Genetic conditions Flashcards
________, meaning ‘on top of’ traditional
genetic inheritance, is a study of changes in
genetic expression or cellular phenotype caused
by mechanisms other than changes in the DNA
sequence
Epigenetics
All people carry a small number of ______genes,
which are carried asymptomatically
recessive
The background risk that any couple will bear a
child with a birth defect is about _______. This risk is
doubled for a__________) couple
4%
first-cousin (consanguineous
Although the majority of cancers are not inherited,
some people carry inherited genetic mutations
for certain cancers, notably _____, ________, ______l and others on a lesser scale,
such as prostate cancer and melanoma
breast and ovarian
(linked), colorectal
A GP caring for 1000 patients would expect to
have _____patients with a hereditary cancer
predisposition
15–17
Carrier screening is now widely used for
________, ________ and _____
thalassaemia, Tay–Sachs disorder and cystic fibrosis
Prenatal screening and testing for genetic disorders
is also a reality, especially for _______
Down syndrome,
fetal abnormalities and the haemoglobinopathies
_______ and ________ are the future
hope for targeted treatments based on a person’s
genetic profile
Pharmacogenetics and gene therapy
The _______ is a valuable pedigree chart that
usually covers at least three generations of a
family tree
genogram
__________ which is a
disorder of iron overload, is the most common serious
single gene genetic disorder in our population.
Hereditary haemochromatosis (HHC),
Iron load in pts with HHC
It is a common condition in which the total
body iron concentration is increased to 20–60 g
(normal 4 g).
The excess iron is deposited in and can
damage several organs:
- liver: ________
- pancreas:__________
- skin: ________
—cirrhosis (10% develop cancer)
—‘bronze’ diabetes
—bronze or leaden grey colour
The excess iron is deposited in and can
damage several organs:
- heart_________
- pituitary: _________
- joints—___________
—restrictive cardiomyopathy
—hypogonadism, impotence
arthralgia (especially hands),
chondrocalcinosis
Etiology of HHC
It is usually hereditary (autosomal recessive = AR)
or may be secondary to chronic haemolysis and
multiple transfusions
Hereditary haemochromatosis is the genetic
condition; ______ is the secondary condition
haemosiderosis
Genetic mutations for HHC
The two common identified specific mutations in
the HFE gene are C282Y and H63D
Genetic mutation high risk for HHC:
homozygous C282Y
Genetic mutation unlikely to develop clinical
HHC
homozygous H63D
Genetic mutation milder form of HHC
heterozygous C282Y and H63D
Serum markers for HHC
The key diagnostic sensitive markers are serum
transferrin saturation and the serum ferritin level
T or F, Serum Fe is a good indicator for HHC
F
An
elevated ferritin level is not diagnostic of HHC but is
the best serum marker of_____
iron overload.
Ssx of HHC:
May have extreme lethargy, signs of chronic
liver disease, polyuria and polydipsia, arthralgia,
erectile dysfunction, loss of libido and joint signs
Signs for HHC
look for hepatomegaly, _____, ______, ______, _______
very tanned skin,
cardiac arrhythmias, joint swelling, testicular atrophy
Dx of HHC;
- Increased serum _____saturation >45%
- Increased serum ______ level
transferrin
ferritin
Dx of HHC;
• CT or MRI—increased iron deposition in liver
• Liver biopsy (if liver function test enzymes
are abnormal or ferritin________ or
hepatomegaly). MRI may take over from biopsy
to evaluate liver status
> 1000 mcg/L
Dx of HHC
Genetic studies: HFE gene—a ______ and _____ mutation
C282Y and/or
H63D
Dx of HHC
Full blood count (FBE) and erythrocyte
sedimentation rate are_______
Normal
Mx of HHC
Weekly venesection 500 mL (250 mg iron) until
serum iron stores are normal (may take at least
2 years), then every 3–4 months to keep serum
ferritin leve______ (usually 40–80 mcg/L),
serum transferrin saturation_______, and iron
levels norm
l <100 mcg/L
<50%
Mx of HHC
_________ can be used but not as effective
as venesection
Desferrioxamine
The________, the most common human singlegene
disorders in the world, are a group of hereditary
disorders characterised by a defect in the synthesis
of one or more of the globin chains ( α or β
thalassaemias
What kind of anemia do pts with thalassemia have?
hypochromic
microcytic anaemia. α
______ -thalassaemia is usually seen in
people of Asian origin while______thalassaemia is seen
in certain ethnic groups from the Mediterranean,
the Middle East, South-East Asia and the Indian
α
β -
degree of alpha thalassemia:
deletion of all four genes: ________
of three genes—________, which results
in lifelong anaemia of mild-to-moderate degree;
of one or two genes—_______
α -thalassaemia (hydrops fetalis);
haemoglobin H disease
a symptomless carrier
degree of beta thalassemia
People who have two mutations (one in each β -globin
gene) have ________
• β _______—a single mutation
(heterozygous)—the carrier or trait state
_________—two mutations
(homozygous)—the person who has the disorder
β -thalassaemia major
-thalassaemia minor
• β -thalassaemia major
Patients with
thalassaemia major present with symptoms of severe
anaemia______
(haemolytic anaemia).
Without treatment,
children with thalassaemia major are lethargic and
inactive, show a ________, ________, _______, _______
failure to thrive or to grow normally,
and delayed puberty, hepatosplenomegaly and
jaundice.
