| Category | Key values |
|---|---|
| Disease name / definition | **Kennedy disease**; **spinal and bulbar muscular atrophy (SBMA)**; an adult-onset, slowly progressive, X-linked neuromuscular / lower motor neuron disease caused by polyglutamine-expanded androgen receptor, with both motor neuron and skeletal muscle involvement (pqac-00000002, pqac-00000003, pqac-00000004, pqac-00000040) |
| Identifiers | **MONDO:** MONDO_0010735 (OpenTargets disease association for Kennedy disease) (pqac-00000000); **OMIM:** 313200 (reported as “X-linked spinal and bulbar muscular atrophy (SMAX1, Kennedy disease, OMIM 313200)”) (pqac-00000009); **MeSH:** *Bulbo-Spinal Atrophy, X-Linked* **D055534** (ClinicalTrials.gov MeSH mapping) (pqac-00000011, pqac-00000012, pqac-00000013) |
| Synonyms / alternative names | Spinal and bulbar muscular atrophy; SBMA; Kennedy disease / Kennedy’s disease; X-linked spinal and bulbar muscular atrophy; X-linked recessive bulbospinal neuronopathy; progressive proximal spinal and bulbar muscular atrophy of late onset (pqac-00000005, pqac-00000008, pqac-00000009, pqac-00000015) |
| Causal gene / locus | **Gene:** **AR** (*androgen receptor*); **location:** Xq11-12 / Xq12; disease caused by CAG trinucleotide expansion in exon 1 producing an expanded polyglutamine tract in AR protein (pqac-00000003, pqac-00000004, pqac-00000005, pqac-00000040) |
| Pathogenic repeat ranges / thresholds | Common pathogenic thresholds in evidence: **≥38 CAG** in trial eligibility and mechanistic literature (pqac-00000001, pqac-00000004, pqac-00000018); review evidence gives **normal 9–36 CAG** vs **SBMA 39–72 CAG** (pqac-00000003, pqac-00000015); AJ201 trial used **≥36 repeats** for enrollment (pqac-00000017) |
| Inheritance / sex bias | **X-linked recessive / sex-linked** disorder; primarily affects **adult males**; females are usually carriers and may be mildly affected; androgen dependence explains marked male predominance (pqac-00000003, pqac-00000004, pqac-00000006, pqac-00000040) |
| Epidemiology | Prevalence estimates in cited sources: **1–2 per 100,000** (review) (pqac-00000003, pqac-00000040); **2–5 per 100,000 worldwide** (mechanistic study intro) (pqac-00000004); Italy trial record: about **1,000 affected individuals**, **prevalence 1.5/100,000**, **annual incidence 0.19/100,000 males** (pqac-00000001, pqac-00000018) |
| Typical onset / course | Adult onset, often **30–40 years** (range **18–64** in one review); slowly progressive; tremor may precede weakness by >10 years; wheelchair often needed 10–15 years after onset in some reports (pqac-00000003, pqac-00000030, pqac-00000041) |
| Hallmark phenotypes | Progressive limb and bulbar weakness/atrophy, fasciculations, cramps, postural hand tremor, dysarthria, dysphagia, laryngospasm, reduced/absent reflexes, distal vibration sensory loss; androgen-insensitivity features including gynecomastia, testicular atrophy, erectile dysfunction, infertility/decreased fertility; aspiration pneumonia is a major cause of death (pqac-00000005, pqac-00000030, pqac-00000031, pqac-00000040) |
| Quality-of-life / functional impact | ADL domains notably affected: walking, handwriting, falling, swallowing, speech; SF-36v2 physical component mean **34.3 ± 11.0** in a landmark cohort; substantial diagnostic delay (~2 years to first medical attention plus ~3 more years to diagnosis) (pqac-00000031) |
| Key diagnostic tests | **Genetic confirmation of AR CAG expansion** is definitive; supportive tests include EMG/neurophysiology, quantitative muscle assessment, timed walk tests, SBMAFRS/ALSFRS-R, tongue pressure, pulmonary metrics (%FVC, %PEF), muscle MRI with Dixon fat quantification, and cardiac ECG/CMR when indicated (pqac-00000018, pqac-00000019, pqac-00000029, pqac-00000032, pqac-00000033) |
| Biomarkers / outcome measures | Prominent biomarkers: **serum creatinine** (declines before overt weakness), CK/liver enzymes, MRI muscle fat fraction, MUNE, tongue pressure; trial/research outcomes include **6MWT**, **2MWD**, **AMAT**, **QMA**, **SBMAFRS**, **ALSFRS-R**, **%FVC**, **%PEF**, neurophysiology, and mutant AR in muscle/skin (pqac-00000017, pqac-00000018, pqac-00000019, pqac-00000029, pqac-00000030, pqac-00000032, pqac-00000040) |
