Genetic Disorders Flashcards
How common are genetic diseases? Are all pediatric diseases genetic? What is the difference between congenital and hereditary diseases?
Extremely common, 67% frequency
Not all manifest in childhood or infancy, many peds diseases are not of genetic origin
Hereditary disorders: derived from parents, transferred through gametes
Congenital disorder: present at birth (does not mean genetic)
What are the 3 types of genetic diseases?
Single gene: mutation in the sequence of one gene, highly penetrant, follow Mendelian
Multifactorial (multigenic): complex interaction of multiple variant forms of genes and environmental factors
Chromosomal: abnormalities in chromosomal structure or numerous alterations (missing, breaks), high penetrant
What are mutations? Name 3 examples.
Permanent change in DNA
Germaine or somatic tisssues
Point: substitution of single nucleotide base
Frameshift: occur when insertion or deletion of one or two base pairs alters the reading frame of the DNA strand
Trinucleotide repeat: amplification of a seq. Of 3 nucleotides, nucleotides have G and C
What are other alterations that can occur in genes beside point, frameshift and trinuleotide repeat?
Alteration in protein coding genes-nonmutations: structural changes (deletions/inversion, translocations), epigenetic changes
Alterations in non coding RNAs: miRNAs and siRNAs
What are single gene defects?
Follow Mendelian
Autosomal dominant: heterozygous expression, males and females equally, receptor and structural proteins affected not enzymes)
Autosomal recessive: both copies mutated, males and females equally, enzyme affected)
X-linked: females to sons who manifest disease, females usually safe due to random inactivation by one X chromosome)
Describe the X inactivation “Lyon Hypothesis”.
Females have only a single active X chromosome in each cell.
In a given cell, which of a female’s X chromosomes becomes inactivated and converted into a Barr body is a matter of chance.
All descendant will have the same chromosome inactive
X-chromosome inactivation creates clones with different
effective gene content.
The Xist gene is expressed at high levels on the Xi and is not expressed on the Xa
A fraction of the genes along the X chromosome escape inactivation on the Xi.
Describe Marfan Syndrome (autosomal dominant, structural protein effects)
Mutation in FBN1 gene encoding firbillin required for structural integrity of connective tissues
Fibrillin secreted by fibroblasts incorporated into microfibrils for elastin
Skeleton (tall, long extremities, kyphosis or scoliosis), eyes (ectopia lentis, elastic zonules, chorioretinal degeneration) and heart (mitral valve, aortic aneurysm, acute aortic dissection) are effected
Mostly familial, some sporadic
describe the sequence of events for Marfan syndrome. What is the treatment?
Abnormal fibrillin→→reduced removal of transforming growth factor ß (TGF-ß)→→excess TGF-ß→→abnormal vascular smooth muscle development and matrix production
Drugs inhibit TGF-b signaling such as angiotensin 2 receptor blockers (Losartin),
What is the most striking ocular manifestation of Marfan’s syndrome?
Enlargement of the globe caused by scleral stretching
Dislocation of lens
Increased axial length
No keratoconus
Describe Ehlers-Danlos Syndrome.
Defects in collagen synthesis or structure →loss of tensile strength
Six variants caused by mutations
Skin, ligaments and joints frequently involved
Clinical findings: fragile, hyperextensible skin vulnerable to trauma, hypermobile joints, and ruptures involving colon, cornea, or large arteries. Wound healing is poor.
What mutation lead to Ehlers-Danlos Syndromes?
Deficiency of the enzyme lysyl hydroxylase (autosomal recessive): enzyme necessary for hydroxylation of lysine residues during collagen synthesis, hydroxylysine is essential for the cross-linking of collagen fibers
Deficient synthesis of type III collagen resulting from
mutations affecting the COL3A1 gene (AD): affect BV and bowel wall
Deficient synthesis of type V collagen due to mutations
in COL5A1 and COL5A2 (AD): Classical EDS
What are the ocular manifestations of ehlers-danlos syndrome?
The eye is made up of 80% collagen
Keratoconus
High Myopia
Blue Sclera
Lens Subluxation
Angioid Streaks
Posterior Staphyloma
Corneal rupture
Describe familial hypercholesterolemia (autosomal dominant) (mutation affecting receptor proteins or channels)
Mutation in LDLR gene encoding LDL
Consequence of impaired transport of LDL into cells (stays in blood)
Increases risk of atherosclerosis, coronary artery disease in heterozygotes
Increase in serum cholesterol and ischemic heart disease for homozygotes
Xanthomas result from cholesterol deposits along tendon sheaths
Homozygotes develop cutaneous xanthomas in childhood and often die of myocardial infarction before the age of 20 years.
Describe cystic fibrosis (autosomal recessive) (receptor proteins or channels)
Mutations in CFTR gene encoding CF transmembrane regulator.
Defect in chloride transport, high salt in sweat and in secretions of respiratory and gastrointestinal
Can be severe (F508) leading to multi system disease or mild
Most common lethal genetic disease, white people
What are the clinical manifestation of CF?
Cardiopulmonary complications (most common cause of death)
Pulmonary infections (resistant pseudomonads)
Pancreatic insufficiency
Infertility
Liver disease
Prone to frequent infection (dehydrated mucous)
