Autosomal Recessive Flashcards
Familial Mediterranean Fever
Familial Mediterranean Fever (FMF, also known as recurrent polyserositis) is an autosomal recessive disorder which typically presents by the second decade. It is more common in people of Turkish, Armenian and Arabic descent
Features - attacks typically last 1-3 days
- pyrexia
- abdominal pain (due to peritonitis)
- pleurisy
- pericarditis
- arthritis
- erysipeloid rash on lower limbs
Management
COLCHICINE may help - v effective in treating episodes of abdominal pain and fever and can be used both as a treatment and prevention for condition provided stomach protection is prescribed
NB Can be assoc with an amyloid associated nephropathy
Example Question:
A 38-year-old Armenian visitor presents with 3 day history of pyrexia, shortness of breath, chest pain and abdominal pain, associated with temperature of 38.5 degrees. She has no other known past medical history and reports at least 2 other episodes of similar pain, both times spontaneously resolving without treatment or diagnosis. On examination, she has a pleural rub and a swollen, tender left 3rd metcarpal-phalangeal joint. Her mother has recently been admitted for similar symptoms last month. Her blood tests are as follow:
Hb 14.5 g/dl
Platelets 560 * 109/l
WBC 17.8 * 109/l
Na+ 143 mmol/l K+ 4.6 mmol/l Urea 5.2 mmol/l Creatinine 78 µmol/l CRP 78 mg/l
A chest radiograph demonstrates mild bilateral pleural effusions with no significant focus of consolidation, her Mantoux test is negative. Urine dip is negative, urine MC+S grows no organisms, urinary porphobilinogen is negative. A rheumatology review was requested regarding the synovitis and colchicine prescribed. She responds well with resolution of all symptoms within 24 hours. An infectious diseases opinion and induced sputum is awaited. What is the most likely diagnosis?
Tuberculosis Acute intermittent porphyria (AIP) Coxsackie B virus infection > Familial mediterranean fever Systemic lupus erythematous (SLE)
The patient is of Mediterranean descent is experiencing an acute attack of abdominal pain, chest pain, synovitis and pyrexia with an acute phase response. There appears to be a previous history of similar symptoms and a possible genetic element. Familial Mediterranean fever would fit with all these symptoms, with almost all patients presenting with abdominal pain, pleuritis and synovitis, associated with fever greater than 38 degrees. The main differentials in this case are with SLE and AIP: during an acute event, urinary porphobilinogen is likely positive in AIP. The distinguishing feature against SLE is the resolution of symptoms with colchicine, which is a key diagnostic feature1
Alkaptonuria
Alkaptonuria
Alkaptonuria (ochronosis) is a rare autosomal recessive disorder of phenylalanine and tyrosine metabolism caused by a lack of the enzyme homogentisic dioxygenase (HGD) which results in a build-up of toxic homogentisic acid. The kidneys filter the homogentisic acid (hence black urine) but eventually it accumulates in cartilage and other tissues.
Alkaptonuria is generally a benign and often asymptomatic condition. Possible features include:
pigmented sclera
urine turns black if left exposed to the air
intervertebral disc calcification may result in back pain
renal stones
Treatment
high-dose vitamin C
dietary restriction of phenylalanine and tyrosine
Haemochromatosis
Haemochromatosis is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*. It is often asymptomatic in early disease and initial symptoms often non-specific e.g. lethargy and arthralgia
*there are rare cases of families with classic features of genetic haemochromatosis but no mutation in the HFE gene
Epidemiology
1 in 10 people of European descent carry a mutation genes affecting iron metabolism, mainly HFE
prevalence in people of European descent = 1 in 200
(NB more common than CF!)
