Genetic conditions Flashcards
(177 cards)
1
Q
________, 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
A
Epigenetics
2
Q
All people carry a small number of ______genes,
which are carried asymptomatically
A
recessive
3
Q
The background risk that any couple will bear a
child with a birth defect is about _______. This risk is
doubled for a__________) couple
A
4%
first-cousin (consanguineous
4
Q
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
A
breast and ovarian
(linked), colorectal
5
Q
A GP caring for 1000 patients would expect to
have _____patients with a hereditary cancer
predisposition
A
15–17
6
Q
Carrier screening is now widely used for
________, ________ and _____
A
thalassaemia, Tay–Sachs disorder and cystic fibrosis
7
Q
Prenatal screening and testing for genetic disorders
is also a reality, especially for _______
A
Down syndrome,
fetal abnormalities and the haemoglobinopathies
8
Q
_______ and ________ are the future
hope for targeted treatments based on a person’s
genetic profile
A
Pharmacogenetics and gene therapy
9
Q
The _______ is a valuable pedigree chart that
usually covers at least three generations of a
family tree
A
genogram
10
Q
__________ which is a
disorder of iron overload, is the most common serious
single gene genetic disorder in our population.
A
Hereditary haemochromatosis (HHC),
11
Q
Iron load in pts with HHC
A
It is a common condition in which the total
body iron concentration is increased to 20–60 g
(normal 4 g).
12
Q
The excess iron is deposited in and can
damage several organs:
- liver: ________
- pancreas:__________
- skin: ________
A
—cirrhosis (10% develop cancer)
—‘bronze’ diabetes
—bronze or leaden grey colour
13
Q
The excess iron is deposited in and can
damage several organs:
- heart_________
- pituitary: _________
- joints—___________
A
—restrictive cardiomyopathy
—hypogonadism, impotence
arthralgia (especially hands),
chondrocalcinosis
14
Q
Etiology of HHC
A
It is usually hereditary (autosomal recessive = AR)
or may be secondary to chronic haemolysis and
multiple transfusions
15
Q
Hereditary haemochromatosis is the genetic
condition; ______ is the secondary condition
A
haemosiderosis
16
Q
Genetic mutations for HHC
A
The two common identified specific mutations in
the HFE gene are C282Y and H63D
17
Q
Genetic mutation high risk for HHC:
A
homozygous C282Y
18
Q
Genetic mutation unlikely to develop clinical
HHC
A
homozygous H63D
19
Q
Genetic mutation milder form of HHC
A
heterozygous C282Y and H63D
20
Q
Serum markers for HHC
A
The key diagnostic sensitive markers are serum
transferrin saturation and the serum ferritin level
21
Q
T or F, Serum Fe is a good indicator for HHC
A
F
22
Q
An
elevated ferritin level is not diagnostic of HHC but is
the best serum marker of_____
A
iron overload.
23
Q
Ssx of HHC:
A
May have extreme lethargy, signs of chronic
liver disease, polyuria and polydipsia, arthralgia,
erectile dysfunction, loss of libido and joint signs
24
Q
Signs for HHC
look for hepatomegaly, _____, ______, ______, _______
A
very tanned skin,
cardiac arrhythmias, joint swelling, testicular atrophy
25
Dx of HHC;
* Increased serum _____saturation >45%
* Increased serum ______ level
transferrin
ferritin
26
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
27
Dx of HHC
Genetic studies: HFE gene—a ______ and _____ mutation
C282Y and/or
| H63D
28
Dx of HHC
Full blood count (FBE) and erythrocyte
sedimentation rate are_______
Normal
29
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%
30
Mx of HHC
_________ can be used but not as effective
as venesection
Desferrioxamine
31
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
32
What kind of anemia do pts with thalassemia have?
hypochromic
| microcytic anaemia. α
33
______ -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 -
34
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
35
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
36
Patients with
thalassaemia major present with symptoms of severe
anaemia______
(haemolytic anaemia).
37
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.
