PEDBASE.org - The Pediatric Database - Detailed information of KENNEDY'S DISEASE

KENNEDY'S DISEASE

DEFINITION:

A progressive neurodegenerative disorder characterized by muscle weakness and signs of androgen insensitivity.

EPIDEMIOLOGY:

incidence: rare (about 50 families reported worldwide)
age of onset:
- 15-59 years of age (1OO% after age 15 years)
risk factors:
- familial - X-linked recessive
  - chrom.#: Xq12-q21
  - gene: androgen receptor gene
- Males only

PATHOGENESIS:

1. Background

in 1968, Kennedy's Disease or X-linked Spinal and Bulbar Muscular Atrophy (SBMA) was first described by Kennedy et al., Neurology 18, 671 (1968)
in 1986, the SBMA gene defect was mapped to the Xq12-21 region
in 1989, the androgen receptor gene was cloned and mapped to the same region
Kennedy's Disease belongs to an expanding family of disorders where the genetic mutation involves unstable trinucleotide repeats (C_G):

Disorder - Trinucleotide Repeats

Fragile X Syndrome - CGG

Myotonic Dystrophy - CTG

Huntington Disease - CAG

Kennedy's Disease - CAG

Spinocerebellar Ataxia-I - CAG

Machado-Joseph Disease - CAG

in this family of disorders, the number of repeats tends to increase with succeeding generations ("genetic anticipation")
in Kennedy's Disease:
- an unstable part of the gene was identified in the coding region characterized by numerous repeats of single trinucleotide sequences containing the bases cytosine, adenine, and guanine (CAG)
- in normal individuals, there are between 11-31 repeats of CAG but in those with SBMA, there may be between 40-62 CAG repeats
- the altered gene in Kennedy's Disease is that coding for the androgen receptor

2. Genetic Defect

genetic defect -> amplification of the sequence of unstable trinucleotide repeats (CAG) to between 40-62 -> encodes a long tract of glutamine residues beginning at amino acid 58 twice the size seen in normal individuals -> altered protein - there may be a correlation between the disease severity and CAG repeat length (La Spada et al., Nature Genetics, Vol. 2, 301-304, 1992)

CLINICAL FEATURES:

1. Overall Manifestations

muscle fasiculations (90%)
facial weakness (75%)
bulbar symptoms (75%)
sexual dysfunction (75%)
gynecomastia (50%)

2. Neurological Manifestations

1. Muscle Weakness

1. Proximal Spinal

progressive but variable clinical severity
- ranges from loss of ambulation in 6th decade to no loss of ambulation

2. Bulbar

bulbar muscle involvement with recurrent aspiration +/- pneumonia in the 5th decade

3. Facial

facial weakness
muscle atrophy and fasiculations especially around lips, chin, and tongue

2. Others

cramps
tremor

3. Endocrine Manifestations

1. Androgen Insensitivity

may present in the 2nd decade before the onset of muscle weakness
- decreased libido
- gynecomastia
- reduced fertility +/- impotence
- testicular atrophy
sperm production may decrease with diminished fertility as the disease progresses
less severely affected patients may remain mobile and express no signs of androgen insensitivity

INVESTIGATIONS:

1. Diagnostic

identification of amplified CAG sequences in the androgen receptor gene in affected individuals

2. Neurological

1. Nerve Conduction Velocity

normal

2. EMG

low amplitude, polyphasic, giant motor unit potentials

3. Muscle Biopsy

degeneration, denervation, regeneration

3. Endocrine

reduced sperm count

MANAGEMENT:

1. Supportive

no treatment for underlying disorder
multidisciplinary approach
- Neurology, Endocrinology, Genetics, OT, PT

2. Prognosis

normal life span and intelligence

Pediatric Database - KENNEDY'S DISEASE

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