1: Intro to Medical Genetics Flashcards
Mutation: a ______, heritable change in
the sequence of genomic DNA. Mutations can occur at either the molecular or cytogenetic level. _____ is a branch of genetics that is concerned with the study of the structure and function of the cell, especially the chromosomes.
Mutation: a permanent, heritable change in
the sequence of genomic DNA. Mutations can occur at either the molecular or cytogenetic level. Cytogenetics is a branch of genetics that is concerned with the study of the structure and function of the cell, especially the chromosomes.
Indicate whether the following are neutral, positive, or negative mutations:
______: blue eyes
______: sickle cell trait
______: sickle cell disease, cancer
Neutral: blue eyes
Positive: sickle cell trait
Negative: sickle cell disease, cancer
One of the most important effects is that mutation allows change to occur. Individuals can adapt to their environment. New species can arise to fill new environmental niches.
In countries with endemic malaria, individuals with sickle cell trait tend to be healthier than normal individuals who are more susceptible to malaria. Unfortunately, being homozygous for the sickle cell mutation is not a good thing.
Inherited gene complement = mutation _____ in the embryo.
Acquired gene complement - a subset of cells in an individual that arose by clonal _____ from a single mutation in one cell. Clonal proliferation = acquired disease. Mutation ____ in the zygote.
Inherited gene complement = mutation present in the embryo
Acquired gene complement - a subset of cells in an individual that arose by clonal propagation from a single mutation in one cell. Clonal proliferation = acquired disease. Mutation not in the zygote.
Syndrome:
• Set of characteristics which occur ______ and are assumed to have a common basis
• _____ all characters occur in all affected individuals
• Range of _____ within a population
Syndrome:
• 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 those findings. However, for the diagnosis to be made, an individual diagnosed with a particular disorder must have a core group of the cardinal characters associated with that disease.
What is Biochemical Genetics?
Subspeciality of genetics that deals with the diagnosis, treatment, and research of inborn errors of metabolism.
Inborn Errors of Metabolism = Genetically determined biochemical disorder in which a specific ____ defect produces a metabolic block. There is ____ of substrate & deficiency of products.
Alcaptonuria, cystonuria, pentosuria, albinism are all _____ and are autosomal _____.
Inborn Errors of Metabolism = Genetically determined biochemical disorder in which a specific enzyme defect produces a metabolic block. There is accumulation of substrate & deficiency of products.
Alcaptonuria, cystonuria, pentosuria, albinism are all inborn errors of metabolism and are autosomal recessive
Mutation of _____ prevents any biochemical change and the lack of pigment results in an albino. Albinos are highly succeptible to ____ light. Wear clothes & sunglasses. Albinism can be partial (blue eyes) or complete (red eyes).
Mutation of tyrosine oxidase prevents any biochemical change and the lack of pigment results in an albino. Albinos are highly succeptible to UV light. Wear clothes & sunglasses. Albinism can be partial (blue eyes) or complete (red eyes).
Enzymes are not necessarily dedicated to one pathway. They may function in ____ different, related or unrelated pathways. The downside of this is that a single mutation can affect ____ cellular processes.
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.
Inborn Errors of Metabolism:
____ enzyme defect
Autosomal ____
Inborn Errors of Metabolism:
Single enzyme defect
Autosomal recessive
One of the challenges of medicine is to figure out which pathway is affected and sidestep the problem to treat the patient.
The hyperphenylalaninemias are a group of biochemical disorders related to the function of ______ which converts phenylalanine to tyrosine.
PKU (phenylketonuria) is the most common of the three disorders. It occurs when a mutation of phenylalanine hydroxylase (PAH) prevents conversion of phenylalanine (PHE) to tyrosine. This results in an accumulation of _____ in cells. A small fraction of the PHE may then be converted to _____ which can be detected in the urine.
PKU is autosomal _____
PKU Diet = foods ____ in phenylalanine & high in _____.
PKU is the first genetic disease linked specifically to mental retardation.
PHE is an important amino acid and is necessary for normal cell function. However, high levels in the cells can be to_____. Continued high levels damage the nervous system causing developmental delay and brain malfunctions.
