question

Histone proteins

answer

H1 linker H2A H2B H3 H4 x2 nucleosome

question

Amino acids rich in histone

answer

Lysine and arginine

question

Phase during mitosis that DNA and histone synthesis occur

answer

S phase

question

Heterochromatin

answer

Condensed, inactive, high methylation, low acetylation

question

Barr bodies

answer

Inactive X chromosomes, heterchromatine

question

Euchromatin

answer

Less condensed, active

question

DNA methylation sites

answer

Cytosine and adenine

question

CpG islands

answer

DNA methylation at CpG islands represses transcription

question

Histone methylation

answer

Usually represses transcription, activates in some cases depending on methylation location

question

Histone acetylation

answer

Activates transcription

question

Purine

answer

A, G 2 rings

question

Pyrimidines

answer

C, U, T 1 ring

question

Deamination of cytosine

answer

Uracil

question

Deamination of adenine

answer

Guanine

question

Methylation of uracil

answer

Thymine

question

Amino acids necessary for purine synthesis

answer

Glycine Aspartate Glutamine

question

Leflunomide

answer

Inhibits dihydroorotate dehydrogenase

question

Methotrexate Trimethoprim Pyrimethamine

answer

Inhibit dihydrofolate reductase in humans, bacteria, and Protozoa, respectively Decrease dTMP

question

5-flurouracil

answer

Forms 5-F-dUMP inhibits thymidylate synthase Decrease dTMP

question

6-mercaptopurine

answer

Inhibits de novo purine synthesis Prodrug is azathioprine

question

Mycophenolate Ribavirin

answer

Inhibit inosine monophosphate dehydrogenase Decrease GMP

question

Hydroxyurea

answer

Inhibits ribonucleotide reductase

question

Adenosine deaminase deficiency

answer

ADA is required for degradation of adenosine and deoxyadenosine Increase dATP -> toxicity in lymphocytes Autosomal recessive SCID

question

Lesch-Nyhan syndrome

answer

Absent HGPRT, which converts hypoxanthine to IMP and guanine to GMP Excess uric acid Increased de novo purine synthesis X-linked recessive Hyperuricemia Gout Pissed off (agreesion, self-mutilation) Retardation (intellectual disability) Dystonia Orange "sand" [sodium urate crystals] in diaper Tx: allopurinol, febuxostat (2nd line)

question

RNA codon for tryptophan

answer

UGG

question

RNA codon for methionine

answer

AUG

question

Eukaryotic topoisomerse I inhibitor

answer

Irinotecan Topotecan

question

Eukaryotic topoisomerase II inhibitor

answer

Etoposide Teniposide

question

Fluoroquinolones

answer

Inhibit prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV

question

DNA polymerase III

answer

Prokaryotes only 5'-;3' synthesis and proofreads with 3'-;5' exonuclease

question

DNA polymerase I

answer

Prokaryotes only 5'-;3' synthesis and proofreads with 3'-;5' exonuclease Excises RNA primer with 5'-;3' exonuclease

question

Transition mutation in DNA

answer

Purine to purine Pyrimidine to pyrimidine

question

Transversion mutation in DNA

answer

Purine to pyrimidine Pyrimidine to purine

question

Example of missense mutation

answer

Sickle cell disease (glutamic acid to valine)

question

Examples of frameshift mutation

answer

Duchenne muscular dystrophy Tay-Sachs disease

question

Examples of splice site mutation

answer

Rare cause of cancers, dementia, epilepsy, some types of b-thalassemia

question

Nucleotide excision repair

answer

Occurs in G1 Xeroderma pigmentosum

question

Base excision repair

answer

Glycosylase AP site AP-endonuclease Lyase DNA polymerase-b DNA ligase Occurs throughout cell cycle Repair spontaneous/toxic deamination

question

Mismatch repair

answer

Occurs predominantly in G2 Lynch syndrome (HNPCC)

question

Nonhomologous end joining

answer

Some DNA may be lost Ataxia telangiectasia Breast/ovarian cancers with BRCA1 mutation Fanconi anemia

question

mRNA start codons

answer

AUG rarely GUG methionine in eukaryotics, may be removed before translation is completed N-formylmethionine (fMet) in prokaryotes

question

mRNA stop codons

answer

UAG UAA UGA

question

a-amanitin

answer

Found in Amanita phalloides (death cap mushrooms Inhibits RNA polymerase II severe hepatotoxicity

question

Actinomycin D

answer

Inhibits RNA polymerase in both prokaryotes and eukaryotes

question

Rifampin

answer

Inhibits DNA-dependent RNA polymerase in prokaryotes

question

Capping of 5' end of hnRNA

answer

Addition of 7-methylguanosine cap

question

P-bodies

answer

Cytoplasmic processing bodies for mRNA quality control Exonuclease Decapping enzymes MicroRNAs mRNA may be stored for future translation

question

Anti-smith antibodies

answer

Antibodies to spliceosomal snRNPs Highly specific for SLE

question

Anti-U1 RNP antibodies

answer

Highly associated with mixed connective tissue disease (MCTD)

question

microRNAs

answer

Targeting 3' UTR of specific mRNAs for degradation or translational repression

question

tRNA 3' end

answer

Covalently binds to amino acid CCA

question

tRNA T-arm

answer

T¥C ribothymidine, pseudouridine, cytidine tRNA-ribosome binding

question

tRNA D-arm

answer

Dihydrouridine residues necessary for tRNA recognition by the correct aminoacyl-tRNA synthetase

question

p53

answer

Induced p21, which inhibits CDKs Hypophosphorylation of Rb (activation) Inhibition of G1-S progression Mutations result in unrestrained cell division (Li-Fraumeni syndrome)

question

Permanent cell type

answer

Remain in G0, regenerate from stem cells Neurons, skeletal and cardiac muscle, RBCs

question

Stable (quiescent) cell type

answer

Enter G1 from G0 when stimulated Hepatocytes, lymphocytes

question

Labile cell type

answer

Never go to G0 Divide rapidly with a short G1 Most affected by chemotherapy Bone marrow, gut epithelium, skin, hair follicles, germ cells

question

RER

answer

Synthesis of secretory proteins N-linked oligosaccharide addition Nissl bodies (neuron) synthesize peptide neurotransmitters Free ribosomes Mucus-secreting goblet cells of small intestine, antibody-secreting plasma cells

question

SER

answer

Steroid synthesis, detoxification of drugs and poisons Liver hepatocytes, steroid hormone-producing cells of the adrenal cortex, gonads

question

N-oligosaccharides

answer

On asparagine, in Golgi

question

O-oligosaccharides

answer

On serine and threonine, in Golgi

question

Inclusion cell disease

answer

I-cell disease Mucolipiododis type II Inherited lysosomal storage disorder Defect in N-acetylglucosoaminyl-1-phosphotransferase Failure of Golgi to phosphrylate mannose residues on glycoproteins Decreased mannose-6-phosphate Proteins are secreted extracellularly rather than delivered to lysosomes Coarse facial feature, clouded corneas, restricted joint movement, high plasma levels of lysosomal enzymes Often fatal in childhood

question

Peroxisome

answer

Catabolism of very-long-chain fatty acids, branched-chain fatty acids, amino acids, and ethanol Disorders commonly lead to neurologic diseases due to deficits in synthesis of plasmalogens, important phospholipids in myelin

question

Zellweger syndrome

answer

Peroxisomal disease Hypotonia Seizures Hepatomegaly Early death

question

Refsum

answer

Peroxisomal disease Scaly skin Ataxia Cataracts/night blindness Shortening of 4th toe Epiphyseal dysplasia

question

Defects in the ubiquitin-proteasome system have been implicated in some cases of which disease?

