Lecture 1 - Enzyme and CV disorders

A biological catalyst that causes a biochemical reaction to occur or inc the rate of a specific reaction within a cell, body tissue or organ is called an _____.

Known mutations in specici enzymes lead to accumulation of specific ____ acids or the buildup of the _____ product w lysosomes.

Common facts abt genetic enzyme deficiencies is that:

1. Neither parent has an ____ problem.

2. The affected newborn does not have ____ at birth

3. The ___ enzymes cross placenta and perform function in fetal cells

4. Many disorders can be cured by hematopoeitic stem cell ____ but the procedure is both ____ and dangerous.

In hyperaminoacidemias, the amino acids accumulate in ____ and tissues.

In lysosomal storage disorders, the undegraded products are trapped in the _____.

enzyme; amino; precursor; obvious; syymptoms; maternal; transplant; costly; blood; lysosome

Phenylketonuria is an example of ______. A mutated gene ____ results in deficiency of phenylalanine hydroxylase, leading to build up of _____. There are also dec amounts of ____ which is normally made from the conversion of phenylalanine. This is an autosomal ____ disorder. This is most common in ____ Americans from Ireland and Scotland

Symptoms include:

1. ____ disability

2. A dec in ___ production leading to hypopigmentation

3. A ___ odor

4. Blood ph is _____

5. Seizures and ____.

6. A ____ stature and head size

A test is done 24 hrs agter beginning ____.

Management includes:

1. A low phenylalanine diet (300-500mg), so they cannot have ____ and proteins.

2. Tyrosine _____

3. A Bh3 supplement which prevents ____ and dec effect of low cognition.

Drug therapy includes sapropterin which improves ____ of phenylalanine to tyrosine.

hyperaminoacidemias; PAH; phenylalanine; tyrosine; recessive; european; intellectual; melanin; musty; low; tremors; small; milk; meats; supplementation; acidosis; conversion

Gaucher disease is a type of ____ storage disorder. There is a mutated beta- _____ gene resulting in buildup of glucoslyceramide in lyosomes of macrophages and other WBC. This is an autosomal ___ diosrder. This is most common in Ashkenazi ____ and amongst French _____ in Quebec.

There are different types with the common one being Type 1 which is NOT going to affect the ____ system. Instead there is buildup in the macrophages in the ____, spleen, bone marrow, and lungs. The excessively large macrophages exert _____ on nearby organ cells. This changes ____ and oxygenation of those cells which affects organ function.

Bc the macrophages become filled, there is ___ of the spleen and liver.

Once they fill the bone marrow, this crowds out the other cells leading to:

1. Easy ___ and bleeding bc of thrombocytopenia

2. Fatigue due to ____

3. Bone __ and crisis, abdominal pain

Management includes:

1. ____ supplementation and enzyme replacement

2. Stem cell ____

3. Admin platelet and RBC ____ factors

4. Transfusions and _____ to prevent rupture

5. Admin _____ to prevent bone density loss

6. Joint protheses

lysosomal; glucosidase; recessive; jewish; canadians; nervous; liver; pressure; perfusion; enlargement; bruising; anemia; pain; vitamin; transplant; growth; splenectomy; bisphosphonates

____ syndrome is associated with a mutated alpha-L-iduronidase gene. This results in excess buildup of _______ in the lysosomes of most cells AKA MPS I. This is an example of _____ storage disorder and is autosomal _____.

S/S includes:

1. ____ facial features and a large head

2. H = _______

3. U = unusual facial features

4. R = recessive

5. L = L-iduronidase deficiency

6. E = eyes ____

7. R = _____

8. S = _____ stubby fingers

Management includes:

1. Enzyme replacement which is expensive and must be started before aged ____ and does not prevent ____ dysfunction.

2. Drug therapy for ____ infection and to improve CO

3. Specific TXT is hematopoeitic stem cell _____.

hurler; mucopolysaccharides; lysosomal; recessive; coarse; hepatosplenomegaly; clouded; retardation; short; 2; CNS; respiratory; transplant

_____ syndrome is when there is mutated iduronate sulfatase gene. This results in excess buildup of mucopolysaccharides or _____. AKA MPS II. This is ____ linked recessive. It affects ____ almost exclusively.

This has a ____ onset and less ____ effects.

