Genetics (Part II) Flashcards
What are the clinical features of Marfan’s syndrome? (9)
Unusually tall, exceptionally long extremities, long tapered fingers and toes, “double jointed”, long headed with frontal bossing, pectus excavatum, ectopia lentis, mitral valve prolapse, aortic dissection
What is usually the cause of death in Marfan patients?
Aortic dissection
How many different variants of EDS are there?
6
What is the defect in Ehlers-Danlos Syndromes?
Defect in the synthesis or structure of fibrillar collagen
What are some clinical features of Ehlers-Danlos Syndromes?
Skin is hyperextensible and the joints are hypermobile; skin is extraordinarily stretchable, extremely fragile, and vulnerable to trauma
If a patient has Ehlers-Danlos Syndrome, what happens if there is a minor injury to the skin?
It produces gaping defects- surgical repair or intervention is difficult due to lack of normal tensile strength
What is the number 1 risk of Ehlers-Danlos syndrome?
Serious internal complications- rupture of the colon and large arteries
What type of EDS does the patient have if there is rupture of the colon and large arteries?
Vascular EDS
What type of EDS does the patient have if they have ocular fragility with rupture of cornea and retinal detachment?
Kyphoscoliosis EDS
What type of EDS does the patient have if they have a diaphragmatic hernia?
Classic EDS
What are the clinical findings associated with Classic (I/II) EDS? (3)
Skin and joint hypermobility, atrophic scars, and easy bruising
What is the specific gene defect in classic (I/II) EDS?
COL5A1 and COL5A2
What are the clinical findings associated with Vascular (IV) EDS? (4)
Thin skin, arterial or uterine rupture**, bruising, small joint hyperextensibility
What are the gene defects in the vascular (IV) EDS?
COL3A1
What are the clinical findings associated with Kyphoscoliosis (VI) EDS? (4)
Hypotonia, joint laxity, congenital scoliosis, and ocular fragility
What are the gene defects in the kyphoscoliosis (VI) EDS?
Lysyl hydroxylase (PLOD1 gene)
Which EDS are autosomal dominant?
Classic (I/II), Hypermobility (III), Vascular (IV)
Which EDS are autosomal recessive?
Kyphoscoliosis (VI)
What is the defect in familial hypercholesterolemia?
Mutation of receptor for LDL (LDLR) in 80-85% of the cases; mutation in apolipoprotein B-100 ApoB (the ligand for LDL receptor on the LDL particle) in 5-10% of cases; proprotein convertase subtilisin/kexin type 9 PCSK9 in 1-2% of the cases
What does the mutation in familial hypercholesterolemia lead to?
Inadequate removal of plasma LDL by the liver
How do heterozygotes present with familial hypercholesterolemia?
With a 2-3 fold increase in cholesterol and CAD with tendinous xanthomas
How do homozygotes present with familial hypercholesterolemia?
With a 5-6 fold increase in plasma cholesterol with skin xanthomas, atherosclerosis at early age; MI before 20 yo
The carrier state for Gaucher disease is a risk factor for what?
Developing Parkinson disease
What does Niemann-pick type C increase the risk of?
Developing Alzheimer’s
Where are lysosomes synthesized and where are they then transported?
Synthesized in the ER and then transported to the Golgi
Once in the golgi, what happens to the lysosomes?
They attach terminal mannose-6-phosphate group
What are lysosomal storage diseases?
When there are genetic errors in the sorting mechanism- the catabolism of the substrate of the missing enzyme remains incomplete, leading to the accumulation with the lysosomes= “primary accumulation”
What is primary accumulation?
When lysosomes become stuffed with incompletely digested macromolecules, they become large and numerous enough to interfere with normal cell functions
What is the effect of lysosomal storage diseases on autophagy?
The undigested macromolecules in lysosomes decreases the rate of autophagic vacuoles being processed, this leads to the persistence of dysfunctional mitochondria which generate free radicals and release molecules that trigger apoptosis
What does impaired autophagy give rise to?
Secondary accumulation
What is secondary accumulation?
When there is accumulation of autophagic substrates including ubiquitin and aggregate-prone polypeptides such as alpha-synuclein and Huntingtin protein (hence the neurodegenerative link)
What are the 3 general approaches to the treatment of lysosomal storage diseases?
Enzyme replacement therapy, substrate reduction therapy, and molecular chaperone therapy
What is molecular chaperone therapy?
An exogenous competitive inhibitor of the enzyme can bind to the mutant enzyme and act as a folding template that assists proper folding of the enzyme, thus preventing its accumulation
What is the major accumulating metabolite in Tay-Sachs disease?
G M2 ganglioside
What is the deficiency in Tay-Sachs disease?
Severe deficiency of hexosaminidase A (HEXA)
Where does the mutation occur that causes Tay-Sachs disease?
In the alpha-subunit locus on chromosome 15
Who is an at risk population for being a carrier of the tay-sachs mutation?
Ashkenazic Jew origin
How does Tay-Sachs present?
The child is normal at birth, but around 6 months they present with motor and mental deterioration, they become obtunded, flaccid, blind, and have dementia; around 1-2 years they are in a vegetative state; and death by 2-3 years old
What are some clinical signs of Tay-Sachs disease?
Cheery red spot in the macula; ganglion cells of the retina are swollen (especially around the macula)
In Tay-Sachs disease, where does the GM2 ganglioside accumulate?
