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

SBMA is inherited in an X-linked recessive pattern.
Classification and external resources
Specialty	neurology
ICD-10	G12.1
ICD-9-CM	335.1
OMIM	313200
DiseasesDB	7144
eMedicine	article/1172604
MeSH	D055534
Orphanet	481

Spinal and bulbar muscular atrophy (SBMA), also known as 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] is a debilitating neurodegenerative disorder resulting in muscle cramps and progressive weakness due to degeneration of motor neurons in the brain stem and spinal cord.^[2]

The condition is associated with mutation of the androgen receptor (AR) gene^[3]^[4] 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.^[5]

This condition is rare with an estimated incidence of 1/40,000 males. Although this condition is not normally fatal eventually 20% of those affected may need a wheelchair.

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.^[6]

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.^[7] 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.^[8]
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.^[8]
Respiratory musculature weakness^[8]
Action tremor^[8]
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).^[9]
Decreased or absent deep tendon reflexes ^[8]

Muscular

Cramps: muscle spasms^[8]
Muscular atrophy: loss of muscle bulk that occurs when the lower motor neurons do not stimulate the muscle adequately^[8]

Endocrine

Gynecomastia: breast enlargement^[10]
Erectile dysfunction^[10]
Reduced fertility^[10]
Testicular atrophy: testicles become smaller and less functional^[11]

Other

Late onset: individuals usually develop symptoms in their late 30s or afterwards (rarely is it seen in adolescence) ^[8]

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.^[11]

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.^[2]

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.^[12]

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.^[13]

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.^[11]^[14]

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 be wheelchair-bound in later stages of life.^[15]

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.^[10]

Prognosis

A 2006 study followed 233 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).^[16]

History

This disorder was first described by William R. Kennedy in 1968.^[17] 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 1:50,000 males.^[8]

References

↑ 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 : JMLA. 101 (2): 147–150. doi:10.3163/1536-5050.101.2.010. ISSN 1536-5050. PMC 3634378. PMID 23646030.
1 2 "Spinal and bulbar muscular atrophy". Genetics Home Reference. 2016-03-21. Retrieved 2016-03-23.
↑ 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.
↑ 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. Genetic Instabilities and Neurological Diseases (2nd ed.). Boston: Academic Press. pp. 211–222. ISBN 0-12-369462-0.
↑ 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.
↑ "Kennedy disease | Disease | Overview | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2016-03-23.
↑ 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.
1 2 3 4 5 6 7 8 9 La Spada, Albert (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora JH; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C., eds. Spinal and Bulbar Muscular Atrophy. Seattle (WA): University of Washington, Seattle. PMID 20301508. Update: July 3, 2014
↑ Sikka, Paul K.; Beaman, Shawn T.; Street, James A. (2015-04-09). Basic Clinical Anesthesia. Springer. p. 470. ISBN 9781493917372.
1 2 3 4 http://www.medscape.com/viewarticle/715991
1 2 3 "OMIM Entry - # 313200 - SPINAL AND BULBAR MUSCULAR ATROPHY, X-LINKED 1; SMAX1". omim.org. Retrieved 2016-03-23.
↑ 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.
↑ 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.
↑ "Spinal and bulbar muscular atrophy X-linked - Tests - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-03-23.
↑ "Kennedy's Disease Information Page: National Institute of Neurological Disorders and Stroke (NINDS)". www.ninds.nih.gov. Retrieved 2016-03-23.
↑ Atsuta, Naoki (2006). "Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients". Brain.
↑ 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.

External links

"Kennedy Disease - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2016-03-23.
"Motor Neuron Disease Fact Sheet". NIH.gov. NIH. Retrieved 24 March 2016.

Pathology of the nervous system, primarily CNS (G04–G47, 323–349)

Inflammation

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

Spinal cord	Myelitis: Poliomyelitis Demyelinating disease Transverse myelitis Tropical spastic paraparesis Epidural abscess

Both/either	Encephalomyelitis Acute disseminated Myalgic 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 disease

Demyelinating

Episodic/
paroxysmal

Seizure/epilepsy	Focal Generalised Status epilepticus Myoclonic epilepsy

Headache	Migraine Familial hemiplegic Cluster Tension

Cerebrovascular	TIA Amaurosis fugax Transient global amnesia Acute aphasia Stroke MCA ACA PCA Foville's Millard–Gubler Lateral medullary Weber's Lacunar stroke

Sleep disorders	Insomnia Hypersomnia Sleep apnea Obstructive Congenital central hypoventilation syndrome Narcolepsy Cataplexy Kleine–Levin Circadian rhythm sleep disorder Advanced sleep phase disorder Delayed sleep phase disorder Non-24-hour sleep–wake disorder Jet lag

CSF

Other

Spinal cord/
myelopathy

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 SMA-PCH SMA-LED SMA-PME Progressive muscular atrophy Progressive bulbar palsy Fazio–Londe Infantile progressive bulbar palsy both: Amyotrophic lateral sclerosis

Sex linkage: 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 mental retardation: 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

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)

Genetic disorder, protein biosynthesis: Transcription factor/coregulator deficiencies

(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

Transcription coregulators

Coactivator:	CREBBP Rubinstein–Taybi syndrome

Corepressor:	HR (Atrichia with papular lesions)

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