CNS nontumor
Motor neuron disorders
X linked bulbospinal neuronopathy

Author: Margaret E. Flanagan, M.D., Thomas J. Montine, M.D., Ph.D., Edward D. Plowey, M.D., Ph.D. (see Authors page)

Revised: 21 August 2017, last major update October 2016

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

PubMed Search: X linked bulbospinal neuronopathy Kennedy disease

Cite this page: Flanagan, M.E., Montine, T.J., Plowey, E.D. X linked bulbospinal neuronopathy. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cnsbulbospinal.html. Accessed October 19th, 2017.
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
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
Gross description
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)
Microscopic (histologic) images

Images hosted on other servers:

Angular muscle fiber

Positive stains
Differential diagnosis