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

Other names: 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[1]
SBMA is inherited in an X-linked recessive pattern.
Symptoms| Muscles cramps[2]
Causes| Mutation in the AR gene[3]
Diagnostic method| Clinical features, Family history[4]
Treatment| Physical therapy [4]

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.[5][6]

The condition is associated with mutation of the androgen receptor (AR) gene[7][8] 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.[9] SBMA prevalence has been estimated at 2.6:100,000 males.[10]

## Contents

* 1 Signs and symptoms
* 1.1 Neuromuscular
* 1.2 Homozygous females
* 2 Genetics
* 3 Pathophysiology
* 4 Diagnosis
* 5 Management
* 6 Prognosis
* 7 History
* 8 See also
* 9 References
* 10 Further reading
* 11 External links

## Signs and symptoms[edit | edit source]

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.[6]

### Neuromuscular[edit | edit source]

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.[11] Further signs and symptoms include:

Ideogram of human X chromosome.

Neurological

* Bulbar signs: bulbar muscles are those supplied by the motor nerves from the brain stem, which control swallowing, speech, and other functions of the throat.[4]
* Lower motor neuron signs: lower motor neurons are those in the brainstem and spinal cord that directly supply the muscles, loss of lower motor neurons leads to weakness and wasting of the muscle.[4]
* Respiratory musculature weakness[4]
* Action tremor[4]
* Babinski response: when the bottom of the foot is scraped, the toes bend down (an abnormal response would be an upward movement of the toes indicating a problem with higher-level (upper) motor neurons).[12]
* Decreased or absent deep tendon reflexes [4]

Muscular

* Cramps: muscle spasms[4]
* Muscular atrophy: loss of muscle bulk that occurs when the lower motor neurons do not stimulate the muscle adequately[4]

Endocrine

* Gynecomastia: male breast enlargement[13]
* Erectile dysfunction[13]
* Reduced fertility[13]
* Testicular atrophy: testicles become smaller and less functional[14]

Other

* Late onset: individuals usually develop symptoms in their late 30s or afterwards (rarely is it seen in adolescence) [4]

### Homozygous females[edit | edit source]

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.[14]

## Genetics[edit | edit source]

SBMA is a hereditary syndrome, inherited in an X-linked recessive manner.[7] The AR gene, located in the X chromosome, involves a section consisting of CAG repeats. The number of repeats varies among individuals. Healthy males carry up to 34 repeats. From 35 to around 46 repeats, penetrance (the possibility that the individual manifests the disease) gradually increases, approaching a maximum value (full penetrance).[10] Therefore, males bearing 35 to 46 CAG repeats are at intermediate but increasing risk for developing SBMA. Males bearing 47 or more repeats have nearly 100% risk of developing SBMA.[10] Other, still unidentified genetic factors may also play a role in disease manifestation and symptoms’ severity. Genetic founder effects are likely to be responsible for the higher prevalence of SBMA observed in certain geographic regions.[citation needed]

## Pathophysiology[edit | edit source]

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.[15]

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.[16]

## Diagnosis[edit | edit source]

a) Type 2 ‘saddleback’ pattern (standard V1-V2 precordial lead) b) SBMA muscle

Diagnosis of SBMA is based on identifying the number of CAG repeats in the AR gene using molecular techniques such as PCR. The accuracy of such techniques is nearly 100%.[7] Additionally one should also look for the following:[17]

* Gynecomastia
* Muscle weakness-limbs
* Dysarthria
* No upper motor neuron disease signs
* Family history

## Management[edit | edit source]

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.[18]

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.[13]

## Prognosis[edit | edit source]

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).[19]

## History[edit | edit source]

This disorder was first described by William R. Kennedy in 1968.[5] In 1991, it was recognized that the AR gene is involved in the disease process.[7]

