Genetics Flashcards
(24 cards)
Alkaptonuria
Homogentisic acid oxidase deficiency leads to a defect in tyrosine metabolism and accumulation of homogentisic acid.
Rx is a dietary reduction of tyrosine and phenylalanine.
Autosomal Dominant conditions
Achondroplasia
Ehlers Danlos syndrome
Familial adenomatous polyposis coli
Gilbert syndrome
Hereditary non-polyposis colorectal carcinoma
Huntington disease
Marian syndrome
Von Willebrand disease
Familial Hypercholesterolemia
Autosomal Recessive conditions
Congenital adrenal hyperplasia
Cystic Fibrosis
Haemochromatosis
Wilsons disease
Sickle cell Anemia
Kartagener syndrome
Oculocutaneous albinism
Xeroderma pigmentosum
X- Linked Recessive conditions
Becker Muscular dystrophy
Duchenne muscular dystrophy
Haemophilia A and B
Fabry’s disease
Hunter syndrome
X- Linked Dominant conditions
Vitamin D-resistant rickets
Rett syndrome
Incontinentia pigmenti
Periventricular Nodular heterotopia
Pseudoxanthoma Elasticum
- Autosomal recessive.
- Mutation in ABCC61 gene.
- Skin, eyes, and CVS, GIT
SKIN - yellow papules on the neck
- goosebumps, puckered, plucked chicken appearance
EYES
Angiod streaks
yellow retinal mottling
CVS
Mitral valve prolapse/regurgitation
Intermittent claudication
GIT
Bleeding from bowels
Abdominal angina
Kallmann Syndrome
Kallmann syndrome may arise due to abnormalities of the KAL-1 or KAL-2 gene (encoding anosmin-1 and FGF-1).
Whilst the majority of cases are sporadic, up to 50% of cases are due to genetic inheritance.
Kallmann presents with hypothalamic gonadotrophin-releasing hormone deficiency and deficient olfactory sense: hyposmia or anosmia.
FISH( Fluorescent in situ hybridisation) using a specific chromosomal probe, is currently the best means of a genetic diagnosis of this condition.
Ehler- Danlos syndrome
Ehler-Danlos syndrome is an autosomal dominant connective tissue disorder that mostly affects type III collagen.
Features and complications
>elastic, fragile skin
>joint hypermobility: recurrent joint dislocation
>easy bruising
>aortic regurgitation, mitral valve prolapse and aortic dissection
>subarachnoid haemorrhage
>angioid retinal streaks
Digeorge syndrome
DiGeorge syndrome is a primary immunodeficiency disorder caused by T-cell deficiency and dysfunction.
Cardiac abnormalities of DiGeorge syndrome include truncus arteriosus and tetralogy of Fallot.
CATCH22’ is a mnemonic used to describe some of the key features of this condition:
C - Cardiac abnormalities
A - Abnormal facies
T - Thymic aplasia
C - Cleft palate
H - Hypocalcaemia/ hypoparathyroidism
22 - Caused by chromosome 22 deletion
Bartter’s syndrome
Bartter’s syndrome is an inherited cause (usually autosomal recessive) of severe hypokalaemia due to defective chloride absorption at the Na+ K+ 2Cl- cotransporter (NKCC2) in the ascending loop of Henle.
Loop diuretics work by inhibiting NKCC2 - think of Bartter’s syndrome as like taking large doses of furosemide
Features
usually presents in childhood, e.g.Failure to thrive
polyuria, polydipsia
hypokalaemia
normotension
weakness
DNA mutations
Silent A mutation that does not change the amino acid, often base change in 3rd position of codon.
Nonsense A mutation that results in a stop codon.
Missense A point mutation that changes the amino acid sequence, which in turn may make the protein non-functional.
Frameshift Caused by insertion or deletion of a number of nucleotides which results in the subsequent reading of the DNA ‘downstream’ being completely wrong
Homocystinuria
Homocystinuria is a rare autosomal recessive disease caused by a deficiency of cystathionine beta synthase.
Tall, long-fingered, downward lens dislocation, learning difficulties, DVT - homocystinuria.
Investigations
- increased homocysteine levels in serum and urine
- cyanide-nitroprusside test: also positive in cystinuria.
Treatment is vitamin B6 (pyridoxine) supplements.
Fabrys disease
Fabry disease
Overview
- X-linked recessive
- deficiency of alpha-galactosidase A
Features
- burning pain/paraesthesia in childhood
- angiokeratomas
- lens opacities
- proteinuria
early cardiovascular disease
Turner’s syndrome
Turner’s syndrome is denoted as 45,XO or 45,X.
