Genetic Diseases Flashcards
DNA linkage analysis
Identifies repeat length polymorphisms, to identify disease producing mutations
- certain gene polymorphisms (CCG repeats) are associated with certain diseases (huntingtons, fragile X)
GWAS
Identify genetic susceptibilities in a population and what they look like: link genotype and phenotype
G6PDH deficiency
Does not present Under normal conditions however upon administration of a hemolytic agent such as Primaquine (or azathioprine) Severe hemolytic anemia is the result
Though its an X-linked disorder, a hemizigous female is still at risk because a portion of red cells are from marrow with the normal allele has been inactivated
a1-antitrypsin deficiency
Results in persistent elastic tissue in the lungs, Causing eventual fibrosis and COPD
Marfan syndrome: etiology and pathenogenesis
- Etiology/pathenogenesis: A mutated fibrillation-1 (FBN-1) gene (15q21.1) results in Dysfunctional elastic tissue in the aorta the ligaments and the ciliary Zone supporting the lens of eye. The dysfunctional elastic tissue in the intima of the aorta Oftentimes results in aortic aneurysm, Suspensory ligament of the eye often fail causing lens dislocation. The skeletal abnormalities are result of elastin sequestering growth factors.
Autosomal dominant condition
Ad/ad: autosomal dominant is often age dependent manifesting later in life: sickle cell, huntingtons, neurofibromatosis, familial hypercholesterolanemia
- common in germ cells of older fathers
- marked by incomplete penetrance and variable expressivity
Autosomal recessive disorders
- largest group, mostly inborn errors of metabolism
- most highly expressed in consanguineous offspring
- complete penetrance is common
- presentation of disorder is often early in life
X-linked disorders
- Typically higher expression in males
- ## These conditions are never passed father to son: ALL daughters are carriers.
Familial hypercholesterolemia: etiology, classes (5)
- one of the most common single mutation diseases
- LDL receptor gene mutation -> increased plasma concentration of LDL
- HMG CoA reductase activity is increased (no LDL in cells)
- synthesis (I), transport (II), binding (III), clustering (IV), recycling (V)
Lysosomal storage defects: general, trt
- multiple potential abnormalities
- results in accumulation of substrates
- enzyme replacement is common treatment, but molecular chaperones have also recently begun to be used.
Tay-Sachs disease
- Common among Ashkenazi Jews
- hexosamidase deficiency -> accumulation of Gm2 gangliosides in neuronal tissue. (CNS/eyes and autonomics)
- developmental delays usually first sign
Niemann-Pick disease A/B and C
- also common among Ashkenazi
- A/B sphingomyelinase deficiency, C is a defect in lipid transport
- maternally imprinted
- hepatomegaly followed by failure to thrive followed by death in the first year.
Gaucher’s disease
- most common lysosomal storage deficiency
- mutated glucocerebrocidase
- type 1: (99%) limited to monos and not in the brain, mostly involving Skeleton and bone
- morphologically fat macrophages with crumpled paper in them
Fat macrophages with crumpled paper in them
Gaucher’s disease
- monos not in the brain
Glycogen storage diseases
- specific manifestation depends on exact enzyme affected
- hepatic and myopathic forms
- glycolysis doesn’t occur so lactic acid will not build up during exercise. Muscle pain and weakness mark this form. Both will manifest with hypoglycemia.
- the maltase, and branching enzyme forms are associated with high early mortality.
Alkaponuria
- lack of homogentistic oxidase -> too much homogentistic acid binds collagen and turns it brown black.
- also presents with arthritis
T1DM: susceptibility
HLA genes accounts for about 50% as a single risk factor
Trisomy 21: Down’s syndrome
- Major cause of mental retardation
- detectable by FISH assay and karyotype
- maternal age has a strong influence on development of non mosaic downs.
Down’s syndrome increased risk
- 10-20x the risk of acute forms of leukemia
- most develop neurodegenerative condition consistent with Alzheimer’s disease
- increased risk of lung ifxns and thyroid autoimmunity
22q11.2 deletion syndrome (Digeorges syndrome)
CATCH - cardiac abnormalities - abnormal facies - thymic/ parathyroid aplasia - cleft palate - hypocalcemia There is also an increased risk of schizophrenia (25%) - TBX1 And PAX9 have been implicated
Lyon hypothesis
- Of the two maternal chromosomes, one is selected and inactivated becoming the Barr body (heteropyknosis)
- activation is controlled by XIST gene
Kleinfelters syndrome
- Male hypogonadism: When there are two or more X chromosomes and one or more Y chromosome’s
- Distinctive body habitus: Abnormally long Legs and a long body, and Narrow shoulders.