## See also[edit | edit source]

* Spinal muscular atrophies

## References[edit | edit source]

1. ↑ Arvin, Shelley (2013-04-01). "Analysis of inconsistencies in terminology of spinal and bulbar muscular atrophy and its effect on retrieval of research". Journal of the Medical Library Association. 101 (2): 147–150. doi:10.3163/1536-5050.101.2.010. ISSN 1536-5050. PMC 3634378. PMID 23646030.
2. ↑ "Kennedy disease | Disease | Overview | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2016-04-04. Retrieved 2016-03-23.
3. ↑ "Spinal and bulbar muscular atrophy". Genetics Home Reference. 2016-03-21. Archived from the original on 2016-04-03. Retrieved 2016-03-23.
4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 La Spada, Albert (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C. (eds.). Spinal and Bulbar Muscular Atrophy. Seattle (WA): University of Washington, Seattle. PMID 20301508. Archived from the original on 2017-01-18. Retrieved 2021-08-18. Update: July 3, 2014
5. ↑ 5.0 5.1 Kennedy, W. R.; Alter, M.; Sung, J. H. (1968). "Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait". Neurology. 18 (7): 671–680. doi:10.1212/WNL.18.7.671. PMID 4233749. S2CID 45735233.
6. ↑ 6.0 6.1 A, La Spada (1993–2020). "Spinal and Bulbar Muscular Atrophy". PMID 20301508. `{{cite journal}}`: Cite journal requires `|journal=` (help)
7. ↑ 7.0 7.1 7.2 7.3 Krivickas, L. S. (2003). "Amyotrophic lateral sclerosis and other motor neuron diseases". Physical Medicine and Rehabilitation Clinics of North America. 14 (2): 327–345. doi:10.1016/S1047-9651(02)00119-5. PMID 12795519.
8. ↑ Chen CJ, Fischbeck KH (2006). "Ch. 13: Clinical aspects and the genetic and molecular biology of Kennedy's disease". In Tetsuo Ashizawa, Wells, Robert V. (eds.). Genetic Instabilities and Neurological Diseases (2nd ed.). Boston: Academic Press. pp. 211–222. ISBN 978-0-12-369462-1.
9. ↑ Browne SE, Beal MF (Mar 2004). "The energetics of Huntington's disease". Neurochem Res (Review). 29 (3): 531–46. doi:10.1023/b:nere.0000014824.04728.dd. PMID 15038601. S2CID 20202258.
10. ↑ 10.0 10.1 10.2 Laskaratos, Achilleas; Breza, Marianthi; Karadima, Georgia; Koutsis, Georgios (2020-06-22). "Wide range of reduced penetrance alleles in spinal and bulbar muscular atrophy: a model-based approach". Journal of Medical Genetics: jmedgenet–2020–106963. doi:10.1136/jmedgenet-2020-106963. ISSN 0022-2593. PMID 32571900.
11. ↑ Grunseich, Christopher; Fischbeck, Kenneth H. (2015-11-01). "Spinal and Bulbar Muscular Atrophy". Neurologic Clinics. 33 (4): 847–854. doi:10.1016/j.ncl.2015.07.002. ISSN 1557-9875. PMC 4628725. PMID 26515625.
12. ↑ Sikka, Paul K.; Beaman, Shawn T.; Street, James A. (2015-04-09). Basic Clinical Anesthesia. Springer. p. 470\. ISBN 9781493917372.
13. ↑ 13.0 13.1 13.2 13.3 "Clinical Features of Spinal and Bulbar Muscular Atrophy". Archived from the original on 2020-08-05. Retrieved 2021-08-18.
14. ↑ 14.0 14.1 "OMIM Entry - # 313200 - SPINAL AND BULBAR MUSCULAR ATROPHY, X-LINKED 1; SMAX1". omim.org. Archived from the original on 2016-05-10. Retrieved 2016-03-23.
15. ↑ Adachi, H.; Waza, M.; Katsuno, M.; Tanaka, F.; Doyu, M.; Sobue, G. (2007-04-01). "Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy". Neuropathology and Applied Neurobiology. 33 (2): 135–151. doi:10.1111/j.1365-2990.2007.00830.x. ISSN 1365-2990. PMID 17359355. S2CID 73301743.
16. ↑ Merry, D. E. (2005). "Animal Models of Kennedy Disease". NeuroRx. 2 (3): 471–479. doi:10.1602/neurorx.2.3.471. PMC 1144490. PMID 16389310.
17. ↑ La Spada, Albert (1993). "Spinal and Bulbar Muscular Atrophy". GeneReviews®. University of Washington, Seattle. Archived from the original on 18 January 2017. Retrieved 19 October 2021.
18. ↑ "Kennedy's Disease Information Page: National Institute of Neurological Disorders and Stroke (NINDS)". NIH. Archived from the original on 2017-01-04. Retrieved 2016-03-23.
19. ↑ Atsuta, Naoki (2006). "Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients". Brain. 129 (6): 1446–1455. doi:10.1093/brain/awl096. PMID 16621916.

