ALL BIOCHEM IN FIRST AID Flashcards
ADA DEFICIENCY
ADA—require for degradation of adenosine and deoxyadenosine
Increased levels of dATP—> leads to lymphotoxicity
One of the major causes of AR SCID
LESCH-NYHAN SYNDROME
Defective purine salvage due to absent HGPRT
(Converts hypoxanthine to IMP and guanine to GMP)
Results:
Excess Uric acid production
X—linked Recessive
Findings: intellectual disability, SELF-MUTILATION, aggression, hyperuricemia (orange “sand” in diaper), gout, dystonia
TX:
Allopurinol
Febuxostat (2nd line)
XERODERMA PIGMENTOSUM
Defective nucleotide excision repair —> inability to repair DNA pyrimidine dimers caused by UV exposure Findings: Dry skin Extreme light sensitivity Skin cancer
I-CELL DISEASE (INCLUSION CELL DISEASE)
Inherited lysosomal storage disorder
Defect in—> N-acetylglucosaminyl-1-phosphotransferase
Failure of the Golgi to phosphorylate mannose residues (DECREASE mannose-6-phosphate)
Proteins are secreted extracellularly rather than sent to lysosomes
Findings: Coarse facial features Gingival hyperplasia Clouded corneas Restricted joint movements Claw hand deformities Kyphoscoliosis High plasma levels of lysosomal enzymes FATAL IN CHILDHOOD
ZELLWEGER SYNDROME
AR Mutated PEX genes—leads to peroxisome biogenesis disorder Findings: Hypotonia Seizures Hepatomegaly Early death
REFSUM DISEASE
AR of alpha-oxidation Findings: Scaly skin Ataxia Cataracts/night blindness Shortening of 4th toe Epiphyseal dysplasia TX: Diet, plasmapheresis
ADRENOLEUKODYSTROPHY
X-linked Recessive disorder of BETA-oxidation
VLCFA buildup in adrenal glands, white matter of brain, testes
KARTAGENER SYNDROME
Immobile cilia due to a dynein arm defect AR Results: Decrease in male/female fertility due to immotile sperm and dysfunctional Fallopian tube cilia Increased risk of ectopic pregnancy Can cause: Bronchiectasis Recurrent sinusitis Chronic ear infections Conductive hearing loss Situs inversus (dextrocardia on CXR)
OSTEOGENESIS IMPERFECTA “Brittle Bone Disease”
Type 1 = Mild
Type 2 = severe and usually lethal in peri-natal period (die due to respiratory failure (pulmonary hypoplasia) or intra-cerebral hemorrhage)
Type 3 = considered progressive and deforming
Type 4 = deforming but with NORMAL sclera
Genetic bone disorder: variety of gene defects in COL1A1 or COL1A2–MC form is AD with decreased production in TYPE 1 collagen
Impaired osteioid production by osteoblasts
Genetic mutation causing alpha peptides deficient in glycine
Problems forming triple helix due to defect in glycosylation
Findings:
Multiple fractures with minimal trauma (may occur during the birth process)
Blue sclera due to translucent CT over choroidal veins
Opalescent teeth that wear easily due to lack of dentin
Hearing loss
TX:
Bisphosphonates to decrease fracture risk
EHLERS-DANLOS SYNDROME:
Classical Type:
Type V collagen mutation—joint and skin sx.
Vascular Type:
Deficient type III pro-collagen (problems with cleavage)
Fragile tissues including vessels, muscles, and organs
Faulty collagen synthesis causing: Hyperextensible skin Hyper mobile joints Tendency to bleed (easy bruising) Can be AD or AR Associated with: Joint dislocation Berry and aortic aneurysms Organ rupture *Hypermobility is the MC type*
MENKES DISEASE
X-linked R Cause: Impaired copper absorption and transport due to defective Menke’s protein ATP7A Leads to—> decreased activity of lysyl oxidase—> defective collagen Results: “Brittle, kinky” hair Growth retardation Hypotonia
MARFAN SYNDROME
AD disorder affecting skeleton, heart and eyes
FBN1 gene mutation on chromosome 15–defective fibrillin
Findings: Tall with long extremities Pectus carinatum or pectus excavatum Hyper mobile joints Long, tapering fingers and toes Cystic medial necrosis of aorta*** aortic incompetence, dissecting aortic aneurysms Floppy mitral valve Subluxation of lenses** typically upward/temporally
PCR
Used to amplify a desired fragment of DNA
Useful as a diagnostic tool
(1) Denaturation (heat)
(2) Annealing (cool + DNA primers)
(3) Elongation (heat)
—looking for a specific sequence for illness or mutation
Southern Blot
DNA sample is cleaved
Put onto a gel then transferred to a filter
Filter is exposed to radiolabeled DNA probe
Resulting DS, labeled DNA is visualized when filter is exposed to film
**Unknown sample
**Used for forensics
Northern Blot
RNA sample is electrophoresis
Useful for studying mRNA levels, which are reflective of gene expression
Detects RNA using a DNA probe
Western Blot
Sample protein is separated via gel electrophoresis and transferred to a membrane
Labeled antibody is used to bind to relevant protein** HIV test screening test
Southwestern Blot
Identifies DNA-binding proteins using labeled oligonucleotide probes
Flow Cytometry
To assess size, granularity, and protein expression (immunophenotype) of individual cells in a sample
FOR: workup of hematologic abnormalities and immunodeficiencies
Cells tagged with antibodies specific to surface or intracellular proteins
Antibodies then tagged with a unique fluorescent dye
Microarrays
Used to look @ entire genome
DNA or RNA probes are hybridized to the chip and a scanner detects the relative amounts of complementary binding