Presenting features
early symptoms include fatigue, erectile dysfunction and arthralgia (often of the hands)
‘bronze’ skin pigmentation
diabetes mellitus
liver: stigmata of chronic liver disease, hepatomegaly, cirrhosis, hepatocellular deposition)
cardiac failure (2nd to dilated cardiomyopathy)
hypogonadism (2nd to cirrhosis and pituitary dysfunction - hypogonadotrophic hypogonadism)
arthritis (especially of the hands)
Questions have previously been asked regarding which features are reversible with treatment:
Reversible Complications:
- Cardiomyopathy
- Skin pigmentation
Irreversible Complications:
- Liver cirrhosis**
- Diabetes mellitus
- Hypogonadotrophic hypogonadism
- Arthropathy
- *whilst elevated liver function tests and hepatomegaly may be reversible, cirrhosis is not
Wilson’s Disease
Wilson’s disease is an autosomal recessive disorder characterised by excessive copper deposition in the tissues. Metabolic abnormalities include increased copper absorption from the small intestine and decreased hepatic copper excretion. Wilson’s disease is caused by a defect in the ATP7B gene located on chromosome 13.
The onset of symptoms is usually between 10 - 25 years. Children usually present with liver disease whereas the first sign of disease in young adults is often neurological disease
Features result from excessive copper deposition in the tissues, especially the brain, liver and cornea:
liver: hepatitis, cirrhosis
neurological: basal ganglia degeneration, speech and behavioural problems are often the first manifestations. Also: asterixis, chorea, dementia
Kayser-Fleischer rings
renal tubular acidosis (esp. Fanconi syndrome)
haemolysis
blue nails
Diagnosis
reduced serum caeruloplasmin
reduced serum copper (counter-intuitive, but 95% of plasma copper is carried by ceruloplasmin)
increased 24hr urinary copper excretion
Management
penicillamine (chelates copper) has been the traditional first-line treatment
trientine hydrochloride is an alternative chelating agent which may become first-line treatment in the future
tetrathiomolybdate is a newer agent that is currently under investigation
CLASSIC PRESENTATION: Ataxia, movement disorder, psychiatric disturbance and deranged liver function tests in a young patient
Usher’s Syndrome
Usher’s syndrome - an autosomal recessive disorder. It is the leading cause of deaf-blindness - assoc with Retinitis Pigmentosa
Example Question:
A 32-year-old man with an inherited condition leading to deafness and retinitis pigmentosa, attends the genetic counselling clinic. His wife is also from the deaf community and has myopia (-2.0) requiring corrective lenses and does not have retinitis pigmentosa or a family history of blindness. She does not carry the gene of the condition described in her husband.
Regarding their children:
25% chance of having an affected child 50% chance of having an affected child 100% chance of having an affected child 50% will carry the gene but not have the condition > 100% will carry the gene but not have the condition
The patient described has Usher’s syndrome - an autosomal recessive disorder. It is the leading cause of deaf-blindness. As you have been told the wife does not have the condition nor carries the gene, so none of their children will have the condition. All children however, will inherit one healthy gene (from mother) and one defective gene (from father) - therefore becoming carriers of the condition.
Haemachromatosis - Ix
Haemochromatosis is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*.
There is continued debate about the best investigation to screen for haemochromatosis.
