Essentials of Pathophysiology-chapter 5

autosomal dominant disorders

"Autosomal" means that the gene in question is located on one of the numbered, or non-sex, chromosomes. "Dominant" means that a single copy of the disease-associated mutation is enough to cause the disease.

Mosaicism

in genetics, the presence in an individual or in an organism of cell cultures having two or more cell lines that different in genetic constitution but are derived from a single zygote

Neurofibromatosis

50% autosomal dominant; 50% mutation chromosome 17 condition that causes tumors to develop from the Schwann cells (nerve cells) of the neurologic system 2 forms: Type 1 NF--von Recklinghausen disease and Type 2 NF-- bilateral acoustic (NF-2) Clinical manifestations: Lisch nodules (gold flecks in the eyes) cafe au lait spots greater than 1.5 cm optic gliomas neurological issues multiple neural tumors anywhere on the body soft pendunculated lesions Pheochromocytomas - tumor on the adrenals

ultrasonography

A noninvasive technique involving the formation of a two-dimensional image used for the examination and measurement of internal body structures and the detection of bodily abnormalities

What does autosomal dominant mean?

A pattern of inherited characteristics of some genetic diseases. "Autosomal" means that the gene in question is located on one of the numbered, or non-sex, chromosomes. "Dominant" means that a single copy of the disease-associated mutation is enough to cause the disease.

Turner Syndrome

ANEUPLOIDY A chromosomal disorder in females in which either an X chromosome is missing, making the person XO instead of XX, or part of one X chromosome is deleted. Most frequently occurring genetic disorder in women. clinical manifestations: type of dwarfism--short stature, normal body proportions, no secondary sex characteristics, infertile, small webbed neck, lymphedema of hands and feet, broad chest with widely placed nipples and poor breast development, multiple pigmented nevi, coarctation of aorta and bicuspid valve, wide carrying angle of arms

Klinefelter syndrome

ANEUPLOIDY condition of testicular dysgenesis extra X chromosomes (47, XXY) clinical manifestations: tall stature, lack of facial hair, narrow shoulders, long arms and legs, gynecomastia, wide hips, decreased pubic hair, testicular atrophy and infertility, language impairment

aneuploidy

Abnormal number of chromosomes 3 types: nondisjunction (45 or 47 chromosomes), monosomy- Turner's (presence of only one member of a chromosome pair-often lean to miscarriage), polysomy-klinefelter (presence of more than 2 chromosomes to a set); trisomy-Down Syndrome (presence of more than 3)

Describe the prenatal testing that can be done for fetal genetic defects.

Amniocentesis and chorionic villus sampling

recessive allele

An allele whose phenotypic effect is not observed in a heterozygote.

Autosomal recessive disorders

Both parents (unaffected) must pass on the defective gene to produce an affected child characterized by loss-of-function mutations: impair or eliminate the function of an enzyme examples: enzyme disorders that disrupt the catabolic pathways--PKU, lysosomal storage diseases; defect in the enzyme-mediated synthesis of an essential protein--cystic fibrosis and Tay-Sachs disease

What does autosomal recessive mean?

Both parents must pass on the same affected gene in order for the child to have the disease If one of your parents passes on a recessive gene to you that can cause disease, then you become a "carrier." You likely won't have any symptoms, since the other gene is normal

What causes cleft palate/cleft lip?

Cleft lip and cleft palate are thought to be caused by a combination of genes and other factors, such as things the mother comes in contact with in her environment, or what the mother eats or drinks, or certain medications she uses during pregnancy.

What are the manifestations of FAS?

Distinctive facial features, including small eyes, an exceptionally thin upper lip, a short, upturned nose, and a smooth skin surface between the nose and upper lip. Deformities of joints, limbs and fingers. Slow physical growth before and after birth. Vision difficulties or hearing problems

Turner's syndrome

Etiology: a condition that affects only females, results when one of the X chromosomes (sex chromosomes) is missing or partially missing; Monosomy; Mosaicism; X chromosome abnormalities; and Y chromosome material Clinical Manifestations: short stature and non-functioning ovaries which causes infertility, some women may also have extra skin on the neck (webbed neck), puffiness or swelling (lymphedema) of the hands and feet, skeletal abnormalities, heart defects, high blood pressure, and kidney problems Risk Factors: The loss or alteration of the X chromosome occurs randomly. Sometimes, it's because of a problem with the sperm or the egg, and other times, the loss or alteration of the X chromosome happens early in fetal development. Family history doesn't seem to be a risk factor, so it's unlikely that parents of one child with Turner syndrome will have another child with the disorder.