answer

Parkinson disease

question

Microfilaments

answer

Function: muscle contraction, cytokinesis Actin, microvilli

question

Intermediate filaments

answer

Function: maintain cell structure Vimentin, desmin, cytokeratin, lamins, glial fibrillary acid proteins, neurofilaments

question

Microtubules

answer

Function: movement, cell division Cilia, flagella, mitotic spindle, axonal trafficking, centrioles

question

Vimentin

answer

Cell type: mesenchymal tissue (fibroblasts, endothelial cells, macrophages) Identifies: mesenchymal tumors (sarcoma), many other tumors (endometrial carcinoma, renal cell carcinoma, meningioma)

question

Desmin

answer

Cell type: muscle Identifies: muscle tumor (rhabdomyosarcoma)

question

Cytokeratin

answer

Cell type: epithelial cells Identifies: epithelial tumors (squamous cell carcinoma)

question

GFAP

answer

Cell type: neuroglia (astrocytes, Schwann cells, oligodendrocytes) Identifies: astrocytoma, glioblastoma

question

Neurofilaments

answer

Cell type: neurons Identifies: neuronal tumors (neuroblastoma)

question

Microtubule

answer

Cylindrical outer structure composed of a helical array of polymerized heterodimers of a- and b-tubulin Each dimer has 2 GTP bound Grows slowly, collapses quickly Slow axoplasmic transport in neurons

question

Molecular motor proteins

answer

Dynein Retrograde + -; - Kinesin Anterograde - -; + Negative end near nucleus Positive end points to periphery

question

Drugs act on microtubules

answer

Mebendazole (antihelminthic) Griseofulvin (antifungal) Colchicine (antigout) Vincristine/Vvinblastine (anticancer) Paclitaxel (anticancer)

question

Cilia structure

answer

9 doublets + 2 singlet arrangement of microtubules Basal body (base of cilium below cell membrane) consists of 9 microtubules triplets with no central microtubules

question

Axonemal dynein

answer

ATPase that links peripheral 9 doublets and causes bending of cilium by differential sliding of doublets

question

Kartagener syndrome

answer

1' ciliary dyskinesia Immotile cilia due to a dynein arm defect Decreased fertility Increased risk of ectopic pregnancy Bronchiectasis Recurrent sinusitis Chronic ear infections Conductive hearing loss Situs inversus

question

Ouabain

answer

Inhibits by binding to K+ site of Na+ - K+ ATPase

question

Cardiac glycosides

answer

Digoxin Digitoxin Directly inhibit Na+ - K+ ATPase -> indirect inhibition of Na+/Ca2+ exchange -> increase [Ca2+]i -> increase cardiac contractility

question

Type I collagen

answer

Most common (90%) Bone, skin, tendon, dentin, fascia, cornea, late wound repair Decrease production in osteogenesis imperfecta type I

question

Type II collagen

answer

Cartilage (including hyaline), vitreous body, nucleus pulposus

question

Type III collagen

answer

Reticulin Skin, blood vessels, uterus, fetal tissue, granulation tissue Deficient in the uncommon, vascular type of Ehlers-Danlos syndrome

question

Type IV collagen

answer

Basement membrane, basal lamina, lens Defective in Alport syndrome Targeted by autoantibodies in Goodpasture syndrome

question

Collagen synthesis 1 Synthesis

answer

Translation of collagen a chains (preprocollagen) Usually Gly-X-Y (X and Y are proline or lysine) Collagen is 1/3 glycine

question

Collagen synthesis 2 Hydroxylation

answer

Hydroxylation of specific proline and lysine residues Requires vitamin C deficiency -> scurvy

question

Collagen synthesis 3 Glycosylation

answer

Glycosylation of pro-a-chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen a chains) Problems forming triple helix -> osteogenesis imperfecta

question

Collagen synthesis 4 Exocytosis

answer

Exocytosis of procollagen into extracellular space

question

Collagen synthesis 5 Proteolytic processing

answer

Cleavage of disulfide-rich terminal regions of procollagen -> insoluble tropocollagen Problems with cleavage -> Ehlers-Danlos syndrome

question

Collagen synthesis 6 Cross-linking

answer

Reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by copper-containing lysyl oxidase) to make collagen fibrils Problems with cross-linking -> Ehlers-Danlos syndrome, Menkes disease

question

Ehlers-Danlos syndrome

answer

Faulty collagen synthesis hyperextensible skin, tendency to bleed (easy bruising), and hypermobile joints Multiple types. Inheritance and severity vary. Can be autosomal dominant or recessive May be associated with joint dislocation, berry and aortic aneurysm, organ rupture Hypermobility type (joint instability): most common type Classical type (joint and skin symptoms): mutation in type V collagen (COL5A1, COL5A2) Vascular type (vascular and organ rupture): deficient type III collagen

question

Menkes disease

answer

X-linked recessive connective tissue disease Caused by impaired copper absorption and transport due to defective Menkes protein (ATP7A) Decrease activity of lysyl oxidase (copper is a necessary cofactor) Brittle, "kinky" hair Growth retardation Hypotonia

question

Osteogenesis imperfecta

answer

Brittle bone disease Genetic bone disorder caused by a variety of gene defects Most commonly COL1A1 and COL1A2 Most common autosomal dominant, decrease production of otherwise normal type I collagen Multiple fractures with minimal trauma, may occur during the birth process Blue sclerae due to the translucent connective tissue over choroidal veins Some forms have tooth abnormalities, including opalescent teeth that wear easily due to lack of dentin (dentinogenesis imperfecta) Hearing loss (abnormal ossicles) May be confused with child abuse

question

Elastin

answer

Stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords, ligmenta flava Rich in nonhydroxylated proline, glycine, lysine Tropoelastin with fibrillin scaffolding Cross-linking takes place extracellularly and gives elastin its elastic properties Broken down by elastase, which is normally inhibited by a1-antitrypsin a1-antitrypsin deficiency results in excess elastase activity, which can cause emphysema Wrinkles of aging are due to decreased collagen and elastin production

question

Marfan syndrome

answer

Autosomal dominant connective tissue disorder Affecting skeleton, heart, and eyes FBN1 gene mutation on chromosome 15 results in defective fibrillin, a glycoprotein that forms a sheath around elastin Tall with long extremities Pectus carinatum (more specific) or pectus excavatum Hypermobile joints Long, tapering fingers and toes (arachnodactyly) Cystic medial necrosis of aorta Aortic incompetence and dissecting aortic aneurysm Floppy mitral valve Subluxation of lenses, typically upward and temporally

question

Codominance example

answer

Blood groups A, B, AB a1-antitrypsin deficiency

question

Variable expressivity example

answer

2 patients with NF1 may have varying disease severity

question

Incomplete penetrance example

answer

BRCA1 gene mutations do not always result in breast or ovarian cancer

question

Pleiotropy example

answer

Untreated PKU manifests with light skin, intellectual disability, and musty body odor

question

Anticipation example

answer

Trinucleotide repeat diseases (Huntington disease)

question

Loss of heterozygosity example

answer

Retinoblastoma and the "two-hit hypothesis" Lynch syndrome (HNPCC) Li-Fraumeni syndrome

question

Dominant negative mutation example

answer

Mutation of a transcription factor in its allosteric site. Non functioning mutant can still bind DNA, preventing wild-type transcription factor from binding

question

Linkage disequilibrium

answer

Tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance. Measured in a population, not in a family, and often varies in different population

question

Mosaicism

answer

Presence of genetically distinct cell lines in the same Individual

question

Somatic mosaicism

answer

Mutation arises from mitotic errors after fertilization and propagates through multiple tissue or organs

question

Gonadal mosaicism

answer

Mutation only in egg or sperm cells. If parents and relatives do not have the disease, suspect gonadal (or germline) mosaicism

question

McCune-Albright syndrome

answer

Example of mosaicism Mutation affecting G-protein signling. Unilateral cafe-au-lait spots with ragged edges Polyostotic fibrous dysplasia At least 1 endocrinopathy (eg, precocious puberty) Lethal if mutation occurs before fertilization (affecting all cells), but survivable in patients with mosaicism

