Unit #9: Genetic and Developmental Disorders ( Flashcards
Define: Chromosome
A linear thread of nuclear DNA that becomes visible under the microscope during cell mitosis.
Define: Genes
A unit of heredity consisting of a segment of DNA nucleotides that encodes a messenger RNA capable of being translated into a protein.
Define: Alleles
One of two or more alternative forms of a gene located at the same site on the homologous chromosomes.
Define: Heterzygous
Having two different alleles for a specific gene product.
Define: Homozygous
Having two identical alleles for a specific gene product.
Define: Mutation/abberation
A heritable change in the nucleotide sequence of a chromosome; it is passed on to daughter cells when the cells divide.
Define: Genotype
The genetic constitution of an individual; often described by listing the allele types at a certain gene locus.
Define: Phenotype
The physical, biochemical, and biological composition of an individual; expressed as a recognizable trait.
Define: Congenital defect
A general term meaning a defect in form or function that is present at birth.
Define: Teratogen
An agent or factor that causes damage or physical defects in a developing embryo.
Describe: Chromosomal disorders
- Generally occur due to an abnormal number of chromosomes or alterations in the structure of one or more chromosomes.
- Errors in separation of chromosome during meiosis may result in abnormal numbers of chromosomes
- Can be tested for during pregnancy
Describe: Autosomal dominant disorders
- Dominant inheritance means an abnormal gene from one parent can cause disease. This happens even when the matching gene from the other parent is normal. The abnormal gene dominates.
- This disease can also occur as a new condition in a child when neither parent has the abnormal gene.
- A parent with an autosomal dominant condition has a 50% chance of having a child with the condition. This is true for each pregnancy.
Describe: Autosomal recessive disorders
- An autosomal recessive disorder means two copies of an abnormal gene must be present in order for the disease or trait to develop.
- Recessive inheritance means both genes in a pair must be abnormal to cause disease. People with only one defective gene in the pair are called carriers. These people are most often not affected with the condition. However, they can pass the abnormal gene to their children.
Describe: Sex-linked (X-linked) disorders
- Sex-linked diseases are passed down through families through one of the X or Y chromosomes.
- Dominant inheritance occurs when an abnormal gene from one parent causes disease even though the matching gene from the other parent is normal. The abnormal gene dominates.
- But in recessive inheritance, both matching genes must be abnormal to cause disease. If only one gene in the pair is abnormal, the disease does not occur or it is mild. Someone who has one abnormal gene (but no symptoms) is called a carrier. Carriers can pass abnormal genes to their children.
- The term “sex-linked recessive” most often refers to X-linked recessive.
- X-linked recessive diseases most often occur in males. Males have only one X chromosome. A single recessive gene on that X chromosome will cause the disease.
- The Y chromosome is the other half of the XY gene pair in the male. However, the Y chromosome doesn’t contain most of the genes of the X chromosome. Because of that, it doesn’t protect the male. Diseases such as hemophilia and Duchenne muscular dystrophy occur from a recessive gene on the X chromosome.
- females can get an X-linked recessive disorder, but this is very rare. An abnormal gene on the X chromosome from each parent would be required, since a female has two X chromosomes.
Describe: Multifactorial (Polygenic) disorders
- Polygenic traits develop in response to more than one gene.
- Multifactorial disorders are very common and result from the interaction of multiple genes and environmental influences. Disorders such as high blood pressure, cancer, and diabetes are multifactorial.
What is the pathogenesis of Down Syndrome?
• An extra chromosome 21 from meiotic non-disjunction or failure of the chromosome pairs to separate during gamete formation is present in about 95% of individuals with DS. Population-based studies show that over 90% of non-disjunction errors leading to trisomy 21 occur in the oocyte and predominantly in maternal meiosis I.
What is the clinical manifestation of Down Syndrome?
- Decreased or poor muscle tone
- Short neck, with excess skin at the back of the neck
- Flattened facial profile and nose
- Small head, ears, and mouth
- Upward slanting eyes, often with a skin fold that comes out from the upper eyelid and covers the inner corner of the eye
- White spots on the colored part of the eye (called Brushfield spots)
- Wide, short hands with short fingers
- A single, deep, crease across the palm of the hand
- A deep groove between the first and second toes
What is the pathogenesis of Turner Syndrome?
- Turner syndrome is associated with the presence of only one normal X chromosome and no Y chromosome.
- The absence of the Y chromosome results in a female phenotype; the overaires fail to develop or fail prematurely.
- In some cases the second X chromosome is not entirely missing but is structurally abnormal.
- In most cases the missing or damaged X chromosomes is of paternal origin
What is the clinical manifestation of Turner Syndrome?
- Short stature
- Webbing of the neck
- A wide chest
- Lymphedema of the hands and feet at birth
- Congenital heart defects
- Failure to develop secondary sexual characteristics
What is the pathogenesis of Klinefelter Syndrome?
- Individuals with this disorder usually have an extra X chromosome (an XXY genotype).
- There have also been cases of more than one extra X chromosome (XXXY and XXXXY).
- The presence of the Y chromosomes determines the sex of the individuals to be male, however, if there is an extra X chromosome it results in abnormal sexual development and feminization
- Rarely diagnosed before puberty
What is the clinical manifestation of Klinefelter Syndrome?
- Lack of testosterone (testicular atrophy and infertility)
- Tall stature with long arms and legs
- Feminine hair distribution
- Gynecosmastia (breast enlargement)
- High-pitched voice
- Impaired intelligence
What is the pathogenesis of Cystic Fibrosis?
• Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces.