## Further reading[edit | edit source]

* Manzano, Raquel; Sorarú, Gianni; Grunseich, Christopher; Fratta, Pietro; Zuccaro, Emanuela; Pennuto, Maria; Rinaldi, Carlo (2018). "Beyond motor neurons: expanding the clinical spectrum in Kennedy's disease". Journal of Neurology, Neurosurgery & Psychiatry. 89 (8): 808–812. doi:10.1136/jnnp-2017-316961. ISSN 0022-3050. PMC 6204939. PMID 29353237.
* "Study of Hepatic Function in Patients With Spinal and Bulbar Muscular Atrophy - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Archived from the original on 2016-04-03. Retrieved 2016-03-23.
* Chedrese, P. Jorge (2009-06-13). Reproductive Endocrinology: A Molecular Approach. Springer Science & Business Media. ISBN 9780387881867. Archived from the original on 2020-09-13. Retrieved 2021-08-18.
* Rhodes, Lindsay E.; Freeman, Brandi K.; Auh, Sungyoung; Kokkinis, Angela D.; Pean, Alison La; Chen, Cheunju; Lehky, Tanya J.; Shrader, Joseph A.; Levy, Ellen W. (2009-12-01). "Clinical features of spinal and bulbar muscular atrophy". Brain. 132 (12): 3242–3251. doi:10.1093/brain/awp258. ISSN 0006-8950. PMC 2792370. PMID 19846582.

## External links[edit | edit source]

Classification|

* ICD-10: G12.1
* ICD-9-CM: 335.1
* OMIM: 313200
* MeSH: D055534
* DiseasesDB: 7144

|

External resources|

* eMedicine: article/1172604
* Orphanet: 481

* v
* t
* e

Diseases of the nervous system, primarily CNS

Inflammation|

| Brain|

* Encephalitis
* Viral encephalitis
* Herpesviral encephalitis
* Limbic encephalitis
* Encephalitis lethargica
* Cavernous sinus thrombosis
* Brain abscess
* Amoebic

|

Brain and spinal cord|

* Encephalomyelitis
* Acute disseminated
* Meningitis
* Meningoencephalitis

Brain/
encephalopathy|

| Degenerative|

| Extrapyramidal and
movement disorders|

* Basal ganglia disease
* Parkinsonism
* PD
* Postencephalitic
* NMS
* PKAN
* Tauopathy
* PSP
* Striatonigral degeneration
* Hemiballismus
* HD
* OA

* Dyskinesia
* Dystonia
* Status dystonicus
* Spasmodic torticollis
* Meige's
* Blepharospasm
* Athetosis
* Chorea
* Choreoathetosis
* Myoclonus
* Myoclonic epilepsy
* Akathisia

* Tremor
* Essential tremor
* Intention tremor
* Restless legs
* Stiff-person

|

Dementia|

* Tauopathy
* Alzheimer's
* Early-onset
* Primary progressive aphasia
* Frontotemporal dementia/Frontotemporal lobar degeneration
* Pick's
* Dementia with Lewy bodies
* Posterior cortical atrophy

* Vascular dementia

Mitochondrial disease|

* Leigh syndrome

Demyelinating|

* Autoimmune
* Inflammatory
* Multiple sclerosis
* For more detailed coverage, see Template:Demyelinating diseases of CNS

Episodic/
paroxysmal|

| Seizures and epilepsy|

* Focal
* Generalised
* Status epilepticus
* For more detailed coverage, see Template:Epilepsy

|

Headache|

* Migraine
* Cluster
* Tension
* For more detailed coverage, see Template:Headache

Cerebrovascular|

* TIA
* Stroke
* For more detailed coverage, see Template:Cerebrovascular diseases

Other|

* Sleep disorders
* For more detailed coverage, see Template:Sleep

CSF|

* Intracranial hypertension
* Hydrocephalus
* Normal pressure hydrocephalus
* Choroid plexus papilloma
* Idiopathic intracranial hypertension
* Cerebral edema
* Intracranial hypotension

