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334 Cards in this Set

  • Front
  • Back
Glycogen Storage Disease

1. Severe fasting hypoglycemia, increase glycogen in the liver, increase blood lactate....

2. Deficient enzyme?
1. Type I (von Gierke's)

2. G-6-P
Glycogen Storage Disease

1. Cardiomegaly and early death (2 yrs)

2. Deficient enzyme?
1. Type II (Pompe's)

2. Lysosomal alpha-1,4 glucosidase (acid maltase)
Glycogen Storage Disease

1. MILD hypoglycemia with normal blood lactate levels

2. Deficient enzyme?
1. Type III (Cori's)

2. (Debranching enzyme) alpha 1,6-glucosidase
Glycogen Storage Disease

1. Increased glycogen in muscles, leads to painful cramps with exercise

2. Deficient enzyme?
1. Type V (McArdle's)

2. glycogen phosphorylase
Glycogen Storage Disease

1. Type I (von Gierke's)

2. Deficient enzyme?
1. Severe fasting hypoglycemia, increase glycogen in the liver, increase blood lactate....

2. G-6-P
Glycogen Storage Disease

1. Type II (Pompe's)

2. Deficient enzyme?
1. Cardiomegaly and early death (2 yrs)

2. Lysosomal alpha-1,4 glucosidase (acid maltase)
Glycogen Storage Disease

1. Type III (Cori's)

2. Deficient enzyme?
1. MILD hypoglycemia with normal blood lactate levels

2. (Debranching enzyme) alpha 1,6-glucosidase
Glycogen Storage Disease

1. Type V (McArdle's)

2. Deficient enzyme?
1. Increased glycogen in muscles, leads to painful cramps with exercise

2. glycogen phosphorylase
Lysosomal Disease

1. Peripheral neuropathy, cadio/renal disease (X-linked)

2. 2. Deficient enzyme?
1. Fabry's Disease

2. alpha-galatosidase
Lysosomal Disease

1. Hepatosplenomegaly, aseptic necrosis of the femur, (macrophages look like?)

2. 2. Deficient enzyme?
1. Gaucher's disease

2. Beta-glucucerebrosidase
Lysosomal Disease

1. Progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on the macula, foam cells

2. 2. Deficient enzyme?
1. Niemman-Pick

2. Sphingomyelinase
Lysosomal Disease

1. Progressive neurodegeneration, NO hepatosplenomegaly, cherry-red spot on the macula, lysosomes have onion skin

2. 2. Deficient enzyme?
1. Tay-Sachs disease

2. Hexosaminidase A
Lysosomal Disease

1. central and peripheral demyelination

2. 2. Deficient enzyme?
1. Metachromatic leukodystrophy

2. Arylsulfatase A
Mucopolysaccharidosis

1. Aggressive behavior w/o cloudy corneal

2. gargoylism w/ cloudy corneal
1. Hurler's

2. Hunter's
Octamer subunits consist primarily of
lysine & arginine
Condensed, transcriptionally INACTIVE sterically inaccessible
Heterochromatin
Less condensed, transcriptionally ACTIVE, sterically accessible
Euchromatin
Purines
A, G
Pyrimidines
C, T, U
Deamination of cytosine makes
Uracil
The bonds between G-C
3 hydrogen bonds
The bonds between A-T
2 hydrogen bonds
Amino acids that are necessary for purine synthesis
Glycine
Aspartate
Glutamine
base + ribose
Nucleoside
base + ribose + phosphate; linked by 3'-5' phosphodiester bond
Nucleotides
Pyrimidine are made from...,w/PRPP added later
Orotate precursor
Accumulation of carbamoyl phosphate, which is then converted to orotic acid
Ornithine transcarbamylase deficiency
Findings:

- increased orotic acid in urine, megaloblastic anemia
- does not improve w/ B12 or folic acid
- No hyperammonemia and normal BUN
Orotic aciduria
- autosomal recessive

- inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway)

- due to defect in orotic acid phosphoribosyltransferase or orotidine 5'-phosphate decarboxylase
Orotic aciduria
Treatment for Orotic aciduria
Oral uridine administration
Excess ATP and dATP imbalances nucleotide pool via feedback inhibition o f ribonucleotide reductase -> prevents DNA synthesis and thus decrease lymphocyte counts
Adenosine deaminase
- Defective purine salvage owing to absence HGPRT

- excess uric acid production
Lesch-Nyhan syndrome
Converts hypoxanthine to IMP and guanine to GMP
HGPRT
Lesch-Nyhan syndrome findings
- self-mutilation
- aggression
- gout
- hyperuricemia
- retardation
- choreoathetosis
Target of allopurinol
Xanthine oxidase
Mutations in DNA/RNA

- Same aa, often base change in 3rd position of codon (tRNA wobble)
Silent mutation
Mutations in DNA/RNA

- Changed aa (conservative- new aa is similar in chemical structure)
Missense mutation
Mutations in DNA/RNA

- Change resulting in early STOP codon
Nonsense mutation
Mutations in DNA/RNA

- Change resulting in misreading of all nucleotides downstream, usually resulting in a truncated. nonfunctional protein
Frame shift
DNA replication

- particular sequence in genome where DNA replication begins

- single in prokaryotes; multiple in eukaryotes
Origin of replication
DNA replication

