Kennedy's Disease

Definition/Description

Kennedy’s Disease is a rare, X-linked recessive, genetic, progressive adult-onset neurodegenerative, neuromuscular disorder. In Kennedy’s Disease, both the spinal and bulbar neurons are affected, which causes muscle weakness and atrophy of the facial, bulbar, and limb muscles, while also causing sensory disturbances and endocrine abnormalities.[1][2]

Synonyms:

  • Kennedy’s syndrome
  • Spinal bulbar muscular atrophy (SBMA)
  • X-linked spinal bulbar muscular atrophy

Epidemiology

Kennedy’s Disease affects approximately 3.3/100,000 males.[2] It very rarely affects females due to its X-linked transmission.[2] Kennedy’s Disease usually appears between the ages of 30-60; however, earlier and later onsets can also occur.[1]

Clinically Relevant Anatomy

In Kennedy’s Disease, there is a mis-folding of the androgen receptor proteins in the body. This mis-folding has been thought to cause aggregation of the receptor in the motor neurons in the body, having toxic effects to motor neurons.[3]

As a result, there is noted degeneration of anterior horn cells in the spinal cord in those living with Kennedy’s Disease. In the spinal cord, the anterior horn is the grey matter containing motor neurons. These motor neurons will exit the spinal cord and eventually synapse onto skeletal muscle. Loss of anterior horn cells may lead to the eventual atrophy of muscles of the trunk and limbs, due to challenges with innervation. Widespread weakness of the limbs and trunk may be seen in Kennedy’s Disease due to this loss of spinal cord anterior horn cells.[4]

Aetiology

Kennedy’s Disease is caused by a mutation of the gene that encodes for the androgen receptor (AR).[2] The AR is in the cytoplasm of cells that make up the skin, kidney, prostate, skeletal muscle, and lower motor neurons in the spinal cord and brainstem.[5] Normally, androgen hormones will bind to the AR, which initiates a cascade of reactions that signals genes to increase protein production for a number of functions within the cell. In Kennedy’s Disease, this function is compromised due to the mutation of the AR gene; nonetheless, the exact mechanism for motor neuron impairment remains relatively unknown.[5]

Clinical Manifestation

Extremities: [2][6][7]

  • Weakness and wasting of facial, bulbar, and extremity muscles
  • Limb weakness and wasting usually asymmetrical and weakness  proximal greater than distal impairment. More weakness on dominant side
  • Weakness may present as difficulty climbing stairs and walking, particularly long distances
  • Tremors of the hands
  • Reduced or absent tendon reflexes
  • Hyperlordotic posture
  • Internally rotated arms
  • Gait disturbances, falls, or trouble with stairs
  • Muscle cramps and fasciculations
  • Myalgias
  • Sensory abnormalities

Cerebrum:[2][6][7]

  • Hanging jaw (jaw drop)
  • Fasciculations of lips, perioral muscles, and tongue
  • Irregular edges or deep furrowing in the midline of tongue
  • Difficulty chewing
  • Dysarthria
  • Dysphagia
  • Nasal voice due to palatal weakness
  • Laryngospasm
  • Twitching movements of chin
  • Postural tremor of jaw

Endocrine:[2]

  • Gynecomastia (most common)
  • Reduced fertility due to testicular atrophy
  • Azoospermia
  • Oligospermia
  • Androgen resistance
  • Erectile dysfunction
  • Reduced libido
  • Diabetes

Diagnosis

Diagnosis of Kennedy’s Disease is based on physical signs and symptoms previously listed in the Clinical Manifestations section.[5]

Diagnosis of the disease can be confirmed by molecular genetic testing on a blood sample for cytosine-adenosin-guanosin (CAG) trinucleotide repeat expansion in the AR gene.[2] Individuals with greater than 36 CAG trinucleotide repeats in the AR gene are diagnosed with Kennedy’s Disease.[5]

Differential Diagnosis

  • ALS, spinal muscular atrophy with adult onset, adrenoleucodystrophy, hexosaminidase A deficiency, poliomyelitis[2][6][7][8]
  • Muscle diseases: fascioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, mitochondrial disorders, polymyositis, myasthenia gravis[2][8]
  • Neuropathies: hereditary sensory and autonomic neuropathy, multifocal motor neuropathy[2][8]

