Intro to Medical Genetics

Question 1

Genetics

Answer 1

-the study of hereditary

Question 2

Human Genetics

Answer 2

-the study of heredity in man

Question 3

Medical Genetics

Answer 3

-the study of human genetic variation of medical significance

Question 4

Subunits of Medical Genetics

Answer 4

• Clinical Genetics- diagnosis
• Genetic Counseling- information
• Molecular genetics- lab
• Biochemical Genetics- lab
• Cytogenetics- lab

Question 5

Mutation

Answer 5

-a permanent, heritable change in the sequence of genomic DNA
-can occur at either the molecular or cytogenetic level
-may give rise to new alleles
-important mechanism of population variation
Neutral- blue eyes
Positive- sickle cell trait
Negative- sickle cell disease, cancer

Question 6

Patterns of Inheritance

Answer 6

• dominant vs recessive

- autosomal vs X linked

Question 7

Inherited gene complement

Answer 7

• mutations may be transmitted from one or both parents

- typically called the constitutional genome

Question 8

Acquired gene complement

Answer 8

-a subset of cells in an individual that arose by clonal propagation from a single mutation in one cell

Question 9

Syndrome

Answer 9

• set of characteristics which occur together and are assumed to have a common basis
• not all characters occur in all affected individuals
• range of variability within a population
• for example there are over 250 known features of the disorder velocardiofacial syndrome but no single individual has all of these findings
• however, for diagnosis to be made,an individual diagnosed with a particular disorder must have a core group of the cardinal characters associated with that disease

Question 10

Biochemical Genetics

Answer 10

-subspeciality of genetics that deals with the diagnosis, treatment and research of inborn errors of metabolism

Question 11

Inborn Errors of Metabolism

Answer 11

• genetically determined biochemical disorder in which a specific enzyme defect produces a metabolic block
• accumulation of substrate
• deficiency of products
• single enzyme defect
• recessive
• many recognized disorders
• challenge to detect the particular substance and pathway involved
• alcaptonuria, cystonuria, pentosuria, albinism

Question 12

Alcaptonuria

Answer 12

• inborn errors of metabolism
• accumulation of homogentisic acid in the blood
• damage to cartilage, heart, kidney

Question 13

Tyrosine to melanin

Answer 13

• Tyrosine to pigment A uses tyrosine oxidase
• if all functions correctly tyrosine will be converted to melanin which phenotypically presents as black or dark brown pigment
• if the pathway is blocked at enzyme X, the conversion is incomplete and only some pigment will be present resulting in a brown or grey color
• mutation of tyrosine oxidase prevents any biochemical change and the lack of pigment results in an albino

Question 14

Albinism

Answer 14

• mutation of tyrosine oxidase
• can be complete- no pigment in any tissue
• red eyess
• can be partial- where some organs or tissue have pigment

Question 15

Deficiency of Shared Enzyme

Answer 15

• enzymes are not necessarily dedicated to one pathway
• they may function in multiple different, related or unrelated pathways
• the downside of this is that a single mutation can affect multiple cellular processes

Question 16

General Clinical Features

Answer 16

• poor growth
• mental retardation
• problems in general metabolism
• neurological problems
• Patient evaluation- clinical picture, onset of MR over time
• Family history- other affected siblings, unexplained infant deaths

Question 17

Hyperphenylalaninemias

Answer 17

• Phenylketonuria (PKU)
• Variant PKU
• defects of tetradhydrbiopterin metabolism BH4
• biochemiical disorders related to the function of pheynlalanine hydroxylase which converts phenylalanine to tyrosine
• clinical heterogeneitiy-three distinct phenotypes from mutation of a single gene

Question 18

Phenylketonuria (PKU)

Answer 18

• most common of 3
• it occurs when a mutation of phenylalanine hydroxylase prevents conversion of phenylalanine to tyrosine
• accumulation of PHE in cells
• small fraction of PHE may then be converted to phenylpyruvic acid which can be detected in the urine
• autosomal recessive, 1/10,000 live births
• treat by diet modification- early in life, pregnancy

Question 19

Variant PKU

Answer 19

• between full PKU and non-PKU hyperphenylalaninemia

- required a diet, but not as restrictive as PKU patients

Question 20

Non-PKU Hyperphenylalanemia

Answer 20

• 10 fold increase in PKU levels
• less damaging, but may be benign
• may not requre a special diet

Question 21

Tetrahydrobiopterine (BH4)

Answer 21

• locus heterogenity- mutations in different genes can lead to the same clinical phenotype
• non-mutant phenylalanine hydroxylase gene
• defect somewhere is Bh4 pathway
• do not respond to PKU diet and develop neurological defects
• BH4 is a cofactor to other enzymes leads to deficit of dopamine and serotonin

Question 22

Lysosomal Storage Disease

Answer 22

• recessive
• mutation of a lysosomal hydroltyic enzyme leads to failure of degradation and the accumulation of macromolecules in lysosomes
• over 50
• common: progressive degeneration
• if the macromolecule is not degraded, it cannot be eliminated, so they are stored in lysosomes
• as the organelles become larger, the affected organs and tissues increase in mass
• enzyme replacement therapy

Question 23

GM2 Gangliosidoses

Answer 23

• GM2 pathway
• three proteins functions together
• alpha, beta subunits and activator

Question 24

Tay Saches Disease

Answer 24

• autosomal recessive
• rare except for Ashkenazi Jewish population
• 3-6 months, death 2-4 years
• deficiency of hexosaminidase A
• inability to degrade GM2 ganglioside
• cherry red spot in retina

Question 25

Mucopolysaccharidoses

Answer 25

• groups of heterogenous disorders
• absence of specific enzyme involved in degradation of glycosaminoglycans
• accumulation of macromolecules in the lysosomes
• not all autosomal recessive, Hunter syndrome is X linked recessive
• permanent, progressive damage
• short stature, delay, skeletal abnormalities and joint stiffness, thickened skin, heart, liver or spleen damage
• bone marrow transplantation, enzyme replacement therapy, gene therapy

Question 26

Connective Tissue Disorders: Collagen

Answer 26

• osteogenesis imperfecta is due to mutations in type 1 collagen with either reduced collagen production or defective collagens
• -4 different classes that range from mild to lethal
• reduced collagen production tends to be brittle bones
• OI type III is perinatal lethal

Question 27

Ehler-Danlos Syndrome

Answer 27

• error in post translational modification of collagen
• multiple subtypes
• autosomal dominant, autosomal recessive and X linked recessive
• characters: skin fragility, joint hypermobility, skin hyperextensibility
• COL5A or COL3A genes

Question 28

Marfan syndrome

Answer 28

-fibrillin gene
=primary targets skeleton, eyes, heart
-Marfan patients are tall and thin with very long thin fingers
-they can have joint laxity and scoliosis
-lung problems pneumothorax
-dislocation of the lungs or myopia- cataracts, glaucoma, retinal detachment
-heart issues include mitral valve prolapse, dilation and dissection of the aorta
-the disease is progressive and heart issues become a major threat in the teens

Question 29

Disomy

Answer 29

-the presence of 2 chromosomes

Question 30

Isodisomy

Answer 30

-2 chromosomes from the same source (duplication of 1 chromosome)

Question 31

Heterodisomy

Answer 31

-2 different chromosomes