- Y-shaped region along DNA template where leading and lagging strands are synthesized
Replication fork
DNA replication

- Unwinds DNA template at replication fork
Helicase
DNA replication

- prevents strands from reannealing
Single-strand binding proteins (SSBRs)
DNA replication

- Creates nicks in the helix to relieve supercoils created during replication
DNA Topoisomerases
DNA replication

- Makes RNA primer on which DNA polymerase III can initiate replication
Primase
DNA replication

- Elongates leading strand be adding deoxynucleotides to the 3' end
- Elongates lagging strand until it reaches primer of preceding fragment
- 3'-5' exonuclease proofreads each added nucleotide
- only in Prokaryotes
DNA polymerase III
DNA replication

- Degrades RNA prime and fills in the gap with DNA

- Prokaryotes only
DNA polymerase I
DNA replication

- Seals Okazaki fragment together
DNA ligases
- Specific endonuclease release the oligonucleotide-containing damaged bases

- DNA polymerase and ligase fill and reseal the gap, respectively
Nucleotide excision repair
- Specidil glycosylase recongnize and remove damaged bases

- AP endonuclease cuts DNA at apyrimidinic site

- empty sugar is removed and the gap is filled and sealed
Base excision repair
- Unmethylated, newly synthesized string is recognized, mismatched nucleotides are removed, and the gap is filled and resealed
Mismatched repair
Part of cell cycle?

- Nucleotide excision repair
G1
Part of cell cycle?

- Base excision repair
G1
Part of cell cycle?

- Mismatch repair
G2
hMLH1, hMSH2

Lynch Syndrome dna repair
Mismatch repair
Xeroderma pigmentosum defect
Nucleotide excision repair defect prevents repair of thymine dimer
Types of RNA

- most abundant
rRNA
Types of RNA

- longest type
mRNA
Types of RNA

- smallest type
tRNA
Types of RNA

- rRNA
link amino acid to proteins
Types of RNA

- mRNA
carries information for protein synthesis
Types of RNA

- tRNA
brings in correct amino acid
mRNA start codon
AUG (sometimes GUG)
mRNA start codon in Eukaryotes
codes for methionine, which maybe removed before translation is completed
mRNA start codon Prokaryotes
codes for formyl-methionine (f-Met)
Stop codons
UGA- "you go away"
UAA- "you are away"
UAG- "you are gone"
Site where RNA polymerase and multiple other transcription factors bind to DNA upstream from gene locus (AT-rich upstream with TATA and CAAT boxes)
Promoter region
Mutation commonly results in dramatic decrease in amount of gene transcribed
Promoter region mutation
Stretch of DNA that alters gene expression by binding transcription factors
Enhancer region
Site where negative regulator (repressors) bind
Silencer
Enhancers and silencers may be located close to, far from, or even within (in an intron) the gene whose expression it regulates
Enhancers and/or silencers
Eukaryotes polymerase

- makes rRNA
RNA polymerase I
Eukaryotes polymerase

- makes mRNA
RNA polymerase II
Eukaryotes polymerase

- makes tRNA
RNA polymerase III
- Found in death cap mushrooms
- inhibits RNA polymerase II
- causes liver failure if ingested
alpha-amanitin
alpha-amanitin
- Found in death cap mushrooms
- inhibits RNA polymerase II
- causes liver failure if ingested
Contain the actual genetic information coding for protein
Exons
Are intervening noncoding segments of DNA
Introns
Tumor suppressors
Rb and p53
Cell cycle stage of tumor suppressors (Rb and p53)
G1 to S
Cell types

- remain in G0, regenerate from stem cells
Permanent

-neurons, skeletal and cardiac muscle, RBCs
Cell types

- enter G1 from G0 when stimulated
Stable (quiescent)

-hepatocytes, lymphocytes
Cell types

- never go into G0, divide rapidly with a short G1
Labile

- bone marrow, gut epithelium, skin, hair follicles
Site of synthesis of secretory (exported) proteins and of N-linked oligosaccharide addition to many proteins; Nissl bodies
Rough Endoplasmic reticulum (RER)
Unattached to any membrane; site of synthesis of cytosolic and organellar proteins
Free ribosomes
Sire of steroid synthesis and detoxification of drugs and poisons
Smooth Endoplasmic Reticulum (SER)
Golgi apparatus

- retrograde; Golgi -> ER
COP I
Golgi apparatus

- anterograde RER -> cis-Golgi
COP II
Golgi apparatus

- trans-Golgi -> lysosomes, plasma membrane -> endosomes (receptor-mediated endocytosis)
Clathrin
- inherited lysosomal storage disorder

- result in coarse facial features, clouded corneas, restricted joints movement (vs. Hurler's)

- failure of addition of mannose-6-phosphate to lysosomal proteins
I-cell disease (Inclusion cell disease)
Molecular motor proteins- transport cellular cargo toward opposite ends of microtubule tracks.

-anterograde?
Kinesin
Molecular motor proteins- transport cellular cargo toward opposite ends of microtubule tracks.

