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Symptoms Insidious, progressive, fatal dementia

Disease Prion disease

Young, African-american child with vaso-occlusive crises

Sickle Cell Anemia

Stretchy skin Baby born with multiple fractures Sailor with subcutaneous hemorrhage (i.e. bleeding gums), aching bones, muscle, joints Really tall person with unusually long limbs and fingers High susceptibility to skin carcinomas and melanomas, high sensitivity to UV irradiation and alkylation Young boy who cant keep up with his classmates at recess, has difficulty standing up

Ehlers Danlos Osteogenesis imperfecta Scurvy

Defective enzyme/protein/pathway/vitamin PrPC (normal) vs. PrPSc: Monomer (PrPC) vs. Oligomer (Sc) Soluble (PrPC) vs. insoluble (Sc) Intra-(PrPC) vs. Inter-molecular disulfide bonds (Sc) Alpha-helical (PrPC) vs. beta sheet(PrPSc) Hemoglobin Specific mutation: E6V What conditions favor sickling? pH, CO2, 2,3 BPG Collagen Collagen Vitamin C (ascorbic acid), defective formation of triple helix, decreased stability of collagen Fibrillin Patient is at increased risk for.? Aortic aneurysm Nucleotide excision repair What type of DNA damage is caused by UV? Thymine dimer Dystrophin Function of protein? Links sarcolemma to cytoskeleton What type of mutation? Out-of-frame deletion What if there is only a partial deletion? Beckers Muscular Dystrophy Sarcomeric proteins (i.e. myosin)

Marfans syndrome

Xeroderma pigmentosum

Duchennes Muscular Dystrophy

Cardiac muscle is coarse, with irregular arrangement of muscle bundles Lysosomal enzymes are secreted (found extracellularly) Neonate with profound lactic acidemia, dies after a few days; or child with moderate lactic acidemia and profound psychomotor retardation Baby becomes hypoglycemic a few hours after feeding

Familial Hypertrophic Cardiomyopathy I cell disease

N-acetyl-glucosamine phosphotransferase What sugar residue targets lysosomal enzymes to lysosomes? M6P Pyruvate Dehydrogenase Deficiency Mode of inheritance? X-linked dominant Subunit most often affected? E1

Glycogen metabolism, Gluconeogenesis, or Fatty acid oxidation? Glycogen metabolism

Baby becomes hypoglycemic after overnight fast

Glycogen metabolism, Gluconeogenesis or Fatty acid oxidation? Gluconeogenesis or fatty acid oxidation 4 gluconeogenic enzymes that are different from glycolysis? Pyruvate Carboxylase, PEPCK, F1,6BPase, G6Pase A deficiency in which transcription factor would inhibit gluconeogenesis? CREB F-1-P aldolase What step in glycolysis is bypassed? PFK-1 Classical galactosemia Gal-1-P uridylyl transferase

Baby becomes cranky and hypoglycemic shortly after drinking juice and has lactic acidosis Baby becomes cranky and hypoglycemic shortly after breastfeeding, has cataracts, mental retardation (not that you could tell at this point) Baby with failure to thrive becomes hypoglycemic within a few hours after feeding, little to no glycogen storage in liver Baby becomes hypoglycemic within a few hours after feeding, releases 10% of expected amount of glucose based on glycogen degradation (2% of expected increase in blood glucose) Baby becomes hypoglycemic within a few hours after feeding, hepatosplenomegaly, glycogen precipitates in liver Normoglycemia, but has muscle cramping and fatigue with exercise Patient releases insulin, but at higher than normal blood glucose level, therefore almost always hyperglycemic

Hereditary Fructose Intolerance

Type 0 glycogen storage disease

Liver Glycogen Synthase Treatment? Frequent small meals

Type 1 glycogen storage disease (von Gierkes)

Glucose-6-phosphatase

Type IV glycogen storage disease (Andersons)

Liver branching enzyme Treatment? Liver transplant

Type V glycogen storage disease (McArdles) MODY

Muscle glycogen phosphorylase

Glucokinase What are the 2 critical metabolites? ATP and NADPH

Baby/patient becomes hypoglycemic after overnight fast, high levels of acylcarnitines, no ketone bodies, build-up of lipid in muscles, muscle cramping and weakness with exercise