Features
- short stature
- shield chest, widely spaced nipples
- webbed neck
- bicuspid aortic valve (15%), coarctation of the aorta (5-10%)
- An increased risk of aortic dilatation and dissection are the most serious long-term health problems for women with Turner’s syndrome
regular monitoring in adult life for these complications is an important component of care
- primary amenorrhoea
- cystic hygroma (often diagnosed prenatally)
- high-arched palate
- short fourth metacarpal
- multiple pigmented naevi
- Lymphoedema in neonates (especially feet)
- Gonadotrophin levels will be elevated
- Hypothyroidism is much more common in Turner’s
- Horseshoe kidney: the most common renal abnormality in Turner’s syndrome
Marfan’s Syndrome
Marfan’s syndrome is an autosomal dominant connective tissue disorder. It is caused by a defect in the FBN1 gene on chromosome 15 that codes for the protein fibrillin-1. It affects around 1 in 3,000 people.
Features
- tall stature with arm span to height ratio > 1.05
- high-arched palate
- arachnodactyly
- pectus excavatum
- pes planus
- scoliosis of > 20 degrees
heart:
- dilation of the aortic sinuses (seen in 90%) which may lead to aortic aneurysm, aortic dissection, aortic regurgitation
- mitral valve prolapse (75%),
- Lungs: repeated pneumothoraces
eyes:
- upwards lens dislocation (superotemporal ectopia lentis)
- blue sclera
- myopia
- dural ectasia (ballooning of the dural sac at the lumbosacral level)
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
second wind phenomenon
occurs when patients experience an improvement in exercise tolerance after a brief rest or reduction in intensity
due to the body’s switch from glycogen-dependent energy metabolism to increased reliance on circulating glucose and fatty acids
his adaptation allows for better energy utilisation during prolonged activity despite the underlying myophosphorylase deficiency.
rhabdomyolysis & myoglobinuria
low lactate levels during exercise.
- Alpha-1 antitrypsin (A1AT) deficiency is a common inherited condition caused by a lack of a protease inhibitor (Pi) normally produced by the liver. The role of A1AT is to protect cells from enzymes such as neutrophil elastase. It classically causes emphysema (i.e. chronic obstructive pulmonary disease) in patients who are young and non-smokers.
Genetics
- located on chromosome 14
- inherited in an autosomal recessive / co-dominant fashion*
alleles classified by their electrophoretic mobility - M for normal, S for slow, and Z for very slow
normal: PiMM
heterozygous: PiMZ
evidence base is conflicting re: risk of emphsema
however, if non-smoker low risk of developing emphsema but may pass on A1AT gene to children
homozygous PiSS: 50% normal A1AT levels
homozygous PiZZ: 10% normal A1AT levels
Features
- Patients who manifest disease usually have PiZZ genotype
lungs: panacinar emphysema, most marked in the lower lobes
Liver: cirrhosis and hepatocellular carcinoma in adults, cholestasis in children
Investigations
- A1AT concentrations
- Spirometry: obstructive picture
Management
- no smoking
- supportive: bronchodilators, physiotherapy
- Intravenous alpha1-antitrypsin protein concentrates
- Surgery: lung volume reduction - Surgery, lung transplantation
Friedreich’s Ataxia
Friedreich’s ataxia is autosomal recessive.
Down’s Syndrome
Nondisjunction 94%
1 in 100 if under mother < 35 years
Robertsonian translocation
(usually onto 14) 5% 10-15% if mother is translocation carrier
2.5% if father is translocation carrier
Mosaicism* 1%
variant Creutzfeldt-Jakob disease
variant Creutzfeldt-Jakob disease (vCJD).
The typical presentation is that of a younger patient with progressive dementia (less rapid the sporadic CJD) with myoclonus and, in the later stages, mutism and vertical upgaze palsy (found in 50%).
An MRI brain reveals a characteristic ‘hockey stick sign’ where the pulvinar region and dorsomedial thalamus are hyperintense on T2-weighted imaging (or pulvinar sign where the pulvinar region is hyperintense only).
CSF protein for 14-3-3 and periodic sharp wave complexes on the EEG are more commonly seen in sporadic CJD.
William’s Syndrome
William’s syndrome is an inherited neurodevelopmental disorder caused by a microdeletion on chromosome 7
Features
- elfin-like facies
- characteristic like affect - very friendly and social.
- learning difficulties
- short stature
- transient neonatal hypercalcaemia
- supravalvular aortic stenosis
Diagnosis is made by FISH studies
Penetrance
Penetrance
In genetics, penetrance describes the proportion of a population of individuals who carry a disease-causing allele who express the related disease phenotype.
Describes ‘how likely’ it is that a condition will develop.
Examples of conditions with incomplete penetrance include retinoblastoma and Huntington’s disease
In contrast, achondroplasia shows 100%, or complete, penetrance.
Expressivity
Expressivity
describes the ‘severity’ of the phenotype
- A condition with a high level of expressivity is neurofibromatosis.
Autosomal dominant
Autosomal dominant diseases:
- Both homozygotes and heterozygotes manifest disease (there is no carrier state)
- Both males and females affected
- Only affected individuals can pass on the disease
- the disease is passed on to 50% of children
- normally appears in every generation.
- The risk remains same for each successive pregnancy
