Trinucleotide Repeat Disorders and Anticipation Mnemonics

Anticipation in genetics refers to an increase in severity and decrease in age of onset in successive generations, most likely due to increased size of trinucleotide repeats.

• Paternal anticipation: Huntington’s disease, Friedreich’s Ataxia
• Maternal anticipation: Myotonic dystrophy, Fragile X syndrome

Friedrich’s ataxia

• Trinucleotide repeat: GAA (Out of the four, only one to start with letter G).
• Chromosomal mapping of affected gene: Chromosome 9 (Mnemonic: FRIEDRICH has 9 letters).
• Clinical features: Mnemonic – FRIEDREICH’S Ataxia
  • Foot – Pes cavus
  • Reflexes (Knee and Ankle jerks) – Absent
  • Intention tremors
  • Extensor plantar response, Eye – Optic atrophy
  • Diabetes mellitus, Dorsal column degeneration
  • Recessive Inheritance
  • Cerebellar signs, Cranial nerve 7, 10 and 12 involvement
  • Hypertrophic cardiomyopathy
  • Scoliosis
  • Ataxia, Axonal neuropathy

Trinucleotide repeat of the other 3 disorders, starts with C and ends with G, i.e. C_G.

Huntington’s disease

Mnemonic: Hunter’s CAGe

• Trinucleotide repeat: CAG
• Chromosomal mapping of affected gene: Chromosome 4 (Cage has 4 letters).
• Clinical features and Pathophysiology: Mnemonic – CAGED
  • Caudate and putamen atrophy and Choreiform movements
  • Agression/psychosis, depression and dementia
  • Glutamate excitotoxicity mediated death
  • Ex-vacuo hydrocephalus
  • Dopamine increased; GABA and ACh decreased
  • Deacetylation of histone increased – Deacetylation makes DNA-histone bond strong and genomes unavailable for transcription (transcriptional repression or silencing)

Myotonic dystrophy

Mnemonic: See the 4th letter. dysTrophia myoTonica

• Trinucleotide repeat: CTG
• Chromosomal mapping of affected gene: Chromosome 19 (dystrophia myotonica has 19 letters)
• Clinical features: Mnemonic – DySTROPHIC
  • Distal muscles weakness and wasting, Dysmotility of GI muscles and biliary tree, Dementia
  • Swan-like neck
  • Testicular atrophy
  • Reflexes depressed or absent
  • Ocular cataract and ptosis
  • Pilomatrixomas (skin), Pulmonary infections, Pseudodrop attack due to quadriceps weakness
  • Haggard or Hatchet facies, Hair loss (frontal balding)
  • Intrinsic muscles of hand wasting, IQ low, Irritable Bowel Syndrome
  • Cardiomyopathy and arrhythmias

Fragile X syndrome

Mnemonic: See the 4th letter. fraGile

• Trinucleotide repeat: CGG
• Chromosomal mapping of affected gene: X chromosome (fragile X)
• Clinical features and Pathophysiology: Everything is big
  • Thick brain: Mental retardation (2nd most common genetic cause of mental retardation after Down’s syndome), ADHD (female), Autism
  • Long face
  • Large jaw
  • Large ears
  • Large testicles (macro-orchidism)
  • Increased methylation (Hypermethylation of FMR gene due to >200 CGG repeats) leading to inactivation and prevention of transcription.