Beyond motor neurons: expanding the clinical spectrum in Kennedy’s disease

Kennedy’s disease, or spinal and bulbar muscular atrophy (SBMA), is an X-linked neuromuscular condition clinically characterised by weakness, atrophy and fasciculations of the limb and bulbar muscles, as a result of lower motor neuron degeneration. The disease is caused by an abnormally expanded triplet repeat expansions in the ubiquitously expressed androgen receptor gene, through mechanisms which are not entirely elucidated. Over the years studies from both humans and animal models have highlighted the involvement of cell populations other than motor neurons in SBMA, widening the disease phenotype. The most compelling aspect of these findings is their potential for therapeutic impact: muscle, for example, which is primarily affected in the disease, has been recently shown to represent a valid alternative target for therapy to motor neurons. In this review, we discuss the emerging study of the extra-motor neuron involvement in SBMA, which, besides increasingly pointing towards a multidisciplinary approach for affected patients, deepens our understanding of the pathogenic mechanisms and holds potential for providing new therapeutic targets for this disease.

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X-linked spinal and bulbar muscular atrophy (Kennedy’s disease): the first case described in the Brazilian Amazon

Einstein (São Paulo) ◽

10.1590/s1679-45082018rc4011 ◽

2018 ◽

Vol 16 (2) ◽

Cited By ~ 1

Author(s):

Camila Nascimento Alves ◽

Tiago Kiyoshi Kitabayashi Braga ◽

Danusa Neves Somensi ◽

Bruno Sérgio Vilhena do Nascimento ◽

José Antônio Santos de Lima ◽

...

Keyword(s):

Androgen Receptor ◽

Muscular Atrophy ◽

Receptor Gene ◽

Brazilian Amazon ◽

Androgen Receptor Gene ◽

Thoracic Spinal Cord ◽

Kennedy’S Disease ◽

Kennedy's Disease ◽

First Case ◽

Patient Reported

ABSTRACT The X-linked spinal and bulbar muscular atrophy (Kennedy’s disease) is a rare X-linked, recessive, lower motor neuron disease, characterized by weakness, atrophy, and fasciculations of the appendicular and bulbar muscle. The disease is caused by an expansion of the CAG repetition in the androgen receptor gene. Patients with Kennedy’s disease have more than 39 CAG repetitions. We report a case of 57-year-old man, resident of Monte Dourado (PA, Brazil) who complained of brachiocrural paresis evolving for 3 years along with fasciculations and tremors of extremities. In addition, he also developed dysarthria, dysphagia, and sexual dysfunction. The patient clinical picture included gait impairment, global hyporeflexia, proximal muscle atrophy of upper limbs, deviation of the uvula to right during phonation and tongue atrophy with fasciculations. The patient reported that about 30 years ago he had undergone gynecomastia surgery. His electroneuromyography suggested spinal muscular atrophy, and nuclear magnetic resonance imaging showed tapering of the cervical and thoracic spinal cord. Patient’s creatine kinase level was elevated. In view of the findings, an exam was requested to investigate Kennedy’s disease. The exam identified 46 CAG repetitions in the androgen receptor gene, which confirmed the diagnostic suspicion. This was the first case of Kennedy’s disease diagnosed and described in the Brazilian Amazon. To our knowledge only other four papers were published on this disease in Brazilian patients. A brief review is also provided on etiopathogenic, clinical and diagnostic aspects.

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Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy and Related Neurological Disorders

Genes ◽

10.3390/genes13010109 ◽

2022 ◽

Vol 13 (1) ◽

pp. 109

Author(s):

Tomoki Hirunagi ◽

Kentaro Sahashi ◽

Katherine G. Meilleur ◽

Masahisa Katsuno

Keyword(s):