general population: transferrin saturation is considered the most useful marker. Ferritin should also be measured but is not usually abnormal in the early stages of iron accumulation
testing family members: genetic testing for HFE mutation
These guidelines may change as HFE gene analysis become less expensive
Diagnostic tests
molecular genetic testing for the C282Y and H63D mutations
liver biopsy: Perl’s stain
Typical iron study profile in patient with haemochromatosis
transferrin saturation > 55% in men or > 50% in women
raised ferritin (e.g. > 500 ug/l) and iron
low TIBC
Monitoring adequacy of venesection
transferrin saturation should be kept below 50% and the serum ferritin concentration below 50 ug/l
Joint x-rays characteristically show chondrocalcinosis
*there are rare cases of families with classic features of genetic haemochromatosis but no mutation in the HFE gene
Haemochromatosis - Diagnosis
Hereditary haemochromatosis presents with nonspecific and insidious symptoms, with the result that in some cases, the diagnosis is not suspected until after damage to end-organs has occurred. In such individuals, the risk of death from liver cancer, cirrhosis, cardiomyopathy and diabetes are increased compared to the general population. However, detection and treatment of the condition in a susceptible individual prior to the development of cirrhosis or diabetes results in normal survival. Therefore, genetic testing for HFE gene mutations (specifically, the C282Y and H63D mutations) is indicated for an individuals meeting one of the following criteria:
Elevated serum ferritin (> 300 microgram / L in males; > 200 microgram / L in females)
Elevated transferrin saturation (> 45 %)
First degree relative with haemochromatosis
Cystinuria
Cystinuria
Cystinuria is an autosomal recessive disorder characterised by the formation of recurrent renal stones. It is due to a defect in the membrane transport of cystine, ornithine, lysine, arginine (mnemonic = COLA)
Genetics
chromosome 2: SLC3A1 gene, chromosome 19: SLC7A9
Features
recurrent renal stones
are classically yellow and crystalline, appearing semi-opaque on x-ray
Diagnosis
cyanide-nitroprusside test
Management
hydration
D-penicillamine
urinary alkalinization
Familial Mediterranean Fever and Amyloid Associated Nephropathy - Example Question
A 30 year-old man from Crete presents with recurrent episodes of abdominal pain and fever. He has a family history of his father suffering from similar episodes. HIs only regular medication includes taking high doses of paracetamol and ibuprofen for around ten years to help with his symptoms.
He had a blood test nine months ago and the two sets of results are compared below:
Results 9 months ago:
Na+ 145 mmol/l
K+ 3.7 mmol/l
Urea 7.9 mmol/l
Creatinine 96 µmol/l
Results today:
Na+ 137 mmol/l
K+ 4.8 mmol/l
Urea 13.9 mmol/l
Creatinine 196 µmol/l
Which of the following is this most diagnostic test?
Intravenous urogram > Renal biopsy Genetic analysis Serum amyloid P component Blood culture
This man most likely has familial Mediterranean fever, given his frequent episodes of severe abdominal pain, fever, his positive family history and country of birth. A renal biopsy would be an important diagnostic investigation in any young patient with an unexplained creatinine rise. Furthermore, in this case a renal biopsy would be not only useful to diagnose the amyloid associated nephropathy that can come with familial Mediterranean fever but also for any analgesic nephropathy caused by his high intake of analgesics for the pain.
Alpha-1-Antitrypsin Deficiency
- Common inherited condition
- Located on chromosome 14
- Autosomal recessive/co-dominant
- Alleles classified by electrophoretic mobility
M = Normal
S = Slow
Z = V.Slow
Normal = PiMM Heterozygote PiMZ (A1AT levels 35% of normal, low risk of developing clinically relevant disease) Homozygous = PiSS (A1AT levels 50% of normal) Homozygous = PiZZ (A1AT levels 10% of normal)
Features:
- Patients who manifest disease usually have PiZZ genotype
Lungs: Panacinar emphysema, most marked in lower lobes
Liver: Cirrhosis and Hepatocellular Carcinoma in adults, Cholestasis in children
Mx:
- NO SMOKING
- Supportive > Bronchodilators and Physiotherapy
- IV A1AT protein concentrates
- Surgery > Volume reduction surgery, Lung Transplant
Gilbert’s Syndrome
Gilbert’s syndrome
Gilbert’s syndrome is an autosomal recessive* condition of defective bilirubin conjugation due to a deficiency of UDP glucuronyl transferase. The prevalence is approximately 1-2% in the general population
Features unconjugated hyperbilinaemia (i.e. not in urine) jaundice may only be seen during an intercurrent illness
Investigation and management
investigation: rise in bilirubin following prolonged fasting or IV nicotinic acid
no treatment required
*the exact mode of inheritance is still a matter of debate
Familial Mediterranean Fever Difficult Diagnosis - Example Question
A 31-year-old female presents with abdominal pain. She reports a fever at home and last opened her bowels 3 days ago. She has vomited twice. On examination, she is alert and well-oriented. She has a diffusely tender but non-distended abdomen.