The good news is that once diagnosed, patients can be put on a low PHE diet, and, if they stick to the therapy, can be problem free for life. It is particularly important for expectant mothers to maintain the diet because excess PHE can cross the placenta and _____ a developing fetus – even though that fetus may not be affected with PKU him- or herself. It is also critical that the diagnosis be done early in life, and PKU is one of the foundation diseases on newborn screening panels.
The hyperphenylalaninemias are a group of biochemical disorders related to the function of phenylalanine hydroxylase which converts phenylalanine to tyrosine.
PKU (phenylketonuria) is the most common of the three disorders. It occurs when a mutation of phenylalanine hydroxylase (PAH) prevents conversion of phenylalanine (PHE) to tyrosine. This results in an accumulation of PHE in cells. A small fraction of the PHE may then be converted to phenylpyruvic acid which can be detected in the urine.
PKU is autosomal recessive
PKU Diet = foods low in phenylalanine & high in tyrosine.
PKU is the first genetic disease linked specifically to mental retardation.
PHE is an important amino acid and is necessary for normal cell function. However, high levels in the cells can be toxic. Continued high levels damage the nervous system causing developmental delay and brain malfunctions.
The good news is that once diagnosed, patients can be put on a low PHE diet, and, if they stick to the therapy, can be problem free for life. It is particularly important for expectant mothers to maintain the diet because excess PHE can cross the placenta and damage a developing fetus – even though that fetus may not be affected with PKU him- or herself. It is also critical that the diagnosis be done early in life, and PKU is one of the foundation diseases on newborn screening panels.
Different mutations in the phyenylalanine hydroxylase gene. Examples of clinical heterogeneity. Three distinct phenotypes from mutation of a single gene.
Non-PKU hyperphenylalaninemia: 10 fold increase in PKU levels Less damaging, may be benign May ____ require a special diet.
Variant PKU: Between full PKU and non-PKU
hyperphenylalaninemia. _____ a diet, but not as restrictive as PKU patients.
_____ heterogeneity: mutations in different genes can lead to the same clinical phenotype.
In this case, there are several different genes involved in the BH4 pathway, and mutations at any step can knock out BH4 function leading to hyperphenylalaninemia. Because of the addition defect, patients do ____ completely respond to the PKU diet and develop neurological defects. The problem is that BH4 is a cofactor for other enzymes, and its absence in other pathways leads to a deficit of neurotransmitters such as _____ and ______. Treatment here differs from the other hyperphenylalaninemias. PAH is normal, but for it to work, individuals will require oral BH4. Secondly, to normalize the neurotransmitters in the brain, patients require supplementation with the products of the disrupted step. With BH4 deficiency you lose ability to make Tyrosine, Epi & Norepi, & serotonin.
Different mutations in the phyenylalanine hydroxylase gene. Examples of clinical heterogeneity. Three distinct phenotypes from mutation of a single gene.
Non-PKU hyperphenylalaninemia: 10 fold increase in PKU levels Less damaging, may be benign May not require a special diet.
Variant PKU: Between full PKU and non-PKU
hyperphenylalaninemia. Requires a diet, but not as restrictive as PKU patients.
Locus heterogeneity: mutations in different genes can lead to the same clinical phenotype.
In this case, there are several different genes involved in the BH4 pathway, and mutations at any step can knock out BH4 function leading to hyperphenylalaninemia. Because of the addition defect, patients do not completely respond to the PKU diet and develop neurological defects. The problem is that BH4 is a cofactor for other enzymes, and its absence in other pathways leads to a deficit of neurotransmitters such as dopamine and serotonin. Treatment here differs from the other hyperphenylalaninemias. PAH is normal, but for it to work, individuals will require oral BH4. Secondly, to normalize the neurotransmitters in the brain, patients require supplementation with the products of the disrupted step. With BH4 deficiency you lose ability to make Tyrosine, Epi & Norepi, & serotonin.
Lysosomal Storage Diseases: The lysosomes have numerous different enzymes that function to _____ macromolecules. Failure of any one enzyme can have catastrophic consequences. If the macromolecule is not degraded, it cannot be eliminated, so they are stored in the lysosomes. As the organelles become _____, the affected organs and tissues increase in mass.
