to p < 0.0056. We found that radial diffusivity (D^⊥) within the ICP significantly correlated with scores on the Friedreich Ataxia Rating Scale (FARS, Spearman’s ρ = 0.883, p = 0.0016, all two-sided) and, at trend level, with number of trinucleotide repeats (ρ = 0.812, p = 0.008). D^⊥ in the SCP correlated with scores on the Scale for the Assessment and Rating of Ataxia (SARA, ρ = 0.867, p = 0.0025). These findings support the role of DTI, and especially D^⊥, as an informative biomarker in FRDA.     

Altered soleus responses to magnetic stimulation in pure cerebellar ataxia.

OBJECTIVE: Transcranial magnetic stimulation (TMS) over the leg motor area elicits a soleus primary response (SPR) and a soleus late response (SLR). We evaluated the influence of the cerebellofugal pathway on the SPR and SLR in patients with 'pure' cerebellar ataxia. METHODS: SPRs and SLRs were recorded from 11 healthy subjects and 9 patients with 'pure' cerebellar cortical degeneration; 5 with spinocerebellar ataxia type 6 (SCA6), and 4 with late cortical cerebellar ataxia (LCCA). In addition, three patients with localized cerebellar lesions were tested. RESULTS: The SPR latency was significantly longer in patients than in controls, but primary responses in the tibialis anterior muscle were normal. The frequency of abnormal SLR was 38.9% in the supine position and 83.3% in the standing position. Two out of three patients with localized cerebellar lesions also showed abnormal SLR. CONCLUSIONS: Altered SPRs in patients may result from a dysfunction of the primary motor cortex caused by crossed cerebello-cerebral diaschisis. In addition, our results suggest that 'pure' cerebellar degeneration involves the mechanism responsible for evoking SLR which is related to the control of posture. SIGNIFICANCE: SLR can be a useful neurophysiological parameter for evaluating cerebellofugal function.     

Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum and characterized by a typical motor syndrome. In addition, the presence of cognitive impairment is now widely acknowledged as a feature of SCA2. Given the extensive connections between the cerebellum and associative cerebral areas, it is reasonable to hypothesize that cerebellar neurodegeneration associated with SCA2 may impact on the cerebellar modulation of the cerebral cortex, thus resulting in functional impairment. The aim of the present study was to investigate and quantitatively map the pattern of cerebellar gray matter (GM) atrophy due to SCA2 neurodegeneration and to correlate that with patients’ cognitive performances. Cerebellar GM maps were extracted and compared between SCA2 patients (n = 9) and controls (n = 33) by using voxel-based morphometry. Furthermore, the relationship between cerebellar GM atrophy and neuropsychological scores of the patients was assessed. Specific cerebellar GM regions were found to be affected in patients. Additionally, GM loss in cognitive posterior lobules (VI, Crus I, Crus II, VIIB, IX) correlated with visuospatial, verbal memory and executive tasks, while additional correlations with motor anterior (V) and posterior (VIIIA, VIIIB) lobules were found for the tasks engaging motor and planning components. Our results provide evidence that the SCA2 neurodegenerative process affects the cerebellar cortex and that MRI indices of atrophy in different cerebellar subregions may account for the specificity of cognitive symptomatology observed in patients, as result of a cerebello-cerebral dysregulation.     

Orthogonal diffusion-weighted MRI measures distinguish region-specific degeneration in cerebellar ataxia subtypes

The cerebellar peduncles are excellent candidates for composite indicators of regional degeneration in posterior fossa structures, as the peduncles show histopathological changes in degenerative ataxia. We postulate that magnetic resonance imaging will reveal evidence of disease specific peduncle degeneration through macrostructural (cross-sectional area) and microstructural (fractional anisotropy, mean diffusivity) measures. This study presents a “proof of principle” using orthogonal diffusion tensor imaging cross-sections of the cerebellar peduncles to distinguish categories of cerebellar disease.     

The cerebellar form of acquired hepatocerebral degeneration: The hepatic ataxia

This article reports a patient with acquired hepatocerebral degeneration that presented with progressive cerebellar ataxia, cerebellar atrophy, and middle cerebellar peduncle lesions. He had a marked improvement after liver transplantation. We reinforce that hepatic failure should be investigated in patients with pure cerebellar syndrome, resembling neurodegenerative diseases.     

