Test 2 Flashcards
Monogenic definition
strong genetic influence by 1
gene
Recessive definition
Need two defective copies to be
affected
Cystic fibrosis is due to:
mutations in the gene for the CF transmembrane conductance regulator
(CFTR) gene, Cl- channel
Characteristics of cystic fibrosis:
- fatal monogenic recessive disease
- congenital (present at birth)
- highest frequency in Northen Europe
- Heterozygote/carrier frequency of 1/20
- General frequency in Caucasian populations: 1/1600-3000
- less common in African, Arab or Asian populations
Inheritance pattern of CF with two carriers as parents:
- 25% offspring unaffected, 50% carriers (unaffected), 25% have the disease
Inheritance pattern of CF with one normal parent and one parent as a carrier
- 50% of offspring are carriers (unaffected), 50% of offspring do not carry the mutation at all (unaffected)
Phenotype/clinical presentation of CF:
– increased sweat Na and Cl
– pancreatic insufficiency
– pulmonary infections
- thick mucous production
- 90% of males are infetile - congenital bilateral absence of the vas deferens
- > 90% of deaths due to recurrent infection, most commonly with Pseudomonas aeruginosa
Root of pathophisology of CF
Stems from a defect in CFTR, a
chloride transporter on cell
membrane
Pathophysiology of CF
- less chloride channel activity
- change in regulation of epithelial sodium channel
- increased sodium, increased water absorption, decreased water content of secretions (also increased sodium in sweat)
- mucous becomes thicker -> impaired flow, plugs and obstructions
Effect of pathophysiology of CF on GIT
- Blockage of pancreatic ducts.
- Loss of water from GIT
- Meconium ileus
- Constipation
- Rectal prolapse
Effect of pathophysiology of CF on lungs
Decreased periciliary volume + thick
mucus leads to poor ciliary clearance of pathogens and recurrent infections
CFTR gene
- Chromosome 7q31-32 - 250Kb region
- 27 exons, 6.5Kb transcript
- Regulated by cAMP sensitive protein kinase
CFTR protein
- A 1480 aa membrane protein.
- A Cl- ion channel expressed in the apical membrane of exocrine
epithelial cells. - Member of the ATP binding cassette family of transporters
Mutations in CTFR
- > 1,000 mutations described.
- One major mutation in Caucasians, ΔF508, accounts for ~ 70%
- A few at frequency of 1-3%; the rest at very low frequency.
Classic CF clinical phenotype is associated with:
- Pancreatic exocrine insufficiency (highest correlation between genotype and phenotype)
- COPD (lowest correlation between genotype and phenotype for lung manifestations)
- Abnormal concentrations of sweat electrolytes
- No vas deferens in males
- Bowel obstruction
Pulmonary manifestations in genotype/phenotype correlations (CF)
- Most common cause of morbidity and mortality.
- But there is a poor correlation with severity of genotype and the age on
onset, severity and progression. - For example, even among homozygotes for the most common mutation
(DF508), lung function may vary from normal to severe dysfunction
How heterozygous CF patients have an advantage against diarrhoea
- in normal patients: toxins released by cholera and E coli act on CFTR, cause increased fluid flow in intestine –> diarrhoea
- CF homozygotes don’t secrete chloride ions in response to bacteria
- Mutations can protect against diarrhoea
How heterozygous CF patients have an advantage against typhoid fever
- Salmonella typhi enter epithelial cells via interactions with CFTR.
- One study, showed an 86% reduction in internalization of S. typhi into the gastrointestinal tract, of mice
heterozygous for Cftr-ΔF508, relative to that in wild-type mice - Thus, selection for typhoid fever resistance provides another possible
explanation for the high frequency of CFTR mutations
Newborn screening for CF
- Measure immunoreactive trypsinogen (IRT), 48-72h after birth (these levels are raised in CF), blood is from heel prick
- Genotyping: two mutations = CF, no mutations = unlikely to have CF, one mutation = carry out sweat test to determine electrolytes
- CF patients cannot absorb NaCl from sweat
Sweat Test Interpretation for CF
- Australian recommended values for sweat chloride in infants in newborn screening (should be done after 1st postnatal week):
- Cl 60 mmol/l, cystic fibrosis;
- Cl 30–59 mmol/l, borderline;
- Cl 29 mmol/l, normal.
- Up to 25% of infants with MI do not have an IRT value above the cutoff level. Any neonate with a family history of CF or Meconium Ileus SHOULD be followed up
Fragile X syndrome:
- most common inherited intellectual disability
- can range from learning disabilities to severe cognitive disabilities to intellectual disabilities
- 30% of individuals with Fragile X have autism
- 2-6% of individuals with autism have Fragile X
- diagnosed with bloods or DNA testing
Prevalence of Fragile X
- Affects 1/4000 males and 1/6000-8000 females
- Can appear in all socio-economic backgrounds
- 50% of females with full mutations have some form of ID
Clinical features of Fragile X
- Large ears, long narrow face w/ prominent forehead, mitral valve prolapse, seizures, eye problems
- FGX mutations affecting brain development - mental impairment, developmental delays, learning disabilities
Cause of Fragile X disorder
- more than 200 repeats in CGG expansion
- this leads to hypermethylation of cytosine residues
- causes deactivation of FMR1 gene (no FMRP produced in Fragile X)
Analysis of mutations of Fragile X
- Stable: <45 repeats, unmethylated, individuals not affected
- Grey zone: 45-54 repeats, unmethylated, individuals not affected
- Pre-mutation: 55-200 repeats, unmethylated, individuals usually not affected
- Full mutation: >200 repeats, completely methylated, 50% of women and 100% of men affected
Fragile X associated primary ovarian insufficiency
- carriers of FX pre-mutation (55-200 CGG repeats)
- produce more mRNA but less FMRP protein
- in females, menopause is 5 years earlier and 23% of female individuals have ovarian insufficiency
- toxic RNA gain is said to be responsible
Fragile X associated tremor ataxia syndrome
- affects older adults that carry pre-mutation (increased rate with age, increased rate of hypertension)
- intention tremor and cerebellar gait ataxia are main clinical features
- affects 40% of male carriers and 8-16% female carriers
FMR1 gene
- chromosome Xq27
- CGG repeats happen in 5’-UTR (healthy individuals have 6-55 copies)
- methylation of CpG site -> silencing gene -> deficiency in FMRP protein and intellectual disability
Lab testing for Fragile X
- PCR, Southern Blot -> no. of CGG expansions
- Microarray and MLPA to detect deletions
- Next Gen sequencing
Fragile X treatment
- Glutamate antagonists - reduce activity of metabotropic receptor
- Lithium - improved behaviour but not cognition
- MMP9 - reversal of structural damage in neurons
- GABA agonists (arbaclofen) - alleviate anxiety and learning disabilities
Clinical features of Huntington’s disease
- Progressive neurodegenerative disease leading to dementia
- Symptoms include mood and character changes, defects in memory and attention, progressing to movement disorders
- Onset is usually at 35-55 years and symptoms evolve over 12-15 years
Genotype/phenotype of Huntington’s
- Autosomal dominant
- Instability of CAG repeat length in sperm and oocyte DNA
- A parent that has Huntington’s (heterozygous) has a 50% chance of passing it to their children if they are with an unaffected partner