Carnitine acyl transferase II (Carnitine palmitoyl transferase II)

Patient becomes hypoglycemic after overnight fast, no acylcarnitines, buildup of lipid in muscles, muscle cramping and weakness with exercise Baby gets a cold and becomes hypoglycemic, or becomes hypoglycemic after overnight fast, high levels of 6-10 carbon dicarboxylic acids, no ketone bodies No insulin production, ketoacidosis vs. Insulin insensitivity, low or no KB A patient is traveling to an area endemic for malaria, so you prescribe him prophylactic anti-malarial medication, which causes a profound hemolytic anemia. Abnormal mitochondria in liver and brain, inability to metabolize very long chain fatty acids GM1 Infant has seizures, macrocephaly, difficulty sitting up, holding head up Cherry red spot on retina GM2

Carnitine deficiency

MCAD deficiency

Type I Diabetes Type II Diabetes

G6PDH deficiency

Zellweger Syndrome

Generalized Gangliosidoses 2 possibilities Tay Sachs Sandhoffs Activator disease

Fatal defect in peroxisome biogenesis, inability to transport peroxisomal enzymes into peroxisomes, cannot synthesize plasmalogens GM1--galactosidase Hexosaminidase A (Hex A gene) Mutation in activator protein, see normal HexA and HexB enzyme activity in vitro

Infant has seizures, macrocephaly, difficulty sitting up, holding head up Cherry red spot on retina GM2 Globoside Cer-glc-gal-gal Lactosyl ceramide (cer-glcgal) Cer-gal-SO3H Galactosyl ceramide Glucosyl ceramide Sphingomyelin Ceramide chylo TG Normal or slightly VLDL HDL, LDL, chylo remnants

Sandhoffs disease

Hexosaminidase A and B (Hex B gene)

Fabrys disease Ceramide lactoside lipidosis Metachromatic leukodystrophy Krabbes disease Gauchers disease Niemann-Pick disease Farbers disease 2 possibilities Familial LPL Deficiency ApoCII deficiency

-galactosidase Mode of inheritance: X-linked recessive -galactosidase Aryl-sulfatase A -galactosidase -glucosidase Sphingomyelinase Ceramidase How do you tell the difference? Assay of absence of LPL activity in postheparin plasma, but appearance of activity upon addition of exogenous CII indicates ApoCII deficiency; if no activity w/ or w/o CII, problem is in LPL Increased risk atherosclerosis? No Increased risk atherosclerosis? Yes

TG content in LDL, HDL, IDL, and chylo remnants Chylo and VLDL unaffected Accumulation of small, dense LDL, cholesterol content of HDL, HDL3 chylo remnant IDL Palmar xanthomas Slightly LDL HDL Normal TG phospholipids Foam cells in eyes and kidneys Absence of HDL Orange tonsils Peripheral neuropathy

Hepatic lipase deficiency

Hepatic lipase excess

Increased risk atherosclerosis? Yes

Dysbetalipoproteinemia

Familial LCAT deficiency

Abnormal apoE2 isoform has reduced affinity for LDL receptors Increased risk atherosclerosis? Yes Increased risk atherosclerosis? No

Tangier disease (Familial Analphalipoproteinemia)

LDL Normal VLDL, IDL

Familial ligand-defective ApoB100

Mutation in ABC-1 gene, ABCA-1 protein mediates bidirectional transport of cholesterol between inner and outer leaflets of PM Increased risk atherosclerosis? Depends on amount of functional ABCA-1 Mutation in ApoB100 gene w/in LDL receptor binding domain Increased risk atherosclerosis? Yes

Absence of chylo, chylo remnants, VLDL, IDL, LDL Enterocytes full of TG LDL Cholesterol deposits in tendons, skin, arteries Heterozygotesheart attack at 40-50 yo Homozygotesheart attack at 10-20 yo Hyperammonemia Cannot activate CPS-1 Hyperammonemia No accumulation of urea cycle intermediates Hyperammonemia Orotic aciduria

