Genetic Disorders Flashcards
What inheritance is achondroplasia?
Autosomal dominant
70% are de novo mutations
What is the mutation in achondroplasia?
FGFR-3 - fibroblast growth factor 3
Chromosome 4
Results in abnormal collagen
Phenotype of achondroplasia?
Short limbs (rhizomelia) with shortened Fingers (brachydactyly)
Large head with frontal bossing and Narrow foramen magnum
Midface hypoplasia with a flattened Nasal bridge
‘trident’ hands
lumbar lordosis
What is alkaptonuria?
rare autosomal recessive disorder of phenylalanine and tyrosine metabolism
lack of the enzyme homogentisic dioxygenase (HGD) which results in a build-up of toxic homogentisic acid
Kidneys filter homogentisic acid –> black urine
However accumulates in other tissues
What is the inheritance of alkaptonuria?
Autosomal recessive
What are the features of alkaptonuria?
Pigmented sclera
Urine turns black if left exposed to the air
Intervertebral disc calcification may Result in back pain
Renal stones
Treatment of alkaptonuria?
High-dose vitamin C
Dietary restriction of phenylalanine and tyrosine
General what type of disorders are autosomal dominant and autosomal recessive?
Recessive: Metabolic
Dominant: Structural
What autosomal dominant conditions are exceptions to the general rule?
Dominant is normally structural
These metabolic conditions are exceptions:
some ‘metabolic’ conditions such as Hunter’s and G6PD are X-linked recessive
Hyperlipidemia type II and hypokalemic periodic paralysis are autosomal dominant
What autosomal recessive conditions are exceptions to the general rule?
Recessive normally metabolic
These sttuructal conditions are exception:
Ataxia telengectasis
Fredricks’ ataxia
What are the features of patau syndrome?
Microcephalic, small eyes
Cleft lip/palate
Polydactyly
Scalp lesions
What is the chromosomal abnormality in patau syndrome?
Trisomy 13
What are the features of Edward’s syndrome?
Micrognathia (undersized jaw)
Low-set ears
Rocker bottom feet
Overlapping of fingers
What is the chromosomal abnormality in Edward’s syndrome?
Trisomy 18
What are the features of fragile X syndrome?
Learning difficulties
Macrocephaly
Long face
Large ears
Macro-orchidism
What are the features of Noonan syndrome?
Webbed neck
Pectus excavatum
Short stature
Pulmonary stenosis
What are the features of Pierre robin syndrome?
Micrognathia (undersized jaw)
Posterior displacement of the tongue (may result in upper airway obstruction)
Cleft palate
What are the features of prayer-willi syndrome?
Hypotonia
Hypogonadism
Obesity
What are the features of William’s syndrome?
Short stature
Learning difficulties
Friendly, extrovert personality
Transient neonatal hypercalcaemia
Supravalvular aortic stenosis
What are the features of criteria du chat?
Characteristic cry (hence the name) due to larynx and neurological problems
Feeding difficulties and poor weight gain
Learning difficulties
Microcephaly and micrognathism
Hypertelorism (large distance between eyes)
What is the genetic mutation in DiGeorge syndrome?
What is the inheritance pattern?
deletion of a section of chromosome 22
22q11.2 deletion
Autosomal dominant
What are the features of DiGeorge Syndrome?
C - Cardiac abnormalities
A - Abnormal facies
T - Thymic aplasia
C - Cleft palate
H - Hypocalcaemia/ hypoparathyroidism
22 - Caused by chromosome 22 deletion
T-lymphocyte deficiency/dysfunction
What are the features of Down syndrome?
Face: upslanting palpebral fissures, epicanthic folds, Brushfield spots in iris, protruding tongue, small low-set ears, round/flat face
Flat occiput
Single palmar crease, pronounced ‘sandal gap’ between big and first toe
Hypotonia
Congenital heart defects (40-50%, see below)
Duodenal atresia
Hirschsprung’s disease
What are the cardiac complications in Down syndrome?