Prognosis

Kennedy’s Disease is a slow progressive disorder. Individuals with Kennedy’s Disease often remain ambulatory on their own until the later stages of the disease. Some may be constrained to wheelchairs in the final stages. The lifespan of individuals with Kennedy’s Disease is typically normal. Common causes of death are pneumonia and respiratory failure.[9]

Medical Management

Kennedy’s Disease is exacerbated by the presence of androgens. Surgery can be performed to suppress androgen activity. However, androgen suppression has negative side effects which include reduced muscle strength, osteoporosis, and altered mood effects. In an attempt to limit these side effects, short term androgen reduction therapy has been attempted but this approach has yet to be clinically tested. Additionally, gonadotropin releasing hormone therapy has been utilized to limit the secretion of androgens. These treatment interventions are novel and require more experimentation trials before they should be recommended as treatment options for individuals with Kennedy’s Disease.[9]

Other health care professionals also play a crucial role in the management of persons with Kennedy’s Disease. Some may include:

  • Speech Language Pathologist - treatments targeted towards re-teaching how to swallow properly and safely. Additionally, the production and development of speech will be an area of focus with SLP intervention.[9]
  • Dietitian - due to increased difficulty to swallow, persons with Kennedy’s Disease may experience weight loss, dehydration, and energy loss. A dietitian may be consulted to prevent these from occurring.[9]
  • Physicians - prescription of medication to reduce symptoms that are characteristic of Kennedy’s Disease.[10]
  • Occupational Therapists - gait aid prescription and adjustment of activities of daily living may be performed by occupational therapists.

Physiotherapy Management

There is no proven treatment for Kennedy's Disease and the effects of exercise is still uncertain, so the aim in Physiotherapy is to help manage the current symptoms and prevent complications experienced by the individual and to help in maintaining functional independence for as long as possible.[6][7][8]

Physiotherapy interventions should be aimed at achieving the following:[11]

  • Maintaining muscle strength, soft tissue length, and joint range of motion
  • Improving posture, balance, and coordination
  • Maximising independence
  • Reducing risk of falls

Physiotherapy intervention may include:[11]

  • Stretching exercises to lengthen shortened/tight muscles and maintain flexibility
  • Strengthening exercises to aid in maintaining the ability to perform functional activities
  • Core and trunk stabilization exercises
  • Balance training
  • Postural education – sitting, lying and standing
  • Practicing functional activities such as standing and walking
  • As the disease progresses, gait aid prescription may be necessary, which can improve ambulation and mobility

Strengthening exercises can include free weights, machine weights, and functional exercises using body weight. Exercises performed in a study by Chris Grunseich, which saw an overall increase in lower extremity strength included knee extensions, squats, single leg stand, lunges, step ups and planks. The exercise parameters were adjusted throughout the 15 week program based on the individuals response to it.[12] These exercises also resulted in an increased stride length and improved balance and coordination.[12]

Outcome Measures

The Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS) has been developed in order to measure level of function in those living with Kennedy’s Disease. This scale breaks down the functional components of the disease into four subscales, including:

  • Bulbar-Related Subscale
  • Upper-Limb Related Subscale
  • Lower-Limb Related Subscale
  • Breathing Related Subscale

This disease-specific functional scale shows good validity and sensitivity; however, requires further testing in control studies to be further validated as an outcome measure.[13]

In one study, the 6 Minute Walk Test was used in those with Kennedy’s Disease, and it was noted that there was a significant decrease in walking distance between those diagnosed with Kennedy’s Disease and a control group (n = 35). The conclusions from this study determined that the 6MWT could be used as a biomarker for disease progression.[14]

A separate study evaluated 34 patients with Kennedy’s Disease using the following outcome measures:

  • Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)
  • Modified Norris Scale
  • Modified Quantitative Myasthenia Gravis Score
  • 6 Minute Walk Test
  • 5-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5)
  • Grip Strength using a Hand Dynamometer

This study performed a longitudinal analysis over a 3 year period and showed a statistically significant change in disease progression in all outcome measures, excluding the ALSAQ-5.[15]

Resources

Kennedy’s Disease Association Website

Recent Related Research

Study identifies possible drug treatment for Kennedy’s Disease

Badders NM, Korff A, Miranda HC, Vuppala PK, Smith RB, Winborn BJ, Quemin ER, Sopher BL, Dearman J, Messing J, Kim NC. Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy. Nature medicine. 2018 Apr;24(4):427.

