Spinocerebellar ataxia type 6 (SCA6): neurodegeneration goes beyond the known brain predilection sites

Aims:  Spinocerebellar ataxia type 6 (SCA6) is a late onset autosomal dominantly inherited ataxic disorder, which belongs to the group of CAG repeat, or polyglutamine, diseases. Although, it has long been regarded as a 'pure' cerebellar disease, recent clinical studies have demonstrated disease signs challenging the view that neurodegeneration in SCA6 is confined to the well-known lesions in the cerebellum and inferior olive. Methods:  We performed a systematic pathoanatomical study throughout the brains of three clinically diagnosed and genetically confirmed SCA6 patients. Results:  This study confirmed that brain damage in SCA6 goes beyond the known brain predilection sites. In all of the SCA6 patients studied loss of cerebellar Purkinje cells and absence of morphologically intact layer V giant Betz pyramidal cells in the primary motor cortex, as well as widespread degeneration of brainstem nuclei was present. Additional damage to the deep cerebellar nuclei was observed in two of three SCA6 patients. Conclusions:  In view of the known functional role of affected central nervous grey components it is likely that their degeneration at least in part is responsible for the occurrence of a variety of SCA6 disease symptoms.     

Spinocerebellar Ataxia Type 2 (SCA2): Identification of Early Brain Degeneration in One Monozygous Twin in the Initial Disease Stage

Spinocerebellar ataxia type 2 (SCA2) is a progressive autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG repeat or polyglutamine diseases. Recent morphological studies characterized the pathoanatomical features in heterozygous SCA2 patients and revealed severe neuronal loss in a large variety of cerebellar and extra-cerebellar brain sites. In the present study, we examined the brain pathoanatomy of a monozygous twin of a large Hungarian SCA2 family with pathologically extended CAG repeats in both SCA2 alleles. This unique patient was in the initial clinical stage of SCA2 and died almost 3?years after SCA2 onset. Upon pathoanatomical investigation, we observed loss of giant Betz pyramidal cells in the primary motor cortex, degeneration of sensory thalamic nuclei, the Purkinje cell layer, and deep cerebellar nuclei, as well as select brainstem nuclei (i.e., substantia nigra, oculomotor nucleus, reticulotegmental nucleus of the pons, facial, lateral vestibular, and raphe interpositus nuclei, inferior olive). All of these degenerated brain gray matter structures are known as consistent targets of the underlying pathological process in heterozygous SCA2 patients. Since they were already involved in our patient within 3?years after disease onset, we think that we were for the first time able to identify the early brain targets of the pathological process of SCA2.     

Disruption of visual and motor connectivity in spinocerebellar ataxia type 7

Spinocerebellar ataxia type 7 (SCA7) is an autosomal‐dominant neurodegenerative disorder characterized by progressive ataxia and retinal dystrophy. It is caused by a CAG trinucleotide expansion in the ataxin7 gene. Anatomical studies have shown severe cerebellar degeneration and region‐specific neocortical atrophy in SCA7 patients. However, the impact of the neurodegeneration on the functional integration of the remaining tissue is still unknown. The aim of this study was to examine functional connectivity abnormalities in areas with significant gray matter atrophy in SCA7 patients and their relationship with number of CAG repeats. Using a combination of voxel‐based morphometry and resting‐state fMRI, we studied 26 genetically confirmed SCA7 patients and aged‐matched healthy controls. In SCA7 patients we found reduced functional interaction between the cerebellum and the middle and superior frontal gyri, disrupted functional connectivity between the visual and motor cortices, and increased functional coordination between atrophied areas of the cerebellum and a range of visual cortical areas compared with healthy controls. The degree of mutation expansion showed a negative effect on both the functional interaction between the right anterior cerebellum and the left superior frontal gyrus and the connectivity between the right anterior cerebellum and left parahippocampal gyrus. We found abnormal functional connectivity patterns, including both hypo‐ and hyperconnectivity, compared with controls. These abnormal patterns show reasonable association with the severity of gene mutation. Our findings suggest that aberrant changes are prevalent in both motor and visual systems, adding significantly to our understanding of the pathophysiology of SCA7. © 2013 International Parkinson and Movement Disorder Society     

Pathoanatomy of Cerebellar Degeneration in Spinocerebellar Ataxia Type 2 (SCA2) and Type 3 (SCA3)

