FA Biochemistry 4

Down syndrome-clinical a. GI b. Heart c. Cancer d. Physical

1. GI-duodenal atresia, Hirschsprung 2. Heart- endocardial cushion defects; ASD-ostium primum 3. Cancer- ALL, AML 4. Physical- prominent epicanthal folds , simian crease [below], gap btw 1st 2 toes

CF- biochemical consequences

1. negative transepithelial potential difference-increased due to increased Na reabsorption via ENac channels 2. decreased Cl- (and H2O) secretion--> increased intracellular Cl- -->compensatory increased Na+ reabsorption

Ehlers-Danlos: clinical

1.) Hyperextensible skin 2.) Tendency to bleed (easy bruising) 3.) Hypermobile joints

Step 5: Proteolytic processing outside fibroblast

Cleavage of disulfide-rich terminal regions of procollagen, transforming it into insoluble tropocollagen

Menkes disease-- what enzyme activity is affected from mutation? What are the S/S presented?

Copper absorption and transport are impaired due to defective Menke protein. Decreased activity of lysyl oxidase due to lack of copper availability. Results in brittle "kinky" hair, growth retardation and hypotonia.

CF-biochemical pathway

Mutations --> misfolded protein --> protein retained in RER and not transported to cell membrane

Genetic terms: Locus heterogeneity

Mutations at different loci can produce a similar phenotype

Alport's syndrome:-symptoms

nephritis and deafness. May be associated w/ ocular disturbances.

Autosomal Dominant dz's: Multiple endocrine neoplasias (MEN)

pancreas, parathyroid, thyroid, and adrenal medula. Men II and III associated w/ ret gene.

Elastin-composition

proline and glycine, nonglycosylated forms. Tropoelastin w/ fibrillin scaffolding.

CF-clinical

recurrent pulmonary infections (e.g., Pseudomonas), chronic bronchitis and bronchiectasis; pancreatic insufficiency; infertility in males (absent vas deferens)

Down Syndrome: first trimester

serum pregnancy-associated plasma protein A (PAPP-a)- decreased; free B-hCG (increased)

Fluoresence in situ Hybridization (FISH)-use

specific localization of genes, direct visualization of anomalies (e.g., microdeletions) at molecular level (when deletion is too small to be visualized by karyotype)

Autosomal Dominant: Osler-Weber-Rendu syndrome

telangiectasia, recurrent epistaxis, skin discolorations, arteriovenous malformations (AVMs).

Genetic terms: Linkage disequilibrium

tendency for certain alleles at 2 linked loci to occur together more often than expected by chance. Measured in a population

Step 1: Synthesis (RER) inside fibroblasts- what process occurs

translation of collagen alpha chains (preprocollagen ) -

Mitochondrial inheritance.

transmitted only thru mother. All offspring of affected females may show signs of dz. Variable expression in population due to heteroplasmy.

Patau's syndrome-genetics

trisomy 13

Edward's syndrome- genetics

trisomy 18

Down syndrome-genetics

trisomy 21

Edward's syndrome-clinical

Rocker-bottom feet micrognathia, clenched hands, small jaw

Osteogenesis imperfecta: clinical

1.) Multiple fractures w/ minimal trauma; may occur during the birthing process. May be confused with child abuse. 2.) Blue sclera due to the translucency of the connective tissue over the choroid. 3.) Hearing loss (abnormal middle ear bones) 4.) Dental imperfections due to lack of dentin

Assumptions of Hardy-Weinberg (there are 4)

1.) No mutation occurring at the locus 2.) No selection for any of the genotypes at the locus 3.) Completely random mating 4.) No migration

Prader-Willi and Angelman's syndromes: Location? Mechanism?

Both syndromes due to inactivation or deletion of genes on chromosome 15. Can also occur as a result of uniparental disomy.

Autosomal Dominant dz's: Neurofibromatosis type 2

Bilateral acoustic neuroma, juvenile cataracts. NF2 gene on chromosome 22

Genetic terms: Codominance

Both alleles contribute to the phenotype of the heterozygote.