question

Locus heterogeneity

answer

Mutations at different loci can produce similar phenotype Albinism

question

Allelic heterogeneity

answer

Different mutations in the same locus produce the same phenotype b-thalassemia

question

Heteroplasmy

answer

Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease

question

Uniparental disomy

answer

Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent Heterodisomy (heterozygous) indicates a meiosis I error. Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair. Uniparental is euploid (correct number of chromosomes), not aneuploid. Most occurrences of uniparental disomy (UPD) -> normal phenotype. Consider UPD in an individual manifesting a recessive disorder when only one parent is a carrier

question

Hardy-Weinberg population genetics

answer

p2+2pq+q2=1 p+q=1 p2= frequency of homozygosity for A q2= frequency of homozygosity for a 2pq= frequency of heterozygosity (carrier frequency, if an autosomal recessive disease) The frequency of an X-linked recessive disease in males = q and in females = q2 Assumptions: No mutation occurring at the locus Natural selection is not occurring Completely random mating No net migration

question

Imprinting

answer

At some loci, only one allele is active; the other is inactive (imprinted/inactivated by methylation) With one allele inactivated, deletion of the active allele -> disease Prader-Willi and Angelman syndromes are due to mutation or deletion of genes on chromosome 15

question

Prader-Willi syndrome

answer

Mutation of deletion of genes on chromosome 15 Maternal imprinting: gene from mom is normally silent and paternal gene is deleted/mutated Hyperphagia Obesity Intellectual disability Hypogonadism Hypotonia 25% of cases due to maternal uniparental disomy (two maternally imprinted genes are received; no paternal gene received)

question

Angelman syndrome

answer

Paternal imprinting: gene from dad is normally silent and maternal gene is deleted/mutated Inappropriate laughter ("happy puppet") Seizures Ataxia Severe intellectual disability 5% of cases due to paternal uniparental disomy (two paternally imprinted genes are received; no maternal gene received)

question

Autosomal dominant

answer

Often due to defects in structural genes Many generations Both males and females are affected Often pleiotropic (multiple apparently unrelated effects) and variably expressive (different between individuals) Family history crucial to diagnosis With one affected (heterozygous) parent, on average, 1/2 of children affected

question

Autosomal recessive

answer

Often due to enzyme deficiencies Usually seen in only 1 generation Commonly more severe than dominant disorders; patients often present in childhood Increased risk in consanguineous families With 2 carrier (heterozygous) parents, on average: 1/4 of children will be affected (homozygous) 1/2 of children will be carriers 1/4 of children will be neither affected nor carriers

question

X-linked recessive

answer

Sons of heterozygous mothers have a 50% chance of being affected No male-to-male transmission Skips generations Commonly more severe in males Females usually must be homozygous to be affected

question

X-linked dominant

answer

Transmitted through both parents Mothers transmit to 50% of daughters and sons Fathers transmit to all daughters but no sons Hypophosphatemic rickets (Vitamin D-resistant rickets) Fragile X syndrome Alport syndrome

question

Hypophosphatemic rickets

answer

X-linked dominant Formerly known as vitamin D-resistant rickets Inherited disorder resulting in increased phosphate wasting at proximal tubule Results in rickets-like presentation

question

Mitochondrial inheritance

answer

Transmitted only through the mother All offspring of affected females may show signs of disease Variable expression in a population or even within a family due to heteroplasmy Mitochondrial myopathies

question

Mitochondrial myopathies

answer

Mitochondrial inheritance Rare disorders Often present with myopathy, lactic acidosis, and CNS disease, eg, MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes 2' to failure in oxidative phosphorylation Muscle biopsy often shows "ragged red fibres" (due to accumulation of diseased mitochondria)

question

List of autosomal dominant diseases

answer

Achondroplasia ADPKD FAP Familial hypercholesterolemia Hereditary hemorrhagic telangiectasia Hereditary spherocytosis Huntington disease Li-Fraumeni syndrome Marfan syndrome Multiple endocrine neoplasias NF1, von Recklinghausen disease NF2 Tuberous sclerosis von Hippel-Lindau disease

question

List of autosomal recessive diseases

answer

Albinism ARPKD CF Glycogen storage diseases Hemochromatosis Kartagener syndrome Mucopolysaccharidoses (except Hunter syndrome) PKU Sickle cell anemia Sphingolipidoses (except Fabry disease) Thalassemias Wilson disease

question

CF genetics

answer

Autosomal recessive Defect in CFTR gene on Ch7 Commonly deletion of Phe508 Most common lethal genetic disease in Caucasian

question

CF pathophysiology

answer

CFTR encoded ATP-gated Cl- channel Secrets Cl- in lungs, GI tract Reabsorbs Cl- in sweat glands Most common mutation-; misfolded protein -; retained in RER -; decreased Cl- and H2O secretion Increased intracellular Cl- -; compensatory increased Na+ reabsorption via epithelial Na+ channels -; increased H2O reabsorption -; abnormally thick mucus secreted into lungs and GI tract Increased Na+ reabsorption also -; more negative transepithelial potential difference

question

CF diagnosis

answer

Increased Cl- concentration ;60mEq/L in sweat is Dx Can present with contraction alkalosis and hypokalemia (ECF effects analogous to a patient taking a loop diuretic) because of ECF H2O/Na+ losses and concomitant K+/H+ wasting Increased immunoreactive trypsinogen (newborn screening)

question

CF complications

answer

Recurrent pulmonary infection (S aureus [infancy], P aeruginosa [adolescence]), chronic bronchitis and bronchiectasis -; reticulonodular pattern on CXR, opacification of sinuses Pancreatic insufficiency, malabsorption with steatorrhea, fat-soluble vitamin deficiencies (A, D, E, K), biliary cirrhosis, liver disease. Meconium ileus in newborns Infertility in men (absence of vas deferens, spermatogenesis may be unaffected) and subfertility in women (amenorrhea, abnormally thick cervical mucus) Nasal polyps, clubbing of nails

question

CF treatment

answer

Multifactorial: chest physiotherapy, albuterol, aerosolized dornase alfa (DNAase), hypertonic saline facilitate mucus clearance Azithromycin used as anti-inflammatory agent Ibuprofen shows disease progression Pancreatic enzymes for insufficiency

question

List of X-linked recessive disorders

answer

Ornithine transcarbamylase deficiency Fabry disease Wiskott-Aldrich syndrome Ocular albinism G6PD deficiency Hunter syndrome Bruton agammaglobulinemia Hemophilia A and B Lesch-Nyhan syndrome Duchenne (and Becker) muscular dystrophy

question

Lyonization

answer

Female carriers variably affected depending on the pattern of inactivation of the X chromosome carrying the mutant vs normal gene

question

Duchenne muscular dystrophy

answer

X-linked framshift or nonsense mutations -; truncated or absent dystrophin protein -; progressive myofiber damage Weakness begins in pelvic girdle muscles and progresses superiorly Psedohypertrophy of calf muscles Waddling gait Onset before 5ya Dilated cardiomyopathy is common cause of death Dystrophin gene (DMD) is the largest protein-coding human gene -; increased chance of spontaneous mutation Dystrophin helps anchor muscle fibres, primarily in skeletal and cardiac muscle It connects intracellular cytoskeleton (actin) to transmembrane protein a- and b-dystroglycan, which are connected to ECM Loss of dystrophin -; myonecrosis Increased CK and aldolase Genetic testing confirms dx

question

Becker muscular dystrophy

answer

X-linked Non-frameshift deletions in dystrophin gene (partially functional instead of truncated) Less severe than Duchenne Onset in adolescence or early adulthood Deletion can cause both Duchenne and Backer muscular dystrophies 2/3 of cases have large deletions spanning one or more exons

question

Myotonic type 1 muscular dystrophy

answer

Autosomal dominant CTG trinucleotide repeat expansion in the DMPK gene -; abnormal expression of myotonin protein kinase -; myotonia, muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia

question

Grower sign

answer

Patient uses upper extremities to help stand up Classically seen in Duchenne muscular dystrophy, but also seen in other muscular dystrophies and inflammatory myopathies (polymyositis)

question

Fragile X syndrome

answer

X-linked dominant CGG repeat in FMR1 gene -; hypermethylation -; decreased expression Most common cause of inherited intellectual disability and autism 2nd most common cause of genetically associated mental deficiency (after Down syndrome) Post-pubertal macroorchidism Long face with large jaw Large everted ears Autism Mitral valve prolapse

question

Trinucleotide repeat expansion disease

answer

Huntington disease CAG Myotonic dystrophy CTG Fragile X syndrome CGG Friedreich ataxia GAA May show genetic anticipation (disease severity increases and age of onset decreased in successive generations)

question

Down syndrome physical findings

answer

Intellectual disability Flat facies Prominent epicanthal folds Single palmar crease Gap between 1st 2 toes Duodenal atresia Hirschsprung disease Congenital heart disease (AVSD) Brushfield spots Associated with early-onset Alzheimer disease (Ch21 codes for amyloid precursor protein) High risk of ALL and AML Most common viable chromosomal disorder and cause of genetic intellectual disability

question

Down syndrome causes

answer

95% meiotic nondisjunction (increase with advanced maternal age, from 1:1500 in 45ya) overall 1:700 4% unbalanced Robertsonian translocation, most typical between Ch14 and 21 1% mosaicism (no association with maternal nondisjunction; postfertilization mitotic error)

question

Down syndrome prenatal findings

answer

1st Tri U/S increased nuchal translucency Hypoplastic nasal bone Low serum PAPP-A High free b-hCG 2nd tri quad screen Low a-fetoprotrin High b-hCG Low estriol High inhibin A

question

Edwards syndrome (trisomy 18)

answer

Prominent occiput Rocker-bottom feet Intellectual disability Nondisjunction Clenched fists with overlapping fingers Low-set ears Micrognathia (small jaw) Congenital heart disease Death usually occurs by 1ya Incidence 1:8000 2nd most common autosomal trisomy resulting in live birth (after Down syndrome) 1st Tri: low PAPP-A and free b-hCG Quad screen: low AFP, b-hCG, estriol, low or normal inhibin A

question

Patau syndrome (trisomy 13)

answer

Severe intellectual disability Rocker-bottom feet Microphthalmia Microcephaly Cleft lip/palate Holoprosencephaly Polydactyly Cutis aplasia Congenital heart disease Death at 1ya Incidence 1:15000 1st Tri: low free b-hCG, PAPP-A

question

Genetic disorders by chromosome 3

answer

von Hippel-Lindau disease Renal cell carcinoma

question

Genetic disorders by chromosome 4

answer

ADPKD (PKD2) Achondroplasia Huntington disease

question

Genetic disorders by chromosome 5

answer

Cri-du-chat syndrome Familial adenomatous polyposis

question

Genetic disorders by chromosome 6

answer

Hemochromatosis (HFE)

question

Genetic disorders by chromosome 7

answer

Williams syndrome Cystic fibrosis

question

Genetic disorders by chromosome 9

answer

Friedreich ataxia

question

Genetic disorders by chromosome 11

answer

Wilms tumor b-globin gene defects (sickle cell disease, b-thalassemia, MEN1)

question

Genetic disorders by chromosome 13

answer

Patau syndrome Wilson disease Retinoblastoma (RB1) BRCA2

question

Genetic disorders by chromosome 15

answer

Prader-Willi syndrome Angelman syndrome Marfan syndrome

question

Genetic disorders by chromosome 16

answer

ADPKD (PKD1) a-globin gene defects (a-thalassemia)

question

Genetic disorders by chromosome 17

answer

NF1 BRCA1 p53

question

Genetic disorders by chromosome 18

answer

Edwards syndrome

question

Genetic disorders by chromosome 21

answer

Down syndrome

question

Genetic disorders by chromosome 22

answer

NF2 DiGeorge syndrome (22q11)

question

Genetic disorders by chromosome X

answer

Fragile X syndrome X-linked agammaglobulinemia Klinefelter syndrome (XXY)

question

Robertsonian translocation

answer

Commonly involves chromosome pairs 13, 14, 15, 21, 22 One of the most common types of translocation Occurs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2 short arms are lost Balanced translocations normally do not cause any abnormal phenotype Unbalanced translocations can result in miscarriage, stillbirth, chromosomal imbalance (Down syndrome, Patau syndrome)

question

Cri-du-chat syndrome

answer

Congenital microdeletion of short arm of ch5 (46, XX or XY, 5p-) Microcephaly Mod to severe intellectual disability High-pitched crying/meowing Epicanthal folds Cardiac abnormalities (VSD)

question

William syndrome

answer

Congenital microdeletion of long arm of ch7 (deleted region includes elastin gene) Distinctive "elfin" facies Intellectual disability Hypercalcemia (high sensitivity to vitamin D) Well-developed verbal skills Extreme friendliness with strangers Cardiovascular problems

question

22q11 deletion syndromes

answer

Microdeletion Due to aberrant development of 3rd and 4th branchial pouches Variable presentations Cleft palate Abnormal facies Thymic aplasia -; T-cell deficiency Cardiac defects Hypocalcemia 2' to parathyroid aplasia

question

DiGeorge syndrome

answer

Thymic Parathyroid Cardic defects

question

Velocardiofacial syndrome

answer

Palate Facial Cardiac defects

question

Vitamins: fat soluble

answer

A, D, E, K Absorption dependent on gut and pancreas Toxicity more common than for water-soluble vitamins because fat-soluble vitamins accumulate in fat Malabsorption syndromes with steatorrhea, eg. CF, celiac disease, mineral oil intake can cause fat-soluble vitamin deficiencies

question

Vitamins: water soluble

answer

B1 thiamine: TPP B2 riboflavin: FAD, FMN B3 niacin: NAD+ B5 pantothenic acid: CoA B6 pyridoxine: PLP B7 biotin B9 folate B12 cobalamin C ascorbic acid All wash out easily from body except B12 and B9 B12 stored in liver for 3-4 years B9 stored in liver for 3-4 months B-complex deficiencies often result in dermatitis, glossitis, diarrhea Can be coenzymes (ascorbic acid) or precursors to organic cofactors (FAD, NAD+)

question

Vitamin A (retinol) function

answer

Antioxidant Constituent of visual pigments (retinal) Essential for normal differentiation of epithelial cells into specialized tissue (pancreatic cells, mucus-secreting cells) Prevents squamous metaplasia Used to treat measles and acute promyelocytic leukemia (APL) Found in liver and leafy vegetables Oral isotretinoin to treat severe cystic acne Use all-trans retinoic acid to treat acute promyelocytic leukemia

question

Vitamin A (retinol) deficiency

answer

Night blindness (nyctalopia) Dry, scaly skin (xerosis cutis) Corneal degeneration (keratomalacia) Bitot spots on conjunctiva Immunosuppression

question

Vitamin A (retinol) excess

answer

Acute toxicity Nausea, vomiting, vertigo, blurred vision Chronic toxicity Alopecia, dry skin (scaliness), hepatic toxicity and enlargement, arthralgias, pseudotumor cerebri Taratogenic (cleft palate, cardiac abnormalities) -ve preg test + 2 forms of contraception required before prescribing isotretinoin

question

Vitamin B1 (thiamine) function

answer

In thiamine pyrophosphate (TPP), cofactors for: Pyruvate dehydrogenase a-ketoglutarate dehydrogenase (TCA) Transketolase (HMP shunt) Branched-chain ketoacid dehydrogenase

question

Vitamin B1 (thiamine) deficiency

answer

Impaired glucose breakdown -> ATP depletion worsened by glucose infusion Highly aerobic tissues (brain, heart) affected first EtOH or malnourished patients, give thiamine before dextrose to decrease risk of precipitating Wernicke encephalopathy Dx made by increase in RBC transketolase activity following vitamin B1 administration Dry beriberi: polyneuritis, symmetrical muscle wasting Wet beriberi: high-output cardiac failure (dilated cardiomyopathy), edema