-retrograde?
Dynein
Chediak-Higashi syndrome
-microtubule polymerization defect
- resulting in decreased phagocytosis
- recurrent pyogenic infections, partial albinism
- peripheral neuropathy
Kartagener's syndrome
- immotile cilia due to a dynein arm defect
- loud right heart sounds
- result in male and female infertility
- bronchiectasis and recurrent sinusitis
Immunohistochemical stains

- Connective tissue
Vimentin
Immunohistochemical stains

- Muscle
Desmin
Immunohistochemical stains

- Epithelial cells
Cytokeratin
Immunohistochemical stains

- Neuroglia
GFAP (glial fibrillary acid proteins)
Immunohistochemical stains

- Neurons
Neurofilaments
Drugs that act on microtubules
- Mebendazole/thiabendazole
- Griseofulvin
- Vincristine/vinblastine
- Paclitaxel
- Colchicine
Collagen

- Bone, Skin, Tendon, dentin, fascia, cornea, late would repair
Type I
Collagen

- Cartilage (including hyaline), vitreous body, nucleus pulposus
Type II
Collagen

- skin, BLOOD VESSELS, uterus, fetal tissue, granulation tissue
Type III
Collagen

- Basement membrane or basal lamina
Type IV
Ehlers-Danlos syndrome
Faulty collagen synthesis causing
- Hyperextensible skin
- Tendency to bleed (easy bruising)
- Hypermobile joints
- dislocations, berry aneurysms, organ rupture
Collagen affected in Ehlers-Danlos
Type III collagen defect
Osteogenesis imperfecta
Genetic bone disorder (brittle bone disease)
- autosomal dominant
- Type I collagen defect
- Multiple fractures
- Blue sclerae (translucent CT over the choroid)
- hearing loss
- dental imperfections due to lack of dentin
Alport's syndrome
- abnormal type IV collagen
- progressive hereditary nephritis and deafness
- associated w/ocular disturbances
Elastin
- Stretchy protein within lungs, large arteries, elastic ligament, vocal cords, ligamenta flava (spine)

- rich in glycine and proline

-tropoelastin w/fibrillin scaffolding
Inhibits breakdown elastase
alpha-1-antitrypsin
Defect in fibrillin
Marfan's syndrome
Molecular biology laboratory procedure used to amplify a desired fragment of DNA
Polymerase chain reaction (PCR)
Blotting procedure for a DNA sample
Southern blot
Blotting procedure for a RNA sample
Northern blot
Blotting procedure for a protein sample
Western blot
Genetic terms

-Definition: Neither of 2 alleles is dominant
Codominance
Genetic terms

-Definition: Nature and severity of phenotype vary from 1 individual to another
Variable expression
Genetic terms

-Definition: Not all individuals w/mutant genotype show the mutant phenotype
Incomplete penetrance
Genetic terms

-Definition: 1 gene has more than 1 effect on individual's phenotype
Pleiotropy
Genetic terms

-Definition: Differences in phenotype depend on whether the mutation is of maternal or paternal origin
Imprinting
Genetic terms

-Definition: Severity of disease worsens or age of onset is earlier in succeeding generation
Anticipation
Genetic terms

-Definition: If a Pt inherits or develops a mutation is a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops; Not true of oncogenes
Loss of heterozygosity
Genetic terms

-Definition: exerts a dominant effect. Heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning
Dominant negative muation
Genetic terms

-Definition: tendency for certain alleles at 2 links loci to occur together more often than expected by chance. Measured in a population, not in a family, and often varies in different populations
Linkage disequilibrium
Genetic terms

-Definition: occurs when cell in the body have different genetic makeup
-can be a germ-line; which may produce disease that is not carried by parent's somatic cells
Mosaicism
Genetic terms

-Definition: Mutation at different loci can produce that same phenotype
Locus heterogeneity
Genetic terms

-Definition: presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease
Heteroplasmy
Genetic terms

-Definition: offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parents
Uniparental disomy
Genetic terms

-Example: Blood groups (A, B, AB)
Codominance
Genetic terms

-Example: Two Pts w/NF type 1 may gave varying disease severity
Variable expression
Genetic terms

-Example: PKU cause many seemingly unrelated symptoms ranging from mental retardation to hair/skin changes
Pleiotropy
Genetic terms

-Example: Prader-Willi and Angelman's syndromes
Imprinting
Genetic terms

-Example: Huntington's disease
Anticipation
Genetic terms

-Example: Retinoblastoma
Loss of heterozygosity
Genetic terms

-Example: Mutation of Tx factor in its allosteric site. Nonfunctioning mutant can still bind DNA preventing wild-type Tx factor from binding
Dominant negative mutation
Genetic terms

-Example: Lyonization- random X inactivation in females
Mosaicism
Genetic terms

-Example: Marfan's syndrome, MEN 2B, and homocystinuria; all cause marfanoid habitus
Locus heterogeneity
Hardy-Weinberg population genetics

- law assumes
- no mutation occurring at the locus

- no selection for any of the genotypes at the locus

- completely random mating

- no migration
Hardy-Weinberg population genetics

- disease prevalence formula
p^2 + 2pq + q^2= 1
Hardy-Weinberg population genetics

