Single Gene Disorders: DMD & CF Flashcards
Describe the inheritence of DMD [1]
What is important to know about aetiology of DMD? [1]
DMD: X-linked recessive conditions (get from mother)
De novo mutations make 30% of incidence
Describe the pathophysiology of DMD
Defective gene for dystrophin on the X-chromosome.
Dystrophin is a protein that helps hold muscles together at the cellular level.
Given thatFemale carriers of the condition do not usually notice any symptoms. This makes Duchennes muscular dystrophy an X-linked recessive condition. If a mother is a carrier (meaning she has one faulty gene) and she has a child, that child will have a 50% change of being a carrier if they female and 50% change of having the condition if they are male.
Describe why girls are carriers of DMD but boys are not [1]
If a mother is a carrier, what is the % of her daughter being a carrier [1] and son being affected? [1]
Boys have a single X-chromosome and girls have two, girls have a spare copy of the dystrophin gene.
50% daughter will be carrier
50% son will be affected
Describe the clinical presentation of a patient with DMD
Progressive weakness
- Starts proximally and moves distally - starts in muscles around hip
- Lower limbs affected before upper limbs
- In a wheel chair by teens
- Often develop scoliosis and have poor pulmonary function
Delaued milestones - inability to walk independently
Waddling gait
When perfoming a clinical exam of a person with muscular dystrophy (like DMD), what would you particularly look out for? [6]
Gower’s sign
- the child climbs up their legs when rising from the floor
Weakness:
- typically the proximal and distal leg muscles in the earlier phases of the disease.
Calf pseudohypertrophy:
- due to the accumulation of connective tissue and fat replacing muscle tissue.
Waddling gait:
- typically exacerbated when attempting to run.
Tip-toe walking
- occurs due to shortening of the Achilles tendon.
Loss of the arches of the feet (i.e. flat feet)
Difficulty or inability to squat
When you suspect a child with DMD (e.g. they cant walk by 18months), what blood test should you check? [1]
How do you confirm a diagnosis? [1]
Creatine kinase levels
- Is nearly always raised and serves as a good screening test prior to more specialist assessment
Genetic testing is used to confirm the diagnosis
TOM TIP: [] sign is a favourite in exams.
If there is a 5 year old boy presenting with vague symptoms of muscle weakness and the description is that you notice them [] to stand up, the answer is probably Duchennes muscular dystrophy.
They may ask “what is the underlying genetic inheritance of the most likely cause?” The answer is []
TOM TIP: Gower’s sign is a favourite in exams.
If there is a 5 year old boy presenting with vague symptoms of muscle weakness and the description is that you notice them using their hands on their legs to help them stand up, the answer is probably Duchennes muscular dystrophy. They may ask “what is the underlying genetic inheritance of the most likely cause?” The answer is X-linked recessive.
Describe the management of DMD [2]
There is no curative treatment for muscular dystrophy.
Management is aimed at allowing the person to have the highest quality of life for the longest time possible. This usually involves input from occupational therapy, physiotherapy and medical appliances (such as wheelchairs and braces) as well as surgical and medical management of complications such as spinal scoliosis and heart failure.
- Oral prednisolone is used to improve muscle function
- Creatine supplementation can give a slight improvement in muscle strength
Describe what Becker’s MD is like [2]
In very simple terms it is often thought of as a ‘less severe’ version of Duchenne muscular dystrophy.
- due to mutation in the gene encoding dystrophin, dystrophin gene on Xp21
- gene is less severely affected and maintains some of its function.
Describe the pathophysiological differences between Duchenne and Becker’s MD [1]
Duchenne muscular dystrophy
- there is a frameshift mutation resulting in one or both of the binding sites are lost leading to a severe form
Becker muscular dystrophy
- there is a non-frameshift insertion in the dystrophin gene resulting in both binding sites being preserved leading to a milder form
Give 4 differential diagnoses of MDs
DMD (X-linked recessive)
BMD (X-linked recessive)
Spinal Muscular Atrophy (Autosomal recessive)
Limb-Girdle Dystrophy (Autosomal Dominant
- Limb-girdle muscular dystrophy usually presents in teenage years with progressive weakness around the limb girdles (hips and shoulders).
