L38 Introduction to Clinical Genetics 2 Flashcards
(29 cards)
how can you make a confident diagnosis of Neurofibromatosis type 1 (NF1)?
six or more café au lait spots (coffee-coloured skin patches) that are larger than 5mm in children, or 15mm in adults
freckles under the arms or around the groin
two or more neurofibromas (bumps on or under the skin), or one plexiform neurofibroma (aneurofibroma that develops where multiple branches of nerves come together)
a tumour on the optic nerve (an optic glioma), which rarely causes symptoms or affects sight
two or more tiny brown spots in the iris (the coloured part of the eye). These are known asLisch nodules
bone defects, such as bowing of the lower leg
a family history of NF1
what are the early signs and symptoms of huntington disease?
irritability, depression, small involuntary movements, poor coordination, and trouble learning new information or making decisions
involuntary jerking or twitching movements known as chorea. as disease progresses these become more pronounced.
Affected individuals may have trouble walking, speaking, and swallowing. also changes in personality + decline in thinking + reasoning abilities
usually live about 15 to 20 years after signs and symptoms begin.
how does huntington disease change as it is passed onto offspring?
As the altered HTT gene is passed from one generation to the next, the size of the CAG trinucleotide repeat often increases in size. A larger number of repeats is usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation.
what does genetic counselling involve?
psychological/emotional aspects
- non-directive
- non-judgemental
- bereavement
choices and options
- carrier testing
- presymptomatic diagnosis
- prenatal diagnosis
- risk calculations (Mendelian, empirical or Bayesian?)
why might a patient undergo genetic testing?
confirm or refute a suspected clinical diagnosis
- includes a biochemical diagnosis for metabolic disorders
assess carrier status
- for individuals or couples
prenatal diagnosis
predictive testing
- adult onset inherited disorders
what is amniocentesis and chorionic villus sampling?
amniocentesis - a prenatal test in which a small amount of amniotic fluid is removed from the sac surrounding the fetus for testing. The sample of amniotic fluid (less than one ounce) is removed through a fine needle inserted into the uterus through the abdomen, under ultrasound guidance
chorionic villus sampling - a prenatal test that is used to detect birth defects, genetic diseases, and other problems during pregnancy. During the test, a small sample of cells (called chorionic villi) is taken from the placenta where it attaches to the wall of the uterus
what is alkaptonuria (AKU)?
a rare disorder of autosomal recessive inheritance. It is caused by a mutation in a gene that results in the accumulation of homogentisic acid (HGA). Characteristically, the excess HGA means sufferers pass dark urine, which upon standing turns black. This is a feature present from birth.
what did archibald garrod discover?
shortly after the rediscovery of Mendel’s work, Archibald Garrod, a practicing physician, determined that Mendelian genes could affect biochemical processes. He called such inherited defects “inborn errors of metabolism” and, on his own, essentially founded biochemical genetics. Like Mendel, he was well ahead of his time, so that his work was largely unnoticed until the later efforts of Beadle and others established the “one gene — one enzyme” hypothesis.
which conditions may occur between the catabolism of L-tyrosine and L-phenylalanine?
phenylalanine –phenylalanine hydroxylase (PAH) –> tyrosine
PHENYLKETONURIA
tyrosine –> 4-hydroxyphenylpyruvate
TYROSINAEMIA II
4-hydroxyphenylpyruvate –> homogentisate
TYROSINAEMIA III
homogentisate – homogentisate dioxygenase –> maleylacetoacetate
ALKAPTONURIA
maleylacetoacetate –> fumarylacetoactetate
fumarylacetoactetate –> fumarate + acetoacetate
TYROSINAEMIA I
what is phenylketonuria and what may be symptoms of phenylketonuria?
most prevalent inherited defect in amino acid metabolism
1 in 10,000 live births
untreated phenylketonuria: intellectual disability (the most common finding overall), behavioural problems
phenylalanine plasma levels >20 mg/dL
epilepsy (in 50%)
extrapyramidal manifestations (eg Parkinsonism)
musty or mousy odour
fair skin and hair: impaired melanin synthesis
eye abnormalities (eg hypopigmentation)
neuropsychological deficits still exist in patients
how is phenylketonuria treated?