Endocardial cushion defect (most common, 40%, also known as atrioventricular septal canal defects)
Ventricular septal defect (c. 30%)
Secundum atrial septal defect (c. 10%)
tetralogy of Fallot (c. 5%)
Isolated patent ductus arteriosus (c. 5%)
What are adult complications of Down syndrome?
Subfertility
Learning difficulties
Short stature
Repeated respiratory infections (+hearing impairment from glue ear)
Acute lymphoblastic leukaemia
Hypothyroidism
Alzheimer’s disease
Atlantoaxial instability
What is the genetic disorder and inheritance in fabry’s disease?
X-linked recessive
deficiency of alpha-galactosidase A
What are the features of fabry’s disease?
burning pain/paraesthesia in childhood
angiokeratomas
lens opacities
proteinuria
early cardiovascular disease
What are the features of fragile X syndrome?
learning difficulties
large low set ears, long thin face, high arched palate
macroorchidism
hypotonia
autism is more common
mitral valve prolapse
What is the genetic mutation in fragile X syndrome?
Trinucleotide repeat disorder
Features in females (who have one fragile chromosome and one normal X chromosome) range from normal to mild
How should fragile X be investigated?
Analysis of the number of CGG repeats using restriction endonuclease digestion and Southern blot analysis
What are the features of homocystinuria ?
often patients have fine, fair hair
Marfanoid body habitus: arachnodactyly etc
osteoporosis
kyphosis
neurological: may have learning difficulties, seizures
ocular
downwards (inferonasal) dislocation of lens
severe myopia
increased risk of arterial and venous thromboembolism
also malar flush, livedo reticularis
What the mutation in homocystinuria and its inheritance?
Autosomal recessive disease caused by a deficiency of cystathionine beta synthase. This results in severe elevations in plasma and urine homocysteine concentrations.
What is the test for homocystinuria?
Increased homocysteine levels in serum and urine
Cyanide-nitroprusside test: also positive in cystinuria
What is the treatment of homocystinuria ?
Vitamin B6 (pyridoxine) supplements.
What is Mccune Albright syndrome?
Precocious puberty
Cafe-au-lait spots
polyostotic fibrous dysplasia (fibrous dysplasia of bone)
short stature
How is Mccune Albright syndrome inherited?
Somatic mutation in the GNAS gene.
By what mechanism does mitochondrial disease pass on ?
inheritance is only via the maternal line
all of the children of an affected female will inherit the disease
generally, encode rare neurological diseases
poor genotype:phenotype correlation - within a tissue or cell there can be different mitochondrial populations - this is known as heteroplasmy
How are mitochondrial disorders investigated?
Muscle biopsy classically shows ‘red, ragged fibres’ due to increased number of mitochondria
What is MELAS?
MELAS syndrome: mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes
Mitochondrial disorder
What is MERRF?
MERRF syndrome: myoclonus epilepsy with ragged-red fibres
Mitochondrial disorder
What is Kearns-Sayre syndrome?
Kearns-Sayre syndrome: onset in patients < 20 years old, external ophthalmoplegia, retinitis pigmentosa. Ptosis may be seen
What are the features of Noonan syndrome?
cardiac: pulmonary valve stenosis
ptosis
triangular-shaped face
low-set ears
coagulation problems: factor XI deficiency
As well as features similar to Turner’s syndrome (webbed neck, widely-spaced nipples, short stature, pectus carinatum and excavatum),
What is the inheritance of Noonan syndrome?
autosomal dominant
What are features of fredreick’s ataxia?
Presents 5-15
Dysarthria, and ataxia (broad-based gait)
Areflexic
Echocardiographic findings of hypertrophic cardiomyopathy
Inheritance: autosomal recessive
What is the genetic features of pheynlkeonuria?
defect in phenylalanine hydroxylase, an enzyme which converts phenylalanine to tyrosine.
High levels of phenylalanine lead to problems such as learning difficulties and seizures.
gene for phenylalanine hydroxylase is located on chromosome 12.