Other|

* Brain herniation
* Reye syndrome
* Hepatic encephalopathy
* Toxic encephalopathy
* Hashimoto's encephalopathy

Both/either|

| Degenerative|

| SA|

* Friedreich's ataxia
* Ataxia–telangiectasia

|

MND|

* UMN only:
* Primary lateral sclerosis
* Pseudobulbar palsy
* Hereditary spastic paraplegia

* LMN only:
* Distal hereditary motor neuronopathies
* Spinal muscular atrophies
* SMA
* SMAX1
* SMAX2
* DSMA1
* Congenital DSMA
* Spinal muscular atrophy with lower extremity predominance (SMALED)
* SMALED1
* SMALED2A
* SMALED2B
* SMA-PCH
* SMA-PME
* Progressive muscular atrophy
* Progressive bulbar palsy
* Fazio–Londe
* Infantile progressive bulbar palsy

* both:
* Amyotrophic lateral sclerosis

* v
* t
* e

X-linked disorders

X-linked recessive

Immune|

* Chronic granulomatous disease (CYBB)
* Wiskott–Aldrich syndrome
* X-linked severe combined immunodeficiency
* X-linked agammaglobulinemia
* Hyper-IgM syndrome type 1
* IPEX
* X-linked lymphoproliferative disease
* Properdin deficiency

Hematologic|

* Haemophilia A
* Haemophilia B
* X-linked sideroblastic anemia

Endocrine|

* Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy
* KAL1 Kallmann syndrome
* X-linked adrenal hypoplasia congenita

Metabolic|

* Amino acid: Ornithine transcarbamylase deficiency
* Oculocerebrorenal syndrome

* Dyslipidemia: Adrenoleukodystrophy

* Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency
* Pyruvate dehydrogenase deficiency
* Danon disease/glycogen storage disease Type IIb

* Lipid storage disorder: Fabry's disease

* Mucopolysaccharidosis: Hunter syndrome

* Purine–pyrimidine metabolism: Lesch–Nyhan syndrome

* Mineral: Menkes disease/Occipital horn syndrome

Nervous system|

* X-linked intellectual disability: Coffin–Lowry syndrome
* MASA syndrome
* Alpha-thalassemia mental retardation syndrome
* Siderius X-linked mental retardation syndrome

* Eye disorders: Color blindness (red and green, but not blue)
* Ocular albinism (1)
* Norrie disease
* Choroideremia

* Other: Charcot–Marie–Tooth disease (CMTX2-3)
* Pelizaeus–Merzbacher disease
* SMAX2

Skin and related tissue|

* Dyskeratosis congenita
* Hypohidrotic ectodermal dysplasia (EDA)
* X-linked ichthyosis
* X-linked endothelial corneal dystrophy

Neuromuscular|

* Becker's muscular dystrophy/Duchenne
* Centronuclear myopathy (MTM1)
* Conradi–Hünermann syndrome
* Emery–Dreifuss muscular dystrophy 1

Urologic|

* Alport syndrome
* Dent's disease
* X-linked nephrogenic diabetes insipidus

Bone/tooth|

* AMELX Amelogenesis imperfecta

No primary system|

* Barth syndrome
* McLeod syndrome
* Smith–Fineman–Myers syndrome
* Simpson–Golabi–Behmel syndrome
* Mohr–Tranebjærg syndrome
* Nasodigitoacoustic syndrome

X-linked dominant

* X-linked hypophosphatemia
* Focal dermal hypoplasia
* Fragile X syndrome
* Aicardi syndrome
* Incontinentia pigmenti
* Rett syndrome
* CHILD syndrome
* Lujan–Fryns syndrome
* Orofaciodigital syndrome 1
* Craniofrontonasal dysplasia

* v
* t
* e

Non-Mendelian inheritance: anticipation

Trinucleotide|

| Polyglutamine (PolyQ), CAG|

* Dentatorubral-pallidoluysian atrophy
* Huntington's disease
* Kennedy disease
* Spinocerebellar ataxia 1, 2, 3, 6, 7, 17 (Machado-Joseph disease)

|

Non-polyglutamine|

* CGG (Fragile X syndrome)
* GAA (Friedreich's ataxia)
* CTG (Myotonic dystrophy type 1)
* CTG (Spinocerebellar ataxia 8)
* CAG (Spinocerebellar ataxia 12)