Thalassemia
FBE: in most carriers the mean corpuscular
haemoglobin/mean corpuscular volume is
_________
low but can be normal
Thalassemia
__________ measures relative
amounts of normal adult haemoglobin (HbA) and
other variants (e.g. HbA 2 , HbF). This will detect
most carriers
Haemoglobin electrophoresis:
Thalassemia:
_________helps distinguish from iron
deficiency, which has a similar blood film
Serum ferritin level:
Thalassemia:
________ for mutation detection (mainly
used to detect or confirm carriers).
DNA analysis:
Thalassemia:
Treatment is based on a regular blood transfusion
schedule for anaemia. Avoid ______
iron supplements
Thalassemia:
_________ and a low-iron diet are
advisable
Folate supplementation
Thalassemia:
Excess iron is removed by _______
(e.g. desferrioxamine). ________has been used with success.
_______ may be appropriate
iron chelation
Allogenic bone marrow transplantation
Splenectomy
_______ is the result of a defect in an ion channel
protein, the transmembrane receptorfound in the membranes of cells lining the
exocrine ducts
Cystic fibrosis
CF
The defect affects the normal transport
of ________ ions, leading to a decreased sodium and
water transfer, thus causing viscid secretions that
affect the lungs, pancreas and gut
chloride
CF:
A mutation ( δ -F508) of\_\_\_\_\_\_\_ is the most common of some 500 possible mutations of the gene. This deletes a single \_\_\_\_\_\_\_\_\_\_\_from a 1480-aminoacid chain.
chromosome 7
phenylalanine
residue
CF
Gastrointestinal: malabsorption, pale loose bulky
stools, jaundice (__________),
__________ (10% of newborn babies)
• Infertility in males ________
• Pancreatic insufficiency
• Early mortality but improving survival rates
_______
pancreatic effect)
meconium ileus
(atrophy of vas deferens)
(mean age now 31 years)
CF DX
• Screening for immunoreactive _________ in
newborns detects 75%
• Sweat test for elevated ______ and _____ levels
• DNA testing for carriers identifies only the most
common mutations (70–75%)
trypsin
chloride and sodium
There is currently no cure for cystic fibrosis;
treatment is based on correcting the_______ and minimising ________
nutritional deficiencies
chest infections
- NF1—______
* NF2—________
peripheral neurofibromatosis (von Recklinghausen disorder)
central type, bilateral acoustic neuromas
schwannomas) (rare
The gene for NF1 is carried on chromosome _____
and NF2 on chromosome ______
17
22.
General rule for NF
• One-third _____ only have skin stigmata
• One-third _______ mainly cosmetic
• One-third significant problems (e.g. neurological
tumours)
asymptomatic,
minor problems,
_______ is a progressive proximal muscle weakness disorder
with replacement of muscle by connective tissue.
DMD
_______is a less severe variant of DMD
Becker
muscular dystrophy
DMD is an X-linked recessive condition.
It is caused by a mutation in the gene coding for ________, a protein found inside the muscle cell membrane.
dystrophin
SSx of pts with dmd
• Usually diagnosed from_______ years
• Weakness in hip and shoulder girdles
• Walking problems: delayed onset or starting in
boys aged _________
• Waddling gait, falls, difficulty standing and
climbing stairs
_________of muscles, especially calves
2–5
3–7
• Pseudohypertrophy
SSx of pts with dmd
• Most in wheelchair by age ______
• ± Intellectual retardation
• Most die of _________ by age 25
___________: patient uses ‘trick’ method by using
hands to climb up his or her legs when rising to
an erect position from the floor
10–12
respiratory problems
• Gowers sign
dx of dmd
- Elevated _______ level
- Electromyography
- Direct _______ gene testing
- Muscle biops
serum creatinine kinase
dystrophin
Dx
Typically presents 20–30 years as myotonia
(tonic muscle spasm)
• Muscle weakness esp. hands, legs, face, neck
• Slow relaxation of hand grip
• ‘Hatchet face’—long haggard look with atrophy
of facial muscles
MD
• Inherited as an AD disorder.
• The responsible mutant gene has been located on
the short arm of chromosome 4.
Huntington disease
________ is another psychological disorder
that has a hereditary basis through an autosomal
dominant gene with variable expression (penetrance
Tourette syndrome
Other inherited conditions that can cause
haemolytic anaemia are those with a red cell membrane
defect and include ______,_________,_________
hereditary spherocytosis, hereditary
elliptocytosis and hereditary stomatocytosis.
Sickle cell disorders: The most important abnormality in the haemoglobin (Hb) chain is sickle cell haemoglobin (HbS), which results from a single base mutation of adenine to thymine leading to a substitution of valine for
glutamine at __________
position 6 on the β -globin chain
This varies from being mild or asymptomatic to a
severe haemolytic anaemia and recurrent painful
crises. It may present in children with anaemia and
mild jaundice
Sickle cell anemia
What is this phenomenon?
• bone pain (usually limb bones) • abdominal pain • chest—pleuritic pain • kidney—haematuria • spleen—painful infarcts • precipitated by cold, hypoxia, dehydration or infection
Sickle cell crisis
________is needed to confirm the
diagnosis of sickle cell crisis
Hb electrophoresis
Sickle cell crisis
Long-term problems include
chronic leg ulcers,
susceptibility to infection, aseptic necrosis of bone
(especially head of femur), blindness and chronic
kidney disease.
People with this usually have no symptoms unless
they are exposed to prolonged hypoxia, such as
anaesthesia and flying in non-pressurised aircraft.
sickle cell trait
sickle cell trait
The disorder is protective against ____
malaria.