Down's Syndrome (Trisomy 21)

Etiology: a genetic disorder caused when abnormal cell division results in an extra full or partial copy of chromosome 21 Clinical Manifestations: Flattened face Small head Short neck Protruding tongue Upward slanting eye lids (palpebral fissures) Unusually shaped or small ears Poor muscle tone Broad, short hands with a single crease in the palm Relatively short fingers and small hands and feet Excessive flexibility Tiny white spots on the colored part (iris) of the eye called Brushfield's spots Short height Risk Factors: advanced maternal age, Being carriers of the genetic translocation for Down syndrome, Having had one child with Down syndrome

Marfan's syndrome

Etiology: caused by a defect in the gene affecting fibrillin 1 production that enables your body to produce a protein that helps give connective tissue its elasticity and strength. Clinical Manifestations: 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 Risk Factors: affects men and women equally and occurs among all races and ethnic groups. Because it's a genetic condition, the greatest risk factor for Marfan syndrome is having a parent with the disorder.

Neurofibromatosis

Etiology: caused by genetic defects on gene NF1, NF2 and Schwannomatosis Clinical Manifestations: Neurofibromatosis 1- Flat, light brown spots on the skin (cafe au lait spots) freckling in the armpits or groin area tiny bumps on the iris of the eye (Lisch nodules0 soft, pea-sized bumps on or under the skin (neurofibromas) bone deformities tumor on the optic nerve (optic glioma) learning disabilities short stature Neurofibromatosis 2 gradual hearing loss ringing in the ears poor balance numbness and weakness in the arms or legs pain balance difficulties facial drop vision problems or cataracts seizures headache Schwannomatosis chronic pain, which can occur anywhere in the body can be disabling numbness or weakness in various parts of the body loss of muscle

When is a fetus most susceptible to congenital defects?

In general, major defects of the body and internal organs are more likely to occur between 3 to 12 embryo / fetal weeks. This is the same as 5 to 14 gestational weeks (weeks since the first day of your last period). This is also referred to as the first trimester

How and when does fetal alcohol syndrome occur?

It is in the third week after fertilization that specific alcohol-induced birth defects begin to affect the developing embryo. FASDs are caused by a woman drinking alcohol during pregnancy

Infectious agents

TORCH (toxoplasmosis, other, rubella, cytomegalovirus, herpes; varicella-zoster, Epstein-Barr virus, tuberculosis, syphilis clinical manifestations: growth retardation and abnormalities of the brain, eye, ear, liver, hematopoietic system, lungs and heart

chemicals and drugs

cross the placenta and cause damage to the developing embryo and fetus examples: high levels of mercury, lipid-soluble pharmaceuticals (thalidomide), high doses of vitamin A and retinoids

What are the manifestations and long term complications of PKU?

Untreated PKU can lead to: Irreversible brain damage and marked intellectual disability beginning within the first few months of life. Neurological problems such as seizures and tremors. Behavioral, emotional and social problems in older children and adults.

Mitochondrial Gene Disorders

XY-linked only affect the neuromuscular system and produce disorders such as encephalopathies, myopathies, retinal degeneration, loss of extraocular muscle function and deafness disease examples: chronic progressive external ophthalmoplegia, deafness, kearns-sayre syndrome, leber hereditary optic neuropathy, Leigh disease, MELAS, MERRF, Myoclonic epilepsy with ragged red fibers

teratogenic agents

a chemical, physical or biologic agent that produces abnormalities during embryonic or fetal development causes birth defects in 3 ways: (1) by direct exposure of the pregnant female and the embryo or fetus to the agent, (2) through exposure of the soon to be pregnant female to an agent that has a slow clearance, (3) as a result of mutagenic effects of an environmental agent that occur before pregnancy, causing permanent damage to a female's or a male's reproductive cells 3 groups: radiation, drugs and chemical substances, infectious agents

encephalopathies

a disease in which the functioning of the brain is affected by some agent or condition (such as viral infection or toxins in the blood).

maternal serum markers

a prenatal screening test using blood from the mother that can help identify women who may be carrying a baby with certain types of birth defects (such as neural tube defects, Down syndrome, and trisomy 18 syndrome) AFP is elevated in the amniotic fluid when an NTD has occurred; whereas decreased levels are associated with trisomy 21 high levels of hCG indicates trisomy 21 unconugated estriol levers are decreased in trisomy 21 and trisomy 18 (Edward's Disease)

structural chromosomal abnormalities

a result of chromosomal breakage due to exposure to radiation, influence of certain chemicals, extreme changes in the cellular environment and viral infections

tinnitus

a tinkling, buzzing or ringing noise heard in one or both ears

What are sex-linked genetic characteristics?