Clinical Manifestation
What is the clinical manifestation of Cystic Fibrosis?
- Severe chronic lung disease
- Exocrine pancreatic insufficiency
- Nasal polyposis
- Pansinusitis
- Rectal prolapse
- Chronic diarrhea
- Cholelithiasis
- Cirrhosis or other forms of hepatic dysfunction
What is the pathogenesis of Huntington Disease?
- Huntington disease (HD) is an incurable, adult-onset, autosomal dominant inherited disorder associated with cell loss within a specific subset of neurons in the basal ganglia and cortex.
- The most striking neuropathology in HD occurs within the neostriatum, in which gross atrophy of the caudate nucleus and putamen is accompanied by selective neuronal loss and astrogliosis. Marked neuronal loss also is seen in deep layers of the cerebral cortex. Other regions, including the globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and cerebellum, show varying degrees of atrophy depending on the pathologic grade.
- The genetic basis of HD is the expansion of a cysteine-adenosine-guanine (CAG) repeat encoding a polyglutamine tract in the N-terminus of the protein product called huntingtin
What are the clinical manifestations of Huntington’s disease?
- Involuntary jerking or writhing movements (chorea)
- Muscle problems, such as rigidity or muscle contracture (dystonia)
- Slow or abnormal eye movements
- Impaired gait, posture and balance
- Difficulty with the physical production of speech or swallowing
- Difficulty organizing, prioritizing or focusing on tasks
- Lack of flexibility or the tendency to get stuck on a thought, behavior or action (perseveration)
- Lack of impulse control that can result in outbursts, acting without thinking and sexual promiscuity
- Lack of awareness of one’s own behaviors and abilities
- Slowness in processing thoughts or ‘‘finding’’ words
- Difficulty in learning new information
- Feelings of irritability, sadness or apathy
- Social withdrawal
- Insomnia
- Fatigue and loss of energy
- Frequent thoughts of death, dying or suicide
What is the pathogenesis of Marfins Disease?
- Marfan syndrome is a connective-tissue disease inherited in an autosomal dominant manner and caused mainly by mutations in the gene FBN1. This gene encodes fibrillin-1, a glycoprotein that is the main constituent of the microfibrils of the extracellular matrix. Most mutations are unique and affect a single amino acid of the protein.
- Marfan-type fibrillin I appear to be more susceptible to proteolytic degradation than normal fibrillin, which leads to the weakened connective tissue.
What are the clinical manifestations of Marfins Disease?
- Tall and slender build.
- Disproportionately long arms, legs and fingers.
- A breastbone that protrudes outward or dips inward.
- A high, arched palate and crowded teeth.
- Heart murmurs.
- Extreme nearsightedness.
- An abnormally curved spine.
- Flat feet
What is the pathogenesis of cleft lip/palate?
- In facial morphogenesis, neural crest cells migrate into the facial region, where they form the skeletal and connective tissue and all dental tissues except the enamel. Vascular endothelium and muscle are of mesodermal origin
- The upper lip is derived from medial nasal and maxillary processes. Failure of merging between the medial nasal and maxillary processes at 5 weeks’ gestation, on one or both sides, results in cleft lip. CL usually occurs at the junction between the central and lateral parts of the upper lip on either side. The cleft may affect only the upper lip, or it may extend more deeply into the maxilla and the primary palate. (Cleft of the primary palate includes CL and cleft of the alveolus.) If the fusion of palatal shelves is impaired also,
What are the clinical manifestations of cleft lip/palate?
• A child may have one or more birth defects.
• A cleft lip may be just a small notch in the lip. It may also be a complete split in the lip that goes all the way to the base of the nose.
• A cleft palate can be on one or both sides of the roof of the mouth. It may go the full length of the palate.
Other symptoms include:
• Change in nose shape (how much the shape changes varies)
• Poorly aligned teeth
• Problems that may be present because of a cleft lip or palate are:
• Failure to gain weight
• Feeding problems
• Flow of milk through nasal passages during feeding
• Poor growth
• Repeated ear infections
• Speech difficulties
How do drugs and chemicals have an effect on a developing fetus/embryo?
- Chemicals and drugs that have been proven to have an effect on developing embryo/fetus includes thalidomide, alcohol, anticonvulsants, warfarin, foliate antagonists, androgenic hormones, angiotensin-converting enzyme inhibitors, and organic mercury.
- May increase the incidence of congenital limb deformities
- Associated with a very high risk of fetal malformation, both mild and extreme deformities occur.
- Alcohol consumption may lead to FAS (fetal alcohol syndrome) which may cause growth retardation, developmental delay, learning and behavioural problems, malformations of the head and face, and cardiac defects.
How do infectious agents have an effect on a developing fetus/embryo?
- Many prenatal infections have been implicates in the development of congenital malformations.
- The gestational age of the fetus at the time of the infection is critically important
- The acronym TORCH was developed to alert clinicians to the potential teratogenicity of these infections.
- TORCH stands for Toxoplasmosis, Others, Rubella, Cytomegalovirus, Herpes.
- The other category includes things such as hepatitis B, coxsackievirus B, mumps, poliovirus, and others.
- All of the microorganisms of the TORCH complex may cross from the placenta to the fetus.
- Infants who do not contract the virus while in utero may still contract it while traveling through the birth canal.
How does radiation have an effect on a developing fetus/embryo?
• Malformations in children with mothers who underwent irradiation of the cervix for cancer and in children whom were atomic bomb victims in World War II. It is recommended that women avoid any type of radiation during pregnancy or uses appropriate protection.
