Non-cancer genetic disorders Flashcards
When is the onset of Huntington’s?
30-50 years
Describe the clinical presentation of Huntingtons
Progressive chorea (involuntary movements), dementia and psychiatric symptoms
Describe the genetics of Huntingtons disease
- Autosomal dominant with genetic anticipation
- unstable length mutation in the gene: Huntingtin HTT
- Up to 35 repeats means they are not affected
- 36-39 repeats = incomplete penetrance
- prone to expansion during meiosis, especially from the father
- CAG repeat unit within the coding sequence encodes a polyglutamine tract, expansion of this causes insoluble protein aggregates and neurotoxicity
Describe the clinical management of Huntingtons disease
- DNA testing is possible
- No cure for the condition, testing unaffected relative can be performed but for a presymptomatic test it can only be done once pros and cons have been fully discussed and there is full written consent
Describe the clinical presentation of myotonic dystrophy
- Progressive muscle weakness in early adulthood
* Myotonia and cataracts
Describe the genetics of myotonic dystrophic
- unstable length mutation of a CTG repeat
- located in the 3’ transcribed but translated region of the DMPK gene
- affected 50 or more repeats
- higher chance of expansion when transmitted by females
What is the pathogenic mechanism of myotonic dystrophy?
- Abnormal DMPK mRNA in the non coding region
* Indirect toxic effect upon splicing of other genes e.g. causing the choride ion channel CLCN1 gene causing myotonia
Describe the clinical presentation of cystic fibrosis
- recurrent lung infections
* exocrine pancreatic insufficiency
Describe the clinical management of cystic fibrosis
- screening of newborns by immunoreactive trypsin (IRT) level
- confirmation by DNA testing (for CF mutations) and/or sweat testing (for increased chloride conc.)
Describe the pathogenic mechanism of cystic fibrosis
- CFTR mutation resulting defective chloride ion channels
- This causes increased thickness of secretions
- there are over 1000 different mutations in the CFTR gene, the most common F508del
Describe the f508del mutation
- In frame deletion of 3 base pairs (one codon)
- deletion of a phenylalanine (‘F’”) at position 508
- Prevents the normal folding of protein and insertion into the plasma membrane
What does cascade screening allow
Identification of mutations, allowing the prenatal diagnosis if desired and the subsequent identification of carrier relatives
Describe the clinical presentation of neurofibromatosis type 1
- Cafe au lait macules
- neurofibromas (from teens)
- Short stature
- Macrocephaly (big head)
- Learning difficulties in 30% (severe in 3% or less)
- Very variable expressivity
- Lisch nodules (brown spots on the iris)
What are the possible complications of neurofibromatosis?
- Hypertension
- Scolliosis
- Pathological tibial fractures
- Significant tumours e.g. phaeochromocytomas, sarcomas, optic pathway gliomas and plexiform neuromas
- need annual follow up for BP, peripheral vision and legs and spine
What are the similarities and differences between Duchenne and Becker Mjuscular dystrophy?
- BothDMD gene: Xp21 (largest human gene) - dystrophin forms link between F-actin intracellularly and the dystroglycan complex
- DMD is more severe, onset at 3yrs, wheelchair by 12yrs
- BMD less severe, onset at 11yrs, wheelchair much later on or not at all
- DMD deletions are mostly out of frame so disrupt the amino sequence after
- Most deletions in BMD are in frame
