A severe phenotype of Kennedy disease associated with a very large CAG repeat expansion

Madeira, João; Souza, Alexandre Barbosa Câmara de; Cunha, Flávia Siqueira; Batista, Rafael Loch; Gomes, Nathália Lisboa; Rodrigues, Andresa De Santi; Jorge, F.E.; Chadi, Gerson; Callegaro, Dagoberto; Mendonca, Berenice B.; Costa, Elaine Maria Frade; Domenice, Sorahia

doi:10.1002/mus.25952

Cited by 10 publications

(7 citation statements)

References 15 publications

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“…21 At the high end of the disease range clinical features of abnormal genital development and dilated cardiomyopathy have been reported. 22,23 There is evidence of a founder effect in the Japanese population, where the normal repeat length distribution is somewhat higher, and clusters have also been reported in western Finland and northern Italy.…”

Section: Biomarkersmentioning

confidence: 99%

Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)

Hashizume

Fischbeck

Pennuto

et al. 2020

J Neurol Neurosurg Psychiatry

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Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.

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Section: Biomarkersmentioning

confidence: 99%

Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)

Hashizume

Fischbeck

Pennuto

et al. 2020

J Neurol Neurosurg Psychiatry

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“…The CAG sequence is translated into elongated polyQ tract in the AR N-terminus (ARpolyQ). In the healthy population, the AR CAG repeat is highly polymorphic (15-35 repetitions) (294), with variations within human races (295); in SBMA patients the AR CAG repeat becomes expanded from 37 to a maximum of 72 repetition (282,294,296). An inverse correlation exists between polyQ size and SBMA age-of-onset, progression rate and disease severity (231,297), although exceptions to this rule (evidenced in siblings) suggest that some factors may act as disease modifiers (298).…”

Section: DI a Mutation Of Ar The Molecular Basis Of The Diseasementioning

confidence: 99%

The Role of Sex and Sex Hormones in Neurodegenerative Diseases

et al. 2019

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Neurodegenerative diseases (NDs) are a wide class of disorders of the central nervous system (CNS) with unknown etiology. Several factors were hypothesized to be involved in the pathogenesis of these diseases, including genetic and environmental factors. Many of these diseases show a sex prevalence and sex steroids were shown to have a role in the progression of specific forms of neurodegeneration. Estrogens were reported to be neuroprotective through their action on cognate nuclear and membrane receptors, while adverse effects of male hormones have been described on neuronal cells, although some data also suggest neuroprotective activities. The response of the CNS to sex steroids is a complex and integrated process that depends on (i) the type and amount of the cognate steroid receptor and (ii) the target cell type—either neurons, glia, or microglia. Moreover, the levels of sex steroids in the CNS fluctuate due to gonadal activities and to local metabolism and synthesis. Importantly, biochemical processes involved in the pathogenesis of NDs are increasingly being recognized as different between the two sexes and as influenced by sex steroids. The aim of this review is to present current state-of-the-art understanding on the potential role of sex steroids and their receptors on the onset and progression of major neurodegenerative disorders, namely, Alzheimer’s disease, Parkinson’s diseases, amyotrophic lateral sclerosis, and the peculiar motoneuron disease spinal and bulbar muscular atrophy, in which hormonal therapy is potentially useful as disease modifier.

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“…The CAG sequence is expressed in exon 1 of the mRNA and then translated into a polyglutamine tract in the AR N-terminus (ARpolyQ). In normal individuals, the polyQ length of AR is highly polymorphic, ranging from 15 to 35 Qs (Edwards et al, 1992 ; Kuhlenbäumer et al, 2001 ); in SBMA patients the polyQ size becomes longer than 37 Qs (to a maximum of 72; Fischbeck, 1997 ; Kuhlenbäumer et al, 2001 ; Grunseich et al, 2014 ; Madeira et al, 2018 ). CAG repeat expansions coding for elongated polyQ tracts have been found in other eight genes, which are unrelated to AR; the mutant protein products of these genes cause other similar NDs (Ross, 2002 ).…”

Section: Misfolded Proteins Associated With Motor Neuron Diseasesmentioning

confidence: 99%

A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

Cristofani

Crippa

Cicardi

et al. 2020

Front. Aging Neurosci.

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Motor neuron diseases (MNDs) are fatal diseases characterized by loss of motor neurons in the brain cortex, in the bulbar region, and/or in the anterior horns of the spinal cord. While generally sporadic, inherited forms linked to mutant genes encoding altered RNA/protein products have also been described. Several different mechanisms have been found altered or dysfunctional in MNDs, like the protein quality control (PQC) system. In this review, we will discuss how the PQC system is affected in two MNDs-spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS)-and how this affects the clearance of aberrantly folded proteins, which accumulate in motor neurons, inducing dysfunctions and their death. In addition, we will discuss how the PQC system can be targeted to restore proper cell function, enhancing the survival of affected cells in MNDs.

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A severe phenotype of Kennedy disease associated with a very large CAG repeat expansion

Cited by 10 publications

References 15 publications

Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)

Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)

The Role of Sex and Sex Hormones in Neurodegenerative Diseases

A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

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