Understanding Genetic Disorders

Genetic Disorders Overview

• A genetic disorder is an illness resulting from one or more genome abnormalities and is present from birth.
• These disorders are rare, affecting one person in thousands or millions.
• Genetic disorders may or may not be heritable, relating to whether they are passed down genetically.
• Defects in non-heritable genetic disorders stem from new mutations or changes to DNA.
• A defect will only be heritable if it occurs in the germ line.

Historical Milestones

• In 1866, Gregor Mendel studied inherited characteristics.
• Francis Crick and James Watson unraveled the DNA molecule.
• The work of Crick and Watson led to understanding the human genome sequence.
• In the 1950s, Maurice Wilkins, Rosalind Franklin, Francis H.C. Crick, and James D. Watson discovered the chemical structure of DNA.
• The discovery of chemical structure of DNA marked the start of molecular biology.
• In 1957, Arthur Kornberg of the U.S. produced DNA in a test tube.
• In 1966, the Genetic code was discovered.
• In 1983, Barbara McClintock discovered that "Genes are able to change position on chromosomes".
• In the late 1980s, a global team of scientists initiated a project to map the human genome.
• In 1990, gene therapy was first used for a patient.

Earliest Evidence

• The oldest evidence of a hereditary genetic disorder discovered is a 1.5 million-year-old fossil.
• The fossil belonged to a two-year-old Homo erectus child.
• Homo erectus was a precursor to modern man.

Classification of Genetic Disorders

• Single gene disorder
• Chromosomal genetic disorder
• Multifactorial genetic disorder

Single Gene Disorders

• Single gene disorders involve mutations in the DNA sequences of single genes.
• These mutations result in an altered or missing protein coded by the gene.
• Over 4000 human diseases are caused by single gene defects.
• Examples include Adenosine deaminase deficiency, Alpha-1 Antitrypsine deficiency, Cystic fibrosis, Galatosemia, Huntington’s disease, Maple syrup urine disease, Phenylketonuria, Severe combined immunodeficiency, Sickle cell disease, and Smith-Lemil-Optiz Syndrome.

Cystic Fibrosis

• Cystic fibrosis is a genetic disorder affecting the respiratory and digestive systems.
• People with cystic fibrosis inherit a defective CFTR gene on chromosome 7.
• CFTR is a cystic fibrosis transmembrane conductance regulator.
• The protein produced by the CFTR gene normally helps salt (sodium chloride) move in and out of cells.
• If the CFTR protein malfunctions, movement is blocked, leading to abnormally thick, sticky mucus outside the cell.
• Lung cells are most seriously affected, as mucus clogs airways and increases the risk of bacterial infections.
• Thick mucus also blocks ducts in the pancreas, preventing digestive enzymes from reaching the intestines.

Galactosemia

• Galactosemia is a rare disorder affecting the body's ability to break down galactose.
• The body breaks down lactose into galactose and glucose, then uses these sugars for energy.
• Most people with galactosemia are missing the GALT enzyme.
• GALT helps to further break down galactose.
• Defects in galactose metabolism lead to a buildup of toxic chemicals in body cells.

Severe Combined Immunodeficiency (SCID)

• SCID is a group of rare and potentially fatal inherited disorders related to the immune system.
• People with SCID have an immune system defect that makes them vulnerable to deadly infections.
• The most common form results from a mutation in the SCIDX1 gene on the X chromosome.
• This gene encodes a protein used to construct the IL2RG (interleukin-2 receptor).
• These receptors are in the plasma membrane of immune cells.
• The job of these receptors is to allow T and B cells to communicate.
• When the gene is mutated, the receptors cannot form and are absent from immune cells.
• The immune cells cannot communicate about invaders in the environment.
• A lack of T and B cells to fight off infections leaves the body defenseless.
• Infections that can result include pneumonia, meningitis, and sepsis.

Sickle Cell Disease

• This disease affects red blood cells.
• Red blood cells use hemoglobin to transport oxygen from the lungs.
• Normally, red blood cells are round and flexible, allowing them to travel freely through narrow blood vessels.
• Hemoglobin molecules contain two parts: an alpha and a beta.
• Sickle cell disease patients have a mutation on chromosome 11.
• The mutation is in a gene that codes for the beta subunit of the hemoglobin protein.
• Hemoglobin molecules do not form properly and red blood cells become rigid.
• Red blood cells rigid shape becomes concave causing it to be like a sickle.

