Biochemistry/Genetics Flashcards
Fragile X Syndrome
X-linked defect affecting the methylation and expression of the FMR1 gene.
The 2nd most common cause of genetic intellectual disability (after Down Syndrome)
Findings: post-pubertal macroorchidism (enlarged testes), long face with a large jaw, large everted ears, autism, mitral valve prolapse
Trinucleotide repeat disorder (CGG)n
Trinucleotide repeat expansion diseases (4)
Huntington disease - CAG
Myotonic dystrophy - CTG
Friedreich Ataxia - GAA
Fragile X - CGG
May show genetic anticipation (disease severity increases and age of onset decreases in successive generations)
Down Syndrome
Findings (11):
Intellectual disability
Flat facies
prominent epicanthal folds
single palmar crease
Gap btw 1st 2 toes
duodenal atresia
Hirschsprung disease (part or all of the LI lacks innervation
by ganglia like aurbach’s and messenteric plexi and
cannot function)
ASD
Brushfield spots (small white or grayish/brown spots in
corner of Iris due to aggregation of connective tissue)
Associated with early-onset Alzheimers (chrom 21 also
codes for amyloid precursor protein)
Higher risk of ALL and AML
95% of cases due to meiotic nondisjunction (associated with advanced maternal age)
4% of cases due to Robertsonian translocation
1% due to mosaicism (no maternal association; post-fert mitotic error)
Most common viable chromosomal disorder and most common cause of genetic intellectual disability
1st trimester ultrasound shows: High nuchal translucency, hypoplastic nasal bone, serum PAPP-A is low, free B-hCG is high.
2nd trimester quad screen: high B-hCG, low estriol, high inhibin A
Edwards Syndrome
trisomy 18 (1:8000)
Severe intellectual disability Rocker-bottom feet micrognathia (small jaw) low-set ears clenched hands with overlapping fingers prominent occiput congenital heart disease Death usually within 1 yr of birth
2nd most common trisomy resulting in live birth
PAPP-A and fre B-hCG are low in 1st trimester
2nd tri quad screen shows: low alpha-fetoprotein, low B-hCG, low estriol, low (or normal) inhibin A
Patau syndrome
trisomy 13 (1:15,000)
Severe intellectual disability rocker-bottom feet microphthalmia microcephaly cleft lip/palate holoprosencephaly polydactyly congenital heart disease cutis aplasia Death usually within 1 yr of birth
1st trimester screen: low B-hCG, low PAPP-A, high nuchal translucency
Diseases associated with Chromosome 3
1) von-Hippel-Lindau disease
2) Renal Cell Carcinoma
Diseases associated with Chromosome 4
1) ADPKD with PKD2 defect
2) Huntington Disease
Diseases associated with Chromosome 5
1) Cri-du-chat Syndrome
2) Familial Adenomatous polyposis
Diseases associated with Chromosome 7
1) Williams Syndrome
2) Cystic Fibrosis
Diseases associated with Chromosome 9
Friedreich ataxia
Diseases associated with Chromosome 11
Wilms tumor
Diseases associated with Chromosome 13
1) Patau Syndrome
2) Wilson Disease
Diseases associated with Chromosome 15
1) Prader-Willi Syndrome
2) Angelman Syndrome
Diseases associated with Chromosome 16
ADPKD with PKD1 defect
Diseases associated with Chromosome 17
Neurofibromatosis type 1
Diseases associated with Chromosome 18
Edwards Syndrome
Diseases associated with Chromosome 21
Down Syndrome
Diseases associated with Chromosome 22
1) Neurofibromatosis type 2
2) DiGeorge syndrome (22q11)
Diseases associated with Chromosome X
1) Fragile X Syndrome
2) X-linked agammaglobulinemia
3) Klinefelter Syndrome
Cri-du-chat syndrome
Congenital microdeletion of short arm of chromosome 5 (46, XX or XY, 5p-)
Microcephaly Mod-severe intellectual disability high-pitched crying/mewing epicanthal folds cardiac abnormalities (VSD)
Williams Syndrome
Congenital microdeletion of long arm of chromosome 7 (deleted region includes the elastin gene)
Distinctive "elfin" facies Intellectual disability Hypercalcemia (higher sensitivity to vitamin D) Well-developed verbal skills Extreme friendliness with strangers Cardiovascular problems
22q11 deletion syndromes
Due to aberrant development of 3rd and 4th branchial pouches.
