Spinal and bulbar muscular atrophy

 This article is about a type of spinal muscular atrophy linked to a genetic defect in the AR gene.
   For a list of other conditions with similar names, see Spinal muscular atrophies.

Spinal and bulbar muscular atrophy
Synonyms	spinobulbar muscular atrophy, bulbo-spinal atrophy, X-linked bulbospinal neuropathy (XBSN), X-linked spinal muscular atrophy type 1 (SMAX1), Kennedy's disease (KD), and many other names<ref>Arvin, Shelley, Analysis of inconsistencies in terminology of spinal and bulbar muscular atrophy and its effect on retrieval of research, Journal of the Medical Library Association : JMLA, Vol. 101(Issue: 2), pp. 147–150, DOI: 10.3163/1536-5050.101.2.010, PMID: 23646030, PMC: 3634378,</ref>
Pronounce
Field
Symptoms	Muscles cramps<ref name=web/>
Complications
Onset
Duration
Types
Causes	Mutation in the AR gene<ref name=nih/>
Risks
Diagnosis	Clinical features, Family history<ref name=gene/>
Differential diagnosis
Prevention
Treatment	Physical therapy <ref name=gene/>
Medication
Prognosis
Frequency
Deaths

Spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease, is a progressive debilitating neurodegenerative disorder resulting in muscle cramps and progressive weakness due to degeneration of motor neurons in the brainstem and spinal cord.<ref name="nih">

Spinal and bulbar muscular atrophy(link). Genetics Home Reference.

2016-03-21.

Accessed 2016-03-23.

</ref>

The condition is associated with mutation of the androgen receptor (AR) gene<ref name=kennedy>,

 Amyotrophic lateral sclerosis and other motor neuron diseases, 
 Physical Medicine and Rehabilitation Clinics of North America, 
 2003,
 Vol. 14(Issue: 2),
 pp. 327–345,
 DOI: 10.1016/S1047-9651(02)00119-5,
 PMID: 12795519,</ref><ref name="isbn0-12-369462-0">, 
  
 Genetic Instabilities and Neurological Diseases, 
 2nd edition, 
 Boston:Academic Press, 
 2006, 
  
  
 ISBN 978-0-12-369462-1, 
  
  
  
 Pages: 211–222,</ref> and is inherited in an X-linked recessive manner. As with many genetic disorders, no cure is known, although research continues. Because of its endocrine manifestations related to the impairment of the AR gene, SBMA can be viewed as a variation of the disorders of the androgen insensitivity syndrome (AIS). It is also related to other neurodegenerative diseases caused by similar mutations, such as Huntington's disease.<ref name=BrowneBea2004>, 
 The energetics of Huntington's disease, 
 Neurochem Res, 
 
 Vol. 29(Issue: 3),
 pp. 531–46,
 DOI: 10.1023/b:nere.0000014824.04728.dd,
 PMID: 15038601,</ref>

Signs and symptoms

Individuals with SBMA have muscle cramps and progressive weakness due to degeneration of motor neurons in the brain stem and spinal cord. Ages of onset and severity of manifestations in affected males vary from adolescence to old age, but most commonly develop in middle adult life. The syndrome has neuromuscular and endocrine manifestations.<ref name="web">

Kennedy disease | Disease | Overview | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program(link). rarediseases.info.nih.gov.

Accessed 2016-03-23.

</ref>

Neuromuscular

Early signs often include weakness of tongue and mouth muscles, fasciculations, and gradually increasing weakness of limb muscles with muscle wasting. Neuromuscular management is supportive, and the disease progresses very slowly, but can eventually lead to extreme disability.<ref>Grunseich, Christopher,

 Spinal and Bulbar Muscular Atrophy, 
 Neurologic Clinics, 
 
 Vol. 33(Issue: 4),
 pp. 847–854,
 DOI: 10.1016/j.ncl.2015.07.002,
 PMID: 26515625,
 PMC: 4628725,</ref> Further signs and symptoms include:

Ideogram of human X chromosome.