38
Thalassemia
FBE: in most carriers the mean corpuscular
haemoglobin/mean corpuscular volume is
_________
low but can be normal
39
Thalassemia
__________ measures relative
amounts of normal adult haemoglobin (HbA) and
other variants (e.g. HbA 2 , HbF). This will detect
most carriers
Haemoglobin electrophoresis:
40
Thalassemia:
_________helps distinguish from iron
deficiency, which has a similar blood film
Serum ferritin level:
41
Thalassemia:
________ for mutation detection (mainly
used to detect or confirm carriers).
DNA analysis:
42
Thalassemia:
Treatment is based on a regular blood transfusion
schedule for anaemia. Avoid ______
iron supplements
43
Thalassemia:
_________ and a low-iron diet are
advisable
Folate supplementation
44
Thalassemia:
Excess iron is removed by _______
(e.g. desferrioxamine). ________has been used with success.
_______ may be appropriate
iron chelation
Allogenic bone marrow transplantation
Splenectomy
45
_______ 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
46
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
47
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
48
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)
49
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
50
There is currently no cure for cystic fibrosis;
| treatment is based on correcting the_______ and minimising ________
nutritional deficiencies
chest infections
51
* NF1—______
| * NF2—________
peripheral neurofibromatosis (von Recklinghausen disorder)
| central type, bilateral acoustic neuromas
schwannomas) (rare
52
The gene for NF1 is carried on chromosome _____
| and NF2 on chromosome ______
17
22.
53
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,
54
_______ is a progressive proximal muscle weakness disorder
| with replacement of muscle by connective tissue.
DMD
55
_______is a less severe variant of DMD
Becker
| muscular dystrophy
56
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
57
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
58
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
59
dx of dmd
* Elevated _______ level
* Electromyography
* Direct _______ gene testing
* Muscle biops
serum creatinine kinase
dystrophin
60
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
61
• Inherited as an AD disorder.
• The responsible mutant gene has been located on
the short arm of chromosome 4.
Huntington disease
62
________ is another psychological disorder
that has a hereditary basis through an autosomal
dominant gene with variable expression (penetrance
Tourette syndrome
63
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.
64
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
65
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
66
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
67
________is needed to confirm the
| diagnosis of sickle cell crisis
Hb electrophoresis
68
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.
69
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
70
sickle cell trait
The disorder is protective against ____
malaria.
71
This is the commonest cause of inherited haemolytic
anaemia in northern Europeans. It is an autosomal
dominant disorder of variable severity, although in
25% of patients neither parent is affected,
Hereditary spherocytosis
72
The
common significant bleeding disorders are:
• haemophilia A (_______deficiency)—X-linked
recessive
• haemophilia B (_______ deficiency)—X-linked
recessive
• ____________ (deficiency of factor
VIII:C + defective platelet factor)—autosomal
dominant
Others to consider are:
* hereditary haemorrhagic telangiectasia _______
* inherited thrombocytopen
factor VIII
factor IX
von Willebrand disease
(Osler–
Weber–Rendu disease)
73
This should be considered in patients with a past and/
| or family history of DVT or other thrombotic episodes
Thrombophilia
74
Examples of inherited thrombophilia
```
• factor V Leiden gene mutation (activated protein
C resistance)
• prothrombin gene mutation
• protein C deficiency
• protein S deficiency
• antithrombin deficiency
```
75
In _______the most common factor in this
group, there is a 35-fold increased risk of thrombosis
for those taking the OCP.
factor V Leiden,
76
In DS
| 95% have extra chromosome of ______ origin
trisomy 21
maternal
77
Mech of mutation in DS
Remainder due to either unbalances,
| translocations or mosaicism
78
Dx tests for DS
Prenatal screening tests include early ______and maternal serum screening in first trimester________
ultrasound (nuchal lucency)
(serum maternal and
fetal DNA)
79
In DS,
__________sampling on amniocytes for pregnancies at risk
is available.