dietary restriction of natural phenylalanine intake from protein, supplementation with the other amino acids
new therapeutic approaches
more palatable medical foods
enzyme replacement
- treatment with “PEGylated” enzyme to substitute for deficient phenylalanine hydroxylase: reduces blood phenylalanine levels
- Pegvaliase (Palynziq) is a PEGylated phenylalanine ammonia lyase (PAL)
- PEG reduces immunogenicity of the protein conjugate
- PAL metabolizes phenylalanine into trans-cinnamic acid and ammonia
which foods are limited with phenylketonuria?
inability to consume any meat, fish, milk, cheese, eggs, nuts, seeds, foods with flour, soya or tofu is socially difficult
unable to consume potatoes or protein-rich vegetables without calculating the phenylalanine or natural protein load
no aspartame in artificially sweeteners because phenylalanine is a major component
patients “cheat” by failing to limit foods such as potatoes, pasta, and bread (slice of bread contains 120-150 mg of phenylalanine)
why is neonatal screening required?
population screening may be justifiable: if therapeutic intervention is available or early diagnosis reduces morbidity or mortality
new-born blood spot (heel prick) testing from Guthrie cards
congenital hypothyroidism, cystic fibrosis, hemoglobinopathies (sickle cell anaemia)
which other inborn errors of metabolism can be detected by neonatal screening?
- phenylketonuria (PKU)
- medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
- maple syrup urine disease (MSUD)
- isovaleric acidaemia (IVA)
- glutaric aciduria type 1 (GA1)
- homocystinuria: pyridoxine unresponsive (HCU)
detection by tandem mass spectrometry
what is familial hypercholesterolaemia (FH)?
most common inherited metabolic disease (1 in 300 - 500)
disorder of cholesterol metabolism
leads to premature atherosclerosis, cardiovascular disease (CVD), often death at very young age
main cause are autosomal dominant mutations in LDLR: encodes low-density lipoprotein (LDL) cholesterol receptor
what is the familial hypercholesterolaemia measured biomarker?
elevated plasma levels of LDL cholesterol >4.9mmol/L (190mg/dL)
family history of either elevated LDL cholesterol or CVD
what is tendinous xanthomas?
clinically characterized by papules and nodules found in the tendons of the hands, feet, and heel. in patients with heterozygous familial hypercholesterolaemia
what is arcus cornealis?
a deposition of lipids in the cornea. This deposition starts as a sickle-shaped structure at the bottom or top of the cornea and expands over the years, eventually circumscribing the whole cornea; there are no consequences to vision of these deposits. in patients with heterozygous familial hypercholesterolaemia
what is xanthelasmata?
deposits of lipids on the upper and lower eyelids. they become more-severe with age; they can be modest at younger age, beginning in the third decade of life, and become more-pronounced as the patient ages. in patients with heterozygous familial hypercholesterolaemia
where is most cholesterol derived from?
hepatic synthesis
which enzye catalyses the rate-limiting step in Pathways in LDL particle synthesis and LDLR-mediated uptake?
3-hydroxy-3-methylglutaryl-CoA (HMG)-CoA reductase
how do lysosome storage disorders occur?
> 40 autosomal recessive or X-linked deficiencies of specific enzymes that process lysosomal macromolecules
accumulation of un-degraded substrates within lysosomes
disruption of normal cellular organization & function: characteristic organ distribution patterns of abnormal metabolites
diseases are grouped according to the major stored substance
what is the route of lysosomal enzyme cycling?
Extracellular enzyme binds to the plasma membrane via mannose 6-phosphate receptors and is internalized by a clathrin-coated vesicle into an early endosome.
As the early endosome acidifies to become a late endosome, the enzyme dissociates from the mannose 6-phosphate receptor, which recycles to the plasma membrane.
The late endosome fuses with a primary lysosome derived from the Golgi apparatus to form a secondary lysosome, which may remain in the cell as a residual body or fuse with the plasma membrane in the process of exocytosis of digested products.
name some common lysosome storage diseases
tay-sachs
fabry
gaucher
niemann-pick
krabbe
matechromatic leukodystrophy