question

Wernicke-Korsakoff syndrome

answer

Confusion Ophthalmoplegia Ataxia (classic triad) Confabulation Personality change Memory loss (permanent) Damage to medial dorsal nucleus of thalamus, mammillary bodies

question

Vitamin B2 (riboflavin) function

answer

Component of flavins FAD and FMN Cofactors in redox reactions Succinate dehydrogenase reaction in TCA cycle

question

Vitamin B2 (riboflavin) deficiency

answer

Cheilosis (inflammation of lips, scaling and fissures at the corners of the mouth) Corneal vascularization

question

Vitamin B3 (niacin) function

answer

Constituent of NAD+, NADP+ (used in redox reactions) Derived from tryptophan Synthesis requires vitamin B2 and B6 Used to treat dyslipidemia, lowers levels of VLDL and raises levels of HDL

question

Vitamin B3 (niacin) deficiency

answer

Glossitis Severe deficiency leads to pellagra, which can be caused by Hartnup disease, malignant carcinoid syndrome (high tryptophan metabolism), isoniazid (lowers vitamin B6) Symptoms of pellagra: Diarrhea Dementia (also hallucinations) Dermatitis (C3/C4 dermatome circumferential "broad collar" rash [Casal necklace], hyperpigmentation of sun-exposed limbs

question

Hartnup disease

answer

Autosomal recessive Deficiency of neutral amino acid (tryptophan) transportors in proximal renal tubular cells and on enterocytes -> neutral aminoaciduria and decreased absorption from the gut -> decreased tryptophan for conversion to niacin -> pellagra-like symptoms Tx with high-protein diet and nicotinic acid

question

Vitamin B3 (niacin) excess

answer

Facial flushing (induced by prostaglandin, not histamine; can avoid by taking aspirin with niacin) Hyperglycemia Hyperuricemia

question

Vitamin B5 (pantothenic acid) function

answer

Essential component of coenzyme A (CoA, a cofactor for acyl transfers) and fatty acid synthase

question

Vitamin B5 (pantothenic acid) deficiency

answer

Dermatitis Enteritis Alopecia Adrenal insufficiency

question

Vitamin B6 (pyridoxine) function

answer

Converted to pyridoxal phosphate (PLP), a cofactor used in transamination (ALT and AST), decarboxylation reactions, glycogen phosphorylase. Synthesis of cystathionine, heme, niacin, histamine, and neurotransmitters including serotonin, epinephrine, norepinephrine (NE), dopamine, GABA

question

Vitamin B6 (pyridoxine) deficiency

answer

Convulsions Hyperirritability Peripheral neuropathy (deficiency inducible by isoniazid and oral contraceptives) Sideroblastic anemias due to impaired hemoglobin synthesis and iron excess

question

Vitamin B7 (biotin) function

answer

Cofactor for carboxylation enzymes: Pyruvate carboxylase: pyruvate (3C) -> oxaloacetate (4C) Acetyl-CoA carboxylase: acetyl-CoA (2C) -> malonyl-CoA (3C) Propionyl-CoA carboxylase: propionyl-CoA (3C) -> methylmalonyl-CoA (4C)

question

Vitamin B7 (biotin) deficiency

answer

Relatively rare Dermatitis Alopecia Enteritis Caused by antibiotic use or excessive ingestion of raw egg whites

question

Vitamin B9 (folate) function

answer

Converted to THF, a coenzyme for 1-carbon transfer/methylation reactions Important for the synthesis of nitrogenous bases in DNA and RNA Found in leafy green vegetables Absorbed in jejunum Small reserve pool stored primarily in the liver

question

Vitamin B9 (folate) deficiency

answer

Macrocytic, megaloblastic anemia Hypersegmented PMNs Glossitis No neurological symptoms (as opposed to vitamin B12 deficiency) High homocysteine Normal methylmalonic acid levels Most common vitamin deficiency in USA Seen in alcoholism and pregnancy Deficiency can be caused by several drugs (phenytoin, sulfonamides, methotrexate) Supplemental maternal folic acid at least 1 month prior to conception and during early pregnancy to reduce risk of neural tube defects

question

Vitamin B12 (cobalamin) function

answer

Cofactor for methionine synthase (transfers CH3 groups as methylcobalamin) and methylmalonyl-CoA mutase Important for DNA synthesis

question

Vitamin B12 (cobalamin) deficiency

answer

Macrocytic, megaloblastic anemia Hypersegemented PMNs Paresthesias and subacute combined degeneration (dorsal columns, lateral corticospinal tracts, spinocerebellar tracts) due to abnormal myelin High serum homocysteine and methylmalonic acid levels 2' folate deficiency Prolonged deficiency -; irreversible nerve damage

question

Vitamin B12 (cobalamin) deficiency causes

answer

Found in animal products Synthesized only by microorganisms Very large reserve pool (several years) stored primarily in the liver Deficiency caused by malabsorption (sprue, enteritis, Diphyllobothrium latum), lack of intrinsic factor (pernicious anemia, gastric bypass surgery), absence of terminal ileum (surgery resection, for Crohn disease), insufficient intake (veganism) Anti-intrinsic factor antibodies diagnostic for pernicious anemia

question

Vitamin C (ascorbic acid) function

answer

Antioxidant Facilitates iron absorption by reducing it to Fe2+ state Necessary for hydroxylation of proline and lysine in collagen synthesis Necessary for dopamine b-hydroxylase, converts dopamine to NE Found in fruits and vegetables Ancillary Tx for methemoglobinemia by reducing Fe3+ to Fe2+

question

Vitamin C (ascorbic acid) deficiency

answer

Scurvy Swollen gums Bruising Petechiae Hemarthrosis Anemia Poor wound healing Perifollicular and subperiosteal hemorrhages Corkscrew hair Weakened immune response

question

Vitamin C (ascorbic acid) excess

answer

Nausea Vomiting Diarrhea Fatigue Calcium oxalate nephrolithiasis Increased risk of iron toxicity in predisposed individuals (transfusions, hereditary hemochromatosis)

question

Vitamin D forms

answer

D2 ergocalciferol - ingested from plants D3 cholecalciferol - consumed in milk, formed in sun-exposed skin (stratum basale) 25-OH D3 storage form 1,25-(OH)2 D3 calcitriol active form

question

Vitamin D function

answer

Increases intestinal absorption of calcium and phosphate Increases bone mineralization at low Levels Increases bone resorption at higher levels

question

Vitamin D deficiency

answer

Rickets in children (deformity, genu varum) Osteomalacia in adults (bone pain and muscle weakness) Hypocalcemia tetany Breastfed infants should receive oral vitamin D Deficiency is exacerbated by low sun exposure, pigmented skin, prematurity

question

Vitamin D excess

answer

Hypercalcemia Hypercalciuria Loss of appetite Stupor Seen in granulomatous disease (high activation of vitamin D by epithelioid macrophages

question

Vitamin E (tocopherol/tocotrienol) function

answer

Antioxidant (protects RBCs and membranes from free radical damage) High-dose supplementation may alter metabolism of vitamin K -; enhanced anticoagulant effects of warfarin

question

Vitamin E (tocopherol/tocotrienol) deficiency

answer

Hemolytic anemia Acanthocytosis Muscle weakness Posterior column and spinocerebellar tract demyelination Neurologic presentation may appear similar to vitamin B12 deficiency, but without megaloblastic anemia, hypersegmented PMNs, or high serum methylmalonic acid levels

question

Vitamin K (phytomenadione, phylloquinone, phytonadione) function

answer

Activated by epoxide reductase to the reduced form Cofactor for the gamma-carboxylation of glutamic acid residues on various proteins required for blood clotting Synthesized by intestinal flora II, VII, IX, X, C, S Warfarin inhibits vitamin K-dependent synthesis of these factors and proteins