List of Categories

References

  1. 1.0 1.1 Kennedy’s Disease Association. What is Kennedy’s disease [Internet]. Coarsegold, CA: [publisher unknown]; [date of publication unknown; cited 2018 May 06]. Available from https://www.kennedysdisease.org/index.php/about-kennedys-disease/what-is-kennedys-disease
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 Finsterer J. Perspectives of Kennedy's disease. Journal of the neurological sciences. 2010 Nov 15;298(1):1-0. DOI: 10.1016/j.jns.2010.08.025
  3. Davey RA, Grossmann M. Androgen receptor structure, function and biology: from bench to bedside. The Clinical Biochemist Reviews. 2016 Feb;37(1):3.
  4. La Spada A. Spinal and bulbar muscular atrophy. Available from:https://www.ncbi.nlm.nih.gov/books/NBK1333/
  5. 5.0 5.1 5.2 5.3 Kim, J., & La Spada, A. Rare Diseases [Internet]. Danbury, CT: National Organization for Rare Disorders; [publication date unknown] Kennedy disease; [updated 2015; cited 2018 May 05]. Available from https://rarediseases.org/rare-diseases/kennedy-disease/
  6. 6.0 6.1 6.2 6.3 Grunseich C, Rinaldi C, Fischbeck KH. Spinal and bulbar muscular atrophy: pathogenesis and clinical management. Oral diseases. 2014 Jan 1;20(1):6-9. DOI: 10.1111/odi.12121
  7. 7.0 7.1 7.2 7.3 Greenland KJ, Zajac JD. Kennedy's disease: pathogenesis and clinical approaches. Internal medicine journal. 2004 May 1;34(5):279-86. DOI: 10.1111/j.1444-0903.2004.00588.x
  8. 8.0 8.1 8.2 8.3 Finsterer J. Bulbar and spinal muscular atrophy (Kennedy’s disease): a review. European journal of neurology. 2009 May 1;16(5):556-61. DOI: 10.1111/j.1468-1331.2009.02591.x
  9. 9.0 9.1 9.2 9.3 NINDS Kennedy’s Disease Information Page [Internet]. [Unknown Place of Publication]: National Institute of Neurological Disorders and Stroke, NIH; [Last Updated 2017 May 22], [Location Unknown]. Cited May 07, 2018. Available from https://www.ninds.nih.gov/Disorders/All-Disorders/Kennedys-Disease-Information-Page#disorders-r2
  10. Kennedy’s Disease [Internet]. Northhampton, ENG: Motor Neuron Disease Association; [publication date unknown]. Information for people with or affected by Kennedy’s Disease; [Updated 2015, cited 2018 May 07]. Available from https://www.mndassociation.org/wp-content/uploads/2015/07/02b-kennedys-disease.pdf
  11. 11.0 11.1 Physio.co.uk [Internet]. Manchester, ENG: [publisher unknown], [publication date unknown]. Kennedy’s disease; [2018 May 05], [location unknown]. Available from: www.physio.co.uk/what-we-treat/neurological/conditions/kennedys-disease.php
  12. 12.0 12.1 Kennedy’s disease association [Internet]. [Unknown place of publication]: National Institute of  Neurological Disorders and Stroke, NIH. [Date of publication unknown]. Exercise training in Kennedy’s disease; [cited 2018 May 06], [location unknown]. Available from https://www.kennedysdisease.org/images/stories/PDFs/2016DrChristopherGrunseichExerciseinKD.pdf
  13. Hashizume A, Katsuno M, Suzuki K, Banno H, Suga N, Mano T, Araki A, Hijikata Y, Grunseich C, Kokkinis A, Hirakawa A. A functional scale for spinal and bulbar muscular atrophy: cross-sectional and longitudinal study. Neuromuscular Disorders. 2015 Jul 1;25(7):554-62. DOI: 10.1016/j.nmd.2015.03.008
  14. Takeuchi Y, Katsuno M, Banno H, Suzuki K, Kawashima M, Atsuta N, Ito M, Watanabe H, Tanaka F, Sobue G. Walking capacity evaluated by the 6‐minute walk test in spinal and bulbar muscular atrophy. Muscle & nerve. 2008 Aug 1;38(2):964-71. DOI: 10.1002/mus.21077
  15. Hashizume A, Katsuno M, Banno H, Suzuki K, Suga N, Mano T, Atsuta N, Oe H, Watanabe H, Tanaka F, Sobue G. Longitudinal changes of outcome measures in spinal and bulbar muscular atrophy. Brain. 2012 Jul 6;135(9):2838-48. DOI: 10.1093/brain/aws170