SBMA AR

Kennedy's disease, also known as bulbospinal muscular atrophy (BSMA), is a rare X-linked recessive motor neuron disease characterized by proximal and bulbar muscle wasting¹.

Prevalence

1 30,000

1-2/100,000 (population-specific, higher in Finnish population, Canadian population)²; 1/30,000³; mutation frequency of 1:3182 10x more frequent than reported disease prevalence of 1 in 30,000⁴. Only documented in patients with European/Asian ancestry, including Scandinavian, English, Belgian, French, Italian, German, Polish, Spanish, Swiss, Moroccan, Turkish, Chinese, Japanese (more common because of a founder effect), Korean, and Vietnamese populations⁵.

Age of Onset Details

Typical: 20-49⁶, Range: 8⁷- 83⁸.

Locus

hg19

chrX:66765159-66765261

hg38

chrX:67545317-67545419

t2t

chrX:65975148-65975250

Details

Intermediate alleles indicate reduced penetrance⁵. Expansions larger than the pathogenic threshold in the AR gene should be evaluated carefully. Interruptions have not been observed in patient cases; it has been proposed that longer alleles with interruptions may not be pathogenic⁹. Non-canonical motif CAA observed¹⁰. Expansions are also detected ten-fold more often in a general population than would be expected by disease prevalence⁴. Clinical evaluation and phenotypic matching may be necessary to determine diagnosis even in the presence of a pure expanded allele. It has been proposed that contractions may play a role in disease¹¹. Disease may be subclinical in females¹², and can be clinically heterogeneous even within the same family¹³.

Mechanism

GoF

Polyglutamine alters protein conformation leading to gain-of-function neurodegeneration^14,15. Transcriptional dysregulation, axonal transport disruption, and mitochondrial dysfunction also play causative roles in the neurodegeneration¹⁶.

Year

1991¹⁷; the first triplet disease to be discovered¹⁸

Location in Gene

Exon 1

Gene Strand

Alleles

Ref. Motif

GCA

Pathogenic (ref.)

GCA

Pathogenic (gene)

AGC

gnomAD

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0010735

Advancing Epidemiology and Genetic Approaches for the Treatment of Spinal and Bulbar Muscular Atrophy: Focus on Prevalence in the Indigenous Population of Western Canada.

Harry,Wilton-Clark, Ammar,Al-Aghbari, Jessica,Yang, Toshifumi,Yokota

Genes · 2023-08-17

pmid:37628685

Orphanet: Kennedy disease

orphanet:481

Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population.

Matteo,Zanovello, Kristina,Ibáñez, Anna-Leigh,Brown, Prasanth,Sivakumar, Alessandro,Bombaci, Liana,Santos, Joke J F A,van Vugt, Giuseppe,Narzisi, Ramita,Karra, Sonja W,Scholz, Jinhui,Ding, J Raphael,Gibbs, Adriano,Chiò, Clifton,Dalgard, Ben,Weisburd, Michael G,Hanna, Linda,Greensmith, Hemali,Phatnani, Jan H,Veldink, Bryan J,Traynor, James,Polke, Henry,Houlden, Pietro,Fratta, Arianna,Tucci

Brain : a journal of neurology · 2023-07-03

pmid:36797998

Spinal and Bulbar Muscular Atrophy

Albert,La Spada

GeneReviews® · 1993-01-01

genereviews:NBK1333

Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world.

A,Lund, B,Udd, V,Juvonen, P M,Andersen, K,Cederquist, M,Davis, C,Gellera, C,Kölmel, L O,Ronnevi, A D,Sperfeld, S A,Sörensen, L,Tranebjaerg, L,Van Maldergem, M,Watanabe, M,Weber, L,Yeung, M L,Savontaus

European journal of human genetics : EJHG · 2001-06-01

pmid:11436124

A family with early-onset and rapidly progressive X-linked spinal and bulbar muscular atrophy.

A,Echaniz-Laguna, E,Rousso, M,Anheim, M,Cossée, C,Tranchant

Neurology · 2005-04-26

pmid:15851746

A Case of Very Late Onset Spinobulbar Muscular Atrophy with Normal Creatine Kinase

Joseph,Conway, Yuebing,Li, Sakhi,Bhansali

RRNMF Neuromuscular Journal · 2024-12-17

doi:10.17161/2tmg0f25

Sequencing analysis of the spinal bulbar muscular atrophy CAG expansion reveals absence of repeat interruptions.

Pietro,Fratta, Toby,Collins, Sally,Pemble, Suran,Nethisinghe, Anny,Devoy, Paola,Giunti, Mary G,Sweeney, Michael G,Hanna, Elizabeth M C,Fisher

Neurobiology of aging · 2013-09-13

pmid:24041967

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing.

Igor,Stevanovski, Sanjog R,Chintalaphani, Hasindu,Gamaarachchi, James M,Ferguson, Sandy S,Pineda, Carolin K,Scriba, Michel,Tchan, Victor,Fung, Karl,Ng, Andrea,Cortese, Henry,Houlden, Carol,Dobson-Stone, Lauren,Fitzpatrick, Glenda,Halliday, Gianina,Ravenscroft, Mark R,Davis, Nigel G,Laing, Avi,Fellner, Marina,Kennerson, Kishore R,Kumar, Ira W,Deveson

Science advances · 2022-03-04

pmid:35245110

CAG repeat contraction in the androgen receptor gene in three brothers with mental retardation.

R F,Kooy, E,Reyniers, K,Storm, L,Vits, D,van Velzen, P E,de Ruiter, A O,Brinkmann, A,de Paepe, P J,Willems

American journal of medical genetics · 1999-07-30

pmid:10398229

Kennedy disease in two sisters with biallelic CAG expansions of the androgen receptor gene.