Karyotyping of chorionic villus
80
Associated DO in DS
```
• Seizures (usually later onset)
• Impaired hearing
• Leukaemia
• Hypothyroidism
• Congenital anomalies (e.g. heart, duodenal
atresia, Hirschsprung, TOF)
• Alzheimer-like dementia (fourth–fifth decade)
• Atlantoaxial instability
• Coeliac disease
• Diabetes
```
81
Whats the Dx
These include:
• incidence 1 in 2000 live births (approx.)
• microcephaly
• facial abnormalities e.g. cleft lip/palate
• malformations of major organs
• malformations of hands and feet—clenched hand
posture
• neural tube defect
Edward/Trisomy 18
82
About Trisomy 18
Prognosis is poor—about one-third die in first
month,_____________-- live beyond 12 months
<10% live beyond 12 months
83
```
Clinical features
These include:
• incidence 1 in 7000 (approx.)
• microcephaly
• brain and heart malformation
• cleft lip/palate
• polydactyly
• neural tube defec
```
Patau/Trisomy 13
84
Patau/Trisomy 13 progonis
Prognosis is poor—50% die within first month.
85
presents as a classic physical phenotype with
large prominent ears, long narrow face, macroorchidism
and intellectual disability. It is the most
common inherited cause known of developmental
disability and should always be considered.
Fragile X syndrome (FXS) 14
86
What is the cause of FXS
The cause
is the result of an increase in the size of a trinucleotide
repeat in the FMR-I gene on the X chromosome
(the number of sequences determines carrier or
full mutant status).
87
Any individual with significant
| _____________--should be tested for FXS.
development delay
88
FXS
* Up to 1 in 300 females may be _________
* Family history of __________
* Affects all ethnic groups
* __________may appear normal but may be affected
carriers
intellectual disability
Females
89
Dx of FXS
• Cytogenetic testing (karyotyping)
• DNA test (specific for full mutation as well as
carriers)
90
Associated DO with FXS
```
• Intellectual disability (IQ <70)
• Autism or autistic-like behaviour
• Attention deficit in 10% (with or without
hyperactivity)
• Seizures (20%)
• Connective tissue abnormalities
• Learning disability and speech delay
• Coordination difficulty
```
91
This uncommon disorder (1 in 10 000 to 15 000)
has classic features, especially a bizarre appetite and
eating habits, of which the GP should be aware. It is
probable that there are many undiagnosed cases in
the communit
Prader Willi
92
Chromosomal abn with PWS
Chrom 5
93
PWS
Hypotonic infants with weak suction and failure
to thrive, then voracious appetite causing _________
morbid
| obesity
94
(idiopathic hypercalcaemia or
| elfin face syndrome
Williams
95
Chrom abn in Williams
7
96
Triad of Williams
elfin ’ face + intellectual disability +
| aortic stenosis
97
This is a systemic connective tissue disorder
characterised by abnormalities of the skeletal,
cardiovascular and ocular systems. It has variable
expressions and is a potentially lethal disorder. If
untreated, death in the 30s and 40s is common
Marfan syndrome
98
Triad of Marfans
tall stature + dislocated lens and
| myopia + aortic root dilatation
99
Genetic profile of Marfans
* Mutations in the ___________on chromosome 15
* Autosomal dominant
* Prevalence about ________
* No specific laboratory test to date
fibrillin gene
5 per 100 000
100
Signs of Marfan
```
• Disproportionally tall and thin
• Long digits—______
• Kyphoscoliosis
• Joint laxity (e.g.________
• Myopia and ectopic ocular lens
• High arched palate
___________
```
_______
arachnodactyly
genu recurvatum)
* Aortic dilatation and dissection
* Mitral valve prolapse
101
This is an autosomal dominant disorder due
to mutations in one of two genes located on
chromosomes 9 and 16. A feature is tube-like growths
that affect multiple systems including the brain.
