[Treatment for Spinocerebellar Degeneration].

No disease-modifying therapy has been established for spinocerebellar degeneration and multiple system atrophy, and only symptomatic therapy is currently available. Taltirelin and protirelin are drugs covered by health insurance for cerebellar ataxia symptoms, and are expected to suppress the progression of symptoms. Muscle relaxants are used for spasticity associated with spinocerebellar degeneration, and vasopressors and therapeutic agents for dysuria are used for autonomic symptoms of multiple system atrophy. It is necessary to develop a new therapeutic agent with a different mechanism of action, aimed specifically at modifying the disease progression in patients with spinocerebellar degeneration and multiple system atrophy.

Differential effects of thyrotropin releasing hormone (TRH) on motor execution and motor adaptation process in patients with spinocerebellar degeneration.

BACKGROUND: The cerebellum is known to play a crucial role in sensori-motor adaptation, which includes the prism adaptation. TRH has been widely used as a treatment for cerebellar ataxia in Japan, however effects of TRH on cerebellar adaptation process have not been studied. Here, we studied effects of TRH treatment on the prism adaptation task. METHODS: Eighteen spinocerebellar degeneration (SCD) patients participated in this study. The participants received intravenous injection of 2 mg/day protirelin tartrate once a day for 14 days. In the prism adaptation task, the participants reached to the target on the screen wearing wedge prisms. We compared the Scale for Assessment and Rating of Ataxia (SARA), baseline errors and the aftereffect (AE) of the prism adaptation task between before and after TRH therapy. RESULTS: TRH therapy improved SARA significantly (p = .005). Multiple regression analysis revealed that improvement of SARA score was mainly due to improvement of "Stance" category score. TRH decreased baseline errors of the prism adaptation task (p = .021), while unaffected AEs (p = .252). CONCLUSION: TRH differentially affected clinical cerebellar ataxia including baseline reaching performance in the prism adaptation task, whereas TRH did not affect the learning process of prism adaptation. Different cerebellar functional aspects may underlie the learning process of sensori-motor adaptation and simple motor execution (clinically evaluated cerebellar ataxia).

Ameliorating effect of rovatirelin on the ataxia in rolling mouse Nagoya.

Rovatirelin is a newly synthetized thyrotropin-releasing hormone (TRH) analog. This study aimed to investigate the effect of rovatirelin on motor function using rolling mouse Nagoya (RMN), a mouse model of hereditary ataxia, and compare it with that of taltirelin, which is clinically used to treat spinocerebellar degeneration in Japan. We also examined the effect of rovatirelin on glucose metabolism in various brain regions of RMN using autoradiography (ARG). Rovatirelin (1, 3, 10, and 30 mg/kg) dose-dependently reduced the fall index in RMN, and its effect was more potent than that of taltirelin (3, 10, 30, and 100 mg/kg). No attenuation of the effect was observed by repeated daily administration for 2 weeks. Furthermore, the reduction in the fall index by rovatirelin persisted for 2 weeks after completing treatment. In the ARG study, rovatirelin induced a significantly elevated uptake of glucose in the prefrontal cortex, nucleus accumbens shell, nucleus accumbens core, striatum, anterior cingulate cortex, secondary motor area, pretectal area, ventral tegmental area, black pars compacta, locus coeruleus, nucleus cerebellaris middle nucleus, medial nucleus of the vestibular nerve, fourth/fifth lobule, and third lobule. Furthermore, rovatirelin increased cerebellar mRNA level of brain derived neurotrophic factor. These results suggest that rovatirelin activates the cerebellum and other parts of the central nervous system to improve motor function in spinocerebellar ataxia (SCA) model animals, and its action is more potent than that of taltirelin. Therefore, rovatirelin can be a potential alternative to the traditionally used therapeutics for SCA.

Loss-of-function BK channel mutation causes impaired mitochondria and progressive cerebellar ataxia.