a trait in which a gene is located on a sex chromosome. In humans, the term generally refers to traits that are influenced by genes on the X chromosome. ... In a sex-linked disease, it is usually males who are affected because they have a single copy of X chromosome that carries the mutation.

cleft lip and cleft palate

abnormal facial appearance and defective speech may be unilateral or bilateral occurs on day 35 when craniofacial and maxillary bones fuse causes speech and feeding issues

chromosomal disorders

account for a large proportion of early miscarriages, congenital malformation and intellectual disability

X-linked dominant disorders

affect both males and females inherited from mom examples: fragile X syndrome and Rett syndrome

X-linked recessive disorders

affects only males, passed on from mother who is carrier of the gene Examples: color blindness, G6PD Deficiency, hemophilia A and X-linked agammaglobulinemia

Disorders due to environmental influences

alcohol: fetal alcohol syndrome radiation in heavy doses: microcephaly, skeletal abnormalities, intellectual disabilities vitamin A overdose (accutane): cleft palate, heart defects, retinal/optic nerve damage, CNS malformations thalidomide: Phocomelia (malformations of the arms and legs), eyes, ears, heart, renal, GI abnormalities, cleft palate, facial nerve, skeletal

PKU

an autosomal recessive metabolic disorder leads to toxic levels of phenylalanine in the brain due to inability of the body to convert metabolite accumulates caused by a deficiency of the liver enzyme phenylalanine hydroxylase, which allows toxic levels of the amino acid, phenylalanine to accumulate in tissues and the blood Clinical manifestations: mental retardation, microcephaly, delayed speech and signs of impaired neurologic development, seizures, eczema, musty body odor treatment: modified diet with little protein

Marfan Syndrom

autosomal dominant disorder of the connective tissue affects gene controlling fibrillin 1 production chromosome 15 signs and symptoms affect: eyes (bilateral dislocation of the lens, myopia and predisposition of retinal detachment) the cardiovascular system (mitral valve prolapse, progressive dilation of the aortic valve ring and weakness of the aorta and other arteries, dissection and rupture of the aorta may lead to premature death) the skeletal system (long, thin body with exceptionally long extremities and long, tapering fingers sometimes called arachnodactyly or spider finger; hyper-extensible joints and a variety of spinal deformities including kyphosis and scoliosis, chest deformities, pectus excavatum-deeply depressed sternum, or pigeon chest deformity)

gene mutation

biochemical event that produces a new allele for a particular gene

congenital defects

birth defects; abnormalities of a body structure, function or metabolism that are present at birth; leading cause of infant death

What is a multifactorial genetic disorder?

caused by a combination of environmental factors and mutations in multiple genes

How does phenylketonuria occur?

caused by a defect in the gene that helps create the enzyme needed to break down phenylalanine. Without the enzyme necessary to process phenylalanine, a dangerous buildup can develop when a person with PKU eats foods that contain protein or eats aspartame, an artificial sweetener.

Single-gene disorders

caused by a defective or mutant allele at a single gene locus and follow mendelian patterns of inheritance

Genetics and Clinical Manifestations of Tay Sachs Disease

caused by mutations in the HEXA gene; the HEXA gene provides instructions for making part of an enzyme called beta-hexosaminidase A, which plays a critical role in the brain and spinal cord Characteristic features include muscle weakness, loss of muscle coordination (ataxia) and other problems with movement, speech problems, and mental illness

Tay-Sachs Disease

caused by the absence of an enzyme that helps break down fatty substances. These fatty substances, called gangliosides, build up to toxic levels in the child's brain and affect the function of the nerve cells autosomal recessive chromosome 15 a genetic lysosomal storage disease, in which there is a failure to break down the GM2 gangliosides of cell membranes lipid accumulation in lysosomes due to deficient of lysosomal enzyme hexosaminidase A Jews 1:30 clinical manifestations: rapid deterioration in muscular weakness, muscle flaccidity, decreased responsiveness starting at 6-10 months of age, generalized seizures, visual impairment and blindness exaggerated startling of noise

inherited multifactorial disorders

caused by the influence of multiple genes along with environmental factors leads to disorders later in life: CHD, cancer, DM HTN, mental illness examples: cleft lip or palate, clubfoot, congenital dislocation of the hip, congenital heart disease, pyloric stenosis and urinary tract malformation 1. involve a single organ or tissue 2. risk of recurrence in future pregnancies is high 3. 1st degree relatives have an increased risk of having a child with the disease