Microdeletion at chromosome 22q11 leads to variable presentations including:
Cleft Palate
Abnormal Facies
Thymic aplasia leading to T cell deficiency
Cardiac defects
Hypocalcemia secondary to parathyroid aplasia
1) DiGeorge - thymic, parathyroid, and cardiac defects
2) Velocardiofacial syndrome - palate, facial, and cardiac defects
Fat soluble vitamins - list them
KADE
K = phytomenadione/phylloquinone/phytonadione A = Retinol E = Tocopherol/tocotrienol
Absorption dependent on gut and pancreas.
Toxicity is more common bc fat-soluble vitamins accumulate in fat
Malabsorption syndromes with steatorrhea such as CF and sprue or mineral oil intake can cause fat-soluble vitamin deficiencies
Water soluble vitamins - list them
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 folate (stored in liver)
B-complex deficiencies often result in dermatitis, glossitis, and diarrhea
Vitamin A deficiency
Night blindness (nyctalopia) Dry, scaly skin (xerosis cutis) Corneal degeneration (keratomalacia) Bilot spots on conjunctiva Immunosuppression
Vitamin A toxicity
Acute - nausea, vomiting, vertigo, blurred vision
Chronic - alopecia, dry skin, hepatic toxicity/enlargement, arthralgia, pseudotumor cerebri
Teratogenic (cleft palate, cardiac abnormalities): A neg pregnancy test and reliable contraception needed before isotretnoin (Vit A derivative) is given for severe acne.
Isotretnoin
Drug for severe acne
Vit A derivative
Get neg pregnancy test and ensure reliable contraception before prescribing since it’s teratogenic
B1 deficiency
Thiamine
Impaired glucose breakdown leads to ATP depletion worsened by glucose infusion; highly aerobic tissues (brain/heart) are affected first.
Seen in malnutrition and alcoholism (secondary to malnutrition and malabsorption)
Diagnosis made via increased RBC transketolase activity following B1 administration
1) Wernicke-Korsakoff - confusion, ophthalmoplegia, ataxia (classic triad) + confabulation, personality changes, memory loss (permanent). Damage to medial dorsal nucleus of thalamus, mammillary bodies
2) Dry beriberi - polyneuritis, symmetrical muscle wasting
3) Wet beriberi - high output cardiac failure (dilated cardiomyopathy), edema
B1 function
Thiamine
In thiamine pyrophosphate (TPP), a cofactor for several dehydrogenase enzyme reactions:
1) Pyruvate dehydrogenase (links glycolysis to TCA)
2) Alpha-ketoglutarate dehydrogenase (TCA)
3) Transketolase (HMP Shunt)
4) Branched-chain ketoacid dehydrogenase
B2 function
Riboflavin
Component of flavins FAD and FMN, used as cofactors in redox reactions (succinate dehydrogenase rxn in TCA)
B2 deficiency
Riboflavin
Cheilosis (inflammation of lips, scaling and fissures at corners of the mouth)
Corneal vascularization
B3 deficiency
Niacin
Glossitis
Severe deficiency leads to pellagra (3 Ds):
Diarrhea, Dementia (also hallucinations) and Dermatitis (c3/c4 dermatome circumferential “broad collar” rash)
Also hyperpigmentation of sun-exposed limbs
Deficiency can be caused by:
Hartnup Disease (low tryptophan absorption)
Malignant Carcinoid Syndrome (higher trypt metabolism)
Isoniazid (Low B6)
B3 function
Niacin
Makes up NAD+ and NADP+
Derived from Tryptophan
Synthesis requires B2 and B6
Used to treat dyslipidemia - lowers levels of VLDL and raises HDL
B3 toxicity
Niacin
Facial flushing (induced by prostaglandin, not histamine; can avoid by taking aspirin with niacin)
Hyperglycemia
Hyperuricemia
B6 deficiency
Pyridoxine
Convulsions, hyperirritability, peripheral neuropathy (deficiency inducible by isoniazid and oral contraceptives), sideroblastic anemias due to impaired Hb synth and Fe excess.