TS
102
Triad of TS
facial rash + intellectual disability +
| seizures
103
This is an AD disorder with mutation of chromosome
11. It has been described as a male Turner syndrome
but affects both sexes
Noonan syndrome
104
Triad for Noonan
facies + short stature + pulmonary
| stenosis
105
Characteristic facies of Noonan
down-slanting palpebral
| fissures, widespread eyes, low-set ears ± ptosis
106
Other features of Noonan
* Short stature
* Pulmonary valve stenosis
* Webbed neck
* Failure to thrive, usually mild
* Abnormalities of cardiac conduction and rhythm
* ± Intellectual disability
107
```
What is the dx?Hand flapping
• ‘Puppet’-like ataxia
• Frequent laughter/smiling
• Microcephaly by age 2 years
• Developmental delay
• Speech impairment
• Seizures
• Cannot live independently
```
Angelman
108
Chromosomal abn with AngelMan
chrom 15
109
Tx with AngelMan
Treatment with minocycline is promising
110
Sporadic mutation of LMA gene that codes for a
| protein leads to early cell death.
Progeria
111
Feature of Progeria
__________—manifests in early childhood
causing premature death (median age 12 years)
Accelerated ageing
112
COD in patients with Progeria
vascular
113
This is due to an extra X chromosome, resulting in a
| male phenotype and occurring in 1 in 800 live births
Klinefelter
114
Triad of Klinefelter
lanky men + small testes + infertility
115
Genetic profile of Klinefelter
* XXY genotype
* The extra X chromosome is usually of ________
* About 30 or more variants of the disorder
maternal origin
116
key feautures of Klinefelter
Marked variation but usually:
• tall men with long limbs
• small firm testes ≤2 cm
• infertility (azoospermia
117
Tx of Klinefelter
• Transdermal testosterone
118
This is due to only one X chromosome, occurring in
1 in 4000 live female newborns; 99% of conceptions
are miscarried
```
Turner syndrome (gonadal
dysgenesis
```
119
Triad of Turner
short stature + webbed neck + facies
120
```
Genetic profile of Turner
• 45 chromosomes of __________(typical
Turner’s karyotype in 50% of cases)
• Many are _________ (e.g. 45X/46XX chromosomes)
• Phenotypes vary
```
XO karyotype
mosaics
121
Clinical features of typical XO karyotype
* Short stature—average adult height 143 cm
* Primary _____ in XO patient; ____
* Webbing of neck
* Typical facies: ______________
* Lymphoedema of extremities
* Cardiac defects (e.g. ____________)
amenorrhoea
infertility
micrognathia, low hairline
coarctation of aorta
122
Tx of Turners
Hormone-based (e.g. growth hormone, hormone
| replacement therapy)
123
Conditions of Intersex state
* mixed gonadal dysgenesis
* ovotesticular disorder DSD
* 46, XX DSD (androgenised females)
* 46, XY DSD (underandrogenised males)
124
androgen or inadequate response to
androgen, which includes the ‘androgen insensitivity
syndrome’.
• 46, XY DSD (underandrogenised males)
125
This important syndrome is caused by the teratogenic
effects of alcohol (not a chromosomal abnormality)
and is estimated to involve 2 in 1000 live births
FAS
126
Triad of FAS
abnormal facies + growth retardation +
| microcephaly
127
Clinical features of FAS
* Markedly underweight until puberty
* Learning difficulties
* Microcephaly
128
Characteristic facies of FAS
— shortened palpebral fissures*
— long, smooth featureless philtrum*
— thin upper lip*
— upturned nose
129
a common disorder affecting
over 400 million people worldwide. It is the most
common red-cell enzyme defect that causes episodic
haemolytic anaemia because of the decreased ability
of red blood cells to cope with oxidative stresses
Glucose-6-phosphate
| dehydrogenase deficiency
130
Mode of Inheritance G6PD
It is
an X-linked recessive inherited disorder with a high
prevalence among people of African, Mediterranean
or Asian ancestry
131
______infants at risk should be
| observed after delivery (at least 5 days)
neonatal jaundice—
132
G6PD
triggered by
antioxidants and infections, and drugs, especially
antimalarials, sulphonamides, nitrofurantoin,
quinolones, traditional medicines, vitamins C
and K, high dose aspirin, fava (broad) beans and
naphthalene (e.g. moth bal
episodic acute haemolytic anaemia
133
dx of g6pd
Diagnosis is by G-6-PD assay and a blood film
| during an attack.