- allele prevalence formula
p + q= 1
Hardy-Weinberg population genetics

- heterozygote prevalence formula
2pq
At a single locus, only 1 allele is active; the other is inactive (inactivated by methylation). Deletion of the active allele -> disease
Imprinting
Prader-Willi syndrome (genetic defect)
Deletion/inactivation of normally active Paternal allele (on chromosome 15)
Angelman's syndrome (genetic defect)
Deletion/inactivation of normally active Maternal allele (on chromosome 15)
Deletion/inactivation of normally active Maternal allele (on chromosome 15)
Angelman's syndrome
Deletion/inactivation of normally active Paternal allele (on chromosome 15)
Prader-Willi syndrome
Prader-Willi syndrome (clinical presentation)
- obesity
- hypogonadism
- hyperphagia
- hypotonia
- mental retardation
Angelman's syndrome (clinical presentation)
- seizures
- inappropriate laughter
- "happy puppet"
- ataxia
- mental retardation
Modes of inheritance

- often due to defects in structural genes
- Many generations
- both male and females affected
- often pleiotropic
- in many case, presents clinically after puberty
- family history crucial to diagnosis
Autosomal Dominant
Modes of inheritance

- often due to enzyme deficiencies
- seen in only generation
- 25% of offspring from 2 carrier parents are affected
- commonly more severe that dominant disorders
- Pts often present in childhood
Autosomal Recessive
Modes of inheritance

- sons of heterozygous mothers have a 50% chance of being affected
- no male-to-male transmission
- more severe in males
- heterozygous females may be affected
X-linked recessive
Modes of inheritance

- Transmitted through both parents
- 50% of affect mother affected (both male/female)
- ALL females offspring of affect father will be affected
- Hypophosphatemic rickets (vit D resistant rickets)
X-link dominant
Modes of inheritance

- transmitted only through mother
- all offspring of affected female may show signs of disease
- variable expression in population due to heteroplasmy
Mitochondrial inheritance
Autosomal-dominant diseases
- achondroplasia
- ADPKD
- familial adenomatous polyposis
- familial hypercholesterolemia (hyperlipidemia type IIA)
- Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
- Hereditary spherocytosis
- Hunting disease
- Marfan syndrome
- Multiple endocrine neoplasia (MEN 1,2A,2B)
- Neurofibromatosis type 1 (von Recklinghausen's)
- Neurofibromatosis type 2
- Tuberous sclerosis
- von Hippel-Lindau diease
Autosomal-dominant disease

- defect of fibroblast growth factor (FGF) receptor 3
- associated w/advanced paternal age
- dwarfism; short limbs, but head and trunk normal
- achondroplasia
Autosomal-dominant disease

- always bilateral
- Pts w/ flank pain, hematuria, HTN, progressive renal failure
- mutation in APKD1 (Chromosome 16)
- associate w/ berry aneurysms & mitral valve prolase
- ADPKD
Autosomal-dominant disease

- deletion on chromosome 5 (APC gene)
- progresses to cancer unless resected
- familial adenomatous polyposis
Autosomal-dominant disease

- Elevated LDL, defect/absent LDL receptor
- severe atherosclerotc disease
- tendon xanthomas (in Achilles tendon)
- Heterozygotes = 300 mg/dL
- Homozygotes= +700 mg/dL
-familial hypercholesterolemia (hyperlipidemia type IIA)
Autosomal-dominant disease

- telangiectasia
- recurrent epistaxis
- skin discolorations
- arteriovenous malformations
- Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
Autosomal-dominant disease

- defect w/spectrin or ankyrin
- hemolytic anemia
- increased MCHC
- Hereditary spherocytosis
Autosomal-dominant disease

- depression, progressive dementia, choreiform movements
- decrease levels of GABA and ACh in brain
- located on chromosome 4
- Hunting disease
Autosomal-dominant disease

- aortic incompetence/ aortic dissection
- floppy mitral valve
- fibrillin gene mutation
- Marfan syndrome
Autosomal-dominant disease

- associated w/ ret gene
- familial tumors of endocrine glands
- pancreas, parathyroid, pituitary, thyroid, and adrenal medulla
- Multiple endocrine neoplasia (MEN 1,2A,2B)
Autosomal-dominant disease

- cafe-au-lait spots
- Lisch nodules (pigmented iris hamartomas)
- skeletal disorders
- optic pathway gliomas
- long long arm of chromosome 17
- Neurofibromatosis type 1 (von Recklinghausen's)
Autosomal-dominant disease

- bilateral acoustic schwannomas
- juvenile cataracts
- on chromosome 22
- Neurofibromatosis type 2
Autosomal-dominant disease

- facial lesions (adenoma sebaceum)
- hypopigmented "ash leaf spots"
- cortical and retinal hamartomas
- seizures and retardation
- renal cyst and angiomyolipomas
- rhabdomyomas
- Tuberous sclerosis
Autosomal-dominant disease

- hemangioblastomas of retina
- bilateral renal cell carcinomas
- associated w/ deletion of VHL gene on chromo. 3
- constitutive expression of HIF
- von Hippel-Lindau disease
Autosomal-recessive diseases
- Albinism
- ARPKD
- cystic fibrosis
- glycogen storage diseases
- hemochromatosis
- mucopolysaccharidoses (except Hunter's)
- phenylketonuria "PKU"
- sickle cell anemias
- sphingolipidoses (except Fabry's)
- thalassemias
- Autosomal-recessive defect in CFTR on chromo. 7
- deletion of Phe 508
- mutation causes abnormal protein folding resulting in degradation of channel
- defective Cl- channel "thick mucus in lungs, pancreas, and liver"
- recurrent pulmonary infections
- meconium ileus in newborns
Cystic Fibrosis
Diagnostic test for Cystic Fibrosis
sweat test (increased concentration of Cl- ions)
Treatment for Cystic Fibrosis
N-acetylcysteine
X-linked recessive disorders