question

Vitamin K (phytomenadione, phylloquinone, phytonadione) deficiency

answer

Neonatal hemorrhage with high PT and aPTT normal bleeding time Neonates have sterile intestines and are unable to synthesize vitamin K Can also occur after prolonged use of broad-spectrum antibiotics Not in breast milk Neonates are given vitamin K injection at birth

question

Zinc function

answer

Activity of 100+ enzymes Formation of zinc fingers (transcription factor motif)

question

Zinc deficiency

answer

Delayed wound healing Hypogonadism Loss of adult hair (axillary, facial, pubic) Dysgeusia Anosmia Acrodermatitis enteropathica May predispose to alcoholic cirrhosis

question

Kwashiorkor

answer

Protein malnutrition Edema due to low plasma oncotic pressure Anemia Liver malfunction (fatty change due to low apolipoprotein synthesis) Skin lesions (hyperkeratosis/hyperpigmentation) Small child with swollen abdomen

question

Marasmus

answer

Malnutrition not causing edema Diet is deficient in calories but no nutrients are entirely absent Muscle wasting

question

Fomepizole

answer

Inhibits alcohol dehydrogenase Antidote for overdoses of methanol or ethylene glycol

question

Disulfiram

answer

Inhibits acetaldehyde dehydrogenase (acetaldhyde accumulates, contributing to hangover symptoms), discouraging drinking

question

Limiting factor in ethanol metabolism

answer

NAD+

question

Metabolic reactions only in mitochondria

answer

Fatty acid oxidation (b-oxidation) Acetyl-CoA production TCA cycle Oxidative phosphorylation Ketogenesis

question

Metabolic reactions only in cytoplasm

answer

Glycolysis HMP shunt Synthesis of steroids (SER), proteins (ribosomes, RER), fatty acids, cholesterol, nucleotides

question

Metabolic reactions in both mitochondria and cytoplasm

answer

Heme synthesis Urea cycle Gluconeogenesis

question

Rate-determining enzyme of glycolysis

answer

Phosphofructokinase-1 (PFK-1) + AMP fructose-2,6-bisphosphate - ATP citrate

question

Rate-determining enzyme of gluconeogenesis

answer

Fructose-1,6-bisphosphatase + Citrate - AMP Fructose-2,6-bisphosphate

question

Rate-determining enzyme of TCA cycle

answer

Isocitrate dehydrogenase + ADP - ATP NADH

question

Rate-determining enzyme of glycogenesis

answer

Glycogen synthase + Glucose-6-phosphate Insulin Cortisol - Epinephrine Glucagon

question

Rate-determining enzyme of glycogenolysis

answer

Glycogen phosphorylase + Epinephrine Glucagon AMP - Glucose-6-phosphate Insulin ATP

question

Rate-determining enzyme of HMP shunt

answer

Glucose-6-phosphate dehydrogenase (G6PD) + NADP+ - NADPH

question

Rate-determining enzyme of de novo pyrimidine synthesis

answer

Carbamoyl phosphate synthetase II + ATP PRPP - UTP

question

Rate-determining enzyme of de novo purine synthesis

answer

Glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase - AMP Inosine monophosphate (IMP) GMP

question

Rate-determining enzyme of urea cycle

answer

Carbamoyl phosphate synthetase I + N-acetylglutamate

question

Rate-determining enzyme of fatty acid synthesis

answer

Acetyl-CoA carboxylase (ACC) + Insulin Citrate - Glucagon Palmitoyl-CoA

question

Rate-determining enzyme of fatty acid oxidation

answer

Carnitine acyltransferase I - Malonyl-CoA

question

Rate-determining enzyme of ketogenesis

answer

HMG-CoA synthase

question

Rate-determining enzyme of cholesterol synthesis

answer

HMG-CoA reductase + Insulin Thyroxine - Glucagon Cholesterol

question

ATP production number

answer

Aerobic 32 via malate-aspartate shuttle (heart and liver) 30 via glycerol-3-phosphate shuttle (muscle) Anaerobic 2 Arsenic 0

question

Carrier molecules and activated form

answer

ATP: Phosphoryl groups NADH, NADPH, FADH2: Electrons CoA, lipoamide: Acyl groups Biotin: CO2 Tetrahydrofolates: 1-carbon units S-adenosylmethionine (SAM): CH3 groups TPP: Aldehydes

question

Universal electron acceptors

answer

NAD+ NADP+ FAD+

question

NADPH

answer

Product of HMP shunt Used in Anabolic processes Respiratory burst Cytochrome P-450 system Glutathione reductase

question

Glycolysis net reaction

answer

Glucose + 2Pi + 2ADP + 2NAD+ -; 2pyruvate + 2ATP + 2NADH + 2H+ + 2H2O

question

ATP requiring reactions in glycolysis

answer

Glucose -; glucose-6-phosphate Hexokinase/glucokinase Glucose-6-P - hexokinase Fructose-6-P - glucokinase Fructose-6-P -; fructose-1,6-BP Phosphofructokinase-1

question

ATP producing reaction in glycolysis

answer

1,3-BPG 3-PG Phosphoglycerate kinase Phosphoenolpyruvate -; pyruvate Pyruvate kinase + Fructose-1,6-bisphosphate - ATP Alanine

question

Pyruvate dehydrogenase net reaction

answer

Pyruvate + NAD+ + CoA -; acetyl-CoA + CO2 + NADH + NAD+/NADH ratio ADP Ca2+ - ATP Acetyl-CoA NADH

question

Pyruvate dehydrogenase complex cofactors

answer

Thiamine pyrohosphate (B1) Lipoic acid CoA (B5, pantothenic acid) FAD (B2, riboflavin) NAD+ (B3, niacin)

question

Pyruvate dehydrogenase complex deficiency

answer

Build up of pyruvate shunted to lactate (LDH) and alanine (ALT) Neurologic defects Lactate acidosis High serum alanine starting in infancy Tx: increase intake of ketogenic nutrients (high fat or lysine and leucine)

question

Arsenic

answer

Inhibits lipoic acid Vomiting Rice-water stools Garlic breath QT prolongation

question

Number of ATP produced from NADH and FADH2

answer

NADH 2.5 FADH2 1.5

question

Electron transport inhibitor

answer

Decrease proton gradient Block ATP synthesis Rotenone complex1 Antimycin A complex3 Cyanide/CO complex4

question

ATP synthase inhibitor

answer

Increase proton gradient No ATP production Oligomycin

question

Uncoupling agent

answer

Increase permeability Decrease proton gradient Increase O2 consumption ATP synthesis stops Electron transport continues Produce heat 2,4-Dinitrophenol (weight loss) Aspirin Thermogenin (in brown fat)

question

Pyruvate carboxylase

answer

Pyruvate -; oxaloacetate Gluconeogenesis, irreversible enzyme In mitochondria Requires biotin, ATP Activated by acetyl-CoA

question

Phosphoenolpyruvate carboxykinase

answer

Oxaloacetate -; phosphoenolpyruvate Gluconeogenesis, irreversible enzyme In cytosol Requires GTP

question

Fructose-1,6-bisphosphatase

answer

Fructose-1,6-bisphosphate -; fructose-6-phosphate Gluconeogenesis, irreversible enzyme In cytosol - Citrate + AMP Fructose-2,6-bisphosphate

question

Glucose-6-phosphatase

answer

Glucose-6-phosphate -; glucose Gluconeogenesis, irreversible enzyme In ER

question

Gluconeogenesis

answer

Primarily in liver Not muscle (no glucose-6-phosphatase) Odd-chain fatty acids -; 1 propionyl-CoA, enter TCA as succinyl-CoA, gluconeogenesis Even-chain fatty acids -; acetyl-CoA equivalents, no gluconeogenesis

question

HMP shunt (pentose phosphate pathway)