Synaptic neurochemical alterations associated with neuronal degeneration in an inherited cerebellar ataxia of Gordon Setters

Canine Inherited Ataxia (CIA) is an autosomal recessive cerebellar disease of Gordon Setters associated with degeneration of Purkinje and granule cells. To define specific biochemical correlates of neuronal loss, synaptic neurochemical parameters were measured in three cerebellar regions (vermis, "pars intermedia," and hemisphere) at early and late stages of this disease. At one and a half years of age, affected dogs showed the most severe lesions in the "pars intermedia," with a 39% decrease in the number of Purkinje cells and a 29% decrease in granule cells. Neurochemical measurements demonstrated decreased [3H]muscimol binding and elevations in norepinephrine concentration (248% above control) and [3H]glutamate receptor binding (118% above control). At five years of age, reduction of Purkinje cells in the three cerebellar regions ranged from 65 to 91% while loss of granule cells was between 13 and 53%. [3H]Muscimol binding remained low throughout the cerebellum (38 to 59% of control) and norepinephrine concentration and [3H]glutamate binding were markedly reduced from the levels observed at one and a half years. Glutamate decarboxylase activity, [3H]QNB binding and GABA concentration were relatively unaffected. Our results indicate that neurochemical parameters associated with cerebellar neuronal systems demonstrate specific alterations in a chronic degenerative disorder. This study also indicates the importance of evaluating neurochemical measurements with regard to both spared and degenerating neuronal systems and emphasizes the role of compensatory neurochemical alterations in cerebellar degenerative disorders.     

A new sulcus-corrected approach for assessing cerebellar volume in spinocerebellar ataxia

Precise volumetry of the cerebellum still remains challenging, due to thin sulci and gyri. We present a new fast and reliable sulcus-corrected approach for quantitative assessment of cerebellar atrophy, evaluated on patients with spinocerebellar ataxia (SCA). Thin-sliced T1-weighted magnetic resonance images (MPRAGE) were acquired in 11 genetically confirmed SCA6 patients and in a group of age-matched control subjects (n = 14). Post-processing involves a morphological image segmentation pipeline as a basis for a sulcus-corrected cerebellar volume measurement. Cerebellar volumes and intra-rater, inter-rater and scan-rescan reproducibility were quantified. Reliability of the measurements was validated using an anatomical preparation of the cerebellum. Repeatability coefficients (RC: intra-rater/inter-rater/scan-rescan) of the method were 1.07%/1.11%/1.35%. Absolute cerebellar volumes showed good agreement with the actual volume of the anatomical preparation. The cerebellar volume of the SCA 6 was 96.3 ± 12.1 ml (mean ± S.D.), which was significantly lower than the results of the corresponding control groups. The cerebellar volume correlated significantly to clinical dysfunction in SCA6. This is the first study to demonstrate the feasibility of a new sulcus-corrected approach to assess cerebellar volume. In contrast to currently used methods, this new approach may be more sensitive even to small atrophic changes affecting sulcal widening.     

Familial cerebellar ataxia with hypogonadism

Summary A brother and sister with congenital cerebellar ataxia, anosmia, oligophrenia, hypogonadism and anomalies of amino acid distribution are reported. Ties between the different symptoms are difficult to establish. It seems to be a new syndrome rather than a new disease. Once more these associations emphasize the need for metabolic and biochemical research in heredodegenerative diseases. The evolution of the disease in these cases might make it possible to classify and locate it more accurately.

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Zusammenfassung Es wird über einen Patienten und dessen Schwester berichtet, bei welchen eine kongenitale cerebelläre Ataxie mit Oligophrenie, Anosmie, Hypogonadismus und Anomalien der Aminosäureverteilung vorlagen. Es ist schwierig, Zusammenhänge zwischen den einzelnen Merkmalen zu definieren. Es scheint sich eher um ein neues Syndrom als um eine neue Krankheit zu handeln. Aufgrund dieser Beobachtung wird die Notwendigkeit unterstrichen, bei heredodegenerativen Leiden biochemische Untersuchungen durchzuführen.

     

Spatial and temporal pattern of purkinje cell degeneration in shaker mutant rats with hereditary cerebellar ataxia

Temporal-spatial patterns of surviving Purkinje cells were studied quantitatively in a rat mutant (shaker) with differential hereditary cerebellar ataxia and Purkinje cell degeneration. Shaker rat mutants are characterized behaviorally as mild if they are ataxic or as strong if they have ataxia and tremor. Purkinje cells degenerate in both mild and strong shaker mutants, but the temporal and spatial patterns of cell death are strikingly different. In mild shaker mutants, Purkinje cell death is temporally restricted, with 31-46% of the Purkinje cells in lobules I-IX dying by 3 months of age. Very few Purkinje cells degenerate after this age. Purkinje cell death is spatially random. In lobules I-IX, every second, third, or fourth Purkinje cell degenerates. Purkinje cells in lobule X do not degenerate. In strong shaker mutants, Purkinje cell degeneration is temporally protracted and spatially restricted. By 3 months of age, most Purkinje cells in lobules I-VIa, -b, and -d, and -d have degenerated. Numerous Purkinje cells in the paravermis of lobules VIIb-VIII have also degenerated. Surviving Purkinje cells in the vermis and lateral hemisphere of lobules VIIb-VIII are aligned in parasagittally oriented stripes or transversely oriented bands. Purkinje cells continue to degenerate in localized areas of the posterior lobe such that, by 18 months of age, surviving Purkinje cells are limited primarily to lobules VIc, VIIa, IXd, and X. Quantitative analysis indicates that none of the Purkinje cells in these lobules degenerate.     