Despite a growing number of ion channel genes implicated in hereditary ataxia, it remains unclear how ion channel mutations lead to loss-of-function or death of cerebellar neurons. Mutations in the gene KCNMA1, encoding the α-subunit of the BK channel have emerged as responsible for a variety of neurological phenotypes. We describe a mutation (BKG354S) in KCNMA1, in a child with congenital and progressive cerebellar ataxia with cognitive impairment. The mutation in the BK channel selectivity filter dramatically reduced single-channel conductance and ion selectivity. The BKG354S channel trafficked normally to plasma, nuclear, and mitochondrial membranes, but caused reduced neurite outgrowth, cell viability, and mitochondrial content. Small interfering RNA (siRNA) knockdown of endogenous BK channels had similar effects. The BK activator, NS1619, rescued BKG354S cells but not siRNA-treated cells, by selectively blocking the mutant channels. When expressed in cerebellum via adenoassociated virus (AAV) viral transfection in mice, the mutant BKG354S channel, but not the BKWT channel, caused progressive impairment of several gait parameters consistent with cerebellar dysfunction from 40- to 80-d-old mice. Finally, treatment of the patient with chlorzoxazone, a BK/SK channel activator, partially improved motor function, but ataxia continued to progress. These studies indicate that a loss-of-function BK channel mutation causes ataxia and acts by reducing mitochondrial and subsequently cellular viability.

Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials.

OBJECTIVE: To investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD). METHODS: Two multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with predominant cerebellar ataxia, including SCA6, SCA31 or cortical cerebellar atrophy. KPS1301 enrolled patients with truncal ataxia and KPS1305 enrolled patients with truncal and limb ataxia. Each study included 4 weeks of pretreatment, a 28-week or 24-week treatment period and 4 weeks of follow-up. Patients were randomised (1:1:1) to rovatirelin (1.6 or 2.4 mg) or placebo in KPS1301, and randomised (1:1) to rovatirelin 2.4 mg or placebo in KPS1305. The primary endpoint was change in Scale for the Assessment and Rating of Ataxia (SARA) total scores. Pooled analysis was performed in patients who met the SARA recruitment criteria of KPS1305. RESULTS: From October 2013 to May 2014, KPS1301 enrolled 411 patients; 374 were randomised to rovatirelin 1.6 mg (n=125), rovatirelin 2.4 mg (n=126) or placebo (n=123). From November 2016 to August 2017, KPS1305 enrolled 241 patients; 203 were randomised to rovatirelin 2.4 mg (n=101) or placebo (n=102). The primary endpoint showed no significant difference between rovatirelin and placebo in these two studies. In the pooled analysis (n=278), the difference between rovatirelin 2.4 mg (n=140) and placebo (n=138) was -0.61 (-1.64 vs -1.03; 95% CI -1.16 to -0.06; p=0.029) in the adjusted mean change in the SARA total score. CONCLUSIONS: Rovatirelin is a potentially effective treatment option for SCD. TRIAL REGISTRATION NUMBER: NCT01970098; NCT02889302.

Acetazolamide-Responsive Episodic Ataxia Linked to Novel Splice Site Variant in FGF14 Gene.

Here we describe the case of a patient with episodic dizziness and gait imbalance for 7 years and a negative family history. On clinical examination, interictally, the patient presented with gaze-evoked nystagmus and rebound nystagmus and slight dysarthria. MRI of the brain was normal and peripheral-vestibular function was bilaterally intact. Based on genetic testing (episodic ataxia panel), a heterozygote splice site variant in intron 1 of the FGF14 gene was identified. This report adds important new evidence to previous observations that pathogenic variants in the FGF14 gene may result in variable phenotypes, either in progressive spinocerebellar ataxia (type 27) or in episodic ataxia as in our case. Our patient responded well to acetazolamide (reduction in the frequency of attacks by about two thirds), supporting the hypothesis of a sodium channelopathy.

The forgotten effects of thyrotropin-releasing hormone: Metabolic functions and medical applications.

Thyrotropin-releasing hormone (TRH) causes a variety of thyroidal and non-thyroidal effects, the best known being the feedback regulation of thyroid hormone levels. This was employed in the TRH stimulation test, which is currently little used. The role of TRH as a cancer biomarker is minor, but exaggerated responses to TSH and prolactin levels in breast cancer led to the hypothesis of a potential role for TRH in the pathogenesis of this disease. TRH is a rapidly degraded peptide with multiple targets, limiting its suitability as a biomarker and drug candidate. Although some studies reported efficacy in neural diseases (depression, spinal cord injury, amyotrophic lateral sclerosis, etc.), therapeutic use of TRH is presently restricted to spinocerebellar degenerative disease. Regulation of TRH production in the hypothalamus, patterns of expression of TRH and its receptor in the body, its role in energy metabolism and in prolactin secretion are addressed in this review.

Cerebellar degeneration in primary SjÓ§gren syndrome.