answer

Source of NADPH Cytoplasm No ATP used or produced Lactating mammary glands Liver Adrenal cortex (fatty acid or steroid synthesis) RBCs

question

G6PD

answer

Hemolytic anemia Poor RBC defence against oxidizing agents (fava beans, sulfonamides, primaquine, antituberculosis drugs), infections, inflammatory response X-linked recessive Most common human enzyme deficiency More prevalent in African American Increase malarial resistance Heinz bodies (denatured hemoglobin) Bite cells

question

Essential fructosuria

answer

Defect in fructokinase Autosomal recessive Benign, asymptomatic Fructose not trapped in cells Fructose appears in blood and urine Disorders of fructose metabolism milder than galactose metabolism

question

Fructose intolerance

answer

Hereditary deficiency of aldolase B Autosomal recessive Fructose-1-phosphate accumulates -; decrease available phosphate -; inhibition of glycogenolysis and gluconeogenesis Follow eating fruit, juice, honey Urine dipstick -ve (glucose) Reducing sugar in urine Hypoglycemia Jaundice Cirrhosis Vomiting Tx: decrease intake of fructose and sucrose

question

Galactokinase deficiency

answer

Hereditary deficiency Galactitol accumulates (aldose reductase) Relatively mild Autosomal recessive Galactose in blood and urine Infantile cataracts Failure to track objects Develop a social smile

question

Classic galactosemia

answer

Absence of galactose-1-phosphate uridyltransferase Autosomal recessive Accumulation of toxic substances (galactitol in lens of eye) Symptoms develop when infant begins feeding Failure to thrive Jaundice Hepatomegaly Infantile cataracts Intellectual disability Predispose to E coli sepsis in neonates Tx: exclude galactose and lactose from diet The most serious defects lead to PO4 3- depletion

question

Sorbitol

answer

Alcohol counterpart of glucose Intracellular accumulation -; osmotic damage cataracts, retinopathy, peripheral neuropathy

question

Lactase deficiency

answer

Primary: absence of lactase-persistent allele, common in Asian, AA, Native American Secondary: loss of brush border due to gastroenteritis(rotavirus), autoimmune disease Congenital deficiency rare, due to defective gene Stool low pH, breath high hydrogen content Normal mucosa in hereditary lactose intolerance biopsy Bloating, cramps, flatulence, osmotic diarrhea Tx: avoid dairy, add lactase pills, lactose-free milk

question

Essential amino acids

answer

Glucogenic: Met, his, val Glucogenic/ketogenic: Ile, phe, thr, trp Ketogenic: Leu, Lys

question

Acidic amino acids

answer

Asp, glu

question

Basic amino acids

answer

His, lys, arg (most basic)

question

Hyperammonemia

answer

Acquired (liver disease) vs hereditary (urea cycle enzyme deficiencies) Excess NH3, deplets a-ketoglutarate -; inhibition of TCA Tx: limit protein Lactulose Abx (rifaximin) Benzoate, phenylactate, phenylbutyrate react with glycine or glutamine, forming products renally excreted Tremor(asterixis) Slurring of speech Somnolence Vomiting Cerebral edema Blurring vision

question

Ornithine transcarbamylase deficiency

answer

Most common urea cycle disorder X-linked recessive (other urea cycle enzyme deficiencies are autosomal recessive) First few days of life, may present later Excess carbamoyl phosphate converted to orotic acid High orotic acid in blood and urine Low BUN Hyperammonemia symptoms No megaloblastic anemia (vs orotic aciduria)

question

Phenylketonuria

answer

Low phenylalanine hydroxylase or tetrahydrobiopterin (BH4) cofactor (malignant PKU) Excess phenyl ketones in urine Intellectual disability Growth retardation Seizures Fair skin Eczema Musty body odor Tx: low phenylalanine and high tyrosine diet, BH4 supplementation Autosomal recessive, 1:10,000 Screening 2-3days after birth (normal at birth from maternal enzyme) Phenyl ketones - phenylacetate, phenyllactate, phenylpyruvate Disorder of aromatic amino acid metabolism -; musty body odor Must avoid aspartame (contains phenylalanine)

question

Maternal PKU

answer

lack of dietary therapy Microcephaly Intellectual disability Growth retardation Congenital heart defects

question

Maple syrup urine disease

answer

Blocked degradation of branched amino acids: Isoleucine, leucine, valine Low branched-chain a-ketoacid dehydrogenase (B1) High a-ketoacids in blood, esp leucine Severe CNS defects Intellectual disability Death Tx: restriction isoleucine, leucine, valine Thiamine supplementation Autosomal recessive Vomiting, poor feeding, maple syrup/burnt sugar smell urine

question

Alkaptonuria

answer

Homogentisate oxidase deficiency Degradation pathway of tyrosine to fumarate Pigment-forming homogenetisic acid accumulates in tissue Autosomal recessive Usually benign Bluish-black connective tissue, ear cartilage, and sclerae (ochronosis) Urine turns black on prolonged exposure to air Debilitating arthralgias (homogentisic acid toxic to cartilage)

question

Homocystinuria

answer

All autosomal recessive Cystathionine synthase deficiency (Tx: low methionine, high cysteine, B6, B12, folate diet) Decreased affinity of cystathionine synthase for pyridoxal phosphate (Tx: high B6 and cysteine diet) Methionine synthase (homocysteine methyltransferase) deficiency (Tx: high methionine diet) All forms -; excess homocysteine High homocysteine in urine Osteoporosis Marfanoid habitus Ocular change (down and inward lens subluxation) Cardiovascular effects (thrombosis and atherosclerosis -; CVA and MI) Kyphosis Intellectual disability

question

Cystinuria

answer

Defect of renal PCT and intestinal amino acid transporter Prevents reabsorption of cystine, ornithine, lysine, arginine Excess cystine in urine Recurrent hexagonal cystine stones Tx: alkalinization (K citrate, acetazolamide), chelating agents (penicillamine) increase solubility of cystine stones, good hydration Autosomal recessive 1:7000 Dx: urinary cyanide-nitroprusside test Cystine = 2 cystines with disulfide bond

question

Glycogen storage diseases

answer

12 types PAS identifies glycogen I, II, III, V are autosomal recessive

question

Von Gierke disease

answer

Type I glycogen storage disease (AR) Glucose-6-phosphate deficiency Impaired gluconeogenesis and glycogenolysis Severe fasting hypoglycemia High glycogen in liver High blood lactate High triglycerides High uric acid (gout) Hepatomegaly

question

Pompe disease

answer

Type II glycogen storage disease (AR) Lysosomal acid a-1,4-glucosidase with a-1,6-glucosidase activity (acid maltase) deficiency Cardiomegaly Hypertrophic cardiomyopathy Hypotonia Exercise intolerance Systemic findings lead to early death (heart, liver, muscle)

question

Cori disease

answer

Type III glycogen storage disease (AR) Debranching enzyme (a-1,6-glucosidase) deficiency Gluconeogenesis is intact Milder form of von Gierke (type I) with normal blood lactate levels Accumulation of limit dextrin-like structures in cytosol

question

McArdle disease

answer

Type V glycogen storage disease (AR) Skeletal muscle glycogen phosphorylase (myophosphorylase) deficiency Blood glucose levels typically unaffected High glycogen in muscle, but unable to break down Painful muscle cramps Myoglobinuria (red urine) with strenuous exercise Arrhythmia from electrolyte abnormalities Second-wind phenomenon during exercise due to increased muscular blood flow

question

Lysosomal storage diseases

answer

Sphingolipidoses: Tay-Sachs disease Fabry disease Metachromatic leukodystrophy Krabbe disease Gaucher disease Niemann-Pick disease Mucopolysaccharidoses: Hurler syndrome Hunter syndrome High incidence of Tay-Sachs, Neimann-Pick, and some forms of Gaucher disease in Ashkenazi Jews