(Be Wise, Fool's GOLD Heeds Silly Hope)
- Bruton's agammaglobulinemia
- Wiskott-Aldrich syndrome
- Fabry's disease
- G6PD deficiency
- Ocular albinism
- Lesch-Nyhan syndrome
- Duchenne's (Becker's) muscular dystrophy
- Hunter's Syndrome
- Hemophilia A and B
- deletion of dystrophin gene
- x-lined frame shift mutation (deletion)
- accelerated muscle breakdown
- pseudohypertrophy of calf muscles due to fibrofatty
- uses Gower's maneuver (hands aid in getting up)
- onset before 5 years of age
Duchenne's muscular dystrophy
- X-linked mutated dystrophin gene
- less severe muscle breakdown
- in frameshift (no deletion)
Becker's muscular dystrophy
Diagnoses of muscular dystrophies
increased CPK and muscle biopsy
- Findings: macro-orchidism, long face with a large jaw, large everted ears autism, and mitral valve prolapse
- 2nd most common cause of genetic retardation
- X-linked defect in the methylation and expression of the FMR1 gene (associated w/chromosomal breakage) "CGG"
Fragile X syndrome
Trinucleotide repeat expansion diseases
- Huntington's disease
- myotonic dystrophy
- Friedreich ataxia
- fragile X syndrome
Trinucleotide repeat expansion disease

- Huntington's disease: repeat
(CAG)
Trinucleotide repeat expansion disease

- myotonic dystrophy
(CTG)
Trinucleotide repeat expansion disease

- Friedreich ataxia
(GAA)
Trinucleotide repeat expansion disease

- fragile X syndrome
(CGG)
Autosomal trisomies

- Findings: retardation, flat facies, epicanthal fold, simian crease, duodenal atresia
- ASD, ALL, Alzheimer's disease
- due to meiotic nondisjunction (advance maternal age)
Down syndrome (t21)
Autosomal trisomies

- Findings: retardation, rockers bottom feet, micrognathia (small jaw), clenched hands
- death within 1 year of birth
Edward's syndrome (t18)
Autosomal trisomies

- Findings: cleft lip/palate, holoprosencephaly, polydactyly
- death within 1 year of birth
Patau's syndrome (t13)
Most common trisomy resulting in abortion (not viable for life)
t16
- congenital microdeletion of short arm of chromosome 5

- Finding: high-pitched crying/mewing; VSD
Cri-du-chat syndrome
Down syndrome screening test
1- decreased alpha-fetoprotein
- decreased estriol
- increased beta-hCG
- increased inhibind

2- ultrasounds shows increase nuchal translucency
- congenital microdeletion of long arm of chromosome 7 (region includes elastin gene)

- "elfin" facies
- hypercalcemia (sensitive to vit-D)
- well-developed verbal skills
- extremely frendingly with strangers
Williams syndrome
due to aberrant development of 3rd/4th bronchial pouches
DiGeorge syndrome (22q11)
Fat soluble vitamins
A,D,E,K
Water soluble vitamins
B1-6; B12; C; Biotin, and Folate
Water soluble vitamins store in the liver
B12 and folate
result of B-complex vits deficiencies
dermatitis, glossitis, and diarrhea
Retinol
Vitamin A
Thiamine
Vitamin B1
Rivoflavin
Vitamin B2
Niacin
Vitamin B3
Pantothenate
Vitamin B5
Pyridoxine
Vitamin B6
Cobalamin
Vitamin B12
Ascorbic acid
Vitamin C
Vitamin A: Function
- Antioxidant
- visual pigments
- epithelial cells into specialized pancreatic cells
- used to treat measles
Vitamin A: Deficiency
- night blindness
- dry skin
Vitamin A: Excess
- alopecia
- Teratogenic: (cleft palate, cardiac abnormalities)
- pregnancy test before isotRETINOin is prescribed
Vitamin B1: Function
cofactor for
- Pyruvate dehydrogenase
- alpha-ketoglutarate dehydrogenase
- Transketolase
- Branched-chain AA dehydrogenase
Vitamin B1: Deficiency
- impaired glucose breakdown -> ATP depleted