Fibrodysplasia Ossificans Progressiva (FOP)

• Sometimes called "stone man" syndrome.
• FOP is an extremely rare genetic disease.
• FOP causes soft tissue to turn into bone.

Chromosomal Genetic Disorders

• These disorders occur when entire chromosomes or large segments of chromosomes are missing, duplicated, or altered.
• This class can be organized into two basic groups: numerical and structural abnormalities.
• Numerical abnormalities involve missing a chromosome from a pair (monosomy) or having more than two chromosomes of a pair (trisomy).
• Structural abnormalities involve alterations to the chromosome's structure.
• Examples include Cri-Du-Chat, Down Syndrome, 47 XXY Klinefelter Syndrome, Turner Syndrome (Monosomy), and William Syndrome.

Cri-du-chat Syndrome

• The name of this syndrome is French for "cry of the cat" due to the distinctive cry of affected children.
• The cry results from abnormal larynx development, one of the symptoms of this disorder.
• Cri-du-chat is caused by a deletion on the short arm of chromosome 5.
• Multiple missing genes result from this deletion.
• Babies with Cri-du-chat are usually small at birth and may suffer from respiratory problems.
• In those affected, the larynx does not develop correctly, which leads to a signature cat-like cry.

Down Syndrome

• Down syndrome is a developmental disorder caused by an extra copy of chromosome 21 (trisomy 21).
• Having an extra copy of this chromosome means that individuals have three copies of each of its genes instead of two.
• Three copies of each gene makes it difficult for cells to properly control how much protein is made
• Producing too much or too little protein can have serious consequences.
• Common features include a flat face, small broad nose, abnormally shaped ears, a large tongue, and upward slanting eyes with small folds of skin in the corners.
• Risks of medical problems include: respiratory infections, gastrointestinal tract obstruction, leukemia, heart defects, hearing loss, hypothyroidism, and various eye abnormalities.
• There is no cure, but physical and/or speech therapy can help people develop more normally.

Klinefelter Syndrome

• Males are (46, XY) and females (46, XX).
• The genetic condition caused when someone has two X chromosomes and one Y chromosome means they have 47, XXY.
• People with an XXY chromosome arrangement have a Y chromosome, they are considered genetic males.
• Usually XXY individuals develop as males and often do not know they have an extra chromosome.
• Typically, XXY is caused by nondisjunction, where a pair of sex chromosomes fails to separate during egg (or sperm) formation.
• The XXY chromosome arrangement primarily affects sexual development.
• Testes typically do not fully develop, and testosterone hormone levels (important for male sexual development) are lower than average.
• As adults, XXY males are usually unable to make sperm and cannot have biological children.
• Many men only discover their condition after seeking medical help for infertility.
• Changes that appear at puberty include low growth of facial and body hair, breast tissue, and small testes.

Turner Syndrome

• Turner syndrome is caused by a missing or incomplete X chromosome.
• People with Turner syndrome develop as females.
• The genes affected are involved in growth and sexual development.
• Girls with the disorder are shorter than normal and have abnormal sexual characteristics.

Williams Syndrome

• Williams syndrome is a rare genetic disorder.
• Williams syndrome affects a child's growth, physical appearance, and cognitive development.
• People with Williams syndrome are missing genetic material from chromosome 7, including the elastin gene.

Colorblindness

• Mutated genes are located on the X chromosome (for red/green color blindness) or both the X and Y chromosomes (for total color blindness).

Multifactorial Disorders

• These disorders involve variations in multiple genes, often coupled with environmental causes.
• Examples include: Alzheimer's Disease, Breast/Ovarian Cancer, Colon Cancer, Hypothyroidism, Asthma, cancers, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mood disorder, obesity, refractive error, and infertility.

Alzheimer's Disease

• Alzheimer's is a disease that causes dementia, or loss of brain function.
• It affects parts of the brain that deal with memory, thought, and language.
• The brain of a person with Alzheimer's contains abnormal clumps of cellular debris and protein (plaques) and collapsed microtubules (support structures of the cell).
• Microtubule disintegration results from a malfunctioning protein called tau.
• Tau normally stabilizes the microtubules.
• In Alzheimer's patients, tau proteins cluster together to form disabling tangles, damaging healthy cells.
• Because this disease destroys brain cells, people slowly lose their ability to think clearly.
• At first, they may forget words or names or have trouble finding things.
• As the disorder worsens, they may forget how to do simple tasks.