Myotonia type 1 a. inheritence and gene mutation b. abnormal gene product c. clinical S/S

A. AD CTG trinucleotide repeat expansion in the DMPK gene b. abnormal expression of myotonin protein kinase p myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, and arrhythmia.

Autosomal Dominant diseases- List

Achondroplasia Autosomal dominant polycystic kidney disease Familial adenomatous polyposis Familial hypercholesterolemia Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) Hereditary spherocytosis Huntington disease Li-Fraumeni syndrome (SBLA syndrome) Marfan Syndrome Multiple endocrine neoplasias- MEN 1, 2A and 2B Neurofibromatosis type 1 (von Recklinghausen disease) Neurofibromatosis type 2 Tuberous sclerosis Von Hippel-Lindau disease

Autosomal Recessive dz's- List

Albinism ARPKD (formerly known as infantile polycystic kidney disease) Cystic fibrosis Glycogen storage diseases Hemochromatosis Kartagener syndrome Mucopolysaccharidoses (except Hunter syndrome- XL-R) Phenylketonuria Sickle cell anemia Sphingolipidoses (except Fabry disease- XL-R) Thalassemias Wilson disease

Imprinting (def.)

At a single locus, only 1 allele is active; the other is inactive (imprinted/inactivated by methylation). Deletion of the active allele --< dz

Emphysema (one cause)

Can be caused by alpha1-antitrypsin deficiency, resulting in excess elastase activity.

Autosomal Dominant dz's: Achondroplasia

Cell-signaling defect of fibroblasts growth factor (FGF) receptor 3. Results in dwarfism; short limbs, but head and trunk are normal size. Associated w/ advanced paternal age.

Ehlers-Danlos syndrome- cause

Defects in: Type V collagen- joint& skin symptoms Type III collagen- vascular and organ rupture

Autosomal Dominant dz's: Familial adenomatous polyposis-cause

Deletion of APC gene on chromosome 5; Colon becomes covered w/ adenomatous polyps after puberty. Progresses to colon cancer unless resected.

AngelMan's syndrome

Deletion of normally active M aternal allele. Mental retardation, seizures, ataxia, inappropriate laughter

Prader-Willi Syndrome

Deletion of normally active P aternal allele. Mental retardation, hyperphagia, obesity, hypogonadism, hypotonia.

Genetic terms: Imprinting

Differences in phenotype depend on whether the mutation is of maternal or paternal origin

Cardiac glycosides (digoxin and digitoxin)

Directly inhibit Na+/K+ ATPase, which leads to indirect inhibition of Na+/Ca2+ exchange. Incr Ca2+ --< incr cardiac contractility.

Dystrophin gene-function

Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle. It connects the intracellular cytoskeleton (actin) to the transmembrane proteins α- and β-dystroglycan, which are connected to the extracellular matrix (ECM). Loss of dystrophin results in myonecrosis.

Step 4: Exocytosis

Exocytosis of procollagen into extracellular space

Type II osteogenesis imperfecta

Fatal in utero or neonatal period.

X-linked recessive disorders- effects on females

Female carriers can be variably affected depending on the percentage inactivation of the X chromosome carrying the mutant vs. normal gene.

Autosomal Dominant dz's: Marfan's syndrome

Fibrillin gene mutation -->connective tissue d/o affecting skeleton, heart, and eyes. Findings: tall w/ long extremities, hyperextensive, cystic medial necrosis of aorta --< aortic incompetence and dissecting aortic aneurysms; floppy mitral valve. Subluxation of the lenses.

Autosomal Dominant dz's: Huntington's dz

Findings: depression, progressive dementia, choreiform mvmts, caudate atrophy, and decr levels of GABA and ACh in the brain. Sx manifest in affected indvls btw the ages of 20-50. Gene located on Chr 4 ; trinucleotide repeat d/o: (CAG) ("Hunting 4 food")

Autosomal Dominant dz's: von Hippel-Lindau-clinical

Hemangioblastomas, bilateral renal cell carcinomas and other tumors.