The cerebellum is one of the well-known targets of the pathological processes underlying spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Despite its pivotal role for the clinical pictures of these polyglutamine ataxias, no pathoanatomical studies of serial tissue sections through the cerebellum have been performed in SCA2 and SCA3 so far. Detailed pathoanatomical data are an important prerequisite for the identification of the initial events of the underlying disease processes of SCA2 and SCA3 and the reconstruction of its spread through the brain. In the present study, we performed a pathoanatomical investigation of serial thick tissue sections through the cerebellum of clinically diagnosed and genetically confirmed SCA2 and SCA3 patients. This study demonstrates that the cerebellar Purkinje cell layer and all four deep cerebellar nuclei consistently undergo considerable neuronal loss in SCA2 and SCA3. These cerebellar findings contribute substantially to the pathogenesis of clinical symptoms (i.e., dysarthria, intention tremor, oculomotor dysfunctions) of SCA2 and SCA3 patients and may facilitate the identification of the initial pathological alterations of the pathological processes of SCA2 and SCA3 and reconstruction of its spread through the brain.     

Spinocerebellar ataxia type 4 (SCA4): Initial pathoanatomical study reveals widespread cerebellar and brainstem degeneration

Summary. Spinocerebellar ataxia type 4 (SCA4), also known as ‘hereditary ataxia with sensory neuropathy’, represents a very rare, progressive and untreatable form of an autosomal dominant inherited cerebellar ataxia (ADCA). Due to a lack of autopsy cases, no neuropathological or clinicopathological studies had yet been performed in SCA4. In the present study, the first available cerebellar and brainstem tissue of a clinically diagnosed and genetically-confirmed German SCA4 patient was pathoanatomically studied using serial thick sections. During this systematic postmortem investigation, along with an obvious demyelinization of cerebellar and brainstem fiber tracts we observed widespread cerebellar and brainstem neurodegeneration with marked neuronal loss in the substantia nigra and ventral tegmental area, central raphe and pontine nuclei, all auditory brainstem nuclei, in the abducens, principal trigeminal, spinal trigeminal, facial, superior vestibular, medial vestibular, interstitial vestibular, dorsal motor vagal, hypoglossal, and prepositus hypoglossal nuclei, as well as in the nucleus raphe interpositus, all dorsal column nuclei, and in the principal and medial subnuclei of the inferior olive. Severe neuronal loss was seen in the Purkinje cell layer of the cerebellum, in the cerebellar fastigial nucleus, in the red, trochlear, lateral vestibular, and lateral reticular nuclei, the reticulotegmental nucleus of the pons, and the nucleus of Roller. In addition, immunocytochemical analysis using the anti-polyglutamine antibody 1C2 failed to detect any polyglutamine-related immunoreactivity in the central nervous regions of this SCA4 patient studied. In view of the known functional role of affected nuclei and related fiber tracts, the present findings not only offer explanations for the well-known disease symptoms of SCA4 patients (i.e. ataxic symptoms, dysarthria and somatosensory deficits), but for the first time help to explain why diplopia, gaze-evoked nystagmus, auditory impairments and pathologically altered brainstem auditory evoked potentials, saccadic smooth pursuits, impaired somatosensory functions in the face, and dysphagia may occur during the course of SCA4. Finally, the results of our immunocytochemical studies support the concept that SCA4 is not a member of the CAG-repeat or polyglutamine diseases. Y. Hellenbroich and K. Gierga are joint first authors C. Zühlke and U. Rüb are joint senior authors     

A neuropathological study at autopsy of early onset spinocerebellar ataxia 6

Spinocerebellar ataxia type 6 (SCA6) is a late-onset, autosomal dominantly inherited ataxic disorder, and most previous clinical studies consider SCA6 to be a “pure” cerebellar ataxia. We carried out a detailed pathoanatomical study at autopsy of two patients, brother and sister, with genetically confirmed SCA6. The disease in both patients was early onset and short, which is atypical for SCA6. We observed severe neurodegeneration in the cerebellum, dentate nucleus and olivary nuclei. Both patients showed evidence of synaptic modification in the cerebellar cortex, which morphologically confirmed the existence of retrograde and anterograde trans-synaptic degeneration secondary to the cerebellar cortical lesion. Furthermore, our study shows for the first time that neurodegeneration in SCA6 occurs in the spinal cord. Finally, our postmortem study confirms that SCA6 is not a simple “pure” cerebellar disease, but a complex neurodegenerative condition in which many extracerebellar structures are involved.     

