Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients

Querin, Giorgia; Bertolin, Cinzia; Re, Elisa Da; Volpe, M; Zara, Gabriella; Pegoraro, Elena; Caretta, Nicola; Foresta, Carlo; Silvano, Maria; Corrado, Domenico; Iafrate, Massimo; Angelini, Lorenzo; Sartori, Leonardo; Pennuto, Maria; Gaiani, Alessandra; Bello, Luca; Semplicini, Claudio; Pareyson, Davide; Silani, Vincenzo; Ermani, Mario; Ferlin, Alberto; Sorarù, Gian Domenico

doi:10.1136/jnnp-2015-311305

Cited by 68 publications

(83 citation statements)

References 53 publications

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“…As such, altered energy utilization by skeletal muscle may play a part in the systemic manifestations of disease. Recent studies have demonstrated elevated fasting glucose as well as increased total cholesterol, low-density lipoprotein cholesterol and triglyceride levels in a cohort of SBMA patients (Querin et al, 2015). These findings add to a growing appreciation of non-neuronal phenotypes in this disorder, and raise the possibility that targeting metabolic alterations may alleviate disease manifestations.…”

Section: Discussionmentioning

confidence: 99%

Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing

et al. 2016

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Summary Spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder, is caused by a CAG/glutamine expansion in the androgen receptor (polyQ AR). Recent studies demonstrate that skeletal muscle is an important site of toxicity that contributes to the SBMA phenotype. Here, we sought to identify critical pathways altered in muscle that underlie disease manifestations in AR113Q mice. This led to the unanticipated identification of gene expression changes affecting regulators of carbohydrate metabolism, similar to those triggered by denervation. AR113Q muscle exhibits diminished glycolysis, altered mitochondria, and an impaired response to exercise. Strikingly, the expression of genes regulating muscle energy metabolism is rescued following peripheral polyQ AR gene silencing by antisense oligonucleotides (ASO), a therapeutic strategy that alleviates disease. Our data establish the occurrence of a metabolic imbalance in SBMA muscle triggered by peripheral expression of the polyQ AR, and indicate that alterations in energy utilization contribute to non-neuronal disease manifestations.

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Section: Discussionmentioning

confidence: 99%

Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing

et al. 2016

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“…Recently, urological involvement has been described: almost 40% of the patients may present moderate signs and symptoms of lower urinary tract obstruction in absence of prostatic hypertrophy, with some of them needing an indwelling bladder catheter [30]. The precise mechanism is still not clear but it is probably related to androgen insensitivity.…”

Section: Clinical Featuresmentioning

confidence: 99%

“…Anyway, the only study considering the presence of Brugada's syndrome in a Caucasian SBMA population did not clearly confirm an increased prevalence [30]. At the same time, the presence of a primary cardiomyopathy has been ruled out [32].…”

Section: Clinical Featuresmentioning

confidence: 99%

“…Abdominal obesity, dyslipidemia, liver dysfunction and glucose intolerance are also detected in some patients, that frequently develop a complete metabolic syndrome [29] [30]. While gynecomastia and other symptoms of androgen insensitivity appear to result from the partial loss of AR function, the remaining nonneuronal symptoms are likely due to toxicity of the pathogenic AR in these tissues [24].…”

Section: Clinical Featuresmentioning

confidence: 99%

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Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

2017

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Acknowledgments: the authors thank AFM-Téléthon, Téléthon Biobank, Institut pour la Recherche sur la Moelle épinière et l'Encéphale (IRME), Association pour la Recherche sur la SLA (ARSla) and the University of Padova for their research support.Kennedy disease (X-Linked recessive Bulbospinal Neuronopathy): a comprehensive review from pathophysiology to therapy. AbstractKennedy's disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, Xlinked recessive neuromuscular disease. It is caused by expansion of a CAG repeat sequence in exon 1 of the androgen-receptor (AR) gene, encoding a poly-glutamine (polyQ) tract. Poly-Q-expanded AR accumulates in nuclei and initiates degeneration and loss of motor neurons and dorsal root ganglia. The disease has been retained to be a pure lower motor neuron disease for a long time, but recently the presence of important hyper-Creatine-Kinase-emia and of myopathic alterations on muscle biopsy has suggested the presence of a primary myopathy underlying a wide proportion of clinical manifestations. The disease, that affects male adults, is characterized by muscle weakness and atrophy localized proximally in the limbs and by bulbar involvement. Sensory disturbances are associated to the motor phenotype but may be subclinical. The most frequent systemic symptom is gynecomastia related to androgen insensitivity, but other abnormalities, such as heart rhythm and urinary disturbances, have also been reported. The course of the disease is slowly progressive with normal life expectancy. The diagnosis of SBMA is based on genetic testing, with 38 CAG repeats retained to be pathogenic. Even though several therapeutic attempts have been made in mouse models, no effective disease modifying therapy is available but symptomatic therapy is beneficial for the management of weakness, fatigability and bulbar symptoms.

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“…From a clinical point of view, the disease is characterized by slowly progressive lower motor neurons (LMN) degeneration in brainstem and spinal cord, which is associated with multisystem involvement manifesting as androgen insensitivity, heart rhythm abnormalities, metabolic syndrome and sensory neuropathy [6]. The prevalent clinical features of the disease include wasting of proximal limbs muscles with progressive motor impairment [3], associated with mild bulbar involvement.…”

mentioning

confidence: 99%

Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients

Cited by 68 publications

References 53 publications

Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing

Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

Widening the Spectrum of Extra-Neuromuscular Involvement in SBMA: Is there a Role for Brain Pathology?

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