Alternative genetic mechanisms of disease causation

Question 1

TRIPLET REPEAT DISORDERS:
What are they?

What are the levels, and what does each indicate?

What is the Phenomenon of Anticipation? Where is it more common? Why?

Fragile X Syndrome:
How many triplet repeats can it be due to?

What are the physiological symptoms?

What are the physical signs?

What medical issues do they have?

Answer 1

• Triplet repeated over and over again
• • <27 is Normal = Not pathogenic
  • 27-35 = Not pathogenic
  • 36-39 = Pathogenic with risk of HD increasing from 25-90%
  • >39 = Always causes Huntington’s Disease (HD)
• Decreasing age of onset or increasing disease severity through successive generations
  o More common in paternal transmission - Gamete precursors constantly replicate = More opportunities for errors
• Over 200 repeats
• Developmental delay, Learning disability, Behavioural problems, Autism spectrum disorder
• Long face, Prominent forehead, Large ears, Prominent jaw, Very large Testes
• Reflux, Hypotonia, Seizures, Scoliosis, Sleep disorders, Strabismus

Question 2

IMPRINTING DISORDERS:
What is Epigenetics?

What is Imprinting? Where does it occur? What are most of the affected genes involved in?

Prader Willi Syndrome:
What is it?

What are the signs seen in Infancy?

What are the signs seen in Childhood?

What are the signs seen in Adulthood?

Angelman Syndrome:
What are the symptoms and signs?

Answer 2

• A process that alters gene activity without changing the DNA sequence
• Genes being expressed in a parent-of-origin specific manner
  o Takes place in gametes
  o Most affected genes are involved in embryonic and placental development
• Absence of expression of imprinted genes in the paternally-derived PWS region
• Hypotonia, Poor feeding, Global developmental delay
• Excessive eating with Central obesity if uncontrolled
• Cognitive impairment, Mild Intellectual disability, Hypothalamic Hypogonadism
• Severe Intellectual disability, Severe Speech impairment, Gait ataxia, Microcephaly, Seizures, Happy demeanour that includes frequent laughing/smiling/excitability

Question 3

MITOCHONDRIAL DISORDERS:
How is mitochondrial DNA inherited?

Leber Hereditary Optic Neuropathy (LHON):
What is the main symptom?

What are the associated features?

Myoclonic Epilepsy associated with Ragged Red Fibres (MERRF):
What is it? What are the main symptoms?

What are the associated features?

Answer 3

• Only from the MOTHER
• Bilateral, painless, subacute Visual failure
• Postural tremor, Peripheral neuropathy, Myopathy, Movement disorders

- Multisystemic systemic disorder
o Myoclonus (first symptom), Epilepsy, Ataxia, Weakness, and Dementia

• Hearing loss, Lipoma, Short stature, Optic atrophy, Cardiomyopathy, Retinopathy