Type 1 NF

common disorder, characterized by cutaneous and subcutaneous neurofibromas soft, pedunculated (tumor or growth on a stalk) lesions that project from the skin

Kleinfelter's syndrome

etiology: isn't inherited, rather a genetic condition that results when a boy is born with an extra copy of the X chromosome Clinical Manifestations: Many boys with Klinefelter syndrome show few or only mild signs. The condition may go undiagnosed until adulthood or it may never be diagnosed. For others, the condition has a noticeable effect on growth or appearance; low testosterone and reduced muscle mass, facial hair, and body hair. Most males with this condition produce little or no sperm Risk Factors: the risk of Klinefelter syndrome isn't increased by anything a parent does or doesn't do. For older mothers, the risk is higher but only slightly.

genotype

genetic composition of a person

Polymorphism

if more than one allele occupies that gene's locus within a population

folic acid deficiency

implicated in the development neural tube defects Anencephaly: missing forebrain, cerebrum spina bifida: incomplete neural tube closure (splitting of spine or gap in the vertebrae)

amniocentesis

invasive diagnostic procedure that involves the withdrawal of a sample of amniotic fluid from the pregnant uterus useful in women with an elevated risk on first trimester and quad screening, abnormal fetal findings on sonogram or in parents with histories of birth defects conducted after 15 weeks of gestation

percutaneous umbilical cord blood sampling

involves the transcutaneous insertion of a needle through the uterine wall and into the umbilical artery conducted after 16 weeks gestation used to diagnose hemoglobinopathies, coagulation disorders, metabolic and cytogenetic disorders and immunodeficiencies

Myelomeningocele (spina bifida)

most severe form of spina bifida in which the spinal cord and meninges protrude through the spine

pyloric stenosis

narrowing of the opening of the stomach to the duodenum

Codominance allele

neither allele is recessive and the phenotypes of both alleles are expressed.

cytogenetic and DNA analyses

obtained through amniocentesis and chorionic villus sampling used to detect abnormalities of chromosome number and structure

Down Syndrome (trisomy 12)

occurs as a result of a Robertsonian translocation abnormality on the 21st chromosome most common chromosomal disorder risks increase with maternal age distinct physical characteristics: small, square head, flat facial profile, small nose, depressed nasal bridge, small folds on the inner corners of the eyes and upward slanting of the eyes; small, low-set and malformed ears, fat pad at the back of the neck, an open mouth, large and protruding tongue; short, broad hands with simian crease; wide gap between 1st and 2nd toes; congenital heart defects and increased risk of GI malformations; increased risk of Alzheimer disease and acute lymphoblastic leukemia prenatal screening tests: blood tests--AFP, hCG, unconjugated estriol, inhibin A and pregnancy-associated plasma protein A

aleles

one of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome.

organogenesis

organ formation that takes place during the first two months of prenatal development and is the most vulnerable period of development

gene penetrance

penetrance is expressed in mathematical terms: a 50% penetrance indicates that a person who inherits the defective gene has a 50% of getting the disease 2 types: reduced penetrance and variable penetrance examples: Marfan syndrome, Huntington Disease and neurofibromatosis

fetal alcohol syndrome

physical and cognitive abnormalities in children caused by a pregnant woman's drinking clinical features: microephaly, epicanthal folds, smooth philtrum, small chin, flat nasal bridge, small palpebral, short nose and thin vermillion border

phenotype

physical expression of a genotype in terms of physical or biochemical traits

chronic villus sampling

sampling of placental tissues for prenatal diagnosis of potential genetic defects conducted transabdominal or transcervical conducted after 10 weeks gestation

Fragile X Syndrome

single-gene disorder that causes intellectual disability most common form of inherited intellectual disability Pathogenesis: mapped to FMR1 site clinical manifestations and diagnosis: boys are intellectually disabled, long face with large mandible and large, everted ears, hyperextensible joints, a high-arched palate and mitral valve prolapse; girls have normal cognitive development or a learning disability

cytogenetics

study of chromosomal disorders

Radition

teratogenic and mutagenic agent causes microcephaly, skeletal malformations and mental retardation

Type 2 NF

tumors of the acoustic nerve, asymptomatic until 15 years old symptoms include headaches, hearing loss and tinnitus

Prenatal screening methods

ultrasonography, maternal serum markers, amniocentesis, chorionic villus sampling, percutaneous umbilical cord blood sampling and cytogenetic and DNA analyses

dominant allele

when the trait is phenotypically seen in the heterozygote