- Wernicke-Korsakoff syndrome

- Beriberi (Dry/Wet)
- confusion
- ophthalmoplegia
- ataxia + confabulation
- personality changes
- memory loss (permanent)
Wernicke-Korsakoff
Damaged in Wernicke-Korsakoff
Medial dorsal nucleus of thalamus, mamillary bodies
Thiamine deficiency: polyneuritis, symmetrical muscle wasting
Dry Beriberi
Thiamine deficiency: high-output cardiac failure (dilated cardiomypathy), edema
Wet Beriberi
Vitamin B2: Function
Cofactor in oxidation and reduction (FADH2)
Vitamin B2: Deficiency
The 2 C's
- Cheilosis (lip inflammation, fissure a mouth corner)
- Corneal vascularization
Vitamin B3: Function
- Constituent of NAD+ and NADP+
- derived from tryptophan
- synthesis requires B6
Vitamin B3: Deficiency
The 3 D's
- Diarrhea (carcinoid syndrome)
- Dermatitis (pellagra caused by Hartnup disease)
- Dementia (glossitis)
Vitamin B3: Excess
Facial flushing
(due to pharmacologic doses for treatment of hyperlipidemia)
Vitamin B5: Function
Essential component of CoA (cofactor for acyl transfers) and fatty acid synthase
Vitamin B6: Function
- cofactor used in transamination (ALT, AST) & heme synthesis

- required for the synthesis of niacin from trytophan
Vitamin B6: Deficiency
- convulsions
- sideroblastic anemia
- inducible by INH and oral contraceptives
Vitamin B12: Function
Cofactor for homocysteine methyltransferase & methylmalonyl-CoA mutase

(very large reserve pool in liver "several years")
Vitamin B12: Deficiency
- Macrocytic, megaloblastic anemia
- hypersegmented PMNS
- neurologic symptoms
- prolong -> irreversible nerve damage
Vitamin B12 deficiency cause
- Diphyllobothrium latum
- lack of intrinsic factor (pernicious anemia; gastric surgery)
- Crohn's disease (absent terminal ileum)
Test used to detect the etiology of vitamin B12 deficiency
Schilling test
Folic acid: Function
- important for the synthesis of nitrogenous bases in DNA and RNA

- converted to tetrahydrofolate (THF), a coenzyme for 1-carbon transfer/methylation reactions
Folic acid: Deficiency
- Macrocytic, megaloblastic anemia
- Most common vit deficiency
- seen in alcoholism and pregnancy
- *no neurologic symptoms*
Drugs that can cause folic acid deficiency
- Phenytoin
- sulfonamides
- MTX
S-adenosyl-methionine (SAM): Function
- methyl donor
- dependent on vit B12 and folate
- required for conversion of NE to epinephrine
Biotin cofactor for...
- Pyruvate carboxylase (gluconeogenesis)

- Acetyl-CoA carboxylase (fatty acid synthesis)

- Propionyl-CoA carboxylase (Beta Oxidation)
Biotin: Deficiency
- dermatitis, alopecia, enteritis

- caused by antibiotic or raw eggs

- relatively rare
Vitamin C: Function
- Antioxidant
- iron reabsorption by keeping iron in Fe2+ state (ferrus)
- needed for hydroxylation of proline and lysine in collagen synthesis
- Dopamine-beta-hydroxylase (convert dopamine to NE)
Vitamin C: Deficiency
Scurvy
- swollen gums
- bruising
- poor wound healing

Weakened immune response
Vitamin D ingested from plants
D2- ergocalciferol
Vitamin D consumed in milk, formed in sun-exposed skin
D3- cholecalciferol
Vitamin D storage form
25-OH D3
Vitamin D active form
1,25-(OH)2 D3
Vitamin D: Function
- increase intestinal absorption of calcium and phosphate

- increase bone resorption
Vitamin D: Deficincey
- Rickets- kids
- Osteomalacia- adults
- tetany
Vitamin E: Function
Antioxidant for erythrocytes and membranes
Vitamin E: Deficiency
- Fragile erythrocytes (hemolytic anemia)

- posterior column and spinocerebellar tract demyelination
Vitamin K: Function
- Catalyzes gamma-carboxylation of glutamic acid (blood clotting)

- Synthesized by intestinal flora
Vitamin K: Deficiency
- Neonatal hemorrhage w/ increased PT/aPTT, but normal bleed time (give at birth)

- can occur after prolong use of broad-spectrum antibiotics
Zinc: Function
- Essential for the activity of 100+ enzymes

- formation (transcription factor motif)
Zinc: Deficiency
- delayed wound healing
- hypogonadism
- decreased adult hair (face, axilla, pubic)
- anosmia
- predisposed to alcohol cirrhosis
- Antidote for methanol or ethylene glycol poisoning

- inhibits alcohol dehydrogenase
Fomepizole
Protein malnutrition resulting in:
- skin lesions
- edema
- liver malfunction (fatty)
child w/swollen belly
Kwashiorkor
Energy malnutrition resulting in tissue and muscle wasting, loss of subcutaneous fat, and variable edema.
Marasmus
Metabolism sites:

- in the Mitochondria
- fatty acid (beta) oxidation
- acetyl-CoA production
- TCA cycle
- oxidative phosphorylation
Metabolism sites:

- in the Cytoplasm
- Glycolysis
- fatty acid synthesis
- HMP shunt
- protein synthesis (RER)
- steroid synthesis (SER)
Metabolism sites:

- in the Cytoplasm & Mitochondria
- Heme synthesis
- Urea cycle
- Gluconeogenesis
Enzyme terminology

- uses ATP to ADD high-energy phosphate group onto substrate "to make"
Kinase
Enzyme terminology

- oxidizes substrate (creates extra NADPH2 & FADH2)
Dehydrogenase
Enzyme terminology

