CNS nontumor
Movement disorders
X linked bulbospinal neuronopathy
Last author update: 1 October 2016
Last staff update: 22 February 2023 (update in progress)
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PubMed Search: X linked bulbospinal neuronopathy Kennedy disease
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Pathophysiology / etiology | Clinical features | Laboratory | Treatment | Gross description | Microscopic (histologic) description | Positive stains | Differential diagnosisCite this page: Flanagan M.E., Montine T.J., Plowey E.D. X linked bulbospinal neuronopathy. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cnsbulbospinal.html. Accessed March 24th, 2023.
Definition / general
- X linked recessive disorder affecting males, usually in mid 40s, causing slowly progressive lower motor neuron weakness of facial, bulbar and proximal limb muscles
- Often associated with gynecomastia due to an expansion of a repeat of the trinucleotide CAG encoding glutamine in the androgen receptor gene (J Mol Neurosci 2016;58:313, Neurol Clin 2015;33:847)
- Commonly associated with infertility and primary sensory neuronopathy
- Neuronopathy: polyneuropathy involving destruction of the cell bodies of neurons
- Milder form of the disease has been reported in elderly males
Essential features
- Slowly progressive lower motor neuron weakness of facial, bulbar and proximal limb muscles, often associated with gynecomastia (Neurol Clin 2015;33:847)
- X linked recessive disorder affecting males
- Expansion of tandem CAG repeat region in first exon of androgen receptor gene on proximal part of long arm of X chromosome (Nature 1991;352:77)
Terminology
- X linked bulbospinal neuronopathy
- Spinobulbar muscular atrophy
- Kennedy Disease
Epidemiology
- Prevalence of about 2:100,000 males (J Mol Neurosci 2016;58:313)
- Affected males typically develop weakness in mid 40s, plus androgen insensitivity with reduced fertility and gynecomastia (Neurol Clin 2015;33:847)
- Age range: 18 to 64 years
Pathophysiology / etiology
- X linked recessive disorder
- Expansion of tandem CAG repeat region in first exon of androgen receptor (AR) gene on proximal part of long arm of X chromosome
- There is variable phenotypic expression between and within families, which is not clearly related to the size of the CAG expansion
- Repeat lengths of 36 to 68 CAGs have been reported in patients, versus 11 to 32 CAGs in normal individuals
- CAG repeat is expressed as an expanded polyglutamine tract in the androgen receptor; studies indicate that androgen dependent gain of function by the receptor results in toxicity of the mutant protein
- In addition to the toxic effects of the AR, loss of normal receptor function also contributes to the androgen insensitivity aspects of the disease phenotype (Neuron 2014;82:251)
- Translocation of the mutant AR into the nucleus also seems necessary for toxicity
- Deletion of the nuclear localization signal prevents toxicity in a mouse model
Clinical features
- Facial, hypoglossal and spinal cord motor neuron degeneration with neurogenic wasting of corresponding skeletal muscles (particularly tongue)
- Third, fourth and sixth (oculomotor, trochlear and abducens) cranial nerves are spared
- Slowly progressive lower motor neuron weakness of facial, bulbar and proximal limb muscles with fasciculations (Neurol Clin 2015;33:847)
- Progression of weakness is slow, with ~2% decrease in muscle strength by quantitative muscle testing per year
- Tremor and cramping also common
- Often associated with gynecomastia, infertility and primary sensory neuronopathy
Laboratory
- Elevated creatine kinase (CK)
- Electrophysiology studies show evidence of generalized chronic damage of motor neurons with fasciculations and pseudomyotonic discharges (Clin Neuropathol 2015;34:199)
- Genetic testing for confirmation of a CAG repeat expansion is still considered the gold standard for diagnosis
Treatment
- There is currently no effective therapy to prevent progression of the disease
- Management is focused on preventing complications and improving mobility and function
- Clinical trials have focused on reducing AR ligand
- Androgen reduction with leuprorelin and castration mitigates disease manifestations in transgenic animal models (J Neurosci 2004;24:4778, Nat Med 2003;9:768)
Gross description
- Degeneration of facial, hypoglossal and spinal cord motor neurons with neurogenic wasting of corresponding skeletal muscles (particularly the tongue) (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- Third, fourth and sixth cranial nerve nuclei are spared
Microscopic (histologic) description
- Depletion of lower motor neurons through spinal cord segments and brainstem motor nuclei
- Muscle histopathology is atypical for a motor neuron disease
- It lacks cytoplasmic inclusions and shows both neurogenic and myogenic alterations, with neurogenic alterations being more common
- Commonly described morphological changes include groups of small atrophic myofibers with pyknotic nuclei and hypertrophic fibers, sometimes with central nuclei (Clin Neuropathol 2015;34:199)
- Nuclear inclusions may be found in spinal neurons and brainstem motor neurons
- Nuclear inclusions can also be found in non neural tissues including, skin, dermis, kidney, heart and testis (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
- Ultra structurally, most nuclei contain clusters of dense heterochromatin (Clin Neuropathol 2015;34:199)
Positive stains
- Nuclear inclusions: N terminus of AR protein, ubiquitin (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013)
Differential diagnosis
- Amyotrophic lateral sclerosis (ALS)
- Hereditary spastic paraplegia
- Myasthenia gravis
- Secondary causes of motor neuron disease (Ellison: Neuropathology - A Reference Text of CNS Pathology, Third Edition, 2013):
- Infectious
- Acute poliomyelitis
- HIV infection
- Metabolic
- Immune
- Paraproteinemia
- Paraneoplastic
- Infectious
- Spinal muscular atrophy
