Lecture 1 - Intro to medical genetics

Question 1

What are the 2 primary clinical fields?

Answer 1

Clinical genetics and genetic counseling.

Question 2

What are the 3 primary laboratory fields?

Answer 2

Molecular genetics, biochemical genetics, and cytogenetics.

Question 3

What is a permanent, heritable change in the sequence of DNA known as?

Answer 3

Mutation

Question 4

What are the outcomes of DNA mutation? What are some examples?

Answer 4

Positive change - sickle cell trait/malaria protection
Neutral change - blue eyes
Negative change - cancer/sickle cell disease

Question 5

What are the two mechanisms of obtaining a mutation?

Answer 5

Inherited (in the constitutional DNA) or acquired (from clonal propagation of a cell with the mutation).

Question 6

What is a syndrome?

Answer 6

A set of characteristics that occur together that seem to have a common origin. (may be variable in presentation…)

Question 7

The field of genetics that studies treatment, diagnosis, and research of inborn errors of metabolism is known as?

Answer 7

Biochemical genetics.

Question 8

Describe inborn errors of metabolism.

Answer 8

Genetic insufficiency or lack of function of a specific enzyme that causes a deficiency in product and accumulation of substrates.

Question 9

What were the first 4 inborn errors of metabolism that were identified? What is the mode of inheritance of these diseases?

Answer 9

Alcaptonuria, cystonuria, pentosuria, and albinism. They are all autosomal recessive inheritance.

Question 10

Describe albinism. Is it always complete?

Answer 10

Albinism is a lack of pigment in organs and tissues due to deficiency in tyrosine oxidase. It can either by complete (including red eyes) or partial (some organs lack pigment more than others).

Question 11

What are the 4 general clinical features of inborn errors of metabolism?

Answer 11

Poor growth, problems with general metabolism, mental retardation/developmental delay, and neurological problems.

Question 12

What is hyperphenylalaninemia? What are the types?

Answer 12

Hyperphenylalaninemias are errors in phenylalanine metabolism due to phenylalanine hydroxylase activity. There is PKU, variant PKU, and BH4 metabolism defects.

Question 13

In PKU (phenylketonuria), what is the buildup substrate? How is it secreted?

Answer 13

Phenylalanine accumulates in tissues, especially the brain leading to neurological problems. Some can be converted to phenylpyruvic acid and excreted in the urine.

Question 14

What is the treatment course for PKU?

Answer 14

Diet modification with restriction of phenylalanine upon diagnosis. Pregnant mothers must be wary of phenylalanine consumption during pregnancy.

Question 15

What is the difference in PKU and variant PKU and non-PKU hyperphenylalanemia?

Answer 15

These diseases are defects in the same enzyme, but not to the same degree. They may be benign and may not even require a restrictive diet.

Question 16

What is clinical heterogeneity? What is the example?

Answer 16

Mutations in the same gene that present with different phenotypes. PKU and variant PKU is an example.

Question 17

What is non-PKU phenylalaninemia? What is their treatment?

Answer 17

It is a problem with BH4 metabolism, specifically DHPR. These patients do not respond to phenylalanine restrictive diets, but must be given oral BH4 and supplemented L-DOPA and OH-trp as substrates for normal neurotransmitter synthesis.

Question 18

What are lysosomal storage diseases? What is their common clinical presentation?

Answer 18

Mutations in lysosomal hydrolytic enzymes that lead to accumulation of molecules within the lysosome. Effected organs increase in size and there is progressive degeneration.

Question 19

Describe GM2 gangliosidoses.

Answer 19

GM2 gangliosidoses is a 3 component enzyme that functions in the lysosome. Mutation in any of the three enzyme parts can result in disease.

Question 20

What is Tay Sachs disease? What is the buildup product? What population is at risk? What is the outcome?

Answer 20

Tay Sachs results from a mutation in the enzyme hexosaminidase and results in buildup of GM2 ganglioside. Ashkenazi Jews are especially susceptible. Most effected individuals die within two years of life. It is characterized by the “cherry red” spot on the macula and loss of control of the extremities.

Question 21

What is mucopolysaccharidoses?

Answer 21

Diseases that result from the inability to breakdown glycosaminoglycans and thus accumulation in the lysosome.

Question 22

What is the inheritance pattern for mucopolysaccharidoses? What is the exception?

Answer 22

All are autosomal recessive, except Hunter disease which is X-linked recessive.

Question 23

What are the clinical characteristics of mucopolysaccharidoses? What are treatment options?

Answer 23

Short stature, developmental delay, joint stiffness, thickened skin, organ damage, permanent/progressive damage. Treatment may include bone marrow transplant, enzyme replacement, or gene replacement therapy.

Question 24

What is osteogenesis imperfecta? How is it inherited? What are the clinical features?

Answer 24

Osteogenesis imperfecta results from abnormal synthesis of Type I collagen. Its inheritance pattern is autosomal dominant and ranges from classes I-IV. The clinical features are brittle bones, susceptibility to fractures, and skeletal deformities.

Question 25

What is Ehler-Danlos syndrome? How is it inherited? What are the clinical features?

Answer 25

Ehler-Danlos syndrome results from errors in post-translational modification of collagen mostly from COL5A and COL3A genes. It in inherited in multiple ways - autosomal dominant, recessive, and X-linked recessive. Clinically it manifests with skin fagility, joint hypermobility, and skin hyperextenisibility.

Question 26

What is Marfan syndrome? What are the clinical features? What are common health problems with these patients?

Answer 26

Marfan syndrome is a connective tissue disorder resulting from mutation in the fibrillin gene. These individuals are usually tall, thin, and have long thin fingers. They are susceptible to pneumothorax, lens dislocation, myopia, mitral valve prolapse, and aortic dissection.