Mapping of the gene for a novel spinocerebellar ataxia with pure cerebellar signs and epilepsy

We investigated a family with a new type of autosomal dominant cerebellar ataxia (ADCA) in which pure cerebellar ataxia is often accompanied with epilepsy. No CAG repeat expansions were detected at the spinocerebellar ataxia (SCA) type 1, 2, 3, 6, or 7 locus, and SCAs 4 and 5 were excluded by linkage analysis. We found linkage between the disease locus and D22S274 (Zmax = 3.86 at theta = 0.00) and two other makers in 22q13-qter. Haplotype analysis of the crossover events and the multipoint linkage mapping localized the disease locus to an 8.8-cM region between D22S1177 and D22S1160.     

A gene on SCA4 locus causes dominantly inherited pure cerebellar ataxia

BACKGROUND: Several different genes or their loci have been identified for autosomal dominant cerebellar ataxia (ADCA). However, other types of ataxia remain unassigned. OBJECTIVE: To identify a new locus for ADCA. METHODS: Six Japanese families with ADCA with pure cerebellar syndrome (ADCA type III) were examined. These families had been molecularly excluded for spinocerebellar ataxia (SCA) types 1 through 3, 5 through 8, and 10. Clinical examination was undertaken, and a genome-wide linkage search was performed on 250 microsatellite DNA markers. RESULTS: Strong evidence for linkage was found with markers on human chromosome 16q, and haplotype and multipoint analyses further refined the gene locus in a 10.9-cM interval between D16S3089 and D16S515. Linkage disequilibrium was further found with the marker D16S3107 within the interval. The locus was exactly the candidate interval of SCA4, a rare form of ADCA clinically characterized by ataxia with sensory neuropathy and pyramidal tract signs. This would suggest that SCA4 and our ADCA type III are likely to be allelic disorders with different clinical features. CONCLUSION: The current study provides evidence that a gene on the SCA4 locus causes a pure cerebellar syndrome.     

Pontine atrophy precedes cerebellar degeneration in spinocerebellar ataxia 7: MRI-based volumetric analysis

BACKGROUND AND OBJECTIVE: Spinocerebellar ataxia 7 (SCA7) is characterised by cerebellar ataxia and visual loss. The aim of the present study was to elucidate the magnetic resonance imaging (MRI) findings characteristic of patients with SCA7. METHODS: Twenty patients with SCA (eight SCA3, three SCA6, and nine SCA7) and 20 control subjects underwent an MRI-based volumetric analysis. RESULTS: The pontine volume in patients with SCA7 was decreased by a greater amount than in patients with other types of SCA (p<0.01), whereas the cerebellar volume was not different from that in other types of SCA (p>0.05). Pontine atrophy was a consistent finding in all patients with SCA7 regardless of the degree of cerebellar atrophy or the severity or duration of illness. In contrast, cerebellar atrophy was not found in those with a short duration of illness or mild ataxia, but became prominent as the severity and duration of illness progressed. CONCLUSIONS: Our study suggests that neurodegeneration is ongoing during the life of individuals with SCA7, and that the primary pathology in these individuals involves the brainstem rather than the cerebellum. In addition, pontine atrophy is a prominent, consistent finding in SCA7, and may help in establishing the clinical diagnosis of SCA7.     

Infratentorial hypointense lesion volume on T1-weighted magnetic resonance imaging correlates with disability in patients with chronic cerebellar ataxia due to multiple sclerosis.

In multiple sclerosis (MS), hypointense lesions on T1-weighted magnetic resonance imaging are thought to represent areas of tissue disruption and axonal loss. In previous studies of MS patients, infratentorial T1 hypointense lesions were found to be rare. In MS patients selected to have chronic cerebellar ataxia, we have determined the extent of infratentorial T1 hypointense lesions and their relationship with disability. We recruited nine patients with chronic cerebellar ataxia due to MS. An expanded disability status scale (EDSS) assessment was performed on each. The patients' brains were then imaged with axial-oblique dual-echo fast spin-echo and contrast-enhanced T1-weighted conventional spin-echo sequences. The number and total volume of infratentorial high-signal lesions on T2-weighted images and infratentorial hypointense lesions on T1-weighted images were calculated by a blinded observer using a computer-assisted contouring technique. A total of 96 infratentorial high-signal lesions were present, of which 62 (64.6%) appeared isointense and 34 (35.4%) hypointense with respect to the surrounding brain substance on the T1-weighted images. There was a median of 3 (range 0-10) and median volume of 0.43 ml (range 0-0.85 ml) infratentorial T1 hypointense lesions per patient. The EDSS score correlated with both the number (r=0.68, p=0.043) and the volume per patient (r=0.89, p=0.001) of infratentorial T1 hypointense but not T2 high-signal lesions. Infratentorial T1 hypointense lesions are often seen in patients with MS and chronic cerebellar ataxia. They may play a significant role in the disability suffered by these patients.