- adds 1 carbon w/the help of biotin
Carboxylase
Rate-determining (limiting) enzyme

- Glycolysis
Phosphofructokinase-1 (PFK-1)
Rate-determining (limiting) enzyme

- Gluconeogenesis
Fructose-1,6-bisphosphatase
Rate-determining (limiting) enzyme

- TCA cycle
Isocitrate dehydrogenase
Rate-determining (limiting) enzyme

- Glycogen synthesis
Glycogen synthase
Rate-determining (limiting) enzyme

- Glycogenolysis
Glycogen phosphorylase
Rate-determining (limiting) enzyme

- HMP shunt
G6PD (glucose-6-phosphate dehydrogenase)
Rate-determining (limiting) enzyme

- De novo pyrimidine synthesis
carbamoyl phosphate synthetase II
Rate-determining (limiting) enzyme

- De novo purine synthesis
Glutamine-PRPP amidotransferase
Rate-determining (limiting) enzyme

- Urea cycle
Carbamoyl phosphate synthetase I
Rate-determining (limiting) enzyme

- Fatty acid sythesis
Acetyl-CoA carboxylase
Rate-determining (limiting) enzyme

- Fatty acid (beta) oxidation
Carnitine acyltransferase I
Rate-determining (limiting) enzyme

- Ketogenesis
HMG-CoA synthase
Rate-determining (limiting) enzyme

- Cholesterol synthesis
HMG-CoA reductase
First step in glycolysis and glycogen synthesis in the liver
Hexokinase/glucokinase
Feedback inhibition for hexokinase
glucose-6-phosphate
Inhibits lipoic acid

Findings: vomiting, rice water stools, garlic breath
Arsenic posioning
Electron transport chain

- site of NADH+ -> NAD+
Complex I
Electron transport chain

- site of FADH2+ -> FAD+
Complex II
Electron transport chain

- site of 1/2 O2 ->H2O
Complex IV
Electron transport chain

- site of ADP -> ATP
Complex V
Oxidative phosphorylation poison

- Directly inhibit electron transport, causing a decrease proton gradient and block ATP synthesis
Electron transport inhibitors
- Rotenone
- cyanide (CN)
- antimycin A
- carbon monoxide
Oxidative phosphorylation poison

- Directly inhibit mitochondrial ATPase, causing an increase proton gradient. No ATP is produced because electron transport stops
ATPase inhibitor
- Oligomycin
Oxidative phosphorylation poison

- increase permeability of membrane, causing a decrease proton gradient. ATP synthesis stops, but electron transport continues. Produces heat.
Uncoupling agents
- 2,4-DNP
- aspirin
- thermogenin in brown fat
Cannot participate in gluconeogenesis because it lacks G-6-P (glucose-6-phosphatase)
Muscle
Essential fructosuria

- Signs/symptoms
Fructose appears in blood and urine
Essential fructosuria

- Defect
Fructokinase
Fructose intolerance

- Signs/symptoms
- hypoglycemia
- jaundice
- cirrhosis
- vomiting
Fructose intolerance

- Defect
Aldolase B
Treatment for fructose intolerance
decrease both fructose and sucrose
Galactokinase deficiency

- Sign/symptoms
- galactose in blood and urine
- infantile cataracts
- failure to track objects
- failure to develop a social smile
Classic galactosemia

- Defect
absence of galactose-1-phosphate uridyltransferase (UT)
Classic galactosemia

- Sign/symptoms
- jaundice
- hepatomegaly
- infantile cataracts
- mental retardation
- failure to thrive
Treatment for Classic galactosemia
excluded galactose and lactose from diet
Essential Amino acids
- phenylalanine
- valine
- threonine
- tryptophan
- methionine
- leucine
- isoleucine
- lysine
- histidine
- arginine
Acidic amino acids
- Aspartic acid

- Glutamine
Basic amino acids
- Arginine

- Lysine

- Histidine
The most basic amino acid
Arginine
Amino acid w/no charge at body pH
Histidine
Amino acids required during period of growth (childhood)
Arginine and Histidine
Sign/symptom: tremor, slurring speech, somnolence, vomiting, cerebral edema, blurred vision

Labs: excess NH+4; depletes alpha-ketoglutarate; inhibition of TCA cycle
Hyperammonemia
Treatment for Hyperammonemia
- limit protein in diet

- Benzoate or phenylbutyrate (lower ammonia levels)
Excess of this in (OTC) ornithine transcarbamylase deficiency
carbamoyl phosphate -> orotic acid
(OTC) ornithine transcarbamylase deficiency

- Findings
- orotic acid in blood and urine

- decrease BUN

- hyperammonemia
(OTC) ornithine transcarbamylase deficiency vs Orotic aciduria
OTC has decrease BUN and hyperammonemia
Amino acid derivative

- tyrosine -> Thyroxine (T3,T4)
- Dopa -> melanin
- Dopamine
- NE
- Epinephrine
Phenylalanine
Amino acid derivative

