Triplet Repeat Disorders

normal

(Fragile X repeat size)

• <44 CGG

intermediate

(Fragile X repeat size)

• 45-54 CGG

• risk of expansion to the premutation size (especially when maternally inherited/transmitted)

premutation

(Fragile X repeat size)

• 55-200 CGG

• stability of alleles is highly influenced by the number of AGG repeats for expansion sizes 90 or less

full mutation

(Fragile X repeat size)

• 200+ CGG

Fragile X syndrome

• Mutation:

  • 200+ CGG triplet repeat expansion

• Gene(s):

  • FMR1

• Inheritance Pattern:

  • X-linked dominant 

• Features:

  • males are more affected than females

  • ~50-70% of individuals have autism

  • characteristic facies: long face and prominent ears

Fragile X-associated tremor/ataxia syndrome

(FXTAS)

• premutation condition

• Features:

  • characterized by late-onset, progressive cerebellar ataxia and intention tremor that is followed by intellectual disability 

  • age of onset: 60-65 years

  • males are more affected than females 

Fragile X-associated primary ovarian insufficiency

(FXPOI)

• premutation condition

• Features:

  • increased chance for ovaries to stop working before age 40 (hypergonadotropic hypogonadism)

Fragile X-associated neuropsychiatric disorders

• premutation condition

• Features:

  • ~50% of individuals are affected (2018 paper)

  • children may exhibit anxiety, ADHD, social deficits, autism

  • adults may exhibit anxiety, depression (most common), OCD, ADHD, substance abuse

normal

(Huntington’s disease)

• 26 or less CAG 

intermediate

(Huntington’s disease)

• 27-35 CAG

• Features:

  • not at-risk of developing symptoms of HD

  • may be at-risk to have a child w/ an HD-causing expansion range 

reduced penetrance

(Huntington’s disease)

• 36-39 CAG

• Features:

  • risk for HD but may not develop symptoms (not uncommon to be an asymptomatic elderly individual) 

full mutation

(Huntington’s disease)

• 40+ CAG

juvenile 

(Huntington’s disease)

• 60+ CAG 

• Features:

  • symptoms occur before 20 years 

  • accounts for 5-10% of all cases

Huntington’s disease

• Mutation:

  • 40+ CAG repeat expansion 

  • expansion is paternally transmitted 

• Gene(s):

  • HTT

• Inheritance Pattern:

  • autosomal dominant 

• Features:

  • characterized by nerve cells in the brain decaying over time

  • cognitive symptoms:

    • executive dysfunction, impaired verbal learning, impaired visuospatial abilities, memory loss 

  • motor symptoms:

    • chorea, rigidity, dystonia, akinesia, dysarthria, dysphasia 

  • neuropsychiatric symptoms:

    • anxiety, irritability, depression, OCD, aggression, apathy, psychosis 

  • age of symptom onset: 30s-40s

  • predictive testing → extensive consent process

normal

(myotonic dystrophy type I)

• 5-34 CTG

premutation

(myotonic dystrophy type I)

• 35-49 CTG

full mutation

(myotonic dystrophy type I)

• 50+ CTG

myotonic dystrophy type I

• Mutation: 

  • 50+ CTG repeat expansion

• Gene(s): DMPK 

• Inheritance Pattern:

  • autosomal dominant

• Mild: 50-~150 CTG

  • cataracts, mild myotonia

  • age of onset: 20-70 years

• Classic: ~100-~1,000 CTG

  • weakness, myotonia, cataracts, balding, cardiac arrhythmia

  • age of onset: 10-30 years

• Congenital: 1,000+ CTG

  • infantile hypotonia, respiratory deficits, intellectual disability, classic signs in adults

  • age of onset: birth-10 years 

• Tip: myotonic dystrophy type II (proximal myotonic myopathy) 

  • tends to be milder

  • involves CNBP and ZNF9 genes

  • CCTG repeats: affected status is 75+ 

  • maternal transmissions will often result in larger expansions

normal

(Friedreich’s ataxia)

• 5-33 GAA

intermediate

(Friedreich’s ataxia)

• 34-65 GAA

borderline

(Friedreich’s ataxia)

• 44-65 GAA

full mutation

(Friedreich’s ataxia)

• 66-~1,300 GAA

Friedreich’s ataxia

• Mutation:

  • 66-~1,300 GAA repeat expansion

• Gene(s):

  • FXN

• Inheritance Pattern:

  • autosomal recessive

• Features:

  • characterized by progressive ataxia, dysarthria, decreased sensation in lower limbs, muscle weakness, scoliosis, pes cavus, hypertrophic non-obstructive cardiomyopathy, glucose intolerance, diabetes, optic atrophy, and/or deafness

  • 2/3 of patients show hypertrophic cardiomyopathy

  • 75% of individuals have “typical” (average age of onset is 10-15)

  • 25% of individuals have “atypical” (later age of onset)

normal 

(spinocerebellar ataxia)

• 6-35 CAG

gray

(spinocerebellar ataxia)

• 36-44 CAG

• CAT interruptions result in a normal phenotype

• absent CAT interruptions result in a “mutable normal”

full

(spinocerebellar ataxia)

• 39-44 CAG (if there are zero CAT interruptions)

• 46-70 CAG (if there are CAT interruptions)

spinocerebellar ataxia

• Mutation:

  • 39-44 CAG repeat expansion (0 CAT interruptions)

  • 46-70 CAG repeat expansion (CAT interruptions) 

• Gene(s):

  • ATXN1

• Inheritance Pattern:

  • autosomal dominant 

• Features: 

  • progressive cerebellar ataxia, uncoordinated gait/hands/speech