A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia

Zannolli, Raffaella; Buoni, Sabrina; Betti, Gianni; Salvucci, S; Plebani, Alessandro; Soresina, Annarosa; Pietrogrande, Maria Cristina; Martino, Silvana; Leuzzi, Vincenzo; Finocchi, Andrea; Micheli, Roberto; Rossi, Livia N.; Brusco, Alfredo; Misiani, Filippo; Fois, Alberto; Hayek, Joussef; Kelly, Colleen; Chessa, Luciana

doi:10.1002/mds.25126

Cited by 83 publications

(48 citation statements)

References 27 publications

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“…Third, more research concerning the measurement and treatment of childhood ataxia is needed. There are few reports specific to children regarding the measurement 37 and treatment of ataxia (pharmacologic [38][39][40][41][42] and nonpharmacologic [43][44][45] ). This may reflect the fact that the overall prevalence and importance of childhood ataxia has likely been underestimated in the past, despite the fact that ataxia is associated with significant economic cost and decreased quality of life.…”

Section: Resultsmentioning

confidence: 99%

Prevalence of ataxia in children

et al. 2014

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Objective: To estimate the prevalence of childhood ataxia resulting from both genetic and acquired causes.Methods: A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement. Five databases were searched for articles reporting a frequency measure (e.g., prevalence, incidence) of ataxia in children. Included articles were first grouped according to the World Health Organization (WHO) regions and subsequently classified according to etiology (genetic, acquired, or mixed). Each article was assessed for its risk of bias on the domains of sampling, measurement, and analysis. Incidence values were converted to prevalence estimates whenever possible. European prevalence estimates for different etiologies of ataxia were summed to gauge the overall prevalence of childhood ataxia.Results: One hundred fifteen articles were included in the review. More than 50% of the data originated from the Europe WHO region. Data from this region also showed the least susceptibility to bias. Little data were available for Africa and Southeast Asia. The prevalence of acquired ataxias was found to vary more greatly across regions than the genetic ataxias. Ataxic cerebral palsy was found to be a significant contributor to the overall prevalence of childhood ataxia across WHO regions. The prevalence of childhood ataxias in Europe was estimated to be ;26/100,000 children and likely reflects a minimum prevalence worldwide. Conclusions:The findings show that ataxia is a common childhood motor disorder with a higher prevalence than previously assumed. More research concerning the epidemiology, assessment, and treatment of childhood ataxia is warranted. Ataxia refers to a lack or loss of movement coordination. It is associated with damage or dysfunction of the cerebellum or its afferent and efferent projections.1 Ataxia is especially debilitating for children because they are still developing and learning motor competency. The prevalence of some ataxia-causing conditions has been reported. However, most reports are focused on a single condition and a specific geographical location, making it difficult to generalize the prevalence estimates. Furthermore, few studies separate the prevalence of ataxia in children vs adults. [4][5][6][7][8][9][10][11][12] Given the multitude of ataxia-causing conditions and recognizing that each can be quite rare, the overall prevalence of childhood ataxia is likely underestimated. Yet overall prevalence data are needed to accurately assess the impact and societal cost of childhood ataxia.The purpose of this article is to systematically review the literature on the prevalence of ataxia in children across World Health Organization (WHO) regions. The prevalence of childhood From the Department of Neuroscience

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Section: Resultsmentioning

confidence: 99%

Prevalence of ataxia in children

et al. 2014

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“…Ataxia scores (SARA) improved in all patients at the dosage of 0.03 mg/kg/day [63]. In a double-blind, randomized, placebo-controlled crossover trial, oral betamethasone (0.1 mg/kg/day for 2×10 days with 10 days intermediate tapering) improved ataxia assessed by ICARS by 17 points (about 30 %) compared to placebo (improvement of 4.5 points) (Table 3) [64]. However, minimal dosage, long-term effectiveness, and safety need to be established.…”

Section: Drug Therapy For Cerebellar Ataxiamentioning

confidence: 99%

Consensus Paper: Management of Degenerative Cerebellar Disorders

et al. 2013

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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.

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“…Even though steroids are not curative and cannot be proposed for long-term therapies due to their side effects, it is suggested that during the clinical course there is a phase when neurological impairment can be rescued to some extent 56. In a multicenter, double-blind, randomized, placebo-controlled, crossover trial, oral betamethasone use showed significant reduction in ataxia scores 57. Dexamethasone has been shown to induce a splicing event, which leads to the skipping of mutations upstream of nucleotide residue 8450 of the ATM coding sequence.…”

Section: Role Of Atm In Neuroprotectionmentioning

confidence: 99%

Ataxia-telangiectasia: future prospects

Chaudhary¹,

Albaradie²

2014

TACG

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Ataxia-telangiectasia (A-T) is an autosomal recessive multi-system disorder caused by mutation in the ataxia-telangiectasia mutated gene (ATM). ATM is a large serine/threonine protein kinase, a member of the phosphoinositide 3-kinase-related protein kinase (PIKK) family whose best-studied function is as master controller of signal transduction for the DNA damage response (DDR) in the event of double strand breaks (DSBs). The DDR rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell-cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence. DSBs can be generated by exposure to ionizing radiation (IR) or various chemical compounds, such as topoisomerase inhibitors, or can be part of programmed generation and repair of DSBs via cellular enzymes needed for the generation of the antibody repertoire as well as the maturation of germ cells. AT patients have immunodeficiency, and are sterile with gonadal dysgenesis as a result of defect in meiotic recombination. In the cells of nervous system ATM has additional role in vesicle dynamics as well as in the maintenance of the epigenetic code of histone modifications. Moderate levels of ATM are associated with prolonged lifespan through resistance to oxidative stress. ATM inhibitors are being viewed as potential radiosensitizers as part of cancer radiotherapy. Though there is no cure for the disease at present, glucocorticoids have been shown to induce alternate splicing site in the gene for ATM partly restoring its activity, but their most effective timing in the disease natural history is not yet known. Gene therapy is promising but large size of the gene makes it technically difficult to be delivered across the blood–brain barrier at present. As of now, apart from glucocorticoids, use of histone deacetylase inhibitors/EZH2 to minimize effect of the absence of ATM, looks more promising.

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A randomized trial of oral betamethasone to reduce ataxia symptoms in ataxia telangiectasia

Cited by 83 publications

References 27 publications

Prevalence of ataxia in children

Prevalence of ataxia in children

Consensus Paper: Management of Degenerative Cerebellar Disorders

Ataxia-telangiectasia: future prospects

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