Tetranucleotide|

* CCTG (Myotonic dystrophy type 2)

Pentanucleotide|

* ATTCT (Spinocerebellar ataxia 10)

* v
* t
* e

Genetic disorders relating to deficiencies of transcription factor or coregulators

(1) Basic domains|

| 1.2|

* Feingold syndrome
* Saethre–Chotzen syndrome

|

1.3|

* Tietz syndrome

(2) Zinc finger
DNA-binding domains|

| 2.1|

* (Intracellular receptor): Thyroid hormone resistance
* Androgen insensitivity syndrome
* PAIS
* MAIS
* CAIS
* Kennedy's disease
* PHA1AD pseudohypoaldosteronism
* Estrogen insensitivity syndrome
* X-linked adrenal hypoplasia congenita
* MODY 1
* Familial partial lipodystrophy 3
* SF1 XY gonadal dysgenesis

|

2.2|

* Barakat syndrome
* Tricho–rhino–phalangeal syndrome

2.3|

* Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome
* Denys–Drash syndrome
* Duane-radial ray syndrome
* MODY 7
* MRX 89
* Townes–Brocks syndrome
* Acrocallosal syndrome
* Myotonic dystrophy 2

2.5|

* Autoimmune polyendocrine syndrome type 1

(3) Helix-turn-helix domains|

| 3.1|

* ARX
* Ohtahara syndrome
* Lissencephaly X2
* MNX1
* Currarino syndrome
* HOXD13
* SPD1 synpolydactyly
* PDX1
* MODY 4
* LMX1B
* Nail–patella syndrome
* MSX1
* Tooth and nail syndrome
* OFC5
* PITX2
* Axenfeld syndrome 1
* POU4F3
* DFNA15
* POU3F4
* DFNX2
* ZEB1
* Posterior polymorphous corneal dystrophy
* Fuchs' dystrophy 3
* ZEB2
* Mowat–Wilson syndrome

|

3.2|

* PAX2
* Papillorenal syndrome
* PAX3
* Waardenburg syndrome 1&3
* PAX4
* MODY 9
* PAX6
* Gillespie syndrome
* Coloboma of optic nerve
* PAX8
* Congenital hypothyroidism 2
* PAX9
* STHAG3

3.3|

* FOXC1
* Axenfeld syndrome 3
* Iridogoniodysgenesis, dominant type
* FOXC2
* Lymphedema–distichiasis syndrome
* FOXE1
* Bamforth–Lazarus syndrome
* FOXE3
* Anterior segment mesenchymal dysgenesis
* FOXF1
* ACD/MPV
* FOXI1
* Enlarged vestibular aqueduct
* FOXL2
* Premature ovarian failure 3
* FOXP3
* IPEX

3.5|

* IRF6
* Van der Woude syndrome
* Popliteal pterygium syndrome

(4) β-Scaffold factors
with minor groove contacts|

| 4.2|

* Hyperimmunoglobulin E syndrome

|

4.3|

* Holt–Oram syndrome
* Li–Fraumeni syndrome
* Ulnar–mammary syndrome

4.7|

* Campomelic dysplasia
* MODY 3
* MODY 5
* SF1
* SRY XY gonadal dysgenesis
* Premature ovarian failure 7
* SOX10
* Waardenburg syndrome 4c
* Yemenite deaf-blind hypopigmentation syndrome

4.11|

* Cleidocranial dysostosis

(0) Other transcription factors|

| 0.6|

* Kabuki syndrome

|

Ungrouped|

* TCF4
* Pitt–Hopkins syndrome
* ZFP57
* TNDM1
* TP63
* Rapp–Hodgkin syndrome/Hay–Wells syndrome/Ectrodactyly–ectodermal dysplasia–cleft syndrome 3/Limb–mammary syndrome/OFC8

Transcription coregulators|

| Coactivator:|

* CREBBP
* Rubinstein–Taybi syndrome

|

Corepressor:|

* HR (Atrichia with papular lesions)

*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template