• 1:1200 in males --> more severe due to extra X
• 1:2500 in females
• Moderate to severe mental retardation
• Facial dysmorphic features
• fragile site on X chrome
• X-linked dominant with variable penetrance
• post-puberty symptoms
• OCD-like behavior
• Incomplete penetrance, Variable Expression, Unusual Segregation
• transcriptional silencing (loss-of-function) --> loss of RNA binding (impairs translation repression of targets)

• As the disease progresses by generations, more individuals are affected
• Mutation changes during transmission (increases in incidence
• Can turn of methylated genes
• Cannot silence genes because males only have one copy

• Run a restriction digest
• Run probes against the repeats on the digest
• females show both active and inactive
• males only show one
• Repeats mitotically unstable

• As pre-mutations get larger they expand into full mutation (from female) and as they get smaller they are less likely to become full mutations

• autosomal dominant
• 1:10000
• Abnormal involuntary movts
• progressive dementia (onset 40-50)
• CAG repeats (<26 is normal, >36 is affected)
• Phenotype severity increases with length of repeats
• Protein expands and becomes new protein with new function and affects different areas
• loss-of-function

• Characterized by variable clinical symptoms
• myotonia
• muscle weakness
• cataracts
• mental retardation
• 1:8000
• autosomal dominant (some maternal)
• anticipation
• multisystemic affects
• female transmission
• expanded CUG repeat RNA binds to splicing-related proteins and prevent splicing

CLINICAL

• progressive limb/gait ataxia
• severity determined by age of onset and rate of progression
• some overlap with mito disorders (protein acts in mito and causes similar symptoms)
• autosomal rec
• 1:50000
• carrier 1:110
• impair transcriptional elongation - 210 aa frataxin protein (loss-of-function) --> inc iron in mito and reduce heme synthesis
• GAA triplet repeat expansion in intron 1 (>120 repeats)
• loss of gene expression at RNA level

• 2-5x increase in FMR-1 mRNA (gain-of-function)
• neuronal inclusions