Amino acids in a region of ataxin-1 outside of the polyglutamine tract influence the course of disease in SCA1 transgenic mice

Spinocerebellar ataxia type 1 (SCA1) belongs to a family of polyglutamine induced neurodegenerative disorders. Transgenic mice that overexpress a mutant allele of the SCA1 gene develop a progressive ataxia and Purkinje cell pathology. In this report, the pathological importance of a segment of ataxin-1 previously shown to be important for protein-protein interactions was examined. While the absence of a 122 amino acid segment from the protein-protein interaction region of ataxin-1 did not effect the initiation of disease, its absence substantially suppressed the progression of disease in SCA1 transgenic mice. Thus, these data suggest that this region of ataxin-1 has a role in disease progression. Furthermore, these results provide evidence that ataxin-1-induced disease initiation and disease progression involve distinct molecular events.     

Clinical and molecular studies of 73 Italian families with autosomal dominant cerebellar ataxia type I: SCA1 and SCA2 are the most common genotypes

We clinically and genetically evaluated 73 Italian families with autosomal dominant cerebellar ataxia (ADCA) type I. Spinocerebellar ataxia (SCA) type 1 was the most common genotype (SCA1), accounting for 41% of cases (30 families), SCA2 was slightly less frequent (29%, 21 families), and the remaining families were negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped families, SCA1 was found most frequently in families from northern Italy (50%), while SCA2 was the most common mutation in families from the southern part of the country (56%). Slow saccades and decreased deep tendon reflexes were observed significantly more frequently in SCA2 patients, while increased deep tendon reflexes and nystagmus were more common in SCA1. In SCA1 and SCA2 families there was a significant inverse correlation between expansion size and age at onset. Analysis of triplet repeat numbers in parent-offspring pairs showed greater meiotic instability, which was associated with an earlier onset of the disease in SCA2 families than in SCA1 families. Received: 23 April 1998 Received in revised form: 14 September 1998 Accepted: 13 October 1998     

Spinocerebellar ataxia type 1 in Russia

Spinocerebellar ataxia type 1 (SCA1) is one form of autosomal dominant cerebellar ataxia (ADCA) caused by trinucleotide (CAG) repeat expansion within a mutant gene. We investigated 25 patients from 15 Russian ADCA families for SCA1 mutation and found an expanded CAG repeat in 5 families. Mutant chromosomes contained 41–51 CAG repeats (mean 46.1, SD 3.1), and normal chromosomes displayed 21–27 repeat units (mean 24.7, SD 1.3). Progressive cerebellar ataxia in our series of SCA1 patients was very commonly associated with dysarthria (in all cases) and pyramidal signs (in 10 of 11 cases). In three patients from one family we found optic atrophy, which has never been described before in genetically proven cases of SCA1. We observed no specific clinical features distinguishing SCA1 from non-SCA1 patients. In contrast to the high frequency of SCA1 in our series, we found no patients with Machado-Joseph disease, another form of ADCA caused by expanded CAG repeat.     

Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited progressive neurological disorder characterized by neuronal degeneration and reactive gliosis in the cerebellum, brainstem, spinocerebellar tracts, and dorsal columns. Multiple system atrophy is a sporadic progressive neurological disorder with degeneration and gliosis in the basal ganglia, cerebellum, brainstem, and spinal autonomic nuclei, and with argyrophilic glial cytoplasmic inclusions. We describe 4 members of a family with the SCAl mutation and a dominantly inherited progressive ataxia in which autopsy examination of 1 member showed neuropathological changes typical of multiple system atrophy, including glial cytoplasmic inclusions. In this patient, magnetic resonance imaging revealed marked brainstem and cerebellar volume loss and mild supratentorial generalized volume loss. Positron emission tomography with [¹⁸F]fluorodeoxyglucose revealed widespread hypometabolism in a pattern found in sporadic multiple system atrophy and not in dominantly inherited olivopontocerebellar atrophy. Positron emission tomography with [^llC]flumazenil revealed normal benzodiazepine receptor distribution volumes, similar to those seen in sporadic multiple system atrophy. Two other family members still living had similar changes in the imaging studies. The findings in this family suggest that the SCAl gene mutation can result in a disorder similar to multiple system atrophy, both clinically and neuropathologically.     

