Unit 1 Diseases Flashcards
Alcaptonuria
Type: inborn errors of metabolism
accumulation of homogentisic acid in the blood; damage to cartilage, heart, kidney
Phenylketonuria (PKU)
Type: inborn errors of metabolism
o Most common o Mutation of phenylalanine hydroxylase o Accumulation of phenylalanine (essential a.a. but becomes too large in quantity) o Excretion of phenylpyruvic acid o Autosomal recessive o Treat by diet modification • Low PHE diet o Especially during pregnancy, high PHE in mother would be toxic to fetus (can cross the placenta) o Linked to mental retardation
Down Syndrome
Trimsomy 21
o Most common cause of mental retardation o Clinical features: • Incidence: 1/700 live births • Short stature • Low set ears • Microcephaly • Mental retardation • Up slanting eyes • Short hands • Eye folds • Protruding tongue • Usually infertile o Multiple System Defects • Heart, brain, endocrine system (infertility), susceptibility to infectious disease, increased risk of leukemia • High frequency of Alzheimer disease o More problems arise as individual ages o Although most are infertile, some have been known to reproduce sexually
Patau syndrome
Trisomy 13
o Features: • Failure to thrive • Cleft lip and palate • Rocker bottom feet • Polydactyly - condition in which a person has more than five fingers per hand or five toes per foot. • “punched-out” scalp • small head • Heart defect
Edwards syndrome
Trisomy 18
o Incidence: ~1/8000 live births o Features: • Low birth weight • Small mouth/jaw • Ventricular septal defect • Hypoplasia of muscles • Prominent occiput • Low-set malformed ears • Rocker bottom feet • Crossed fingers (CHARACTERISTIC HAND SIGN)
Hereditary Non-Polyposis Colon Cancer (HNPCC)
o The most common form of hereditary colon cancer, can be caused by mutations in any one of the seven mismatch repair genes
o Mutations in these genes cause the so-called “mutator phenotype”
Ataxia Telangiectasia (A-T)
Defect in the replication stress response network
o Susceptible to lymphomas
o Ataxia (abnormalities of balance), dilation of blood vessels (telangiectases) in skin and eyes, chromosome abberations, immune dysfunction
o Sensitive to gamma irradiation
o Mutations in the gene ATM, a protein kinase that is important for replication stress response and regulates p53, causing its accumulation
Bloom syndrome
Defect in the replication stress response network
o Susceptible to carcinomas, leukemias and lymphomas
o Facial telangiectases, chromosome alterations
o Sensitive to mild alkylating agents
o Caused by mutations in the BLM gene, a RecQ helicase, that functions in replication stress response
Xeroderma pigmentosum (XP)
o Severe predisposition to skin cancers
o Seven genetic complementation groups have been identified associated w/ defective NER (nucleotide excision repair)
o Loss of function in XPV also results in XP, but is not associated w/ NER but w/ defects in lesion bypass of UV-induced damage
XXX Female
- Usually due to maternal meiosis I error
- Average to tall stature (other than this, no striking features that would indicate a chromosomal abnormality)
- Learning deficit possible
- Some fertility problems possible
- Often go undetected throughout life
- Generally have chromosomally normal children
- Look phenotypically female
XYY Male
• Failure of paternal meiosis • Tall stature • Normal intelligence • Normal fertility • Clinical indistinguishable from 46,XY o Clinically normal • No Y-inactivation • Often go undetected throughout life
Klinefelter syndrome
47,XXY
- 50% due to meiosis I error in father
- Tall stature and thin
- Infertility – usually due to hyalinized testicular tubules
- Some female characteristics may develop: female-like breast development
- Learning deficit possible
- Most common reason for referral: post pubertal hypogonadism
Turner syndrome
45,X
- Most commonly recognized sex chromosome aneuploidy with a female phenotype
- Highly variable phenotypes
- Short stature
- Webbed neck
- At birth, edema of the hands and feet; after birth – short hands and fingers
- Heart and renal anomalies
- Increased carrying angle of the elbow (cubitus vulgas)
- Shield chest
- Low posterior hairline
- Usually normal intelligence, though may have learning difficulties
- Gonadal dysgenesis, primary amenorrhea (no menses)
- Usually infertile (but not always)
XY Female
