Single Gene Disorders - Part 2

Front 1

Coronary Heart Disease and Stroke

Back 1

-25% all US deaths
-mechanism is atherosclerosis, lipid deposits -> narrowing of arteries
-narrow coronary -> infarction
-narrow brain arteries -> stroke

Front 2

Atheroscelrosis

Back 2

-environmental risk factors: obesity
-smoking
-hypertension
-elevated blood cholesterole
-alcohol
-genetic risk factors: + family history

Front 3

Familial Hypercholesterolemia

Back 3

-HDL lipoprotein in blood
-autosomal dominiant
-mutation in LDL-receptor on ch19 or by mutations in the ApoB gene on ch2
-recent reports of autosomal recessive mutations in Italy
-pre-symptomatic testing
-complications: Xanthomas in skin and tendons
-5% of all myocardial infarctions in persons under the age 60 is cause by FH
-1/500 (hetero) or 1/1mil (homo)
-Disease much more serious in homo

Front 4

Drug Effectiveness
(PharmacoGenetics) of High Cholesterol

Back 4

-High cholesterol is treated with statins (HMG-CoA reductase inhibitors)
-Statins effects: highly positive -> somewhat negative in different patients
-drug response is probably multifactoral
-response to Fluvostatin is partially explained by alleles in CETP (cholesteryl resistance) genes
-independent and additive effects

Front 5

Hypertension

Back 5

-heritability: 20-40%
-environmental risk factors
-sodium intake
-decreased physical activity
-psychosocial stress
-obesity (multifactoral trait)

Front 6

Genetics of Hypertension

Back 6

-Rare single gene disorders lead to hypertension
-angiotensinogen seen to be risk factor for hypertension
-5-6 other ch locations have been implicated, but the genes not conclusively identified
-difference in genetic background when people suffer from metabolic syndrome vs hypertension in other contexts

Front 7

Single Gene mutations in heart defects

Back 7

-several different described
-common theme: congenital defects caused by mutations in transcription factors expressed during development
-in contrast: mutations in structural proteins mostly lead to hypertrophic cardiomyopathy, especially genes for proteins in the cardiac sarcomere

Front 8

Hypertrophic Cardiomyopathy

Back 8

-Asymetric hypertrophy of left ventricle; often strongest in the interventricular septum
-dyspnoea, angina pectoris, fatigue, syncope, or sudden death
-autosomal dominant with reduced penetrance
-incidence is: 1:5000; >50% are familial, rest probably new mutations

Front 9

Treatment for Hypertrophic Cardiomyopathy

Back 9

-behavior
-if outflow tract bloackage: drugs or surgery
-Beta or Ca blockers or removeal of excess cardiac muscle
-for risk of sudden death: Amiodarone or implanable defribillator

Front 10

Tuberous Sclerosis

Back 10

-Autosomal Dom, 1:5000, high penetrance, highly variable expressivity
-epilepsy, learning difficulties, autism, behavioral problems, and skin lesions
-underlying cause: benign tumors especially of skin, kidney and brain
-cardiac rhabdomyoas can cause prenatal death (often seen as repeated spontaneous abortions)
-bening tumors can cause severe problems inside skull
-can also become maglinant and metastatic
-genes involving are normally affecting control of ceullular growth
-inactivating mutations cause the symptoms

Front 11

Cystic Fibrosis

Back 11

-most common single gene disorder in NA and Europe
-inheritance is Autosomal Recessive
-risk (hetero) is 1/25 for US Caucasaians leading to 1/2500 births being affected.
-Medical treatment has imoproved recently

Front 12

Cystic Fibrosis Diagnosis

Back 12

-Symptoms involve intestine, pancreas, liver, make repro and skin
-most severe problem arises from chronic Pseudomaonas aeruginosa infections in the lungs.

Front 13

Cystic Fibrosis - Molecular defect

Back 13

-CFTR gene encodes a chloride transporter
-most common mutation is a deletion of 3bp - dF508 - 90% of all mutated alleles in Denmark, but only abt 75% among US caucasians and 25% algerians
-misregluation in Cl- transport

Front 14

How to detect dF508 mutation

Back 14

1. PCR fragment is short, can be seen on an acrylamide gel
2. Dotblot w/ ASO probe for each of the two alleles to make sure if the person is hetero or homo - high freq of this allele -> most carriers detected using just one allele

Front 15

Allelic Heterogeneity of CF

Back 15

-large # of other mutations detected
-atypical (milder) CF is see when mutation allows residual activity of CFTR transporter (sterile male only)
-one report indicates that heterozygosity for a CF mutation is a risk factor fo Asthma