- autosomal _____
- Mutation of a lysosomal hydrolytic enzyme leads to failure of degradation and the _____ of macromolecules in lysosomes
- Common presentation: progressive degeneration
Lysosomal Storage Diseases: The lysosomes have numerous different enzymes that function to degrade macromolecules. Failure of any one enzyme can have catastrophic consequences. If the macromolecule is not degraded, it cannot be eliminated, so they are stored in the lysosomes. As the organelles become larger, the affected organs and tissues increase in mass.
- autosomal Recessive
- Mutation of a lysosomal hydrolytic enzyme leads to failure of degradation and the accumulation of macromolecules in lysosomes
- Common presentation: progressive degeneration
Tay Sachs = GM2 Gangliosidoses
- Autosomal _____
- _____ except for Ashkenazi Jewish population
- Onset 3-6 months, death 2-4 years
- Deficiency of ______
- Inability to _____ GM2 ganglioside
- No known treatment
One clinically significant finding is the _______ in the retina of the eye. Children become progressively worse, losing control of their extremities, and usually die between the ages of 2 and 4 years of age.
Tay Sachs = GM2 Gangliosidoses
- Autosomal recessive
- Rare except for Ashkenazi Jewish population
- Onset 3-6 months, death 2-4 years
- Deficiency of hexosaminidase A
- Inability to degrade GM2 ganglioside
- No known treatment
One clinically significant finding is the ‘cherry red spot’ in the retina of the eye. Children become progressively worse, losing control of their extremities, and usually die between the ages of 2 and 4 years of age.
The mucopolysaccharidoses are a third group of diseases. This is another example of enzyme failure that results in _____ of the target substance in the lysosomes. In this case, the ______ is a mucopolysaccharide or glycosaminoglycan which are repeating chains of disaccharide subunits. Degradation requires the stepwise _____ of the subunits, starting at one end and moving along the molecule. Each monosaccharide at the end of the chain has a specific enzyme that performs the removal. If that enzyme is absent or defective, the chain will not be degraded. Some of the undegraded macromolecules may be present in the urine which can be screened for diagnosis.
____ stature, delay, skeletal abnormalities and joint stiffness, _____ skin, heart, liver or spleen _____.
Treatment for Mucopolysaccharidoses = Bone marrow ____, Enzyme ____ therapy, & Gene therapy
The mucopolysaccharidoses are a third group of diseases. This is another example of enzyme failure that results in accumulation of the target substance in the lysosomes. In this case, the substrate is a mucopolysaccharide or glycosaminoglycan which are repeating chains of disaccharide subunits. Degradation requires the stepwise removal of the subunits, starting at one end and moving along the molecule. Each monosaccharide at the end of the chain has a specific enzyme that performs the removal. If that enzyme is absent or defective, the chain will not be degraded. Some of the undegraded macromolecules may be present in the urine which can be screened for diagnosis.
Short stature, delay, skeletal abnormalities and joint stiffness, thickened skin, heart, liver or spleen damage.
Treatment for Mucopolysaccharidoses = Bone marrow transplantation, Enzyme replacement therapy, & Gene therapy
Connective tissue disorders are slightly different as the defects affect structural proteins such as collagen and fibrillin.
Osteogenesis imperfecta (OI) is due to mutations in type _ collagen with either reduced collagen production or defective collagen.
There are 4 different classes of OI that range from mild to lethal. All are autosomal _____. The major character is brittle bones and skeletal deformities. Reduced collagen production tends to be the mildest class. Collagen is produced in about half the normal quantity resulting in brittle bones. The three classes of defective collagen production are more severe. OI type __ is a perinatal lethal. Class IV is characterized by mild to moderate bone deformity and fracturing, and Class __ is more severe, being intermediate between Classes II and IV.
Connective tissue disorders are slightly different as the defects affect structural proteins such as collagen and fibrillin.
Osteogenesis imperfecta (OI) is due to mutations in type 1 collagen with either reduced collagen production or defective collagen.
There are 4 different classes of OI that range from mild to lethal. All are autosomal dominant. The major character is brittle bones and skeletal deformities. Reduced collagen production tends to be the mildest class. Collagen is produced in about half the normal quantity resulting in brittle bones. The three classes of defective collagen production are more severe. OI type II is a perinatal lethal. Class IV is characterized by mild to moderate bone deformity and fracturing, and Class III is more severe, being intermediate between Classes II and IV.