Trinucleotide repeat expansion dz's-list

Huntington, Friedrich's ataxia, fragile X syndrome, Myotonic dystrophy

X-linked dominant- disease examples

Hypophosphatemic rickets Rett syndrome Fragile X syndrome Alport syndrome

Genetic terms: Loss of heterozygosity

If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes.

Hardy-Weinberg equilibrium

If a population is in H-W equilibrium and p and q are separate alleles, then: Dz prevalence: p^2 + 2pq + q^2 = 1 Allele prevalence: p + q = 1 2pq = heterozygote prevalence The prevalence of an X-linked recessive dz in males = q and in females = q^2

Dx of muscular dystrophies (Duchenne's, Becker's)

Incr: CK and aldolase labs; confirm w/ muscle biopsy.

Types of Ehlers-Danlos

Inheritance and severity may vary. Can be autosomal dominant or recessive. hypermobility type (joint instability): most common type classical type (joint and skin): type V collagen. vascular type (vascular and organ rupture): type III collagen.

Hypophosphatemic rickets

Inherited d/o resulting in incr phosphate wasting at proximal tubule. Results in rickets-like presentation --X-linked dominant

Ehlers-Danlos syndrome: may be associated with...?

Joint dislocation, Berry & aortic aneurysms, Organ rupture

Autosomal dominant.

Many generations, both male and female, affected; defects in structural genes.

Genetic terms: Variable expression

Nature and severity of the phenotype varies from 1 individual to another.

Genetic terms: Incomplete penetrance

Not all individuals w/ a mutant genotype show the mutant phenotype.

Genetic terms: Uniparental disomy

Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.

Genetic terms: Pleiotropy

One gene contributes to multiple phenotypic effects

X-Linked Recessive disorders- List

Ornithine transcarbamylase deficiency Fabry disease (sphingolipid dz) Wiskott-Aldrich syndrome Ocular albinism G6PD deficiency Hunter Syndrome (mucopolysaccharidose dz) Bruton agammaglobulinemia Hemophilia A and B Lesch-Nyhan syndrome Duchenne (and Becker) muscular dystrophy Mnemonic: Oblivious Female Will Often Give Her Boys Her x-Linked Disorders

Genetic terms: Heteroplasmy

Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited dz's.

Genetic terms: Mosaicism

Presence of genetically distinct cell lines in the same individual. Arises from mitotic errors after fertilization.

Genetic terms: Anticipation

Severity of dz worsens or age of onset of dz is earlier in succeeding generations (e.g., Huntington's dz)

Autosomal Dominant dz's: Hereditary spherocytosis

Spheroid erythrocytes due to spectrin or ankyrin defect; hemolytic anemia; Incr MCHC. Splenectomy is curative.

Quad screen components

a-fetoprotein, b-hCG, estriol, inhibin A

Robertsonian translocation: a. balanced b. unbalanced translocations?

a. Balanced translocations-no abnormal phenotype. b. Unbalanced translocations- miscarriage, stillbirth, and chromosomal imbalance

Type IV collagen a. location b. clinical

a. Basement membrane or basal lamina b. Alport syndrome; Goodpasteur's syndrome

Type I collagen a. location b. clinical

a. Bone, skin, tendon, dentin, fascia, cornea, late wound repair b. Osteogenesis Imperfecta

Type II collagen a. location b. clinical

a. Cartilage (including hyaline), vitreous body, nucleous pulposus. b. NA

X-linked dominant.

Transmitted thru both parents. Either male or female offspring of the affected mother may be affected, while all female offspring of the affected father are diseased.

Autosomal recessive

Usually seen in only 1 generation; 25% of offspring from 2 carrier parents are affected. Often due to enzyme deficiencies.

Collagen a. composition b. function

a. Glycine-X-Y (proline or lysine) b. organizes and strengthens extracellular matrix.

Step 2: hydroxylation (ER) inside fibroblasts a. definition b. clinical

a. Hydroxylation of specific proline and lysine residues b. Scurvy- no Vitamin C (can't hydroxylate proline and lysine)

Menkes disease- List the mode of inheritance, give a brief description and what protein is defective.