B6 function
Pyridoxine
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, NE, dopamine, and GABA
B5 function
Pantothenic acid
essential component of coenzyme A (CoA, a cofactor for acyl transfers) and fatty acid synthase
B5 deficiency
Pantothenic acid
Dermatitis, enteritis, alopecia, adrenal insufficiency
B7 deficiency
Biotin
Relatively rare.
Dermatitis, alopecia, enteritis. Caused by antibiotic use or excessive ingestion of raw egg whites***
Avidin in egg whites avidly binds biotin
B7 function
Biotin
Cofactor for carboxylation enzymes (which add a 1-C group)
1) Pyruvate carboxylase: Pyruvate (3C) to oxaloacetate (4C)
2) Acetyl-CoA carboxylase: acetyl-CoA (2C) to malonyl-CoA (3C)
3) Propionyl-CoA carboxylase: Propionyl-CoA (3C) to methylmalonyl-CoA (4C)
B9 function
Folate
Converted to tetrahydrofolic acid (THF), a coenzyme for 1-C transfer/methylation reactions
Important for synthesis of nitrogenous bases in DNA and RNA
Found in leafy green vegetables
Small reserve pool in liver
B9 deficiency
Folate
Macrocytic, megaloblastic anemia; hypersegmented polymorphonuclear cells (PMNs); glossitis; no neurologic symptoms (as apposed to B12 deficiency)
Labs: High homocysteine, Normal methylmalonic acid
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 in early pregnancy decreases risk of neural tube defects
B12 deficiency
Cobalamin
Macrocytic, megaloblastic anemia; hypersegmented PMNs; paresthesias and subacute combined degeneration (degeneration of dorsal columns, lateral corticospinal tracts, and spinocerebellar tracts) due to abnormal myelin
High serum homocysteine. High methylmalonic Acid
Prolonged deficiency leads to irreversible nerve damage
B12 function
Cobalamin
Cofactor for homocysteine methyltransferase (transfers methyl groups as methylcobalamin) and methylmalonyl-CoA mutase.
Found in animal products. ONLY MADE by microorganisms
Very large reserve pool (several yrs) stored in liver.
Deficiency usually caused by insufficient intake (veganism), malabsorption (sprue, enteritis, Diphyllobothrium latum), lack of intrinsic factor (pernicious anemia, gastric bypass), or absence of terminal ileum (Crohn)
Anti-intrinsic factor antibodies is DIAGNOSTIC for pernicious anemia.
C deficiency
Ascorbic Acid
1) Scurvy
Swollen gums, bruising, petechiae, hemarthrosis, anemia, poor wound healing, perifollicular and subperiosteal hemorrhages, “corkscrew” hair
2) Weakened immune response
Vitamin C deficiency causes Scurvy due to impaired collagen synthesis
C function
Ascorbic Acid
Antioxidant; also facilitates Fe absorption by reducing it to Fe2+ state.
Necessary for hydroxylation of proline and lysine in collagen synthesis
Needed for dopamine B-hydroxylase, which converts dopamine to NE
Vitamin C is a treatment for methemoglobinemia by reducing Fe3+ to Fe2+
Found in fruits and vegetables
C toxicity
Ascorbic Acid
Nausea, vomitting, diarrhea, fatigue, calcium oxalate nephrolithiasis.