Neurological manifestations are reported as a consequence of primary SjÓ§gren syndrome (PSS). Any part of the brain and peripheral nervous system can be involved in PSS. However, cerebellar degeneration and atrophy associated with PSS have been rarely reported. Our report describes a 22-year-old woman who presented with cerebellar ataxia, arthritis and arthralgia. Evaluation of her symptoms, autoantibodies and salivary gland pathology was in favour of the diagnosis of Sjögren syndrome. Also, her brain MRI revealed cerebellar degeneration. There are only four patients reported to be affected by cerebellar atrophy associated with PSS. Administration of high doses of methylprednisolone and cyclophosphamide leads to substantial improvement in the cerebellar symptoms of this case. In addition, after 2 months of follow-up, the patient's ataxia recovered significantly. It could be concluded that in addition to neurological degenerative disorders, in some cases cerebellar atrophy could also be associated with autoimmune conditions such as PSS.

Spinocerebellar Ataxia 27: A Review and Characterization of an Evolving Phenotype.

Background: Spinocerebellar ataxia (SCA) is an uncommon form of progressive cerebellar ataxia with multiple genetic causes and marked variability in phenotypic expression even across patients with identical genetic abnormalities. SCA27 is a recently identified SCA caused by mutations in the Fibroblast Growth Factor 14 gene, with a phenotypic expression that is only beginning to be fully appreciated. We report here a case of a 70-year-old male who presented with slowly worsening tremor and gait instability that began in his early adulthood along with additional features of parkinsonism on examination. Work-up revealed a novel pathogenic mutation in the Fibroblast Growth Factor 14 gene, and symptoms improved with amantadine and levodopa. We also provide a review of the literature in order to better characterize the phenotypic expression of this uncommon condition. Methods: Case report and review of the literature. Results: Review of the literature revealed a total of 32 previously reported clinical cases of SCA27. Including our case, we found that early-onset tremor (12.1 ± 10.5 years) was present in 95.8%, while gait ataxia tended to present later in life (23.7 ± 16.7 years) and was accompanied by limb ataxia, dysarthria, and nystagmus. Other features of SCA27 that may distinguish it from other SCAs include the potential for episodic ataxia, accompanying psychiatric symptoms, and cognitive impairment. Discussion: Testing for SCA27 should be considered in individuals with ataxia who report tremor as an initial or early symptom, as well as those with additional findings of episodic ataxia, neuropsychiatric symptoms, or parkinsonism.

Characterization of Zebrafish Models of Marinesco-Sjögren Syndrome.

SIL1 is a nucleotide exchange factor for the endoplasmic reticulum chaperone, BiP. Mutations in the SIL1 gene cause Marinesco-Sjögren syndrome (MSS), an autosomal recessive disease characterized by cerebellar ataxia, mental retardation, congenital cataracts, and myopathy. To create novel zebrafish models of MSS for therapeutic drug screening, we analyzed phenotypes in sil1 knock down fish by two different antisense oligo morpholinos. Both sil1 morphants had abnormal formation of muscle fibers and irregularity of the myosepta. Moreover, they showed smaller-sized eyes and loss of purkinje cells in cerebellar area compared to controls. Immunoblotting analysis revealed increased protein amounts of BiP, lipidated LC3, and caspase 3. These data supported that the sil1 morphants can represent mimicking phenotypes of human MSS. The sil1 morphants phenocopy the human MSS disease pathology and are a good animal model for therapeutic studies.

TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington's disease.

Corticostriatal atrophy is a cardinal manifestation of Huntington's disease (HD). However, the mechanism(s) by which mutant huntingtin (mHTT) protein contributes to the degeneration of the corticostriatal circuit is not well understood. We recreated the corticostriatal circuit in microfluidic chambers, pairing cortical and striatal neurons from the BACHD model of HD and its WT control. There were reduced synaptic connectivity and atrophy of striatal neurons in cultures in which BACHD cortical and striatal neurons were paired. However, these changes were prevented if WT cortical neurons were paired with BACHD striatal neurons; synthesis and release of brain-derived neurotrophic factor (BDNF) from WT cortical axons were responsible. Consistent with these findings, there was a marked reduction in anterograde transport of BDNF in BACHD cortical neurons. Subunits of the cytosolic chaperonin T-complex 1 (TCP-1) ring complex (TRiC or CCT for chaperonin containing TCP-1) have been shown to reduce mHTT levels. Both CCT3 and the apical domain of CCT1 (ApiCCT1) decreased the level of mHTT in BACHD cortical neurons. In cortical axons, they normalized anterograde BDNF transport, restored retrograde BDNF transport, and normalized lysosomal transport. Importantly, treating BACHD cortical neurons with ApiCCT1 prevented BACHD striatal neuronal atrophy by enhancing release of BDNF that subsequently acts through tyrosine receptor kinase B (TrkB) receptor on striatal neurons. Our findings are evidence that TRiC reagent-mediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons.

