Genetic Disorders Flashcards
How common is CF?
1/2500 live births
How is CF usually picked up?
In the Guthrie heel prick test of neonate
Prognosis of people with CF?
95% ultimately die of respiratory failure
Median age of death is 29yrs, projected life 36 years
Cause of CF?
Chromosome 7 mutations (delta F508)
CFTR protein altered, Cl- ion channel, secretions are dehydrated
Respiratory effects of CF?
Defective mucociliary clearance, mucus obstruction and infection and inflammation. Recurrent chest infections, pneumothorax Productive cough, lots of sputum that is sticky, air trapping, wheeze, clubbing Pseudomonas aeruginosa, staphylococcus aureus, haemophilus influenza
GI effects of CF
Meconium ileus, pancreatic secretion failure, deficiency of enzymes leads to malabsorption
Failure to thrive
Foul smelling pale, floating faeces.
Complications of CF
Diabetes mellitus (pancreatic failure)
Liver disease
Male infertility
Sinusitis
How is CF diagnosed?
Sweat test (high chloride concentration) Genetic testing
Describe CF diabetes
Usually diagnosed over aged 30
HbA1c not useful
Management of CF
Physio BD
Chest percussion
Continuous prophylactic antibiotics (fluclox)
Nebulisers
Creon for pancreatic enzyme insufficiency
Vitamins A, D, E, K
High calorie diet
Treatment of end stage CF
Lung transplantation
What are the 2 types of muscular dystrophy?
Duchenne
Becker’s
Describe Duchenne MD
Severe inherited disorder of muscle weakness
X linked recessive, males affected
1/3500 male births
Female sisters have 50% chance of being a carrier
Dystrophin instability, influx of Ca2+ then necrosis
Failure to produce dystrophin
Signs of Duchenne’s MD
- Gower’s sign (hands to climb up to stand on legs)
* Waddling gait, muscle wasting, calf hypertrophy, absent reflexes
Chronology of Duchenne MD
- Severe disability by aged 10
* Death before the age of 30 due to cardiac and respiratory involvement
Diagnosis of Duchenne MD
Creatine Kinase ++
Abnormal EMG
MRI of muscles
Muscle biposy
Management of Duchenne MD
Physio to reduce contractures
Respirator support can maintain life
Corticosteroids? Genetic therapy?
Describe Becker’s MD
Recessive, X-linked dystrophinopathy
Dystrophin levels are low but still present
Less severe dystrophy
Symptom onset 11 years, nonambulatory 27 years
Death usually resulted from respiratory or cardiac failure at a mean age of 42 years
Dilated cardiomyopathy with congestive heart failure presents in males between age 20 and 40 years
Signs of Becker MD
Delayed gross motor milestones (eg, late walking, running, jumping, difficulty with stair climbing) may be reported.
Increasing numbers of falls, toe walking, and difficulty rising from the floor may be later features.
Progressive, symmetrical, proximal muscle weakness and atrophy with pseudohypertrophic calves
Subclinical cases may manifest later in life; dilated cardiomyopathy can be the first sign of BMD.
Elbow contractures seen later
What is spinal muscular atrophy?
Degeneration of anterior horn cells
Muscle weakness and progressive loss of movement
Autosomal recessive (SMN1 gene)
Signs and types of spinal muscular atrophy
- Limb contractures, absent reflexes, muscle wasting, respiratory distress, bell shaped thorax
- If presents in less than 6months, rarely survive beyond 2yrs (Type 1)
- Type 2: can sit unsupported, cannot cough. Will survive till adulthood
- Type 3: Able to reach major milestones
Management of spinal muscular atrophy
- Bracing/surgery for scoliosis
* Nutrition and feeding management
What is Charcot Marie Tooth?
• Group of inherited conditions affecting peripheral nerves
• Neuronal degenerations (axon/myelin)
Normal life expectancy
Signs and symptoms of Charcot Marie Tooth?
- Loss of balance in early childhood, foot deformities (hammer toes, high arches)
- Weakness, atrophy, sensory loss
Diagnosis of Charcot Marie Tooth
• Diagnosed with nerve conduction studies, EMG, nerve biopsy and genetic testing
What are the 3 types of genetic disorder?