question

Lysosomal storage pathway

answer

1. Hexosaminidase A 2. a-galactosidase A 3. Arylsulfatase A 4. Galactocerebrosidase 5. Glucocerebrosidase (b-glucosidase) 6. Sphingomyelinase

question

Tay-Sachs disease

answer

Lysosomal storage disease Sphingolipidoses Autosomal recessive Hexosaminidase A deficiency GM2 ganglioside accumulation Progressive neurodegeneration Developmental delay Cherry-red spot on macula Lysosomes with onion skin No hepatosplenomegaly (vs Niemann-Pick)

question

Fabry disease

answer

Lysosomal storage disease Sphingolipidoses X-linked recessive a-galactosidase A deficiency Ceramide trihexoside accumulation Early: triad of episodic peripheral neuropathy, angiokeratomas, hypohidrosis Late: progressive renal failure, cardiovascular disease

question

Metachromatic leukodystrophy

answer

Lysosomal storage disease Sphingolipidoses Autosomal recessive Arylsulfatase A deficiency Cerebroside sulfate accumulation Central and peripheral demyelination with ataxia, dementia

question

Krabbe disease

answer

Lysosomal storage disease Sphingolipidoses Autosomal recessive Galactocerebrosidase deficiency Galactocerebroside, psychosine accumulation Peripheral neuropathy Destruction of oligodendrocytes Developmental delay Optic atrophy Globoid cells

question

Gaucher disease

answer

Most common lysosomal storage disease Sphingolipidoses Autosomal recessive Glucocerebrosidase (b-glucosidase) deficiency Glucocerebroside accumulation Hepatosplenomegaly Pancytopenia Osteoporosis Avascular necrosis of femur Bone crises Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper Tx: recombinant glucocerebrosidase

question

Niemann-Pick disease

answer

Lysosomal storage disease Sphingolipidoses Autosomal recessive Sphingomyelinase deficiency Sphingomyelin accumulation Progressive neurodegeneration Hepatosplenomegaly Foam cells (lipid-laden macrophages) Cherry-red spot on macula

question

Hurler syndrome

answer

Lysosomal storage disease Mucopolysaccharidoses Autosomal recessive a-L-iduronidase deficiency Heparan sulfate, dermatan sulfate accumulation Developmental delay Gargoylism Airway obstruction Corneal clouding Hepatosplenomegaly

question

Hunter syndrome

answer

Lysosomal storage disease Mucopolysaccharidoses X-linked recessive Iduronate sulfatase deficiency Heparan sulfate, dermatan sulfate accumulation Milder Hurler + aggressive behavior, no corneal clouding

question

Fatty acid metabolism

answer

Synthesis predominantly occurs in liver, lactating mammary glands, and adipose tissue

question

Systemic 1' carnitine deficiency

answer

Inherited defect in transport of LCFAs into mitochondria -> toxic accumulation Weakness Hypotonia Hypoketotic hypoglycemia

question

Medium-chain acyl-CoA dehydrogenase deficiency

answer

Decreased ability to break down fatty acids into acetyl-CoA -> accumulation of fatty acyl carnitines in blood with hypoketotic hypoglycemia Vomiting Lethargy Seizures Coma Liver dysfunction Sudden death in infants or children Tx: avoiding fasting

question

Ketone bodies

answer

Acetone, acetoacetate, b-hydroxybutyrate Urine test for ketones can detect acetoacetate, but not b-hydroxybutyrate Prolonged starvation, DKA -> oxaloacetate depleted for gluconeogenesis Alcoholism, excess NADH shunts oxaloacetate to malware Buildup of acetyl-CoA, shunts glucose and FFA to ketone bodies

question

Fed state

answer

Glycolysis and aerobic respiration Insulin stimulate storage of lipids, proteins, glycogen

question

Fasting between meals

answer

Hepatic glycogenolysis (major) Hepatic gluconeogenesis Adipose release of FFA (minor) Glucagon and epinephrine stimulate use of fuel reserves

question

Starvation 1-3 days

answer

Blood glucose levels maintained by: Hepatic glycogenolysis Adipose release of FFA Muscle and liver, shift fuel use from glucose to FFA Hepatic gluconeogenesis from peripheral tissue lactate and alanine, from adipose tissue glycerol and propionyl-CoA (odd-chain FA) Glycogen reserves depleted after day 1 RBCs lack mitochondria, cannot use ketones

question

Starvation after day 3

answer

Adipose stores (ketone bodies become main source of energy for brain) After depletion, vital protein degradation accelerates -> organ failure and death Amount of excess stores determines survival time

question

Pancreatic lipase

answer

Degradation of dietary triglycerides in small intestine

question

Lipoprotein lipase (LPL)

answer

Degradation of triglycerides circulating in chylomicrons and VLDLs Found on vascular endothelial surface

question

Hepatic triglyceride lipase (HL)

answer

Degradation of triglycerides remaining in IDL

question

Hormone-sensitive lipase

answer

Degradation of triglycerides stored in adipocytes

question

LCAT

answer

Catalyzes esterification of 2/3 of plasma cholesterol

question

Cholesterol ester transfer protein (CETP)

answer

Mediated transfer of cholesterol esters to other lipoprotein particles

question

Lipoprotein functions

answer

Lipoproteins are composed of varying proportions of cholestrol, TGs, and phospholipids LDL and HDL carry the most cholesterol LDL transports cholesterol from liver to tissues HDL transports cholesterol from periphery to liver

question

Cholesterol

answer

Needed to maintain cell membrane integrity and synthesize bile acid, steroids, and vitamin D

question

Chylomicron

answer

Delivers dietary TGs to peripheral tissues Delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their TGs Secreted by intestinal epithelial cells

question

VLDL

answer

Delivers hepatic TGs to peripheral tissue Secreted by liver

question

IDL

answer

Formed in the degradation of VLDL Delivers TGs and cholesterol to liver

question

LDL

answer

Delivers hepatic cholesterol to peripheral tissues Formed by hepatic lipase modification of IDL in the liver and peripheral tissue Taken up by target cells via receptor-mediated endocytosis

question

HDL

answer

Mediates reverse cholesterol transport from periphery to liver Acts as a repository for apolipoproteins C and E (which are needed for chylomicron and VLDL metabolism Secreted from both liver and intestine Alcohol increases synthesis

question

Abetalipoproteinemia

answer

Autosomal recessive Chylomicrons, VLDL, LDL absent Deficiency in ApoB48, ApoB100 Affected infants present with severe fat malabsorption, steatorrhea, failure to thrive Later manifestations include retinitis pigmentosa, spinocerebellar degeneration due to vitamin E deficiency, progressive ataxia, acanthocytosis Tx: restriction of long-chain fatty acids, large doses of oral vitamin E

question

Type I hyperchylomicronemia

answer

Autosomal recessive Lipoprotein lipase or apolipoprotein C-II deficiency High blood levels of chylomicrons, TG, cholesterol Pancreatitis Hepatosplenomegaly Eruptive/pruritic xanthomas (no increased risk for atherosclerosis) Creamy layer in supernatant

question

Type II familial hypercholesterolemia

answer

Autosomal dominant Absent or defective LDL receptors High blood levels of LDL, cholesterol (IIa) or LDL, cholesterol, VLDL (IIb) Heterozygotes (1:500) have cholesterol 300mg/dL Homozygotes (very rare) have cholesterol 700+ mg/dL Accelerated atherosclerosis (may have MI before 20ya) Tendon (Achilles) xanthomas Corneal arcus

question

Type III dysbetalipoproteinemia

answer

Autosomal recessive Defective ApoE High blood level of chylomicrons, VLDL Premature atherosclerosis Tuberoeruptive xanthomas Xanthoma striatum palmare

question

Type IV hypertriglyceridemia

answer

Autosomal dominant Hepatic overproduction of VLDL High blood levels of VLDL, TG Hypertriglyceridemia >1000 mg/dL can cause pancreatitis

USMLE FIRST AID 2017 Biochemistry – Flashcards

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