S/S include:

1. ____ facial features, a prominent ____, thick lips, heavy eyebrows

2. Abdominal _____ from liver and spleen

3. ____ neck and stature

4. _____ deformities

5. ____ death and respiratory infections

Management includes:

1. Enzyme _____ w idursulfase

2. Hematopoeitic stem cell ____

hunter; GAG; X; males; slow; cognitive; coarse; forehead; enlargement; short; spinal; premature; replacement; transplant

Mutated alpha-glactosidase A gene is called ______ disease. This results in excess buildup of ____ in the lysosomes of many tissues. This is ____ linked recessive.

Large amounts of GL3 can damage the blood ____ and reduces perfusions. As the blood vessels become less efficient, chronic ____ begins which leads to ischemia and eventual tissue/organ _____.

Symptoms usually appear in ____ childhood w males happening earlier. These include:

1. Skin Angio_____

2. ____ cardiomyopathy, N/V/D, abd pain

3. ____ loss, proteinuria, azoospermia

4. ____ manifestations, stroke, MI, premature death

Management includes:

1. Enzyme replacement with replagal aor Frabrazyme which should be adminstered via ____

2. Chaperone therapy ____ the body’s faulty alpha-Gal A.

fabry; GL3; X; vessels; inflammation; failure; late; keratomas; hypertrophic; hearing; psychiatric; IV; stabilizes

_______ disease is when there is a mutated hexosaminidase A gene. This results in buildup of ____ in the brain cells. This is autosomal ______ and common amongst Ashkenazi ____ people.

These collect in espcially _____ which causes them to swell up and lost function over time. Death occurs often by age 2 usually from ____; however late onset is not fatal.

Problems start to become noticeable at around ___ to 6 months. Normal intellectual and motor development halt then _____. Babies lose the ability to ___ over, sit, crawl, have seizures, ____loss, and inability to move. Other S/S includes:

1. A pale retina with a ____ red fovea

2. Progressive ____ weakness and paralysis

3. Loss of normal _____ and a hyperactive ____ reflex

4. Blindness and seizure activity.

taysachs; GM2; recessive; jewish; neurons; pneumonia; 4; regress; turn; hearing; cherry; muscle; reflexes; startle

Collagen is a major component of the ____ tissue in all body tissues. Procollagen is modified in many ways to work with ___ and fibrilin to add strenght and structure to most tissues.

Type 1 collagen is found in bones, skin, ligaments, ___(eye), intervertebral ___, and blood vessel walls

Type 2 is found in _____

Type 3 is found in skin, ____, blood vessels and ____ walls

Type 4 is found in ____ and inner ear

Type 5 is found in skin, ligaments, bones, tendons, _____,and the ____ matrix.

connective; elastin; corneas; disks; cartilage; lungs; intestinal; kidneys; muscles; extracellular

A group of genetic disorders in which collagen formation is impaired, resulting in bones that fracture easily is called ____ _____. This is especially for Type ___ collagen that results in variation in severity. This is autosomal ____ transmission. There are different types:

1. Type 1 is the most ____. Patients will have a ___ sclera

2. Type 2 is ____ in utero. This is bc ____ collagen is produced.

3. Type 3 die prematurely and die before ______. They have high risk for ___ stress fractures

4. Type 4 is less severe but have better function. Scleral coloration is _____ and there are fewer fractures.

The severity depends on the degree of normal collagen reduction present and whether _____ collagen is produced.

Other S/S includes easy ____, thinning of skin, a ___ stature, ___ loss, and ____ abnormalities.

Type 3 specific S/S includes:

1. Fractures and skeletal _____ present at birth

2. A ____ chest and rounded back

3. Bones that are ____ called pseudoarthrosis;

4. Short stature, blue sclera, muscle weakness

Management includes:

1. Using PT and participating in _____

2. Fracture management with ___, splints, or wraps

3. Surgical implantation of ___ bone rods

4. ____ therapy to reduce bone loss

osteogenesis imperfecta; 1; dominant; common; blue; lethal; no; reproduction; low; normal; abnormal; bruising; short; hearing; dental; deformities; barrel; bent; swimming; casts; long; bisphosphonate

A group of different inherited disorders that occur as a result of mutations in the genes responsible for collagen formation or modification is ____ ____ syndrome. Transmission pattern varies but is usually autosomal _____. There are different types:

1. Classical Ehlers-Danos is due to gene mutation in type 1 and ___ collagen. S/S includes skin/joints that are hyperextensible and _____, skin that is ____, chronic joint pain, and joints that ____ easily. It is also associated with ____ floor dysfunction.