X-L Recessive CT disease caused by impaired copper absorption and transport. Due to defect in Menkes protein (ATP7A).

Duchenne's muscular dystrophy-cause

X-linked frame-shift mutation --> deletion of dystrophin gene (DMD; largest protein-encoding gene) --> inhibited muscle regeneration

Becker's muscular dystrophy-cause

X-linked non-frameshift insertion in dystrophin gene--adolescence or early adulthood onset

X-linked recessive.

X-linked recessive. Sons of heterozygous mothers have a 50% chance of being affected. No male-to-male transmission. Commonly more severe in males. Heterozygous females may be affected.

Robertsonian translocation a. definition b. mechanism

a. Nonreciprocal chromosomal transloccation that commonly involves chromosome pairs 13, 14, 15, 21, and 22. b. long arms of two acrocentric chromosomes (chromosomes w/ the centromeres near the ends) fuse at the centromere and the 2 short arms are lost.

Step 6: cross-linking outside fibroblasts a. process b. clinical

a. Reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (byCu+-containing lysyl oxidase) to make collagen fibrils b. Ehlers-Danlos-problems w/cross-linking

Type III collagen a. location b. clinical

a. blood vessels, uterus, fetal tissue, granulation tissue b. Ehlers Danlos (type III & type V)

Patau's syndrome a. clinical b. first trimester screen

a. cleft lip/palate, polydactyly, omphalocele/umbilical hernia, microphthalmia, microcephaly, b. free b-hCG- decreased; PAPP-A-decrease; nuchal translucency

Step 3: Glycosylation (ER) inside fibroblasts a. definition b. clinical

a. glycosylation of pro-alpha-chain hydroxylysine residues --> procollagen via hydrogen & disulfide bonds (triple helix of 3 collagen alpha chains) b. osteogenesis imperfect

Osteogenesis imperfecta aka "brittle bone disease" a. genetics- inheritance and MC gene mutation b. cause

a. variety of gene defects. MC AD defect of COL1A1 and COL1A2 genes. incidence is 1:10,000 b. MC due to decreased production of normal type 1 collagen --> weakens bone matrix; problems forming triple helix (glycosylation in ER)

Alport's syndrome: Due to....? Most common form...?

abnormal type IV collagen.

Down syndrome: results of pregnancy quad screen?

alpha-fetoprotein-decreased; b-hCG-increased; estriol (decreased); inhibin A (decreased)

Autosomal Dominant dz's: Neurofibromatosis type 1

café-au-lait spots, Lisch nodules, scoliosis, pheochromocytoma, mutations in the NF1 gene on chrom 17

Genetic terms: Dominant negative mutation

heterozygote produces a nonfxnl altered protein that also prevents the normal gene product from functioning.

CF-metabolic situation

contraction alkalosis, hypokalemia

What cofactor is necessary for lysyl oxidase enzyme activity?

copper is a necessary cofactor of lysyl oxidase.

Genetics of Cystic fibrosis-cause

defect in CFTR gene on chromosome 7, commonly deletion of Phe 508 (AR)

Marfan's syndrome (cause)

defect in fibrillin (glycoprotein that forms a sheath around elastin)

Leber's hereditary optic neuropathy

degeneration of retinal ganglion cells and axons. Leads to acute loss of central vision.

CFTR-function

encodes an ATP-gated Cl- channel that secretes Cl- in lungs and GI tract, and reabsorbs Cl- in sweat glands.

Fragile X syndrome: findings?

enlarged testes, long face w/ a large jaw, large everted ears, autism.

Autosomal Dominant dz's: Tuberous sclerosis

hypopigmented "ash leaf spots", astrocytomas, cardiac rhabdomyomas, renal angiomyolipomas

Down Syndrome: most significant markers

increased-free B-hCG, inhibin A; nuchal translucency, hypoplastic nasal bone

Down syndrome-cause

meiotic nondisjunction of homogous chromosomes--associated w/ advancced maternal age; robertsonian translocation, mosaicism

Fragile X syndrome-cause

methylation and expression of the FMR1 gene;chromosomal breakage.