What are the features of PKU?
usually presents by 6 months e.g. with developmental delay
child classically has fair hair and blue eyes
learning difficulties
seizures, typically infantile spasms
eczema
‘musty’ odour to urine and sweat*
How is PKU diagnosed?
Guthrie test: the ‘heel-prick’ test done at 5-9 days of life - also looks for other biochemical disorders such as hypothyroidism
hyperphenylalaninaemia
phenylpyruvic acid in urine
What is the molecular mechanism behind prader-willi syndrome?
phenotype depends on whether the deletion occurs on a gene inherited from the mother or father:
Prader-Willi syndrome if gene deleted from father
Angelman syndrome if gene deleted from mother
Absence of the active Prader-Willi gene on the long arm of chromosome 15. This may be due to:
microdeletion of paternal 15q11-13 (70% of cases)
maternal uniparental disomy of chromosome 15
What is the phenotype of prader-willi syndrome?
hypotonia during infancy
dysmorphic features
short stature
hypogonadism and infertility
learning difficulties
childhood obesity
behavioural problems in adolescence
What is the tumour suppressor mutation in lifraumani?
p53
What is the tumour suppressor mutation in colorectal cancer?
APC
Tumour suppressor in wilm’s tumour?
WT1
tumour suppressor in retinoblastoma?
RB1
Tumour suppressor in melanoma?
p16
MTS-1
Features of turner’s syndrome?
short stature
shield chest, widely spaced nipples
webbed neck
bicuspid aortic valve (15%), coarctation of the aorta (5-10%)
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
What additionally are Turner syndrome patients at risk of?
Autoimmune disease (especially autoimmune thyroiditis) and Crohn’s disease
X linked genetic disorders e.g. haemophilia
Examples of X linked dominant conditions?
Alport’s syndrome (in around 85% of cases - 10-15% of cases are inherited in an autosomal recessive fashion with rare autosomal dominant variants existing)
Rett syndrome
Vitamin D resistant rickets
Who is affected in an X linked recessive condition?
Males only Or Turner women
Examples of X linked recessive conditions?
Androgen insensitivity syndrome
Becker muscular dystrophy
Colour blindness
Duchenne muscular dystrophy
Fabry’s disease
G6PD deficiency
Haemophilia A,B
Hunter’s disease
Lesch-Nyhan syndrome
Nephrogenic diabetes insipidus
Ocular albinism
Retinitis pigmentosa
Wiskott-Aldrich syndrome
Chronic granulomatous disease (in > 70%)
Autosomal exceptions?
Autosomal recessive conditions are ‘metabolic’ - exceptions: inherited ataxias
Autosomal dominant conditions are ‘structural’ - exceptions: Gilbert’s, hyperlipidaemia type II
How to differentiate between Marfarns and Homocystinuria?
Marfarns: Upward lens dislocation
Homo: Downward lens dislocation
What Infections are digeorge patients at risk from?
Cryptococcus
Examples of X linked recessive conditions?
A - androgen insensitivity syndrome
B - Becker/Duchenne
C - colour blindness
D - Diabetes insipidus (nephrogenic)
E - eyes (retinitis pigmentosa)
F - Fabry
G - G6PD deficiency
H - haemophilia A/B, Hunter’s
What are the features of Barter’s syndrome?
Metabolic alkalosis + hypokalaemia
usually presents in childhood, e.g. Failure to thrive
polyuria, polydipsia
hypokalaemia
normotension
weakness
Autosomal recessive
Loop diuretics work by inhibiting NKCC2 - think of Bartter’s syndrome as like taking large doses of furosemide
What is the mechanism of Barter’s syndrome?
defective chloride absorption at the Na+ K+ 2Cl- cotransporter (NKCC2) in the ascending loop of Henle.
What cardiovascular problems are seen in digeorge?
Truncus arteriosus and tetralogy of Fallot
Hyperlipidaemia type II inheritance?
Autosomal dominant
Hyperkalaemic periodic paralysis?
Autosomal dominant
Fragile X syndrome genetics?
Trinucleotide repeat disorder
FMR1 gene on X chromosome