Homozygous females

Homozygous females, both of whose X chromosomes have a mutation leading to CAG expansion of the AR gene, have been reported to show only mild symptoms of muscle cramps and twitching. No endocrinopathy has been described.<ref name=omim/>

Genetics

The genetics of spinal and bulbar muscular atrophy have to do with the mutated androgen receptor gene located on the X chromosome. The effects of the mutation may be androgen-dependent, thus only males are fully affected. Females are rarely affected; female carriers tend to have a relatively mild expression of the disease if they show symptoms at all.<ref name=nih/>

Pathophysiology

Androgen receptor

The mechanism behind SBMA is caused by expansion of a CAG repeat in the first exon of the androgen receptor gene (trinucleotide repeats). The CAG repeat encodes a polyglutamine tract in the androgen receptor protein. The greater the expansion of the CAG repeat, the earlier the disease onset and more severe the disease manifestations. The repeat expansion likely causes a toxic gain of function in the receptor protein, since loss of receptor function in androgen insensitivity syndrome does not cause motor neuron degeneration.<ref>Adachi, H.,

 Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy, 
 Neuropathology and Applied Neurobiology, 
 
 Vol. 33(Issue: 2),
 pp. 135–151,
 DOI: 10.1111/j.1365-2990.2007.00830.x,
 PMID: 17359355,</ref>

Spinal and bulbar muscular atrophy may share mechanistic features with other disorders caused by polyglutamine expansion, such as Huntington's disease. No cure for SBMA is known.<ref name="pmid16389310">,

 Animal Models of Kennedy Disease, 
 NeuroRx, 
 2005,
 Vol. 2(Issue: 3),
 pp. 471–479,
 DOI: 10.1602/neurorx.2.3.471,
 PMID: 16389310,
 PMC: 1144490,</ref>

Diagnosis

In regards to the diagnosis of spinal and bulbar muscular atrophy, the AR Xq12 gene is the focus. Many mutations are reported and identified as missense/nonsense, that can be identified with 99.9% accuracy. Test for this gene in the majority of affected patients yields the diagnosis.<ref name=omim/><ref>

Spinal and bulbar muscular atrophy X-linked - Tests - GTR - NCBI(link). www.ncbi.nlm.nih.gov.

Accessed 2016-03-23.

</ref>

Management

In terms of the management of spinal and bulbar muscular atrophy, no cure is known and treatment is supportive. Rehabilitation to slow muscle weakness can prove positive, though the prognosis indicates some individuals will require the use of a wheelchair in later stages of life.<ref>

Kennedy's Disease Information Page: National Institute of Neurological Disorders and Stroke (NINDS)(link). NIH.

Accessed 2016-03-23.

</ref>

Surgery may achieve correction of the spine, and early surgical intervention should be done in cases where prolonged survival is expected. Preferred nonsurgical treatment occurs due to the high rate of repeated dislocation of the hip.<ref name=emed/>

Prognosis

A 2006 study followed 223 patients for a number of years. Of these, 15 died, with a median age of 65 years. The authors tentatively concluded that this is in line with a previously reported estimate of a shortened life expectancy of 10–15 years (12 in their data).<ref>Atsuta, Naoki,

 Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients, 
 Brain, 
 2006,
 Vol. 129(Issue: 6),
 pp. 1446–1455,
 DOI: 10.1093/brain/awl096,
 PMID: 16621916,</ref>

History

This disorder was first described by William R. Kennedy in 1968.<ref name="pmid4233749">,

 Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait, 
 Neurology, 
 1968,
 Vol. 18(Issue: 7),
 pp. 671–680,
 DOI: 10.1212/WNL.18.7.671,
 PMID: 4233749,</ref> In 1991, it was recognized that the AR gene is involved in the disease process. The disease is probably more common than originally thought, SBMA prevalence has been estimated at 1:300,000 males.<ref name=gene/>

See also

• Spinal muscular atrophies

Further reading

• ,

 Beyond motor neurons: expanding the clinical spectrum in Kennedy's disease, 
 Journal of Neurology, Neurosurgery & Psychiatry, 
 2018,
 Vol. 89(Issue: 8),
 pp. 808–812,
 DOI: 10.1136/jnnp-2017-316961,
 PMID: 29353237,
 PMC: 6204939,

Study of Hepatic Function in Patients With Spinal and Bulbar Muscular Atrophy - Full Text View - ClinicalTrials.gov(link). clinicaltrials.gov.

Accessed 2016-03-23.

• P. Jorge,

 Reproductive Endocrinology: A Molecular Approach. online version, 
  
 Springer Science & Business Media, 
  
  
  
 ISBN 9780387881867,

• Rhodes, Lindsay E.,

 Clinical features of spinal and bulbar muscular atrophy, 
 Brain, 
 
 Vol. 132(Issue: 12),
 pp. 3242–3251,
 DOI: 10.1093/brain/awp258,
 PMID: 19846582,
 PMC: 2792370,

External links

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