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model.

Spinocerebellar ataxia type 28 (SCA28) is a neurodegenerative disease caused by mutations of the mitochondrial protease AFG3L2. The SCA28 mouse model, which is haploinsufficient for Afg3l2, exhibits a progressive decline in motor function and displays dark degeneration of Purkinje cells (PC-DCD) of mitochondrial origin. Here, we determined that mitochondria in cultured Afg3l2-deficient PCs ineffectively buffer evoked Ca²âº peaks, resulting in enhanced cytoplasmic Ca²âº concentrations, which subsequently triggers PC-DCD. This Ca²âº-handling defect is the result of negative synergism between mitochondrial depolarization and altered organelle trafficking to PC dendrites in Afg3l2-mutant cells. In SCA28 mice, partial genetic silencing of the metabotropic glutamate receptor mGluR1 decreased Ca²âº influx in PCs and reversed the ataxic phenotype. Moreover, administration of the ß-lactam antibiotic ceftriaxone, which promotes synaptic glutamate clearance, thereby reducing Ca²âº influx, improved ataxia-associated phenotypes in SCA28 mice when given either prior to or after symptom onset. Together, the results of this study indicate that ineffective mitochondrial Ca²âº handling in PCs underlies SCA28 pathogenesis and suggest that strategies that lower glutamate stimulation of PCs should be further explored as a potential treatment for SCA28 patients.

Consensus paper: management of degenerative cerebellar disorders.

Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation.

JC virus granule cell neuronopathy and GCN-IRIS under natalizumab treatment.

Progressive multifocal leukoencephalopathy is the most common clinical presentation of JC virus (JCV)-associated central nervous system (CNS) disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab. Here we report clinical, radiological, and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst patients treated with natalizumab. GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under natalizumab treatment, especially in cases where cerebellar atrophy can be visualized by magnetic resonance imaging.

[Hereditary episodic ataxia]. / Ataxies épisodiques génétiques.

INTRODUCTION: Episodic ataxia (EA) designates a group of autosomal dominant channelopathies that manifest as paroxysmal attacks of imbalance and incoordination. EA conditions are clinically and genetically heterogeneous. Seven types of EA have been reported so far but the majority of clinical cases result from two recognized entities. STATE OF ART: Episodic ataxia type 1 (EA1) is characterized by brief episodes of ataxia and dysarthria, and interictal myokymia. Onset occurs during the first two decades of life. Associated epilepsy has been reported in some EA1 patients. EA1 is caused by mutations of the KCNA1 gene coding for the voltage-gated potassium channel Kv1.1. Mutation is mostly missense mutations. Acetazolamide, a carbonic-anhydrase inhibitor, may reduce the frequency and severity of the attacks in some but not all affected individuals. Episodic ataxia type 2 (EA2) is characterized by episodes lasting longer than in EA1, that manifest by ataxia, dysarthria, vertigo, and also, in most of the cases, an interictal nystagmus. Other clinical features as developmental delay or epilepsy can be present in some patients. Brain MRI shows frequently a vermian atrophy. Onset occurs typically in childhood or early adolescence, but can sometimes be in adulthood. EA2 is caused by mutations in CACNA1A, a gene coding for the neuronal voltage-gated calcium channel Cav1.1. For two-thirds of the cases, mutations lead to a stop codon. This type is most often responsive to acetazolamide that reduces the frequency and severity of attacks, but does not appear to prevent the progression of interictal symptoms. PERSPECTIVES: This article summarizes current knowledge on episodic ataxia type 1 and 2 and describes briefly the other types of EA. CONCLUSION: Molecular analysis of KCNA1 or CACNA1A provides a confirmation of the diagnosis of EA1 and EA2. Other types remain rare phenotypic variants. Among them, only two genes have been identified: CACNB4 in EA5 and SLC1A3 in EA6 and mutations have been found in a very few cases. No mutation can be detected in some familial cases of episodic ataxia, suggesting further heterogeneity.