When asked about her past medical history she says she is generally well but has had occasional joint pains in the past which she attributes to wear and tear. She had an appendectomy at the age of 18, a diagnostic laparoscopy aged 25, and a cholecystectomy aged 29. She has been previously investigated for renal colic in the past but no stones have been identified on CT imaging.
Her blood results are as follows: Hb 105 g/l Na+ 133 mmol/l Platelets 445 * 109/l K+ 3.9 mmol/l WBC 10.4 * 109/l Urea 4.5 mmol/l Neuts 8.5 * 109/l Creatinine 78 µmol/l Lymphs 1.0 * 109/l CRP 22 mg/l Eosin 0.1 * 109/l beta HCG undetectable
An urgent abdominal plain film shows some faecal loading in the large bowel which is 4.5cm at widest point. There is air in the rectum.
How should this patient be managed?
ERCP Urgent CT scan and wide bore NG tube Oral ofloxacin plus metronidazole for 14 days Urinary porphyrins > Analgesia and colchicine
The long surgical history in this relatively young patient should raise a suspicion of familial Mediterranean fever. Constipation can be a feature of acute attacks.
The normal bloods and X-ray make acute bowel obstruction somewhat less likely, and the history does not quite fit for pelvic inflammatory disease or acute intermittent porphyria.
Haemochromatosis - Investigation
Haemochromatosis: investigation
Haemochromatosis is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*.
There is continued debate about the best investigation to screen for haemochromatosis.
general population: transferrin saturation is considered the most useful marker. Ferritin should also be measured but is not usually abnormal in the early stages of iron accumulation
testing family members: genetic testing for HFE mutation
These guidelines may change as HFE gene analysis become less expensive
Diagnostic tests
molecular genetic testing for the C282Y and H63D mutations
liver biopsy: Perl’s stain
Typical iron study profile in patient with haemochromatosis
transferrin saturation > 55% in men or > 50% in women
raised ferritin (e.g. > 500 ug/l) and iron
low TIBC
Monitoring adequacy of venesection
transferrin saturation should be kept below 50% and the serum ferritin concentration below 50 ug/l
Joint x-rays characteristically show chondrocalcinosis
*there are rare cases of families with classic features of genetic haemochromatosis but no mutation in the HFE gene
McArdle’s Disease
McArdle’s disease
Overview
autosomal recessive type V glycogen storage disease
caused by myophosphorylase deficiency
this causes decreased muscle glycogenolysis
Features muscle pain and stiffness following exercise muscle cramps myoglobinuria low lactate levels during exercise
McArdle’s Disease - Example Question
A 21-year-old male presents to his GP complaining of muscle cramps that prevent him from competing in his local park 5 km race. He has always had muscle pains when warming up with exercise but these gradually diminish after 20 minutes. There was no weakness and no abnormalities on neurological exam.
Creatinine kinase was elevated at 1215 IU/L and myoglobinuria was noted on urinalysis. The electromyography (EMG) demonstrated myotonic discharges and fibrillations.
What is the likely diagnosis?
Hypokalaemic periodic paralysis Von Gierke disease > McArdle disease Pompe disease Gaucher disease
McArdle disease (also known as myophosphorylase deficiency or Glycogen storage disease V) often presents in adolescence with exercise intolerance, cramps and weakness. Unfortunately it is often misdiagnosed as chronic fatigue syndrome. Inheritance is autosomal recessive. The diagnostic clues are:
No rise in venous blood lactate on exercise
Muscle biopsy demonstrates elevated glycose concentration and muscle phosphorylase deficiency
Investigations usually reveal an elevated CK and myoglobinuria. Diagnosis is confirmed with forearm muscle exercise testing or genetic testing. Management involves avoidance of low carbohydrate diets and low intensity aerobic exercise.