Name three important clinical complications of DMD [3]
Cardiac
* dilated cardiomyopathy
* annual echocardiograms should be undertaken in all patients
Respiratory
* respiratory failure secondary to muscular weakness
Complications can be seen secondary to longterm corticosteroid use:
* osteoporosis
* impaired glucose tolerance
* obesity
* Addisonian crisis triggered by suddenly stopping steroids or intercurrent illness
Describe the pathophysiology of cystic fibrosis
CFTR is a transmembrane protein, functions as a pump to regulate levels of Chlorine in respiratory epithelium
There are many variants of this mutation, the most common is the delta-F508 mutation
Describe the clinical consequences of cystic fibrosis [4]
Lungs
- Mucus produced by epithelium becomes very thick, obstructs airways, impairs mucociliary clearance, promoting chronic bacterial infections and inflammation.
- This causes bronchiectasis and chronic inflammation of the airways
Pancreatic insufficiency
- CFTR dysfunction in the pancreas leads to viscous secretions that obstruct pancreatic ducts
- Causes a lack of digestive enzymes such as pancreatic lipase subsequent pancreatic insufficiency.
Congenital bilateral absence of the vas deferens in males.
- Patients generally have healthy sperm, but the sperm have no way of getting from the testes to the ejaculate, resulting in male infertility
Liver disease
- Impaired CFTR function in the biliary epithelium leads to cholestasis, bile duct obstruction, and liver damage, which can progress to cirrhosis and portal hypertension.
TOM TIP: Cystic fibrosis is a common exam topic and is a favourite of examiners for testing your knowledge of genetic inheritance.
Remember that cystic fibrosis is [] inheritence.
A popular scenario is: both parents are healthy, one sibling has cystic fibrosis and a second child does not have the disease, what is the likelihood of the second child being a carrier? [1]
cystic fibrosis is autosomal recessive.
We know the child doesn’t have the condition, so the answer is two in three.
Describe what is often the first sign of CF [1]
Meconium ileus is often the first sign of cystic fibrosis.
- Normal meconium: is usually black and should be passed within 24 hours of birth.
- In about 20% of babies with CF, the meconium is thick and sticky, causing it to get stuck and obstruct the bowel.
- This is called meconium ileus, and is practically pathognomonic for cystic fibrosis.
- This presents as not passing meconium within 24 hours, abdominal distention and vomiting
There are three key methods for establishing a diagnosis that you should remember for your exams.
What are they? [3]
- Newborn blood spot testing is performed on all children shortly after birth and picks up most cases
- The sweat test is the gold standard for diagnosis
- Genetic testing for CFTR gene can be performed during pregnancy by amniocentesis or chorionic villous sampling, or as a blood test after birth
Describe the sweat test used to diagnose CF [3]
- A patch of skin is chosen for the test, typically on the arm or leg.
- Pilocarpine is applied to the skin on this patch.
- Electrodes are placed either side of the patch and a small current is passed between the electrodes
- This causes the skin to sweat.
- The sweat is absorbed with lab issued gauze or filter paper and sent to the lab for testing for the chloride concentration.
- The diagnostic chloride concentration for cystic fibrosis is more than 60mmol/l.
Which are they key microbrial colonisers of patients with CF? [2]
What treatment do you give as long term prophylaxis?
TOM TIP: The key colonisers to remember for your exams are staph aureus and pseudomonas.
Patients with cystic fibrosis take long term prophylactic flucloxacillin to prevent staph aureus infection.
Pseudomonas should be remembered as a particularly troublesome coloniser that is hard to treat and worsens the prognosis of patients with cystic fibrosis.
Describe two endocrine consequences of CF [2]
Cystic fibrosis-related diabetes (CFRD)
- Insulin deficiency and impaired glucose tolerance caused by progressive pancreatic damage.
Growth failure:
- Delayed growth and pubertal development due to malabsorption, chronic inflammation, and increased energy expenditure.
