Constitutionally active “always on” tyrosine kinase-type growth factor receptor in MEN 2a

Altered substrate specificity in MEN 2b (activated with other molecules than growth factor, loses specificity)

MEN 2a--:Sipple Syndrome: Pheochromocytoma, Medullary thyroid CA, parathyroid hyperplasia

Familial medullary thyroid CAà20% of medullary thyroid CA is familial, check for RET when this CA is diagnosed

MEN 2b—(same gene, different point mutation) Marfanoid habitus with diffuse neuromas and gangilioneuromas

Fusion gene product of t(9:22) translocation, Constitutively expressed and activated cytoplasmic (non-receptor) tyrosine kinase

100% of Chronic myelogenous leukemia (CML) , 25% of Acute lymphoblastic leukemia (ALL)

“Guardian of the genome”—Normally:

1.   Temporary arrest: increases levels of p21 to block cdk4/Cyclin D, allowing repair time for damaged cells

2.  Induce growth arrest: via MYC and CK4

3.  Trigger cell suicide: upregulate BAX/BAK which decreases BCL-2, causing mitochondrial leak of cytochrome C and triggering apoptosis

AD cancer syndrome: Li-Fraumeni syndrome--> 25x increased chance of cancer with germline loss of single p53 allele-->multiple types of tumors in same person (sarcoma, breast cancer, leukemia, brain tumors, adrenal CA

 Non-familial: Most cancers have a p53 mutationà this is not always  the initiating event but an additional mutation that has occurred with uncontrolled growth

Normal: flips RAS back to inactive state

Abnormal: RAS stays phosphorylated and active, signaling to “keep growing”

AD cancer syndrome: Neurofibromatosis type 1 with increased risk of sarcomas

Non-familial: Neuroblastomas

Normal: can function as nuclear activator or suppressor of transcription

Abnormal: loss of transcription regulation

Familial:

1.   WAGR (Wilms, Aniridia, genital abnormalities, retardation)

2.  Denys-Drash (gonadal abnormalities and early onset nephropathy) both have WT-1 mutation and increased risk of Wilms tumor

Sporadic: 90% of WT is non-familial, and only 10% of them have this mutation

DNA mismatch repair

Familial: Autosomal dominant, Non-poyposis colon cancer, small intestine, endometrium, ovary

Inability to excise and repair thymidine dimers

Autosomal recessive, prone to multiple cancers but especially related to sunlight or radiation

Overexpression of gene product prevents normal progression to apoptosis by blocking cytochrome C release from mitochondria

Follicular lymphoma (a type of Non-Hodgkins lymphoma)

Defect in CD40 on B cell or CD40 ligand on T cellsàsignal required for switching from IgM to other subclasses after antigen stimulation. Normal levels of B cells.

1.   Recurrent pyogenic infections, pneumocystis infection (T cells lise CD40 stimulation so partial T cell defect as well)

2.  Complement-mediated Type II hypersensitivity reaction-->IgM binds antigens on 2 adjacent RBC’s, WBC’s or Platelet and fixes complement-->AIHA, autoimmune neutropenia, or thrombocytopenia

1.   Increased IgM

2.  Decreased IgG,

IgE,

IgA

Failure of 3^rd and 4^th pharyngeal pouch development, also called CATCH-22 syndrome (22q11 deletion syndrome)

4^th pouch à thymus and parathyroid, so manifests as immunodeficiency and/or hypoparathyroidism

Recurrent, T-cell dependent early infections (thrush, diaper candida very soon after birth,) poor weight gain, dev delay, irritability, seizures or tetany due to hypocalcemia

Characteristic facies with low-set ears, micrognathia

Absent thymus /thymic shadow on chest Xray (normally huge thymus in newborn) and parathyroids and radionuclide imaging, decreased paracortical areas of LN’s

Decreased Ca²⁺, Increased PO^4-

Ig levels typically normal

Heterogeneous group of diseases—refers to defects in both B and T cell function

X-linked form—defect in Yc subunit of cytokines, T cell progenitors can’t bind to IL-7

Autosomal recessive form—adenosine deaminase deficiency-->allows buildup of deoxyATP which kills pre-Tcells

Present with candidiasis and severe invasive infections within the days after birth, all infections increased, prognosis fatal without BMT

Decreased to absent T cells,  B cells present but decreased Ig’s since no T cells to signal switching with CD40L

In both forms of SCID the thymus is usually absent

X-linked recessive defect in protein linking antigen receptors to cytoskeleton and cytoskeletal signaling.