In neurons, retina, heart, liver, and spleen
If a person has Tay-Sachs and you stain their neurons or retina- what would you stain it with?
Fat stains: oil red O and Sudan black B both of these will be positive in a person with Tay-Sachs disease
In a person with Tay-Sachs disease, how would a neuron appear under electron microscope?
Prominent lysosomes with whorled configuration
What metabolite accumulates in Niemann-Pick disease?
Sphingomyelin
What enzyme is deficient in Niemann-Pick disease?
Sphingomyelinase
What population is Niemann-Pick disease commonly found?
Ashkenazi Jews
What is the inheritance pattern of Niemann-Pick disease?
Autosomal recessive
Where does the mutation occur for Niemann-Pick disease?
Chromosome 11p15.4
Where is the Niemann-Pick disease mutation preferentially expressed?
On maternal chromosomes due to the epigenetic silencing of paternal
What happens to the heterozygotes who inherit a mutant allele from mother on the chromosome 11p15.4?
They can develop Niemann-Pick disease
How many different types of Niemann-Pick Disease are there?
3 different types: Type A, Type B, and Type C
Describe Type A Niemann-Pick disease?
Missense mutation: complete lack of sphingomyelinase
How does Type A Niemann-Pick Disease present?
Severe infantile form; extensive neuro involvement, marked visceral accumulations of sphingomyelin; progressive wasting; symptoms by 6 months and death before 3 years
How does Type B Niemann-Pick disease present?
Organomegaly, NO CNS involvement; these patients reach adulthood
How does Type C Niemann-Pick disease present?
This is the most common form of the disease; they can transport free cholesterol from lysosomes to the cytoplasm; they have progressive neurological damage, ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, and psychomotor regression
How do cells appear in Niemann-Pick Disease?
They are very enlarged due to the sphingomyelin and cholesterol accumulation; they have a “foamy cytoplasm” they also have “zebra bodies”
What are zebra bodies?
they are lysosomes with concentric lamellations
What are some clinical features of Niemann-Pick disease?
Massive splenomegaly and 1/3-1/2 of patients have a cherry red retinal spot
What is the inheritance pattern of Gaucher disease?
Autosomal recessive
What mutation causes Gaucher disease?
Glucocerebrosidase mutation
What is mutation of the glucocerebrosidase gene associated with?
Genetic risk for development of Parkinson disease
What does a mutation of the glucocerebrosidase gene lead to?
Accumulation of glucocerebroside in phagocytes
What happens when there is an accumulation of glucocerebroside?
There is damage and activation of macrophages and IL-1, IL-6, and TNF are involved
How many subtypes of Gaucher disease are there?
3
What is Type I Gaucher Disease?
Chronic nonneuronpathic; 99% of cases; NO CNS involvement; patients will have spleen and bone symptoms; there will be a slight decrease in life span
Who is at risk for Type I Gaucher Disease?
European Jews
What is Type II Gaucher Disease?
Acute neuronopathic; infantile cerebral pattern; progressive CNS involvement; early death; hepatosplenomegaly; NOT JEWISH
What is Type III Gaucher Disease?
Intermediate- between types I and II; systemic involvement with progressive CNS disease that begins in adolescence or early adulthood
How does Gaucher disease appear morphologically?
Distended phagocytic cells: Gaucher cells in the liver, spleen, and bone marrow; appear as crumpled tissue paper
What is a common clinical feature of Gaucher Disease?
Enlarged spleen, pancytopenia or thrombocytopenia
What causes mucopolysaccharidoses (MPS)?
Deficiency in enzymes degrading glycosaminoglycans
How many different types of MPS are there?
11
What occurs in Mucopolysaccharidoses (MPS)?
Mucopolysaccharides are abundant in ground substance of connective tissue- this means we get an accumulation of dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate
What is the inheritance pattern of MPS?
All of them are autosomal recessive EXCEPT HUNTER SYNDROME which is x-linked recessive
What is the clinical presentation of mucopolysaccharidoses (MPS)?
Coarse facial features, clouding of the cornea, joint stiffness, and intellectual disability
What is Hurler Syndrome?
It is MPS I-H; there is an alpha-L-iduronidase deficiency
How does Hurler syndrome present?
The child is normal at birth, but then experiences hepatosplenomegaly by 6-24 months and death by 6-10 years due to cardiovascular complications mainly; cornea clouding
What is Hunter Syndrome?
MPS II; there is a deficiency of iduronate-2-sulfatase (I2S)
How does Hunter Syndrome present?
There is NO corneal clouding, they have a milder clinical course
In MPS, where are the mucopolysaccharides seen?
In mononuclear phagocytic cells, endothelial cells, intimal smooth cells, and fibroblasts
What organs does MPS affect?
Spleen, liver, BM, lymph nodes, blood vessels, and the heart
What are the cells filled with mucopolysaccharides referred to as?
Balloon cells- they have clear cytoplasm and multiple vacuoles= swollen lysosomes which are PAS +
What do balloon cells of MPS patients contain?
Lamellated zebra bodies (similar to Niemann-Pick disease)
What is common to all MSPs?
Hepatosplenomegaly, skeletal deformities, valvular lesions, and subendothelial arterial deposits (especially in the coronary arteries) and brain lesions
What is the cause of death in MPS patients?
Myocardial infarction and cardiac decompensation
What diseases show zebra bodies in their cells?
MPS and Niemann-Pick