Prolonged cortical silent period but normal sensorimotor plasticity in spinocerebellar ataxia 6

Spinocerebellar ataxia 6 (SCA6) is a hereditary disease characterized by a trinucleotide repeat expansion in the CACNA1A gene and late‐onset bilateral cerebellar atrophy. It is unclear if there is significant pathology outside of the cerebellum. We used transcranial magnetic stimulation to assess sensorimotor cortical circuits and cortical plasticity in 8 SCA6 patients and 8 age‐matched controls. Behavioral performance was assessed using a rhythmic tapping task. Neurophysiological measures of SCA6 patients showed a prolonged cortical silent period (CSP) but normal MEP recruitment curve, short‐latency afferent inhibition, long‐latency afferent inhibition and ipsilateral silent period. Paired‐associative stimulation induction also increased motor‐evoked potentials normally. SCA6 patients had greater variability with cued rhythmic tapping than normals and deteriorated when the cue was removed; in comparison, normal subjects had similar variability between cued and uncued rhythmic tapping. Analysis using a Wing–Kristofferson timing model indicated that both clock variance and motor delay variance were abnormal. Conclusion. In SCA6, the circuits for sensorimotor integration and the mechanisms for LTP‐like plasticity in the sensorimotor cortex are unimpaired. A prolonged CSP in SCA6 just like in other cerebellar atrophies would suggest that this neurophysiological change typifies cerebellar dysfunction. © 2007 Movement Disorder Society     

Spinocerebellar ataxias type 1 and 2: comparison of clinical, electrophysiological and magnetic resonance evaluation

BACKGROUND AND PURPOSE: Spinocerebellar ataxias type 1 (SCA1) and type 2 (SCA2) belong to neurodegenerative disorders of autosomal dominant inheritance, genetically and clinically heterogeneous, caused by the expansion of CAG trinucleotides. Trunk and limb ataxia, dysarthria, dysphagia, gaze palsy, sensory and motor axonal neuropathy are the dominant features in both entities. The aim of the study was to evaluate the differences between genotype and phenotype based on clinical and electrophysiological assessment of the visual, auditory pathways, and EEG alterations in comparison with the cerebellar and brain atrophy in MRI. MATERIAL AND METHODS: 44 patients with SCA1 and 24 cases with SCA2 confirmed molecularly were examined neurologically and using the International Cooperative Ataxia Rating Scale (ICARS). A correlation of clinical symptoms and signs, and CAG repeat numbers with EEG, visual (VEP) and brainstem auditory (BAEP) evoked potentials, and MRI alterations were evaluated. RESULTS: A statistically significant negative correlation between the age of disease onset and number of CAG repeats in both types of SCA was found. Examined patients with SCA2 were younger, with longer disease duration and more pronounced cerebellar and brain atrophy in MRI. We found a significant correlation between ICARS and CAG repeats in this group. The dysphagia, pyramidal tract involvement and depressive reaction were significantly frequent in SCA1 patients. However in SCA2 patients, the peripheral nerve damage and extrapyramidal signs were more prominent. The amplitude of P100 visual evoked potentials was significantly lower in SCA1 patients and negatively correlated with CAG repeats. CONCLUSIONS: These results provide further evidence for the phenotypic differences of genetically defined SCA1 and SCA2 patients, expressed by more frequent involvement of the pyramidal tract and depression reaction in SCA1, in contrast to peripheral nerve involvement and extrapyramidal signs in the clinical feature of SCA2 phenotype. Furthermore, atrophy of the brain and cerebellum revealed in MRI was more pronounced than electrophysiological functional alterations, especially in SCA2. The decreased amplitude of P100 VEP in SCA1 patients was the only electrophysiological parameter differentiating between both groups of patients.     

Varied electrophysiologic patterns in spinocerebellar ataxia type 2

The autosomal dominant ataxias are a heterogenous group of disorders. Almost 30 different genetic loci have been identified. Spinocerebellar ataxia type 2 (SCA2) is one of many autosomal dominant cerebellar ataxias. Electrophysiologic studies in SCA2 have shown mainly a sensory neuropathy or neuronopathy. To determine if electrophysiologic testing reveals concomitant or isolated involvement of motor nerves in SCA2 we reviewed historic and electrophysiologic data on all cases of genetically confirmed SCA2 who underwent nerve conduction studies and needle electromyographic during initial evaluation at our institution. We performed electrophysiologic studies in six genetically confirmed, unrelated, cases of SCA2 and discovered that in three patients, there were findings consistent with motor neuronopathy or neuropathy without sensory involvement. One patient had normal results and only one had a pure sensory neuropathy or neuronopathy. The sixth patients had mixed sensorimotor neuropathy. This is the first study that demonstrates isolated involvement of motor neurons and/or axons occur in SCA2. Therefore, electrophysiologic findings in SCA2 are not limited to mainly a sensory neuropathy but are varied and can even mimic slowly progressive motor neuron disease.     