Eczema, thrombocytopenia with bruising and petechiae, and recurrent infections leading to early death, associated with on-hodgkin B-cell lymphomas

Involution of thymus and poor immunoglobulin response to vaccines and infections

Terminal complement deficiency

C5-C9 deficiency, can’t form membrane attack complex

Recurrent Neisseria infections (thin cell wall)

MC complement deficiency

Asymptomatic to increased incidence of SLE-type autoimmune disease (6% of SLE pts have this)

Shunts towards alternative complement path, elevated C4, (not used up) decreased C3-->in typical SLE, both C3 and C4 used up

C3 required for alternative and classic pathway

Recurrent serious pyogenic  infections, increased rates of immune-complex–mediated glomerulonephritis

Increased C4, decreased C4

Autosomal dominant, commonly familial and more common than any complement deficiency

Life-threatening angioedema of mouth or nausea/vomiting/diarrhea from bowel edema, often after emotional upset

Tx as anaphylaxis with epi and antihistamines, and with pooled C1 inh from donor plasma

LAD type 1-->deficiency of B2 integrins (can’t adhere)

LAD type 2-->deficiency of selectins (can’t roll)

Delayed separation of umbilical cord, poor wound healing, gingivitis

Autosomal recessive, failure to form phagolysosomes (fuse phagosome to lysosome)

Recurrent pyogenic infections,/unresolved abscesses, associated with albinism

Neutrophils with GIANT granules

X-linked recessive OR autosomal recessive

Deficiency of NADPH oxidase, unable to generate O2 free radical ssps.

Catalase + organisms a problem because break down H2O2 naturally produced by bacteria so none to scavenge and make up for enzyme deficiency

Susceptibility to S. aureus and some other catalase positive organisms

1.   NBT test-->nitroblue tetrazolium test, turns blue when in the presence of superoxide free radicals, fails to turn blue in this disease

2.  DHT test (dihydrorhodamine) preferred test, will fail to fluoresce in this disease

Chronic alcoholism, severe chronic malnutrition, diet of white rice

 Found in: protein-rich foods and whole grains

Carbohydrate metabolism and ATP synthesis:

Pentose phosphate pathway (synthesizes ribose for DNA and increases NADPH for fat metabolism)

TCA cycle:

Pyruvateàacetyl CoA

Α-ketoglutarateàsuccinyl CoA

metabolism of branched-chain AA’s (leucine, isoleucine, valine)

Chronic deficiency:

-Muscle cramps, paresthesias, irritability, lactic acidosis

-Wet beriberi (neuropathy, high output heart failure/cardiomyopathy, peripheral edema)

-Dry beriberi (motor and sensory neuropathy)

Precipitated by giving glucose to starved patient with thiamine deficiency: (give thiamine before glucose always!)

-Wernicke encephalopathy (opthalmoplegia, truncal ataxia, confusion, mammillary body hemorrhage)

-Korsakoff syndrome (impaired short-term memory, confabulation)

Found in: dairy products, nuts, green&leafys

-Precursor to coenzymes that can accept or donate hydrogen atoms during amino acid oxidation, fatty acid oxidation, and TCA cycle.

-preserves RBC integrity

-converts tryptophan to niacin

Deficiency rare and caused by severe malnourishment

-glossitis, cheilosis, angular stomatitis, corneal vascularization, seborrheic dermatitis, hemolytic anemia

Risk factors: isoniazid use, malignant carcinoid syndrome (uses up trp), Hartnup syndrome (can’t absorb trp)

Found in: liver, dairy, whole grains (as tryptophan that body converts to niacin via B2)

Used as tx to increase HDL and descrease total and LDL cholesterol, side fx: flushing, itching, hives, nausea—prevent with premedication with aspirin

-created by adding 3 ATP’s to tryptophan, coenzyme in oxidation and reduction reactions

-diarrhea, dermatitis (hyperpigmented, cracked, scaly skin), dementia

-if seen in a child who is fed normally suspect Hartnup’s!

Risk factors: OCP’s, Isoniazid, cyclosporine, penicillamine

Found in: wheat, eggs, meats

-amino acid metabolism (serineàglycine)

-transamination, deamination, decarboxylation, creation of liver enzymes AST and ALT

Deficiency (rare):

-seizures and irritability

Excess:

-irreversible sensory neuropathy

Risk factors: dietary deficiency rare cause as substantial stores in liver (must be deficient for a long time to develop sx’s, most likely in vegans), pernicious anemia, gastrectomy, H. pylori, Diphyllobothrium latum, resection/abnormalities of terminal ileum (crohns), pancreatic insufficiency

Found in: animal products

R protein and intrinsic factor secreted in gastric fundus required for absorption in distal ileum.