2. ____ type was formerly type 3. No specific mutation is known. Use the ___scoring system to see if they need a referral,

3. The ____ type is caused by mutation for typ 3 collagen. They are more prone to early ____ due to arterial dissection, mitral prolapse, and easy ____. They will have ____ blood vessels and organs, a ___ stature, thin/___ skin.

4. The ____ type is formerly type 6 and is caused by mutation responsible for modifying collagen. There is ___ of all joints, progressive spinal curvature, etc.

There is no ____ for any type. Management includes focusing on protecting _____, delay complications, avoid trauma, and ____ therapy.

ehlers danos; dominant; 5; stretchy; fragile; dislocates; pelvic; hyperextensibility; beighton; vascular; death; bruising; fragile; short; translucent; kyphoscoliosis; laxity; cure; joints; physical

A connective tissue disorder in which the gene for fibrillin is mutated is called ____ syndrome. This prevents fibrillin from interacting w collagen and elastin to provide ____ strength to tissues during/after stretching. This autosomal ___ transmission with a high spontaneous mutation rate.

The connective tissue is untable, weak, and becomes and remains _____ with time.

S/S includes:

1. _____ problems which are the primary cause of premature deth

2. A ____ and lanky stature

3. Arms that spread greater than ____

4. ____ or lax joints

5. Very long and hyperextensible ____

6. Spinal curvatures

7. A ____ cornea, small iris, displaced/detached ____

8. A mitral valve ____, ____ aorta and aortic aneurism, and left venticular _____.

Monitoring CV effects w yearly eval of left venticuar function, ____ fraction, ____ valve function, and aorta width. Maintain ____ within ormal range, maintain healthy weight, and avoid _____ exercise.

marfan; recoil; dominant; overstretched; CV; tall; height; loose; fingers; flat; lens; prolapse; widened; enlargement; ejection; mitral; BP; strenuous

Coronary Artery disease is caused by buildup and rupture of ____. A woman’s CAD risk if 70% higher if her ____ had CAD. Many genes are associated with ____ in atherosclerosis.

_____E is a component of VLDL. Ppl who carry apoE4 allele have ___ levels of LDLs. There is no ___ evidence of how much these alleles affect overall CAD risk.

GWAS have shown an association b/w region on chromosome ___(9p21) and onset of CAD. Knocking out this region in ____ results in changes in growth of the heart. Studies differ in wheter variations inc ____ risk.

Environtmental contributions includes ____. Nicotine dependence appears to be ___ and some ppl carry mutations for the nicotine receptor.

Single gene causes include:

1. Tangier disease which is associated w extreme low levels of ____. This is autosomal ____

2. Familiar hyperlipidemia is associated with high LDL and ______. This is autosomal _____

3. Familial apolipoprotein A-1 defieicnecy is rare and leads to low ____. This is autosomal ____.

plaque; father; inflammation; apolipoprotein; high; clear; 9; mice; MI; smoking; polygenic; HDL; codominant; triglycerides; recessive; HDL; recessive

Familial hypercholesteremia is autosomal ____. Heterozygous people have cholesterol levels b/w ___ to 400. Homozygous have b/w 600 and ____.

Management includes:

1. Proper diet

2. A ___ acid absorbign resin like cholestyramine

3. High doses of HMG-CoA reductase inhibitors AKA _____

4. A cholesterol absorption ____ like Ezetimibe

5. LDL ____ which is removal of excess LDL from the blood.

dominant; 300; 1200; bile; statins; inhibitor; apheresis

A ____ HX doubles or triples risk of strole. There are 2 types: ____ and hemorrhagic. The unclear ____ makes genetic study difficult.

Less tghan 1% of strokes are caused by ___ gene variants.

1. CADASIL leads to accmulation of abnormal ___ deposits in walls of small blood vessels in brain.

2. ____ disease is deficient alpha-galactosidase A which causes the glycosphingolipids to accumulate in the body.

3. MELAS causes disfunction of the ____ leading to accumulation of lactic acid and other metabolic abnormaltieis.

4. Factor V Leiden is associated with _____. It results in a protein that cannot be degraded by activated protein ____. This leads to hypercoagulation and heterozygotes have inc risk of blood ____. Homozygotes have a significantly ___ risk.

