Genetic Disorders

Question 1

How common is CF?

Answer 1

1/2500 live births

Question 2

How is CF usually picked up?

Answer 2

In the Guthrie heel prick test of neonate

Question 3

Prognosis of people with CF?

Answer 3

95% ultimately die of respiratory failure

Median age of death is 29yrs, projected life 36 years

Question 4

Cause of CF?

Answer 4

Chromosome 7 mutations (delta F508)

CFTR protein altered, Cl- ion channel, secretions are dehydrated

Question 5

Respiratory effects of CF?

Answer 5

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

Question 6

GI effects of CF

Answer 6

Meconium ileus, pancreatic secretion failure, deficiency of enzymes leads to malabsorption
Failure to thrive
Foul smelling pale, floating faeces.

Question 7

Complications of CF

Answer 7

Diabetes mellitus (pancreatic failure)
Liver disease
Male infertility
Sinusitis

Question 8

How is CF diagnosed?

Answer 8

Sweat test (high chloride concentration)
Genetic testing

Question 9

Describe CF diabetes

Answer 9

Usually diagnosed over aged 30

HbA1c not useful

Question 10

Management of CF

Answer 10

Physio BD
Chest percussion
Continuous prophylactic antibiotics (fluclox)
Nebulisers
Creon for pancreatic enzyme insufficiency
Vitamins A, D, E, K
High calorie diet

Question 11

Treatment of end stage CF

Answer 11

Lung transplantation

Question 12

What are the 2 types of muscular dystrophy?

Answer 12

Duchenne

Becker’s

Question 13

Describe Duchenne MD

Answer 13

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

Question 14

Signs of Duchenne’s MD

Answer 14

• Gower’s sign (hands to climb up to stand on legs)

* Waddling gait, muscle wasting, calf hypertrophy, absent reflexes

Question 15

Chronology of Duchenne MD

Answer 15

• Severe disability by aged 10

* Death before the age of 30 due to cardiac and respiratory involvement

Question 16

Diagnosis of Duchenne MD

Answer 16

Creatine Kinase ++
Abnormal EMG
MRI of muscles
Muscle biposy

Question 17

Management of Duchenne MD

Answer 17

Physio to reduce contractures
Respirator support can maintain life
Corticosteroids? Genetic therapy?

Question 18

Describe Becker’s MD

Answer 18

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

Question 19

Signs of Becker MD

Answer 19

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

Question 20

What is spinal muscular atrophy?

Answer 20

Degeneration of anterior horn cells
Muscle weakness and progressive loss of movement
Autosomal recessive (SMN1 gene)

Question 21

Signs and types of spinal muscular atrophy

Answer 21

• 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

Question 22

Management of spinal muscular atrophy

Answer 22

• Bracing/surgery for scoliosis

* Nutrition and feeding management

Question 23

What is Charcot Marie Tooth?

Answer 23

• Group of inherited conditions affecting peripheral nerves
• Neuronal degenerations (axon/myelin)
Normal life expectancy

Question 24

Signs and symptoms of Charcot Marie Tooth?

Answer 24

• Loss of balance in early childhood, foot deformities (hammer toes, high arches)
• Weakness, atrophy, sensory loss

Question 25

Diagnosis of Charcot Marie Tooth

Answer 25

• Diagnosed with nerve conduction studies, EMG, nerve biopsy and genetic testing

Question 26

What are the 3 types of genetic disorder?

Answer 26

Single gene (eg sickle cell) Chromosomal (eg trisomy 21) Complex, mutations in 2 or more genes (familial colon cancer)

Question 27

What is Down's syndrome | Common?

Answer 27

``` 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) ```

Question 28

What is a syndrome?

Answer 28

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.

Question 29

Risk factors for Down's Syndrome

Answer 29

Maternal age 35: 1/385 40: 1/106 45: 1/30

Question 30

How is Down's diagnosed?

Answer 30

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

Question 31

Clinical features of Down's

Answer 31

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

Question 32

Name 10 major risks and complications of Down's

Answer 32

``` 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 ```

Question 33

What is DiGeorge's syndrome?

Answer 33

22q11.2 deletion 1/4000 births Characteristic facial features including down turned mouth, low set malformed ears, long face.

Question 34

What diseases/defects are common in DiGeorge's? | Treatment?

Answer 34

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

Question 35

What is Angelman's Syndrome?

Answer 35

1/15000 births Microcephaly, intellectual and speech disability, ataxia, epilepsy Happy, excitable, hand flapping

Question 36

``` Which conditions are trinucelotide repeat expansions and which are gene deletions/point mutations? Fragile X CF ß-thalassaemia Huntington's Duchenne MD ```

Answer 36

``` Fragile X- trinuc repeat CF -deletion/point ß-thalassaemia- deletion/point Huntington's- tri repeat Duchenne MD- deletion/point ```

Question 37

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?

Answer 37

Uniparental disomy Deletion of paternal chromosome 15q11-13

Question 38

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

Answer 38

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)

Question 39

``` Children with Down's are at increased risk of: T or F A) Hypothyroidism B) Secretory otitis media C) Coeliac D) Talipes E) Cataracts ```

Answer 39

``` A) T B) T C) F D) F E) T ```

Question 40

``` 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 ```

Answer 40

``` 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 ```