Cofactor in multiple reactions, particularly purine synthesis and active form of folate:

Methylmalonyl-CoA mutase

 Leucine aminomutase, methionine synthase

-neuropathy distinguishes b12 def from folate def:

-subacute combined demyelinating degeneration of posterior/lateral spinal columns (symmetric paresthesias, ataxia, loss of proprioception/vibration, spasticity, clonus, incontinence)

-megaloblastic anemia with hypersegmented neutrophils—gets better with folate but neuropathy progresses

Risk factors: alcoholics, avoidance of raw foods, malabsorption affecting jejunum (sprue, biliary tract disease/obstruction), trimethoprim/SMZ, methotrexate (inhibit DHFR), phenytoin (inhib absorp), pregnancy or hemolytic anemia (increased demand)

Found in: fruits and vegetables but destroyed by cooking

Required for erythropoiesis and one-carbon transfers:

Homocysteine(+b12)àmethionine

Serine(+b6)àglycine

Thymidylate synthesis for DNA

Purine ring formation

Folate enterohepatic cycle:

Dihydrofolate reductase (DHFR) allows folate to be absorbed in jejunum, travels to liver, secreted back into bile, re-absorbed

-megaloblastic anemia NO NEURO Sx’s

Found in: nuts and synthesized by gut flora

Carries carboxylate for carb and lipid metabolism

TCA cycle: Pyruvateàoxaloacetate,

FA synth:

proprionyl CoAàmethylmalonyl CoA

-dermatitis, alopecia, lactic acidosis

Water soluble vitamin, deficiency can develop in weeks

Found in: citrus fruits

Taken up in ileum, Vit C increases iron absorption

Reducing agent for:

-Copper and iron-containing enzymes, including dopa-β-hydroxylase which makes eri and norei from tyrosine

-Hydroxylation of proline/lysine in collagen to allow cross-linking

Scurvy: swollen/bleeding gums and mucosal surfaces, bruising, petechiae, anemia, poor wound healing

Found in: fish oil, meat, dairy, eggs

-Absorbed intestinally via chylomicrons, delivered via binding proteins

-Forms rhodopsin in rod cells of retina and idopsin in cone cells

-Supports mucosal endothelium differentiation throughout body

Deficiency: night blindness, xeropthalmia, Bitot’s spots (squamous metaplasia of corneal epithelium),keratomalacia (corneal softening), respiratory epithelial metaplasia

Excess: teratogenicity, nausea, blurry vision, vertigo, alopecia, hepatotoxicity, papilledema

Risk factors: exclusive breasfeeding (for infant), lack of sun exposure

Found in: dairy, skin exposure to sun

-Absorption regulated by serum calcium.

Vit D activation:

-UV light converts 7-dehydrocholesterol to previtamin D, which then àcholecalciferol.

-Liver adds –OHà25-OH vit D,

-Kidney (stim by PTH, inhib by increased PO₄) adds another –OH via 1-α-hydroxylase enzyme à1,25-OH vit D=calcitriol=active metabolite

Vit D:

-is a steroid hormone (binds nuclear receptors to induce gene expression)

-increases intestinal Ca absorp

-decreases renal Ca excretion (distal tubule)

-increases bone resorption of Ca

-increases mineralization of bone

-increases PTH synthesis

-eventual feedback to decrease further calcitriol and PTH production

Deficiency:

-Rickets (kids)—phos takes place of calcium in bone with open epiphyses. Bowing of long bones, hyocalcemia, poor dentition

-due to true deficiency

-due to genetic defect (Vit D resistant rickets) in 1-α-hydroxylase enzyme (can tx with calcitriol)

-or in 1,25-OH receptor (won’t respond to calcitriol)

-or to renal phosphate wasting (1,25-OH levels will be elevated)

Excess:

-all s/sx of hypercalcemia (renal stones, delirium, constipation, depression, polyuria)

-Seen in sarcoidosis and some lymphomas

Risk factors: any fat malabsorption DZ (sprue, CF, liver DZ)

Found in: multiple sources

Component of cell membranes and antioxidant to scavenge free radicals. Absorption same as vit A.

Deficiency: hemolytic anemia (oxidative damage), peripheral neuropathy, opthalmoplegia

Excess: interferes with Vit K

Found in: multiple sources and made by gut bacteria

Oxidized in liver microsomes by γ-glutamyl carboxylase for post-synthetic modification of clotting factors (prothrombin, factors 7, 9, 10) necessary for function. Warfarin blocks enzyme 2,3 epoxide reductase that recycles vit K so it can be re-used, causing vit K epoxide to be excreted.

Deficiency in adults is rare and will look like warfarin toxicity with major bleeding. Hemorrhagic disease of newborn=vit K deficiency and prevented with vit K injections at birth.