- Y chromosome is intact, and the TDF is present and functional
- Androgen insensitivity
- Mutation of the androgen receptor gene located on the long arm of the X chromosome
- Infertility (female with testes)
XX “Male”
• Congenital adrenal hyperplasia (CAH)
• Mutation results in overproduction of androgens in female fetus
• Chemical imbalance
Treatable
XX Male
- X-Y recombination near pseudoautosomal region
* See Notes for 2 cases
XY Gonal Dysgenesis
See notes
Wolff-Hirschhorn syndrome
terminal deletion of chromosome 4
o “Greek warrior helmet” look o Microcephaly o Micrognathia o Hypotonia – low muscle tone o Epicanthal folds o “Startled or surprised” expression o Arched brows o Long nose with squared off end o Short stature o Developmental delay
Hutchinson Gilford Progeria Syndrome
‘Premature aging’ disease caused by mutations in nuclear Lamin A
Epidermoysis bullosa
Very rare skin blister disease caused by mutations in human epidermal keratins
Kartagener’s Syndrome
(primary ciliary diskinesia; PCD)
o Lack of motility in what should normally be motile cilia, leading to respiratory diseases, infertility in males, and situs invernus (left-right asymmetry or laterality defects)
Polycystic Kidney Disease (PKD)
can be caused by mutations in several genes, but one disease gene encodes a protein needed for assembly of primary (non-motile) cilia, normally present in cells lining the kidney tubules. Lack of normal primary cilia results in abnormal growth regulation of these epithelial cells and formation of cysts
Bardet-Biedl Syndrome
sensory cilia defect
Zellweger syndrome
o Peroxisomal enzymes are synthesized normally in the cytosol, but a defect in their import leads to “empty” peroxisomes.
o These patients suffer severe abnormalities in the brain, liver, and kidneys, and die soon after birth
X-linked adrenoleukodystrophy (ALD)
o Peroxisomes lack a membrane protein required for degradation of very long chain fatty acids
o Build up of these fatty acids leads to demyelination of neurons and dysfunction of the nervous system as well as adrenal insufficiency
o Treatment:
• 1) Allogeneic hematopoietic stem cell transplantation (HCT) – nigh morbidity due to complications; compatible donor cells not always available; must be performed at an early stage of brain lesions
• 2) Gene therapy – recent success in two boys suggests this may be a viable alternative therapy
THIS WAS THE FIRST SUCCESSFUL CLINICAL TEST OF HIV-DERIVED VECTOR IN HSC-BASED GENE THERAPY
Familial hypercholesterolemia
LDL receptors are defective, so cholesterol uptake is blocked and it accumulates in the blood; leads to the formation of plaques in blood vessel walls that can block blood flow and lead to heart attacks
Mucopolysaccharidoses
Lysosomal storage disease
defect in enzyme required for degradation of glycosaminoglycans
Oligosaccharidoses
Lysosomal storage disease
defect in enzyme required for degradation of oligosaccharides
Sphingolipidoses
Lysosomal storage disease
defect in enzyme required for degradation of sphingolipids
Inclusion-cell disease (I-cell disease)
Lysosomal storage disease
o Defect in enzyme responsible for generating the M6P marker on lysosomal hydrolases; w/o the marker, the hydrolases cannot be sorted into the appropriate transport vesicles in the trans Golgi network, so they are secreted from the cell via the default pathway
o Almost all hydrolytic enzymes are missing from lysosomes
o Undigested substrates accumulate in lysosomes and form large inclusions in patients’ cells
Pemphigus
an autoimmune disease (the body generates antibodies to own protein) to skin desmosomal cadherin causing destabilization of cell-cell interactions
Epidermolysis bulosa simplex
a defect in intermediate filament assembly causing loss of integrity of desmosomes and hemidesmosomes
Ehlers Danlos Syndrome
Dysfunction in collagen synthesis/assembly → failure to effectively assemble individual collagen molecules into fibrils
Hyper-extensible skin
Marfans Syndrome
a condition that results in weak artery walls leading, in severe cases to rupturing of the aorta
Alstrom Syndrome
syndrome that involves many different tissues
Rett syndrome
X-linked dominant disorder; lethal in males during the prenatal period
- Systemic Lupus Erythematosus
- Acute Promyelocytic Leukemia
- Spinal Muscular Atrophy
Nuclear diseases
