SPINOCEREBELLAR ATAXIA - TYPE 1
 
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SPINOCEREBELLAR ATAXIA - TYPE 1

 

DEFINITION:

A progressive neurodegenerative disorder characterized by cerebellar dysfunction, amyotrophy, and ophthalmoparesis.

EPIDEMIOLOGY:

  • incidence: rare
  • age of onset:
    • less than 15 years of age (Juvenile Form)
  • risk factors:
    • familial - autosomal dominant
      • chrom.#: 6p22-p23
      • gene: ?

PATHOGENESIS:

1. Background

  • Spinocerebellar Ataxia - Type 1 (SCA1) 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 in-crease with succeeding generations ("genetic anticipation")
    • in Spinocerebellar Ataxia-I:
      • an unstable part of the gene was identified in the coding region characterized by numerous repeats of single tri-nucleotide sequences containing the bases cytosine, aden-ine, and quanine (CAG)
      • in normal individuals, there are between 25-36 repeats of CAG but in those with SCA1, there may be between 43-81 CAG repeats
      • the function of the SCA1 gene product is unknown

    2. Genetic Defect

    • genetic defect -> amplification of the sequence of unstable trinucleotide repeats (CAG) to between 43-81 -> encodes a long tract of glutamine residues -> altered protein -> selective loss of neurons in the cerebellum, brain stem, and spinocerebellar tracts
    • there is a strong inverse correlation between the length of the CAG repeat and the age of onset of the disease (Orr et al., [1993] Nature Genetics 4:221-226):
      • Juvenile-Onset - shows between 59-81 CAG repeats
      • Adult-Onset - shows at least 43 CAG repeats
    • there appears to be a preponderance of male transmission in the juvenile-onset cases

    TYPES:

  • Type 1 - Juvenile-Onset - onset before 15 years of age
  • Type 2 - Adult-Onset - onset after 15 years of age

    • CLINICAL FEATURES:

    1. Type 1 - Juvenile-Onset*

    1. Neurological Manifestations

  • 1. Cerebellar Dysfunction
    • dysarthria
    • dysdiadochokinesia
    • dysmetria
    • dysphagia
    • gait ataxia
  • 2. Others
    • amyotrophy (progressive muscle weakness and atrophy)
    • intellectual deficit
    • ophthalmoparesis

    •  

    Note: The Adult-Onset Variant has the same clinical manifestations but these begin at a later age, progress more slowly, and are less severe.

     

    *Zoghbi et al., 1988; Annals of Neurology 23(6):580-584.

    INVESTIGATIONS:

    1. Diagnostic

    • identification of amplified CAG sequences in the SCA1 gene of affected individuals

    2. Imaging Studies

    1. CT/MRI

    • cerebellar atrophy

    MANAGEMENT:

    1. Supportive

    • no treatment for the disorder
    • multidisciplinary approach
      • Paediatrics, Neurology, Ophthalmology, PT, OT

    2. Prognosis

  • 1. Juvenile-Onset
    • rapidly progressive with loss of ambulation and death

    •  

     

    Pediatric Database - SPINOCEREBELLAR ATAXIA - TYPE 1

     

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