Front 16

Recessive Inheritance

Back 16

-Hetero carrir does not show trait
-Parents of affected are normally NOT affected
-Parents of affected are related more often than expected (more so for rare diseases)
-equally common in both sexes (exception sex-limited traits)
-if both parents are carriers, 25% risk that an offspring will be affected

Front 17

Non-syndromic Deafness

Back 17

=know genes include
-17 A-R
-16 A-D
-1 X-R
=total # of loci are expected to reach about 100
==Incidence==
-congenital deafness 1/1000
-highest in greek, where carrier freq of a mutation (35delG) in the gap junction proteinm beta-2 gene is 3.5% (recessive mutation)

Front 18

Deaf person previously described marries deaf woman. Has child. will child be deaf?

Back 18

-assortive mating
-if same for: YES
-if two different forms: NO
-if dominant: maybe

Front 19

Charcot-Marie-Tooth Disease

Back 19

-peripheral sensory and motor neuropathy
-wasting of muscles in hands, lower arms, feet, lower legs due to miss inervation. mild to moderate disability
-inheritance is heterogeneous, and most common are A-D
-incidence 1/2500
-Mutations: most common is Ia, cause by a duplication of 1.5Mb on ch17 containing the peripheral myelin protein-22 (PMP22) gene
-diagnosis by FISH, PCR or different blotting methods
-PMP22 gene deletion of the same region leads to neuropathy, herediatry, with liability to pressure palsies

Front 20

Marfan Syndrome

Back 20

-Tall stature, long limbs, aarachnodactyly, lens displacement or cataract, progressive aortic dilation leading to aneurysm or heart disease
-1/20,000 to 1/60,000
-inheritance is A-D, with incomplete penetrance/variable expressivity
-molecular defect: fibrillin, an extracellular protein in the connective tissue
-lab: linked markers, due to many different alleles, none of these in large percentage (many different ways to mutate)

Front 21

Ehlers-Danlos Syndrome

Back 21

-Rare
-Heterogeneous
-lose joints in addition to stretchy skin

Front 22

Osteogenesis Imperfecta

Back 22

-two main types + intermediate expressivity
-varies from perinatal lethal to mild forms with normal life span, blue shlerae and occasional fractures.
-Common features are brittle bones and often hearing loss
-1/10,000 >80 mutations in genes for type I collagen, ie COL1A1 or COL1A2 genes
-usually A-D

Front 23

Polycystyic Kidney Disease

Back 23

-Autosomal dominant
-adult onset with variable expressivity
-progressive cyst formation in kidney, may also have involvement of liver, pacreas, or spleen. Some have intracranial aneurysms.
-three loci, the two major encode transmembrane proteins probably involved in cell to cell-matrix interactions
-10% of all patients with end-stage renal disease has this entity

Front 24

Polycystyic Kidney Disease (2)

Back 24

-a related infantile PK disease is caused by a differenty gene with A-R inheritance
-allelic heterogeneity leads to variable expressivity
-quite often a disease of high mortailty and morbidity

Front 25

Hemochromatosis

Back 25

-disease caused by buildup of Fe ions in the liver and blood
-genetic background is A-R in the majority of cases with rare families showing A-D inheritance
-of five causative genes, HFE1 is common in Caucasians, all the others are rare
-homo for HFE1 in 1/200-300 in most Caucasian pops, 1/72 in NE Quebec

Front 26

HFE Clinical Features

Back 26

Among 35 homozygotes, symptoms showed were (progressive disease)
-arthopathy 20
-hepatomegaly 19*
-transaminasemia 16
-skin hyperpigmentation 15 **classic triad present in only 1
-splenomegaly 14
-liver cirrhosis 14
hypgonadism 6
-diabetes 2*

Front 27

HFE symptom development

Back 27

-symptoms develop as iron gets accumulated throug hseveral years to a lifetime
-this explains that
-symptoms worsen w/ age
-women are less often symptomatic than men (blood loss due to menstration)
-presenting problem may involve the liver (majority), heart (15%) or hypogonadism

Front 28

HFE Continued

Back 28

-about 2.5% of homozygotes will develop liver cancer
-infection with Vibrio vulnificus is rare but serious; many of the people infected are HFE homozygotes
-Chromium is completing with iron for transport in transferrin; lack of chromium may explain diabetes, as Cr necessary for insulin function
-Osteopenia also occurs

Front 29

HFE Treatment

Back 29

-Phlebotomy one-two times a week
-Avoidance of iron intake
-Deferoxamine if anemia - iron chelator
-No alcohol
-Symtpom treatment