Can increase risk of iron toxicity in predisposed people (people with transfusions, hereditary hemochromatosis)
D function
Increases intestinal absorption of Ca and phosphate
Increases bone mineralization
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
D deficiency
Rickets in children (bone pain and deformity) - XR shows outward bowing of femurs and tibia (genu varum)
Osteomalacia in adults (bone pain and muscle weakness)
Hypocalcemic Tetany
breastfed infants should receive oral vitamin D. deficiency is exacerbated by low sun exposure, pigmented skin, prematurity
D toxicity
Hypercalcemia, hypercalciuria, loss of appetite, stupor
Seen in granulomatous disease (increased activation of vitamin D by epithelioid macrophages)
E deficiency
Hemolytic anemia, acanthocytosis, muscle weakness, posterior column and spinocerebellar tract demyelination
Neuro presentation may be similar to B12 deficiency, but without megaloblastic anemia, hypersegmented neutrophils, or increased methylmalonic acid levels
E function
Antioxidant (protects RBCs and membranes from free radical damage)
Can enhance anticoagulant effects of warfarin
K deficiency
Neonatal hemorrhage with high PT and high aPTT, but normal bleeding time (neonates have sterile intestines and are unable to make vitamin K)
Can also occur after prolonged antibiotic use
K is not in breast milk; neonates are given vitamin k injection at birth to prevent hemorrhagic disease of the newborn
K function
Cofactor for the gamma-carboxylation of glutamic acid residues on various proteins required for blood clotting
Made by intestinal flora
K is for Koagulation. Needed for the maturation of clotting factors 2, 7, 9, 10 and proteins C and S.
Warfarin = K antagonist
Zinc function
Mineral essential for activity of 100+ enzymes. Important in the formation of zinc fingers (transcription factor motif)
Zinc deficiency
Delayed wound healing, hypogonadism, low adult hair (axillary, facial, pubic), dysgeusia, anosmia, acrodermatitis enteropathica (well-demarcated scaly plaques in intertriginous areas like perineum)
May predispose to alcoholic cirrhosis
Kwashiorkor
Protein malnutrition resulting in skin lesions, edema due to low plasma oncotic pressure, liver malfunction (fatty change due to low apolipoprotein synthesis)
Small child with swollen abdomen
Malnutrition, Edema, Anemia, Liver (fatty) = MEAL
Marasmus
Total calorie malnutrition resulting in tissue and muscle wasting, loss of subQ fat, and variable edema.
Glycolysis rde and regulators
Phosphofructokinase-1 (PFK1)
(+) AMP, fructose-2,6-bisphosphate
(-) ATP, Citrate
Gluconeogenesis rde and regulators
Fructose-1,6-bisphosphate
(+) ATP, acetyl-CoA
(-) AMP, fructose-2,6-bisphosphate
TCA rde and regulators
Isocitrate dehydrogenase
(+) ADP
(-) ATP, NADH
Glycogenesis rde and regulators
Glycogen synthase
(+) Glucose-6-phosphate, insulin, cortisol
(-) Epi, glucagon
Glycogenolysis rde and regulators
Glycogen phosphorylase
(+) Epi, glucagon, AMP
(-) G6P, insulin, ATP
HMP shunt rde and regulators
G6PD
(+) NADP+
(-) NADPH
De novo pyrimidine synth rde and regulators
Carbomoyl phosphate synthetase II
(+) ATP
(-) UTP
De novo purine synth rde and regulators
Glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase
(-) AMP, IMP, GMP
Urea cycle rde and regulators
Carbomoyl phosphate synthetase I
(+) N-acetylglutamate
Fatty acid synthesis rde and regulators
Acetyl-CoA carboxylase (ACC)
(+) insulin, citrate
(-) Glucagon, palmitoyl-CoA
Fatty acid oxidation rde and regulators
Carnitine acyltransferase I
(-) Malonyl-CoA
Ketogenesis rde and regulators
HMG-CoA Synthase
Cholesterol synthesis rde and regulators
HMG-CoA Reductase
(+) insulin, thyroxine
(-) Glucagon, cholesterol
Pyruvate dehydrogenase complex deficiency