Many of the same genes involved with ____ also are involved w stroke. There is ____ progonosis for those with ApoE4 allele. People with ____ are 4-6 times more likely to have a stroke.

family; ischemia; phenotype; single; protein; fabry; mitochondria; thrombophilia; C; clots; greater; CAD; poorer; HTN

HTN is when systolic pressure is equal or greater to ____mmHg or diastolic greater or equal to ___ mmHg without taking meds. It is also diagnosed if the patient is taking ____ for HTN or if they were told on ____ or more occasions by HCP that they have high BP.

Most ppl have primary HTn in which there is no clear ____. Seconday HTN is due to another _____.

Environmental factors consist of ____(eat), exercise, ____ management, social support, sleep, and risky behaviors.

Monogenic causes includes alteration in the ____ pathway.

Polymorphisms includes when a common gene variant in RAAS genes affects whether or not a person will respond to a low ____ diet.:

1. AGT-6-AA which respond ___ to a low salt diet

2. AGT-6-GG will ____ respond to a low salt diet.

140; 90; meds; 2; cause; disease; nutrition; stress; RAAS; salt; well; not

A gene-to-gene interaction in which one gene variant modifies expression of another gene is called _____. This can either ___ or inc that other gene.

epistasis; suppress

Arrhythmias AKA channelopathies can be due to variants in genes coding for ____ channel proteins. Mutations in the ____ channel gene SCN5A leads to brugada syndrome, atrioventricular condutcion defects, congenital sick sinus syndrome, and long ____ syndrome.

The most common arrhythmias seen by clinicians is called ____ fibrillation. It runs in families and is genetic _______ in which lots of diff genes cause atrial fibrillation. This is an _____ disease but there are some single-gene causes but most cases are multifactorial.

Long QT syndrome is a group of disorders that involve a delay in ____. An ____ will show lengthened QT interval. The heart is vulnerale to potentially lethal polymorphic venticular tachycardia called _____ de pointes. Most common genes causing this include:

1. LQT1 which is caused by ____ channel KCNQ1. Triggers for torsades includes exercise, espcially _____.

2. LQT2 is caused by K channel KCNQ2. Triggers includes ____ stimuli.

3. LQR3 is caused by ____ channel SCN5A. Triggers includes rest and ____

Congenital LQTS includes:

1. ____-Ward which is autosomal dominant

2. Jervell and Lange Neilson which is autosomal recessive w _____

Acquired LQTS appears after taking certain ____

ion; sodium; QT; atrial; heterogenity; acquired; repolarization; electrocardiogram; torsades; K; swimming; auditory; Na; sleep; romano; deafness; drugs

______ is associated with a weakened of diseased heart muscle. This leads to inefficient ___ of blood.

Genetic causes include mutation ingenes that code for ___ protiens. Environmental fctors include ____ and cocaine use, viral infections, malnutriiton, preg, and end-stage ____ disease.

Familiar Hypertrophic Cardiomyopathy is associated w:

1. A ___ of microcytes under microscope

2. Autosomal ____

3. Heart muscle that is assymetrically ____

4. Diastolic dysfunction

5. ____ ____ mutations meaning not found in other family members

6. May be ____ until adolescence or later

7. Clinical ____ testing is avilable and diagnosis can occur at any age but ___ is common

8. It is the most frequent cause of sudden cardiac death in young ____

9. There are ___ guidelines for sports preparticipation.

Familial Dilated Cardiomyopahty consists of left ventricular _____. This leads to poor pumping and often leads to heart ____.

Familia Restrictive Cardiomyopathy is less common and leads to less ___ during diastole due to a rigid ventricle. It can be idiopathic or secondary and may not appear until __ to 60 yo.

Arrhythmic Right Ventricular Dyplasia/Cardiomyopathy is associated with fibro or ____ tissue replacement of ventricular myocardial wall. This is a high risk for ventricular ____. This is autosomal _____ and affecs genes fro _____ proteins and genes for cell _____ proteins. Penetrance is ____.

cardiomyopathy; pumping; sarcomere; alcohol; kidney; disarray; dominant; thickened; de novo; asymptomatic; genetic; misdiagnosis; athletes; screening; enlargment; failure; filling; 50; fatty; arrhythmias; dominant; transmembrane; junction; incomplete