Abetalipoproteinemia

Familial hypercholesterolemia

Microsomal triglyceride transfer protein (MTP), rate-limiting step in formation of chylo and VLDL LDL receptor

N-acetylglutamate synthase CPS-1

Hyperammonemia Hypercitrullinemia Moderate hyperammonemia argininosuccinate Moderate hyperammonemia arginine

OTC deficiency Mode of inheritance? X-linked recessive Reason for orotic aciduria? Carbamoylphosphate accumulates w/in mito and leaks into cytosol, bypasses regulated step of pyrimidine biosynthesis Argininosuccinate synthetase Argininosuccinate lyase Arginase Treatment for urea cycle defects? -keto acids of essential amino acids to force transamination rxn with Glu to generate essential aa for protein synthesis and free up -KG to pick up more NH3 Defect in transport of cystine, lysine, arginine, ornithine Defect in transport of LNAA (I, L, F, T, W, V) Main problem is Trp b/c other aa have alternate transporters Defect in Phe metabolism Differences btw treatment? For classical PKU, have low Phe diet; if defect in THB metabolism, also need to add precursors for neurotransmitters

Kidney stones Pellagra symptoms (dermatitis, diarrhea, dementia) if niacin deficient Black urine in diaper homogentisic acid in urine Baby with high levels of phenylpyruvate, phenyllactate in blood and urine, white patches in hair, mental retardation

Cystinuria Hartnups disease

Alcaptonuria 2 possibilties PKUPhenylalanine hydroxylase or THB regeneration

Baby with vomiting, failure to thrive, cabbage-like odor, liver failure, death by age 2-3 yrs fumarylacetoacetate Skin and eye lesions, neurologic problems

Tyrosinemia type 1

Fumarylacetoacetate hydrolase

Tyrosinemia type 2

Dislocation of optic lens, osteoporosis, mental retardation, and possible increased risk of coronary artery disease

Homocysteinemia/uria

Tyrosine aminotransferase Why is this more difficult to treat than PKU? b/c you have to control levels of 2 amino acids (F, Y) Cystathionine synthase (Give B6) Methionine Synthase (Give B12) N5N10 Methylene THF Reductase (Give folate, thermolabile variant in moms may lead to neural tube defects)

Large immature precursor cells in peripheral blood

Megaloblastic anemia

B12 deficiency Folate deficiency Intrinsic factor (pernicious anemia) Which would have neurological deficits? B12 deficiency, intrinsic factor Branched chain -keto acid dehydrogenase Treatment? Restrict Ile, Leu, Val in diet and give Thiamine supplement -aminolevulinic acid dehydratase, and last step that adds Fe to heme What metabolite will be elevated? aminolevulinic acid Defect in heme biosynthesis

Baby with very brown urine, high levels of branched keto acids, mental retardation Kid who lives in old house & eats paint chips, becomes lethargic and has microcytic anemia Photophobia, likes to eat very rare meat, skin infections and scarring, possible mental status changes Yellow baby

Maple Syrup Urine Disease

Lead poisoning

Porphyria

Neonatal jaundice

Sandy urine in diaper Precipitation of uric acid causes red, severely swollen and inflamed toe

Gout

Neurological deficits Self mutilation (bites lips, fingers), gout

Lesch-Nyhan syndrome

Immature liver conjugation system (inability to add glucuronic acid to bilirubin) Gout if activity of the following enzymes: Amidophosphoribosyl tranferase Glucose-6-phosphatase Glucose-6-phosphate dehydrogenase HGPRT PRPP synthetase < 2% activity HGPRT (If have 2-10% activity, just have gout)

T cell deficiency, susceptibility to viral, intracellular infections Hypouricemia No T cells No B cells No thymus Frequent infections starting at early age Growth retardation Hypochromic anemia Orotic aciduria Normal ammonia levels

Purine nucleoside phosphorylase deficiency

Severe combined immunodeficiency disease (SCID)

Adenosine deaminase deficiency

Hereditary orotic aciduria

UMP synthase (reduced activities of orotate phosphoribosyltransferase, orotidine 5 phosphate decarboxylase)

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