Kai Ivar,Müller, Øivind,Nilssen, Maria,Nebuchenykh, Sissel,Løseth, Christoffer,Jonsrud, Gry,Hoem, Marijke,Van Ghelue, Kjell Arne,Arntzen

Neuromuscular disorders : NMD · 2021-11-19

pmid:34922802

Phenotypic differences in a large family with Kennedy's disease from the Middle Black Sea region of Turkey.

Hatice,Karaer, Yüksel,Kaplan, Semiha,Kurt, Asli,Gundogdu, Begüm,Erdoğan, Nazli A,Başak

Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases · 2010-01-01

pmid:20184516

Tandem repeats mediating genetic plasticity in health and disease.

Anthony J,Hannan

Nature reviews. Genetics · 2018-02-05

pmid:29398703

Clinical and neuroimaging review of triplet repeat diseases.

Ryo,Kurokawa, Mariko,Kurokawa, Akihiko,Mitsutake, Moto,Nakaya, Akira,Baba, Yasuhiro,Nakata, Toshio,Moritani, Osamu,Abe

Japanese journal of radiology · 2022-09-28

pmid:36169768

Pathogenesis and therapy of spinal and bulbar muscular atrophy (SBMA).

Masahisa,Katsuno, Fumiaki,Tanaka, Hiroaki,Adachi, Haruhiko,Banno, Keisuke,Suzuki, Hirohisa,Watanabe, Gen,Sobue

Progress in neurobiology · 2012-05-15

pmid:22609045

Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.

A R,La Spada, E M,Wilson, D B,Lubahn, A E,Harding, K H,Fischbeck

Nature · 1991-07-04

pmid:2062380

Bulbospinal muscular atrophy: Kennedy's disease.

Michael,Sinnreich, Christopher Jon,Klein

Archives of neurology · 2004-08-01

pmid:15313856

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Generation of an induced pluripotent stem cell (iPSC) line (INNDSUi007-A) from a patient with Kennedy disease.

Bo,Li, Yitong,Yang, Yingxin,Wang, Didi,Shan, Jianing,Li, Hongxu,Wang, Xiaohan,Sun, Yao,Tang, Yichang,Jiao, Xinbo,Ji, Zexin,Zhan, Bo,Kong, Bo,Gao, Yu,Wang, Ping,Sun, Fuchen,Liu

Stem cell research · 2024-12-25

pmid:39729861

Enhancing Aesthetics in Bilateral DIEP Flap Breast Reconstruction: the Role of Tissue Pre-Expansion.

Robert Jonathan,Musmann, Christoph,Andree, Andreas,Wolter, Mazen,Hagouan, Beatrix,Munder, Dirk,Janku, Marc,Daniels, Kristin,Becker, Alan,Oramary, Julia,Bukowiecki, Annabelle,Bromba, Nora,Stockhausen, Katrin,Seidenstücker, Sonia,Fertsch

Aesthetic plastic surgery · 2024-12-18

pmid:39694906

Androgen receptor CAG repeat polymorphism might be a possible cause of familial constitutional delay of growth and puberty.

Gözde Akın,Kağızmanlı, Reyhan Deveci,Sevim, Hayrullah,Manyas, Ahu,Paketçi, Korcan,Demir, Ece,Böber, Gönül,Çatlı, Ahmet,Anık, Ayhan,Abacı

Journal of endocrinological investigation · 2024-11-21

pmid:39570490

Expanded carrier screening for inherited genetic disease using exome and genome sequencing.

N,Belnap, K,Ramsey, A,Abraham, A,Ryan, S,Rangasamy, A,Bonfitto, M,Naymik, M,Huentelman, S,Strom, D,Perry, A,Subramaniam, W W,Grody, S,Szelinger, V,Narayanan

Journal of genetic counseling · 2024-08-27

pmid:39189540

Patient-Reported Impact of Symptoms in Spinal and Bulbar Muscular Atrophy.

Abdullah,Alqahtani, Angela,Kokkinis, Christine,Zizzi, Nuran,Dilek, Kenneth H,Fischbeck, Chad R,Heatwole, Christopher,Grunseich

Neurology. Clinical practice · 2023-10-31

pmid:39140081

Mutant androgen receptor induces neurite loss and senescence independently of ARE binding in a neuronal model of SBMA.

Jordyn,Karliner, Yuhong,Liu, Diane E,Merry

Proceedings of the National Academy of Sciences of the United States of America · 2024-07-08

pmid:38976730

Short stature and dysmorphic features in Asian Indian siblings with DAAM2-associated steroid-resistant nephrotic syndrome: Expansion of the phenotypic spectrum or a blended phenotype?

T,Pragna Lakshmi, Neelam,Saini, Mehul A,Shah, Swarnalata,Gowrishankar, Ashwin,Dalal, Prajnya,Ranganath

Clinical genetics · 2024-06-11

pmid:38860410

Preimplantation Genetic Diagnosis of Androgen Resistance Syndrome Caused by Mutation on the

Nguyen Thanh,Tung, Trieu Tien,Sang, Tran Van,Khoa, Nguyen Van,Phong, Tran Hoang,Phuong

The application of clinical genetics · 2024-05-06

pmid:38737445

The Influence of Trinucleotide Repeats in the Androgen Receptor Gene on Androgen-related Traits and Diseases.

Takayoshi,Sasako, Yann,Ilboudo, Kevin Y H,Liang, Yiheng,Chen, Satoshi,Yoshiji, J Brent,Richards

The Journal of clinical endocrinology and metabolism · 2024-11-18

pmid:38701087