| Notable recent mechanism (2023) | **LSD1/PRMT6 axis:** androgen-dependent overexpression of AR co-regulators **LSD1** and **PRMT6** specifically in SBMA skeletal muscle; they synergistically enhance AR transactivation, and silencing them suppresses toxic gain-of-function and improves phenotypes in flies and mice (pqac-00000021, pqac-00000023, pqac-00000037, pqac-00000039) |
| Notable recent mechanism (2023) | **Early skeletal-muscle pathology:** defective excitation-contraction coupling and impaired mitochondrial respiration occur **before denervation**; early events are androgen-dependent and reversible with castration or AR silencing; patient biopsies and mouse models support muscle as a primary toxicity site (pqac-00000036, pqac-00000038) |
| Notable recent mechanism (2024) | **Energy metabolism / NAD+ biology:** SBMA muscle shows **reduced NAD+ and ATP**, altered nicotinamide/NAD+ salvage pathways, and **decreased Nmrk2/NRK2**, helping explain why nicotinamide riboside failed to restore muscle NAD+ or improve disease in mice; integrated metabolomics/proteomics implicated glycolysis, PPP, pyruvate, glutathione, and amino-acid pathways (pqac-00000020, pqac-00000022, pqac-00000026) |
| Notable recent mechanism (2024 preclinical) | **Synaptic dysregulation / hyperexcitability:** early postnatal nuclear accumulation of polyQ-AR in motor neurons dysregulates glutamatergic synaptic genes via **Rest/Rest4**; iPSC-derived motor neurons are hyperexcitable; antisense correction rescued pathology in mice (preprint evidence) (pqac-00000023) |
| Anatomy / cell types chiefly affected | Lower motor neurons in spinal cord and brainstem; skeletal muscle is a major primary toxicity site; neuromuscular junction and muscle fiber-type composition are altered; cardiac involvement may occur in a subset (ECG/CMR abnormalities, fibrosis) (pqac-00000030, pqac-00000033, pqac-00000036, pqac-00000038) |
| Cardiac / systemic comorbidity signals | In a 30-patient SBMA cohort, **70%** had abnormal ECGs; diffuse myocardial fibrosis on T1 mapping in **73.9%** vs **9.1%** of controls; metabolic comorbidities include glucose intolerance/insulin resistance and dyslipidemia in some patients (pqac-00000022, pqac-00000033, pqac-00000040) |
| Supportive / real-world implementation | Long-term gait rehabilitation using **wearable HAL** in one 68-year-old patient: 9 courses over ~5 years, 3 sessions/week for 3 weeks each; **2MWD improved from 94 m to 101.8 m**, gait item on ALSFRS-R remained stable at 3, and independent walking was maintained (pqac-00000042, pqac-00000043, pqac-00000047) |
| Historical / completed interventional trials | **NCT00303446** dutasteride 0.5 mg/day vs placebo for 24 months, phase 2; primary endpoint QMA; failed primary outcome in review summary (pqac-00000019, pqac-00000032). **NCT00004771** leuprolide + testosterone, phase 2; genotype-confirmed by AR exon-1 mutation (pqac-00000016). **NCT00851461** goserelin (listed as completed) (clinical-trial search context in conversation). **NCT02024932** BVS857 / IGF-1 mimetic, phase 2, showed muscle-volume signal in review summary (pqac-00000032) |
| Active / recent trials (2023-2025 records) | **NCT06169046** clenbuterol 0.04 mg/day for 48 weeks, phase 2, primary endpoint 6MWT, enrollment 90, requires **AR CAG ≥38** (pqac-00000018); **NCT05517603** AJ201 600 mg/day for 12 weeks, phase 1/2a, enrollment 25, pharmacodynamic endpoint mutant AR in skeletal muscle, requires **AR CAG ≥36** (pqac-00000017); **NCT06411912** NIDO-361 in genetically confirmed SBMA, phase 2, enrollment 54 (pqac-00000011); **NCT06862596** mexiletine hydrochloride phase 2/3 recruiting (clinical-trial search context in conversation) |
| Expert/consensus interpretation | Current expert view is that SBMA combines **androgen-dependent toxic gain-of-function of expanded AR** with elements of **partial AR loss-of-function**; skeletal muscle is not merely secondary but a therapeutically relevant primary target, supporting both endocrine modulation and AR-lowering / co-regulator-targeting strategies (pqac-00000004, pqac-00000021, pqac-00000025, pqac-00000040) |


*Table: This table condenses the main evidence-backed facts about Kennedy disease / SBMA, including identifiers, genetics, epidemiology, phenotypes, biomarkers, mechanisms, and clinical trials. It is designed as a quick-reference summary for knowledge-base curation or report drafting.*