Able to detect SNP’s and CNV’s for a variety of applications: Genotyping Clinical genetic testing Forensic analysis Cancer mutations Genetic linkage analysis
ELISA
Immunologic test used to detect the presence of either a specific antigen or antibody in a patient’s blood sample
Initial test for HIV: confirmed with Western Blot
Direct ELISA—> tests for the antigen directly
Indirect ELISA—> tests for the antibody (thus indirectly testing for the antigen)
Karyotyping
Used to diagnose chromosomal imbalances
Can be performed on: sample of blood, bone marrow, amniotic fluid or placental tissue
Metaphase chromosomes are used
FISH
Fluorescent DNA or RNA probe binds to specific gene site of interest on chromosomes
Used for: specific localization of genes and direct visualization of chromosomal anomalies at the molecular level
MCCUNE-ALBRIGHT SYNDROME
Mutation affecting G-protein signaling
Presents with:
Unilateral cafe-au-lait spots with ragged edges
Polyostotic fibrous dysplasia (bone replaced by collagen and fibroblasts)
Precocious puberty
Lethal if mutation occurs BEFORE fertilization but survivable in patients with mosaicism
PRADER-WILLI SYNDROME
Paternal allele is deleted/mutated Maternally derived genes are silenced (imprinted) **Mutation or deletion of chromosome 15 of PATERNAL origin Results: Hyperphagia (excessive eating) Obesity Intellectual disability Hypogonadism Hypotonia
ANGELMAN SYNDROME
Paternally derived UBE3A gene is silenced
Maternal allele is deleted or mutated
**maternal copy of chromosome 15 deleted*
Results: Inappropriate laughter Seizures Ataxia Severe intellectual disability
Mitochondrial Myopathies
Often present with: Myopathy Lactic acidosis CNS disease [MELAS syndrome] Mitochondrial encephalomyopathy Lactic acidosis Stroke-like episodes
Secondary to oxphos failure
Muscle biopsy = ragged red fibers due to accumulation of disease mitochondria
CYSTIC FIBROSIS
Dx: Increased Cl- concentration in pilocarpine-induced sweat test
Increased trypsinogen (newborn screening)
TX: Azithromycin (anti-inflammation) Ibuprofen slows disease progression**
In patients with deletion: lumacaftor (corrects misfolded proteins) + ivacaftor (opens CL- channels)
AR
Defect in CFTR gene on chromosome 7
Deletion of Phe508
MC lethal genetic disease in Caucasian’s
CFTR—> encodes ATP-gated Cl- channel that secretes Cl- in lungs and GI tract and reabsorbs Cl- in sweat glands
MC mutation = misfolded protein that is retained in the RER causing decreased CL- secretion; increased intracellular Cl- results in compensatory increased Na+ reabsorption via ENAC channels which increases H20 reabsorption =
ABNORMALLY THICK MUCUS
CF complications
Recurrent pulmonary infections (Staph in early infancy, Pseudomonas in adolescence)
Chronic bronchitis and bronchiectasis
(Reticulo-nodular on CXR)
Pancreatic insufficiency
Malabsorption with steatorrhea, fat-soluble vitamin deficiencies, biliary cirrhosis, liver disease
Meconium ileus in newborns**
Infertility in men (absence of vas deferens) and sub-fertility in women
Nasal polyps, clubbing of nails
DUCHENNE MUSCULAR DYSTROPHY
Dystrophin—> connects the intracellular cytoskeleton (actin) to the transmembrane proteins alpha and beta-dystroglycan which are connected to the ECM
Increased CK and Aldolase
X-linked disorder typically due to frameshift or nonsense mutations—> truncated or absent dystrophin—> progressive myofiber damage
Weakness begins in pelvic girdle muscles and progresses superiorly
Pseudohypertrophy of calf muscles + waddling gait
Onset before 5 years of age—dilated cardiomyopathy is MC COD
GOWER SIGN = use UE to help stand up
BECKER MD
X-linked disorder due to NON-frameshift deletions in dystrophin gene
Onset in adolescence or early adulthood (partially functional dystrophin)
MYOTONIC TYPE 1 MUSCULAR DYSTROPHY
AD
CTG trinucleotide repeat expansion in the DMPK gene—> abnormal expression of myotonin protein kinase
SX: Myotonia Muscle wasting Cataracts Testicular atrophy Frontal balding (early balding in men) Arrhythmias
RETT SYNDROME
Sporadic disorder seen almost exclusively in girls
Caused by de novo mutation of MECP2 on X chromosome
SX: Usually appear between ages 1-4 Regression in motor, verbal, and cognitive abilities Ataxia Seizures Growth failure Stereotyped hand-wringing**
FRAGILE X SYNDROME
X-linked dominant
Trinucleotide repeat (CGG) in FMR1–> hypermethylation—> decreases expression
MC cause of inherited intellectual disability
SX: Post-pubertal macroorchidism Enlarged testes Long face with a large jaw Large exerted ears Autism MVP
DOWN SYNDROME (TRISOMY 21)
Intellectual disability Flat facies Prominent epicanthal folds Single palmar crease Gap between 1st two toes Duodenal atresia Hirschsprung disease Congenital heart disease Brushfield spots (grayish brown spots on iris) Associations: early onset Alzheimer disease and increased risk of ALL and AML
95% due to meiotic nondisjunction
4% due to Robertsonian translocation between 14 and 21
Tests: Decreased PAPP-A Increased beta-HCG Decreased AFP Decreased estriol Increased inhibin
EDWARDS SYNDROME (TRISOMY 18)
FINDINGS: Prominent occiput Rocker-bottom feet Intellectual disability Non-disjunction Clenched fists Low-set ears Micrognathia (small jaw) Congenital heart disease Death by age 1 Labs: < beta-HCG, < AFP, < estriol, normal or < inhibin