Single gene (eg sickle cell)
Chromosomal (eg trisomy 21)
Complex, mutations in 2 or more genes (familial colon cancer)
What is Down’s syndrome
Common?
Trisomy 21 (3 copies of chromosome 21) 47XX or 47XY 1/650 live births without screening usually from meiotic non dysjunction 4% unbalanced translocation 2% mosaicism (less delay)
What is a syndrome?
A syndrome is a disease or disorder that has more than one identifying feature or symptom.
Genetic and chromosomal abnormalities cause specific syndromes, depending on which aspects of development those genes or chromosomes influence
The traits of the syndrome may include body deformities, such as cardiac involvement or a dysmorphic face, as well as neurodevelopmental traits, such as poor tone and learning difficulties.
Risk factors for Down’s Syndrome
Maternal age
35: 1/385
40: 1/106
45: 1/30
How is Down’s diagnosed?
USS of nuchal lucency combined with maternal age gives risk. If more than 1/150, further tests are offered:
In utero via amniocentesis/percutaenous umbilical cord sampling/chorionic villus sampling
Maternal blood test
At birth due to clinical features
Clinical features of Down’s
Microcephaly
Flat face
Upward slanted palpebral fissures with epicanthic folds
Single deep crease across the palm of hand, and short fingers
Wide space between the big toe and second toe (sandal gap)
Hypotonia
Protruding tongue
Name 10 major risks and complications of Down’s
Decreases prenatal viability Congenital heart defects (AVD, VSD most common) Duodenal atresia, hirschsprung's Reduced immunity and autoimmune Delayed growth and development Leukaemia is more common Diabetes, cataracts and premature Alzheimer's Atlantoaxial instability
What is DiGeorge’s syndrome?
22q11.2 deletion
1/4000 births
Characteristic facial features including down turned mouth, low set malformed ears, long face.
What diseases/defects are common in DiGeorge’s?
Treatment?
Congenital heart defects are common-> Echo and refer to cardiologist
Cleft palate or incomplete soft palate is common -> Early surgery
Immune deficiencies are common -> Early thymus transplantation
Hypocalcaemia is common -> Test serum calcium and serum PTH and begin supplementation
What is Angelman’s Syndrome?
1/15000 births
Microcephaly, intellectual and speech disability, ataxia, epilepsy
Happy, excitable, hand flapping
Which conditions are trinucelotide repeat expansions and which are gene deletions/point mutations? Fragile X CF ß-thalassaemia Huntington's Duchenne MD
Fragile X- trinuc repeat CF -deletion/point ß-thalassaemia- deletion/point Huntington's- tri repeat Duchenne MD- deletion/point
A child is found to have a syndrome where he has both copies of chromosome 15q11-13 from his mother
What is this called?
What other mechanism could cause this syndrome?
Uniparental disomy
Deletion of paternal chromosome 15q11-13
True of false about X-linked recessive
A)It never results in father-> son transmission
B) The abnormal genetic material is always carried on X chromosome
C) Daughters of affected males are always carriers
D) It is less common than X linked dominant inheritance
E)Can result in both sexes showing clinical abnormalities
A)T (fathers always give Y chromosome to son)
B)T
C)T
D)F (X-linked dominant s very rare)
E)T (occasionally carriers show signs of disease)
Children with Down's are at increased risk of: T or F A) Hypothyroidism B) Secretory otitis media C) Coeliac D) Talipes E) Cataracts
A) T B) T C) F D) F E) T
The following are either autosomal dominant (AD), Autosomal recessive (AR), X-linked recessive (XR), Multifactorial (M) A) Pyloric stenosis B) Phenylketonuria C)Haemophilia A D) Achondroplasia E) Sickle cell F) ß-thalassaemia G)Neurofibromatosis H) Marfan's I) Dysplastic hip
A) Pyloric stenosis- M B) Phenylketonuria- AR C)Haemophilia A- XR D) Achondroplasia- AD E) Sickle cell- AR F) ß-thalassaemia- AR G)Neurofibromatosis- AD H) Marfan's- AD I) Dysplastic hip- M