Mesenchymal stem cells attenuate peripheral neuronal degeneration in spinocerebellar ataxia type 1 knockin mice

Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disorder in which an abnormally expanded polyglutamine tract is inserted into causative ataxin‐1 proteins. We have previously shown that SCA1 knockin (SCA1‐KI) mice over 6 months of age exhibit a degeneration of motor neuron axons and their encasing myelin sheaths, as reported in SCA1 patients. We examined whether axon degeneration precedes myelin degeneration or vice versa in SCA1‐KI mice and then attempted to mitigate motor neuron degeneration by intrathecally administering mesenchymal stem cells (MSCs). Temporal examination of the diameters of motor neuron axons and their myelin sheaths revealed a decrease in diameter of the axon but not of the myelin sheaths in SCA1‐KI mice as early as 1 month of age, which suggests secondary degeneration of the myelin sheaths. We injected MSCs into the intrathecal space of SCA1‐KI mice at 1 month of age, which resulted in a significant suppression of degeneration of both motor neuron axons and myelin sheaths, even 6 months after the MSC injection. Thus, MSCs effectively suppressed peripheral nervous system degeneration in SCA1‐KI mice. It has not yet been clarified how clinically administered MSCs exhibit significant therapeutic effects in patients with SCA1. The morphological evidence presented in this current mouse study might explain the mechanisms that underlie the therapeutic effects of MSCs that are observed in patients with SCA1. © 2015 Wiley Periodicals, Inc.     

Spinocerebellar ataxia type 1: clinical and neurophysiological characteristics in German kindreds

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of an unstable (CAG)_n repeat on chromosome 6p. We investigated 36 German families suffering from hereditary ataxias for the SCA1 mutation and elaborated clinical and neurophysiological characteristics. SCA1 accounts for 10 - 15% of dominant cerebellar ataxias in German kindreds. The clinical presentation is characterized by broad, even intrafamilial variability and multiple system involvement already in early stages. Slowed saccades, ptosis and facial weakness are more prevalent in SCA1 but were unspecific differences compared to non-SCAl ataxias. Two electrophysiological parameters characterize SCA1: markedly prolonged central motor conduction time in motor evoked potentials and predominantly demyelinating polyneuropathy. Molecular genetic analyses are indispensable to diagnose SCA patients precisely. Extensive neurophysiological studies are recommendable in the clinical approach as they are suitable to discover subclinical damage of the nervous system. In contrast to the enormous variability of clinical signs in SCA1 neurophysiological findings are rather constant.     

Spinocerebellar ataxia type 7 (SCA7): widespread brain damage in an adult-onset patient with progressive visual impairments in comparison with an adult-onset patient without visual impairments

Spinocerebellar ataxia type 7 (SCA7) represents a rare and severe autosomal dominantly inherited ataxic disorder and is among the known CAG-repeat, or polyglutamine, diseases. In contrast to other currently known autosomal dominantly inherited ataxic disorders, SCA7 may manifest itself with different clinical courses. Because the degenerative changes evolving during these different clinical courses are not well known, many neurological disease symptoms still are unexplained. We performed an initial pathoanatomical study on unconventional thick tissue sections of the brain of a clinically diagnosed and genetically confirmed adult-onset SCA7 patient with progressive visual impairments. In this patient we observed loss of myelinated fibres in distinct central nervous fibre tracts, and widespread degeneration of the cerebellum, telencephalon, diencephalon and lower brainstem. These degenerative changes offer appropriate explanations for a variety of less-understood neurological symptoms in adult-onset SCA7 patients with visual impairments: gait, stance and limb ataxia, falls, dysarthria, dysphagia, pyramidal signs, Parkinsonian features, writing problems, impairments of saccades and smooth pursuits, altered pupillary functions, somatosensory deficits, auditory deficits and mental impairments.