Nucleic Acid ◽

Motor Neuron ◽

Motor Neurons ◽

Neurological Disorders ◽

Neurodegenerative Disorder ◽

Muscular Atrophy ◽

Receptor Gene ◽

Androgen Receptor Gene ◽

Muscle Pathology ◽

Small Interfering Rnas

The recent advances in nucleic acid therapeutics demonstrate the potential to treat hereditary neurological disorders by targeting their causative genes. Spinal and bulbar muscular atrophy (SBMA) is an X-linked and adult-onset neurodegenerative disorder caused by the expansion of trinucleotide cytosine-adenine-guanine repeats, which encodes a polyglutamine tract in the androgen receptor gene. SBMA belongs to the family of polyglutamine diseases, in which the use of nucleic acids for silencing a disease-causing gene, such as antisense oligonucleotides and small interfering RNAs, has been intensively studied in animal models and clinical trials. A unique feature of SBMA is that both motor neuron and skeletal muscle pathology contribute to disease manifestations, including progressive muscle weakness and atrophy. As both motor neurons and skeletal muscles can be therapeutic targets in SBMA, nucleic acid-based approaches for other motor neuron diseases and myopathies may further lead to the development of a treatment for SBMA. Here, we review studies of nucleic acid-based therapeutic approaches in SBMA and related neurological disorders and discuss current limitations and perspectives to apply these approaches to patients with SBMA.

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Kennedy's disease: A clinicopathologic correlation with mutations in the androgen receptor gene

Neurology ◽

10.1212/wnl.43.4.791 ◽

1993 ◽

Vol 43 (4) ◽

pp. 791-791 ◽

Cited By ~ 99

Author(s):

A. A. Amato ◽

T. W. Prior ◽

R. J. Barohn ◽

P. Snyder ◽

A. Papp ◽

...

Keyword(s):

Androgen Receptor ◽

Receptor Gene ◽

Androgen Receptor Gene ◽

Kennedy’S Disease ◽

Clinicopathologic Correlation ◽

Kennedy's Disease

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Distinct Etiological Roles for Myocytes and Motor Neurons in a Mouse Model of Kennedy's Disease/Spinobulbar Muscular Atrophy

Journal of Neuroscience ◽

10.1523/jneurosci.3599-14.2015 ◽

2015 ◽

Vol 35 (16) ◽

pp. 6444-6451 ◽

Cited By ~ 17

Author(s):

F. Ramzan ◽

M. McPhail ◽

P. Rao ◽

K. Mo ◽

K. Halievski ◽

...

Keyword(s):

Mouse Model ◽

Motor Neurons ◽

Muscular Atrophy ◽

Spinobulbar Muscular Atrophy ◽

Kennedy’S Disease ◽

Kennedy's Disease

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CAG repeats polymorphism of androgen receptor gene, Kennedy’s disease and male infertility

Andrology and Genital Surgery ◽

10.17650/2070-9781-2019-20-2-35-39 ◽

2019 ◽

Vol 20 (2) ◽

pp. 35-39

Author(s):

L. P. Melikyan ◽

V. B. Chernykh

Keyword(s):

Androgen Receptor ◽

Male Infertility ◽

Receptor Gene ◽

Androgen Receptor Gene ◽

Cag Repeats ◽

Kennedy’S Disease ◽

Kennedy's Disease

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Sonic Hedgehog-Gli1 Signaling and Cellular Retinoic Acid Binding Protein 1 Gene Regulation in Motor Neuron Differentiation and Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21114125 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4125

Author(s):

Yu-Lung Lin ◽

Yi-Wei Lin ◽

Jennifer Nhieu ◽

Xiaoyin Zhang ◽

Li-Na Wei

Keyword(s):