A case of Marinesco-Sjögren syndrome: MRI observations of skeletal muscles, bone metabolism, and treatment with testosterone and risedronate.

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive disorder characterized by cerebellar ataxia, congenital cataracts, mental retardation, primary hypogonadism, skeletal abnormalities and myopathy, and patients with MSS are considered to be at risk of falls and bone fractures. We report a patient with MSS who received testosterone replacement therapy and risedronate administration. Muscle strength and the MRI features of the skeletal muscles were not changed, but low bone mass was improved by these treatments, and improvement has continued after risedronate treatment alone. This case suggests that treatment of MSS-related low bone mass using bisphosphonates is likely beneficial.

Congo red, an amyloid-inhibiting compound, alleviates various types of cellular dysfunction triggered by mutant protein kinase cγ that causes spinocerebellar ataxia type 14 (SCA14) by inhibiting oligomerization and aggregation.

Several missense mutations in the protein kinase Cγ (γPKC) gene have been found to cause spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that the mutant γPKC found in SCA14 is susceptible to aggregation that induces apoptotic cell death. Congo red is widely used as a histological dye for amyloid detection. Recent evidence has revealed that Congo red has the property to inhibit amyloid oligomers and fibril formation of misfolded proteins. In the present study, we examine whether Congo red inhibits aggregate formation and cytotoxicity of mutant γPKC. Congo red likely inhibits aggregate formation of mutant γPKC ­ green fluorescent protein (GFP) without affecting its expression level in SH-SY5Y cells. Congo red counteracts the insolubilization of recombinant mutant γPKC, suggesting that the dye inhibits aggregation of mutant γPKC by a direct mechanism. Congo red also inhibits aggregation and oligomerization of mutant γPKC-GFP in primary cultured cerebellar Purkinje cells. Moreover, the dye reverses the improper development of dendrites and inhibits apoptotic cell death in Purkinje cells that express mutant γPKC-GFP. These results indicate that amyloid-inhibiting compounds like Congo red may be novel therapeutics for SCA14.

Evaluation of the effect of thyrotropin releasing hormone (TRH) on regional cerebral blood flow in spinocerebellar degeneration using 3DSRT.

Thyrotropin releasing hormone (TRH) therapy improves cerebellar ataxia in patients with spinocerebellar degeneration (SCD). We investigated the effect of TRH on regional cerebral blood flow (rCBF) using the fully automated region of interest (ROI) technique, 3DSRT. Ten patients with SCD received TRH intravenously (2 mg/day) for 14 days and underwent brain perfusion single photon emission computed tomography before and after therapy. Clinical efficacy was assessed using the International Cooperative Ataxia Rating Scale (ICARS). The rCBF in each ROI was measured using the noninvasive Patlak plot method and calculated using 3DSRT. TRH significantly improved the ICARS scores and increased rCBF in the callosomarginal segment and cerebellum. Cerebellar rCBF increased in 4 of 5 patients with improved ICARS scores and in 3 of 5 patients without improved ICARS scores after TRH therapy. The correlation between the change in cerebellar rCBF and the improved ICARS score, however, was not significant. These findings indicate that TRH therapy may increase cerebellar rCBF in some patients with cerebellar forms of SCD and that 3DSRT may be useful for evaluating the efficacy of TRH for increasing CBF. The beneficial effects of TRH may be due to increased cerebellar rCBF or the increased rCBF may be a secondary effect of TRH therapy.

Neurologic consequences of autoimmune polyglandular syndrome type 1.

BACKGROUND: Autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive disorder that is chiefly characterized by polyendocrinopathy, chronic mucocutaneous candidiasis, and ectodermal dystrophy. The neurologic complications of this disorder have not been well characterized. METHOD: The authors report a patient with a previously undescribed autoimmune cerebellar degeneration occurring in association with APS-1 and review the literature regarding the neurologic complications of this disorder. RESULTS: This 24-year-old woman with APS-1 presented with gait ataxia associated with band-like hyperintense signal abnormalities of both cerebellar hemispheres and a unique antibody to cerebellar Purkinje cells and brainstem neurons. At age 9, she had C. Miller Fisher syndrome, from which she had fully recovered. CONCLUSIONS: Autoimmune neurologic disease may develop with autoimmune polyglandular syndrome type 1. Neurologic disease may also result from the associated endocrinopathies (hypoparathyroidism, hypothyroidism, diabetes mellitus), vitamin deficiency (vitamins B12 and E), and celiac sprue.