134
a deficiency of
the lysosomal enzyme glucocerebrosidase, leads to
anaemia and thrombocytopenia as a result primarily of hypersplenism.
Gaucher disease
135
Ssx of Gaucher disease
There is chronic bone pain and
‘crises’ of bone pain. Consider it in children with
fatigue, bone pain, delayed growth, epistaxis, easy
bruising and hepatosplenomegaly
136
Tx of gaucher
Replacement
| enzyme therapy is available.
137
inborn error of metabolism in
which the body is unable to metabolise galactose to
glucose
Galactosaemia 9
138
enzyme deficiencies in Galactosaemia
________ and ____________, which
causes the classic syndrome.
galactose-1-phosphate uridyl transferase
139
As lactose is the major source of
galactose, the infant becomes _______ and __________within a few days or weeks of taking breast milk or
lactose-containing formula
anorexic and jaundiced
140
T or F,
galactossemia can be fatal
T
141
galactossemia
Management is with a _____________-
galactose (mainly lactose)-free
| formula such as soy with added calcium and vitamins
142
the amino acid, phenylalanine, is caused by a deficiency
of phenylalanine hydroxylase activity, leading to an
elevation of plasma phenylalanine, which if untreated
can cause intellectual disability (often very severe)
and other neurological symptoms, such as seizures.
PKU
143
Test for PKU
Neonatal screening for high blood phenylalanine
| levels (the Guthrie test) is performed routinely.
144
Different forms of Porphyria
The three most common porphyrias are_______-, _______ and _______--,
which are caused by deficiencies of the third, fifth and
eighth enzymes, respectively, of the haem biosynthesis
pathway.
acute
intermittent porphyria, porphyria cutanea tarda
(the commonest) and erythropoietic protoporphyria
145
This autosomal dominant disorder is the most serious
of the porphyrias although it remains clinically silent
in the majority of patients who carry the trait
Acute intermittent porphyria
146
Enzyme deficiency of AIP
porphobilinogen (PBG) deaminase
147
Ssx of AIP
* Usually young women (teens or 20s)
* Recurrent _____________r
* Acute __________
psychiatric illnesses, abnormal behaviour
peripheral or nervous system dysfunction
(e.g. peripheral neuropathy, hypotonia
148
Triggers of AIP
antiepileptics,
| alcohol, sulphonamides, barbiturates
149
Dx of AIP
• Urine________ and ________during ‘attack’
• Erythrocyte PBG deaminase testing to screen
relatives
PBGs (high) and serum sodium (very low)
150
Tx for AIP
* Avoid ‘unsafe’ drugs
| * High-carbohydrate diet, glucose for attack
151
This is a group of inherited disorders caused by
a deficiency of one or more enzymes involved in
glycogen breakdown, leading to the deposition of
abnormal amounts of glycogen in tissues, especially
the liver
Glycogen storage disease (liver
| glycogenoses
152
Best known glycogen strorage disease
The best-known type is 1A (von Gierke
disorder), an autosomal recessive disorder due to
deficiency of glucose-6-phosphatase (G-6-P
153
facies of glycogen storage disease
Children have characteristic
morphological features—short, doll-like facies with
fat cheeks, thin extremities and large abdomen
(hepatomegaly).
