1. Background

• Machado-Joseph Disease (MJD) belongs to an expanding family of disorders where the genetic mutation involves unstable trinucleotide repeats (C_G):

• in this family of disorders, the number of repeats tends to increase with succeeding generations ("genetic anticipation")
• in Machado-Joseph 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 quanine (CAG) (Kawaguchi et al., Nature Genetics 8:221 [1994])
  • in normal individuals, there are between 13-36 repeats of CAG but in those with MJD, there may be between 68-79 CAG repeats
  • the function of the MJD gene product is unknown

2. Genetic Defect

• genetic defect -> amplification of the sequence of unstable trinucleotide repeats (CAG) to between 68-79 -> encodes a long tract of glutamine residues -> altered protein -> the accumulation of the altered gene product may lead to areas and age-specific neurodegeneration -> selective loss of neurons in the central nervous system (substantia nigra, dentate, pontine, motor cranial nerve nuclei, anterior horn cells, Clarke columns, spinal root ganglia)
• there is a strong inverse correlation between the length of the CAG repeat and the age of onset of the disease

1. Neurological Manifestations

2. Other Manifestations

• bulging and injected eyes
• pulmonary infections
• diabetes mellitus
• hyperuricemia

1. Diagnostic

• identification of amplified CAG sequences in the MJD gene of affected individuals

2. Imaging Studies

• CT/MRI

3. Serum

• hyperglycemia
• elevated uric acid levels

1. Supportive

• no treatment for underlying disorder
• multidisciplinary approach:
  • Paediatrics, Neurology, Ophthalmology, Endocrinology
  • genetic counselling