- Often associated with reduced spermatogenesis and infertility
Kleinfelters etiology
Hypogonadism Is a result of inactivation of the X chromosome with the shortest CAG repeat Polymorphism. Since the length of the CAG repeat dictates the strength of the effect of androgens (Shorter is stronger) The long active repeat polymorphism Results in decreased efficacy of androgen stimulation and hypogonadism.
Turners syndrome
- Female hypogonadism, a monosomic condition lacking an X chromosome
- clinical: Short stature, lack of secondary sex characteristics,webbed neck (resultant from cystic hygroma), and often left sides cardiac defects. Amenorrhea is a significant clinical finding suggesting turners.
Turners syndrome: etiology
- Loss of chromosomal information via Isochromosomal, ring or long or short arm deletion.
- ## appears to be significant mosaisicm; true 45 X conseptuses are non-viable
True vs. pseudo hermaphroditism
- true: germ cell mosaics (may appear totally normal)
- pseudo: pheno/genotypic sex do not agree
~ and is generally a result of androgen level issues or insensitivity
Fragile - X syndrome: pathenogenesis/etiology, presentation
- Associated with FMR-1 gene expressed as a result of CGG repeats: anticipation
- often these polyglutamine diseases result in neurodegeneration
- second only to downs in MR etiology
- the fragile portion of the chromosome on which this is found is sensitive to lack of folate
- clinically: long face, large mandible, everted lowset ears,
Anticipation in fragile X
Repeat amplification only happens significantly in oogenesis, thus paternal effect on amplification is limited. It is primarily a maternal effect.
Mtochondrial inheritance
- mom gives it to all her kids, dad never passes it on
- associated with ox phos genes
Genomic imprinting
Imprinting is referred to by which one silences the gene. The silent gene doesn’t get deleted, thus since angelman syndrome is from mom, the Prader-Willi genes are silenced and after deletion, they are active, and visa versa for Prader-Willi
Angelman syndrome
- maternal deletion of 15q11 gene
“Happy puppet” paroxismal laughter, MRDD, severe seizures, ataxic gait
Prader Willi syndrome
Paternal deletion of 15q11
- early obesity, MRDD, small hands and feet, hypogonadism
Nine month old child of Ashkenazi Jewish parents presents with failure to thrive and hepatomegaly.
- pathenogenesis
- etiology
- Lysosomal storage disorder causing accumulation of sphingomyelin
- Maternally imprinted mutated gene
Hurler syndrome
- Deficiency in a-1 iduronidase
- accumulation of mucopolysaccharides (gags) in tissues
- hunters disease: MPS II
Myopathic glycogen storage disease
Glycogen accumulation in muscle due to muscle phosphorylase (or PFK) deficiency
- clinically: cramps after exercise, weakness, myoglobin often excreted in urine (brown pee)
Acid maltase deficiency
Aka lysosomal glucosidase
- pompe’s disease
- glycogen accumulation in myocardium results in cardiomegaly
Pompe’s disease
Deficiency in acid maltase (aka lysosomal glucosidase)
- results in cardiomegaly due to the deposition of glucose in cardiac myocytes
Von Gierke’s disease
- Deficiency of glucose-6-phosphatase
- hepatomegaly
- hypoglycemia
- hyperlipidemia
Muscle cramps, hypoglycemia
McArdles syndrome
Muscle Phosphatase deficiency
Infant Cardiomegaly
Pompe’s disease
Glycogen buildup in cardiac myocytes
Coarse facial features, skeletal abnormalities
Hurlers syndrome
Buildup of mucopolysaccharides
Hepatosplenomegaly and FTT
Von Gierke’s disease
- liver accumulation of glycogen due to lack of Glucose-6-phosphatase
PCR amplification in trinucleotide repeat conditions
- if negative, may not have condition OR may have too much amplification to detect -> southern blot will confirm
Sphingolipidoses disorders (2)
Tay-Sachs
Sandhoff disease
Sulfatidoses conditions (4)
Gaucher’s disease
Neimann-Pick
Metachromatic leukodistrophy
Fabry disease
Mucopolysaccharideoses conditions (2)
Hurlers
Hunters