Retinoic Acid ◽

Motor Neuron ◽

Sonic Hedgehog ◽

Motor Neurons ◽

Muscular Atrophy ◽

Minimal Promoter ◽

Expression Data ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

Acid Binding Protein

Cellular retinoic acid-binding protein 1 (CRABP1) is highly expressed in motor neurons. Degenerated motor neuron-like MN1 cells are engineered by introducing SODG93A or AR-65Q to model degenerated amyotrophic lateral sclerosis (ALS) or spinal bulbar muscular atrophy neurons. Retinoic acid (RA)/sonic hedgehog (Shh)-induced embryonic stem cells differentiation into motor neurons are employed to study up-regulation of Crabp1 by Shh. In SODG93A or AR-65Q MN1 neurons, CRABP1 level is reduced, revealing a correlation of motor neuron degeneration with Crabp1 down-regulation. Up-regulation of Crabp1 by Shh is mediated by glioma-associated oncogene homolog 1 (Gli1) that binds the Gli target sequence in Crabp1′s neuron-specific regulatory region upstream of minimal promoter. Gli1 binding triggers chromatin juxtaposition with minimal promoter, activating transcription. Motor neuron differentiation and Crabp1 up-regulation are both inhibited by blunting Shh with Gli inhibitor GANT61. Expression data mining of ALS and spinal muscular atrophy (SMA) motor neurons shows reduced CRABP1, coincided with reduction in Shh-Gli1 signaling components. This study reports motor neuron degeneration correlated with down-regulation in Crabp1 and Shh-Gli signaling. Shh-Gli up-regulation of Crabp1 involves specific chromatin remodeling. The physiological and pathological implication of this regulatory pathway in motor neuron degeneration is supported by gene expression data of ALS and SMA patients.

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The role of RNA processing in the pathogenesis of motor neuron degeneration

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399410001523 ◽

2010 ◽

Vol 12 ◽

Cited By ~ 24

Author(s):

Dirk Bäumer ◽

Olaf Ansorge ◽

Mara Almeida ◽

Kevin Talbot

Keyword(s):

Motor Neuron ◽

Motor Neurons ◽

Rna Processing ◽

Muscular Atrophy ◽

Rapid Expansion ◽

Motor Neuron Degeneration ◽

Neuron Degeneration ◽

Temporal Gene Expression ◽

Mrna Targeting

Motor neurons are large, highly polarised cells with very long axons and a requirement for precise spatial and temporal gene expression. Neurodegenerative disorders characterised by selective motor neuron vulnerability include various forms of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). A rapid expansion in knowledge on the pathophysiology of motor neuron degeneration has occurred in recent years, largely through the identification of genes leading to familial forms of ALS and SMA. The major emerging theme is that motor neuron degeneration can result from mutation in genes that encode factors important for ribonucleoprotein biogenesis and RNA processing, including splicing regulation, transcript stabilisation, translational repression and localisation of mRNA. Complete understanding of how these pathways interact and elucidation of specialised mechanisms for mRNA targeting and processing in motor neurons are likely to produce new targets for therapy in ALS and related disorders.

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Spinal and bulbar muscular atrophy as a multisystem disease with motor neuron and muscle involvement: literature review and a case report

Neuromuscular Diseases ◽

10.17650/2222-8721-2020-10-1-81-87 ◽

2020 ◽

Vol 10 (1) ◽

pp. 81-87

Author(s):

E. O. Ivanova ◽

E. Yu. Fedotov ◽

S. N. Illarioshkin

Keyword(s):

Case Report ◽

Motor Neuron ◽

Muscular Atrophy ◽

Receptor Gene ◽

Clinical Manifestations ◽

Androgen Receptor Gene ◽

Muscle Pathology ◽

Multisystem Disease ◽

Muscle Involvement ◽

Polyglutamine Expansion

The spinal and bulbar muscular atrophy is a slowly progressive X-linked polysystemic disease associated with polyglutamine expansion in the androgen receptor gene. The mutant protein exhibits toxic properties towards neurons and myocytes. The main motor manifestations of the spinal and bulbar muscular atrophy are weakness, atrophy and fasciculation of the muscles of the limbs and bulbar group. Traditionally spinal and bulbar muscular atrophy belongs to the group of motor neuron diseases, but in recent years there is increasing evidence of a significant role of primary muscle pathology in the pathogenesis and clinical picture of this disease. This article provides a review of the literature on the pathogenesis, clinical manifestations and diagnosis of the spinal and bulbar muscular atrophy. We present a case report of the spinal and bulbar muscular atrophy with a clinical findings resembling metabolic myopathy.

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