Describe reproductive manifestations of CF [2]
Reproductive manifestations:
Male infertility:
- Congenital bilateral absence of the vas deferens (CBAVD) results in obstructive azoospermia and infertility.
Female fertility:
- Thick cervical mucus, irregular menstrual cycles, and decreased fertility may necessitate assisted reproductive technologies.
Describe 5 GI manifestations of CF [5]
Meconium ileus:
- Neonates with CF may present with intestinal obstruction due to thickened meconium.
Pancreatic insufficiency:
- Steatorrhea, weight loss, and malabsorption of fat-soluble vitamins due to pancreatic duct obstruction.
Distal intestinal obstruction syndrome (DIOS):
- Partial or complete intestinal obstruction due to inspissated faecal material.
Biliary cirrhosis:
- Impaired bile flow leading to liver damage, portal hypertension, and potential liver failure.
Gastroesophageal reflux disease (GERD):
- Increased prevalence in CF patients may exacerbate pulmonary complications.
Describe the acid-base change that can occur in CF [1]
metabolic alkalosis:
- Excessive sodium chloride loss in sweat
Describe a finger sign of CF [1]
Clubbing: Chronic hypoxia may lead to digital clubbing, a sign of advanced lung disease.
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Why is colonisation by Pseudomonas Aeruginosa particularly harmful in CF?
Once patients become colonised with pseudomonas, it can be very difficult to get rid of. Often, these bacteria can become resistant to multiple antibiotics.
Colonisation with pseudomonas leads to a significant increase in morbidity and mortality in patients with CF
How do you treat Pseudomonas in CF? [2]
Pseudomonas colonisation can be treated with long term nebulised antibiotics such as tobramycin
Oral ciprofloxacin is also used.
Patients with CF are at increased risk of which malignancies? [3]
Patients with CF are at increased risk of gastrointestinal malignancies - including the large and small bowel, pancreas and biliary tract. Those with cirrhosis are at risk of hepatocellular carcinoma.
Describe the management of CF [7]
Airway clearance techniques
Mucoactive agents
- rhDNase (dornase alfa; recombinant human deoxyribonuclease): advised as the first-line option by NICE. Given via a nebuliser it cleaves extracellular deoxyribonucleic acid and helps reduce viscosity and promote sputum clearance.
- Hypertonic sodium chloride: may be used alone or with rhDNase in those with inadequate response. Given via a nebuliser, it has osmotic action that hydrates airway secretions and promotes their clearance.
- Mannitol dry powder for inhalation: used in patients intolerant, ineligible or not responding to rhDNase and have rapidly declining lung function and where other osmotic agents are not appropriate. Inhaled via a handheld device, it has osmotic action causing water to enter the airways, hydrating secretions and making clearance easier.
Bronchodilators:
- Inhaled β2-agonists and anticholinergics help relax airway smooth muscle, improving airflow and lung function.
Anti-inflammatories:
- Inhaled corticosteroids and oral nonsteroidal anti-inflammatory drugs (e.g., ibuprofen) help reduce airway inflammation and improve lung function.
Antibiotics:
- Regular use of inhaled antibiotics (e.g., tobramycin, aztreonam) helps manage chronic infections, particularly with Pseudomonas aeruginosa. Systemic antibiotics may be required for acute exacerbations.
CFTR modulators:
- Small molecule drugs like ivacaftor, lumacaftor, and elexacaftor target specific CFTR mutations, improving protein function and clinical outcomes. Selection depends on the patient’s specific CFTR genotype.
Patients with CF need monitoring for which conditions? [5]
Patients with cystic fibrosis are managed and followed up in specialist clinics, typically every 6 months. They require regular monitoring of their sputum for colonisation of bacteria like pseudomonas.
They also need monitoring and screening for diabetes, osteoporosis, vitamin D deficiency and liver failure.
What does death usually occur from in CF? [1]
Death usually occurs as a result of respiratory complications.
Diabetes mellitus
Meconium ileus
Autosomal recessive
Nasal polyps
Chromosome 7
Rectal prolapse
