Nucleotide Repeat Expansion Diseases

Question 1

Causes of Nucleotide Repeat Expansions

Answer 1

Question 2

Anticipation on NREDs

Answer 2

Question 3

Huntington’s Disease

Answer 3

• generally begin in the patients’ 30’s to 40’s, although many people have subtle changes in personality and cognition (e.g. clumsiness, apathy, depression) a decade prior to clear symptoms.
• The age of onset varies, however, and people with >60 CAG repeats have been known to start showing severe symptoms in childhood.
• People survive an average of 15-18 years after symptom onset with late symptoms including inability to walk, speak and eat.
• There are currently no effective treatments, although work is being done to identify symptomatic treatments and to perform gene editing.

Question 4

Answer 4

•CAG repeat length correlates with formation of inclusion bodies composed of aggregation of mutant Huntingtin protein.

Question 5

Freidrich’s Ataxia

Answer 5

• Friedrich ataxia is an autosomal recessive condition affecting people around as early teens (age 10-15) that causes ataxia, muscle weakness, spasticity, cardiomyopathy, and diabetes.
• It is caused by GAA repeat expansions in the first intron of the FXN gene, which causes transcription to be repressed. The number of repeats correlates with disease severity.
• Lack of the Frataxin protein causes iron build-up which allows free radicals to damage to mitochondrial membranes leading to nerve and muscle cell dysfunction.
• Treatment is symptomatic with iron chelators and antioxidants being studied.
• About 1/100 people carries an expanded repeat in FXN.

Question 6

Fragile X Syndrome

Answer 6

• increased numbers of CGG repeats in the 5’UTR of the FMR1 gene
• Fragile X syndrome (FXS) is the most common inherited cause of developmental delay in males and occurs in males, and some females, who carry >200 repeats in the 5’ UTR Of FMR1. FXS affects about 1/1500 males and about 1/8000 females.
• FMR1 is found on the X chromosome, thus X-inactivation explains why it is less common in females.
• In addition to developmental delay, people with FXS have a characteristic appearance, joint laxity, large testes, and may have autism spectrum disorder.
• About half of women with full mutations in FMR1 have intellectual disability, although they are often less severely affected than males with a full mutation and often evade diagnosis.

Question 7

Myotonic Dystophy

Answer 7

Question 8

Myotonic Dystrophy Type I

Answer 8

Question 9

Myotonic Dystrophy Type II

Answer 9

Question 10

MOlecular Etiology of DM

Answer 10

Question 11

Potential Therapuetic Options for DM

Answer 11

Question 12

Factors Affecting Pathogenicity of Repeat Expansions

Answer 12

• Sequence of repeat
• Size of repeat
• Location of repeat within gene
• Whether repeat encodes RNA or protein
• Function of repeat-containing gene
• Extent of meiotic and somatic instability

Question 13

Loss of Function Versus Toxic Gain of Function in Repeat Expansion Diseases

Answer 13

Question 14

Answer 14