- Niacin -> NAD+/NADP+

- Serotonin -> Melatonin
Tryptophan
Amino acid derivative

- Histamine
Histidine
Amino acid derivative

- Porphyrin -> Heme
Glycine
Amino acid derivative

- Creatine

- Urea

- NO (nitric oxide)
Arginine
Amino acid derivative

- GABA

- Glutathione
Glutamate
Phenylketonuria

- Defect
- decreased phenylalanine hydroxylase

- decreased tetrahydrobiopterin cofactor

- Tyrosine become essential
Phenylketonuria

- Presentation
- Mental retardation
- growth retardation
- musty body odor
- fair skin, eczema
Alkaptonuria (ochronosis)

- Defect
- deficiency of homogentisic acid oxidase

- no tyrosine to fumarate
Alkaptonuria (ochronosis)

- Presentation
- dark connective tissue
- brown pigmented sclera
- urine turns black on standing
- may have debilitating arthralgias
Homocystinuria

- Defect
- cystathionine synthase deficiency

- decreased affinity of cystathionine synthase

- homocysteine methyltransferase deficiency
Homocystinuria

- Presentation
- increased homocysteine in urine
- mental retardation
- osteoporosis
- tall stature
- atherosclerosis (stroke/MI)
- kyphosis, lens subluxation
Treatment for cystathionine synthase deficiency
- Met, Cys, B12, and folate
Albinism

- Defect
- Tyrosinase

- defective tyrosine transporters
Cystinuria

- Defect
Hereditary defect of renal tubular amino acid transporter for cysteine, ornithine, lysine, and arginine in the PCT of kidney
Cystinuria

- Presentation
- excess cystine in urine -> cystine stones (staghorn)
Bond between two cystine
Disulfide
Maple syrup urine disease

- Defect
- decreased alpha-ketoacid dehydrogenase

blocked degradation of branched amino acids
- Isoleucine
- Leucine
- Valine
Maple syrup urine disease

- Presentation
- increased alpha-ketoacids in urine
- CNS defects (mental retardation)
- death
Hartnup

- Defect
Defective neutral acid transporter on renal and intestinal epithelial
Hartnup

- Presentation
- Tryptophan excretion in urine

- decreased tryptophan absorption in gut

- PELLAGRA
Glycogen storage disease

Findings:
- severe fasting hypoglycemia
- increased glycogen in liver
- increased blood lactate
- hepatomegaly

Deficient enzyme: ?
Glucose-6-phosphatase
Glycogen storage disease

Findings:
- cardiomegaly and systemic findings
- leading to early death (2 yrs of age)

Deficient enzyme: ?
Lysosomal alpha-1,4 glucosidase
(acid maltase)
Glycogen storage disease

Findings:
- milder hypoglycemia
- w/normal blood lactate levels
- gluconeogenesis is intact
Deficient enzyme: ?
alpha-1,6-glucosidase
(Debranching enzyme)
Glycogen storage disease

Findings:
- increased glycogen in muscle
- leading to muscle cramps
- myoglobinuria w/strenuous exercise (lactate)

Deficient enzyme: ?
Glycogen phosphorylase
Lysosomal storage disease

Fabry's disease
- Findings: ?
- peripheral neuropathy of hands/feet

- angiokeratomas

- cardio/renal disease
Lysosomal storage disease

Gaucher's disease
- Findings: ?
- Hepatosplenomegaly

- aseptic necrosis of the head of the femur

- Gaucher's cells (macrophages look like crumpled tissue paper)
Lysosomal storage disease

Niemann-Pick disease
- Findings: ?
- progressive neurodegeneration

- hepatosplenomegaly

- cherry-red macula

- foam cells
Lysosomal storage disease

Tay-Sachs disease
- Findings: ?
- progressive neurodegeneration

- cherry-red macula

- lysosomes w/onion skin
Lysosomal storage disease

Metachromatic leukodystrophy (MML)
- Findings: ?
- Central and peripheral demyelination w/ataxia

- dementia
Lysosomal storage disease

Hurler's syndrome
- Findings: ?
- Gargoylism

- corneal clouding

- airway obstruction (vs. I cell)
Lysosomal storage disease

Hunter's syndrome
- Findings: ?
- personality changes + aggressive behavior

- no corneal clouding
Lysosomal storage disease

Findings:
- peripheral neuropathy of hands/feet
- angiokeratomas
- cardio/renal disease

Deficient enzyme: ?
alpha-galactosidase A
Lysosomal storage disease

Findings:
- Hepatosplenomegaly
- aseptic necrosis of the head of the femur
- Gaucher's cells (macrophages look like crumpled tissue paper)

Deficient enzyme: ?
beta-glucocerebrosidase
Lysosomal storage disease

Findings:
- progressive neurodegeneration
- hepatosplenomegaly
- cherry-red macula

Deficient enzyme: ?
Sphingomyelinase
Lysosomal storage disease

Findings:
- progressive neurodegeneration
- cherry-red macula
- lysosomes w/onion skin

Deficient enzyme: ?
Hexosaminidase A
Lysosomal storage disease

Findings:
- Central and peripheral demyelination w/ataxia
- dementia

Deficient enzyme: ?
Arylsulfatase A
Lysosomal storage disease

Findings:
- Gargoylism
- corneal clouding
- airway obstruction (vs. I cell)

Deficient enzyme: ?
alpha-L-inuronidase
Lysosomal storage disease

Findings:
- personality changes + aggressive behavior
- no corneal clouding

Deficient enzyme: ?
Iduronate sulfatase