154
glycogen storage disease
Diagnosis is by abnormal _______ and _______levels, liver biopsy and recently by gene analysis for
the G-6-P gene
plasma lactate and lipid
155
Treatment is aimed to prevent ________ and ______via frequent carbohydrate
feedings, such as uncooked cornstarch and
overnight nasogastric glucose infusion.
hypoglycaemia
| and lactic acidosis
156
an AR disorder caused
by a total deficiency of hexosaminidase A resulting in
an accumulation of gangliosides in the brain
Tay–Sachs disease
157
Tay Sac
The______-form is fatal by age 3 or 4 with early
progressive loss of motor skills, dementia, blindness,
macrocephaly and cherry-red retinal spots.
infantile
158
Tay Sac
The
________form presents with dementia and
ataxia, with death at age 10–15. The adult form has
progression of neurological symptoms following
clumsiness in childhood and motor weakness in
adolescence.
juvenile onset
159
Examples of SINGLE GENE CARDIAC DISORDERS
cardiomyopathies
• arrhythmia syndromes e.g. long QT syndrome
• sudden cardiac death families
160
This is an autosomal dominant condition with
predisposition to ventricular arrhythmias, syncopal/
fainting spells and sudden death, particularly
during exercise
Congenital long QT syndrome
161
Dx of Congenital long QT syndrome
Confirm or exclude by ECG when
| suspected—interval 0.5–0.7 seconds
162
Mx of Congenital long QT syndrome
Management
includes sports restrictions, β -blockers and
pacemaker or AICD.
163
This is an AD disorder with several genetic mutations.
It is the most common cause of sudden cardiac death
among athletes
Hypertrophic cardiomyopathy
164
identified by elevated cholesterol, corneal arcus juvenalis, tendon xanthomas
in the patient or their first- and second-degree relatives
and also by a DNA mutation
familial
| hypercholesterolaemia
165
The three most significant familial cancer
inherited susceptibility syndromes are:
• hereditary breast–ovarian cancer syndrome
_________
• ________
________
( BRCA 1 and BRCA 2 genes)
hereditary non-polyposis colorectal cancer
(HNPCC)
• familial adenomatous polyposis (FAP
166
Male breast cancer (6% in males with _______-
BRCA2 gene
| mutation
167
Risk indicators for familial breast–
| ovarian cancer
• Two first-degree or second-degree relatives on
one side of the family with cancer
• Individuals with age of onset of cancer <50 years
• Individuals with bilateral or multifocal breast
cancer
• Individuals with ovarian cancer
• Breast cancer in a male relative
• Jewish ancestry
168
```
• Caused by a defect in one of the genes
responsible for DNA mismatch repair
• Affects 1 in 1000 individuals
• Autosomal dominant
• Early age of onset
```
```
Lynch syndrome (hereditary nonpolyposis
colorectal cancer)
```
169
CA risk for Lynch syndrome (hereditary nonpolyposis
| colorectal cancer)
Increased risk of certain extracolonic cancers,
including endometrial, stomach, ovary and
kidney tract cancers
170
Mutation in FAP
Caused by a mutation in the APC gene
171
In FAP
• Eventually almost 100% of cases develop colon
cancer without_____
• Median age of diagnosis ______
prophylactic colectomy
40 years
172
risk of CA in FAP
thyroid, cerebral
173
Relatives at risk for FAP
• Three or more close relatives with bowel cancer
• Two or more close relatives with bowel cancer
and:
— more than one bowel cancer in same relative
— onset of bowel cancer before 50 years
— a relative with endometrial cancer or ovarian
cancer
174
```
Other cancers where family history is
significant
• Melanoma: an inherited mutation in certain
genes ______ is considered to be
involved in up to 5% of melanomas.
```
(e.g. BRAF gene)
175
Approximately 2% of births are associated with
congenital abnormalities, of which 1 in 7 are
chromosomal, the most common of which is________
Down
| syndrome (trisomy 21)
176
Screening for DS
divided into two types: 5
1 screening tests (maternal serum screening/
MSST; ________
2 diagnostic tests _____
free fetal DNA at 10–12 weeks gestation; nuchal transparency ultrasound)
(chorionic villus sampling, amniocentesis
177
Screening for DS
The most reliable method is ______
by these last means but there is a significant risk of
miscarriage (1 in 100 for chorionic villus sampling
and 1 in 200 for amniocentesis).
obtaining fetal tissue