Causes buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT). X-linked
Neuro defects, lactic acidosis. Increased serum alanine starting in infancy
Tx = increase intake of ketogenic nutrients (high fat content or high lysine/leucine)
Lysine/Leucine are the only ketogenic amino acids
Electron transport inhibiters
Rotenone
Cyanide
Antimycin A
CO
Directly inhibit electron transport, causing a lower proton gradient and blockage of ATP synthesis
ATP Synthase inhibitors
Oligomycin
Directly inhibit mitochondrial ATP synthase causing an increased proton gradient. No ATP is produced bc electron transport stops
Uncoupling agents
2,4-Dinitrophenol (used illicitly for weight loss)
Aspirin (fevers often occur after aspirin overdose)
Thermogenin (in brown fat)
Increase permeability of membrane causing a decreased proton gradient and increased O2 consumption. ATP synthesis stops, but electron transport continues and produces heat.
G6PD deficiency
X-linked recessive disorder. Most common human enzyme deficiency. More prevalent among blacks and may increase malarial resistance.
Heinz Bodies - denatured Hb precipitates with RBCs due to oxidative stress
Bite Cells - results from the phagocytic removal of Heinz Bodies by splenic macrophages
NADPH is needed to keep glutathione reduced, which in turn detoxifies free radicals and peroxides. Lower NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (fava beans, sulfonamides, primaquine, antiTB drugs).
Infection can also precipitate hemolysis (free radicals generated via inflammatory response can diffuse into RBCs and cause oxidative damage)
Essential fructosuria
Involves a defect in fructokinase
Autosomal recessive
Benign, asymptomatic condition since fructose is not trapped in cells.
Symptoms: fructose appears in blood and urine
Disorders of fructose metabolism cause milder symptoms than analogous galactose disorders
Fructose intolerance
Hereditary defect in aldolase B. Autosomal recessive.
Fructose-1-phosphate accumulates, causing a decrease in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis
Symptoms happen after consumption of fruit, juice, or honey
Urine dipstick will be (-) since it only tests for glucose
Reducing sugar can be detected in urine (nonspecific test for inborn errors of carb metabolism)
Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting
Tx = lower intake of fructose and sucrose (glucose + fruc)
Galactokinase deficiency
Hereditary deficiency of galactokinase
Galactitol accumulates if galactose is present in diet.
relatively mild condition - autosomal recessive
Symptoms: galactose in blood and urine, infantile cataracts. May present as failure to track objects or to develop a social smile.
Classic Galactosemia
Absence of galactose-1-phosphate uridyltransferase
Auto recess
Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in lens of eye)
Symptoms = failure to thrive, jaundice, hepatosplenomegaly, infantile cataracts, intellectual disability.
Can lead to E. Coli sepsis in neonates
Tx = exclude galactose and lactose (galactose + gluc) from diet.
Lactase deficiency
Insufficient lactase enzyme leads to dietary lactose intolerance. Lactase functions on the brush border to digest lactose (in human and cow milk) into glucose and galactose
Primary: Age-dependent decline after childhood (absence of lactase-persistent allele), common in people of Asian, African, or Native American decent
Secondary: Loss of brush border due to gastroenteritis (rotavirus), autoimmune disease, etc.
Congenital: rare, due to defective gene
Stool demonstrates low pH and breath shows high H content with lactose tolerance test. Intestinal biopsy reveals normal mucosa in patients with hereditary lactose intolerance.
Findings: Bloating, cramps, flatulence, osmotic diarrhea
Tx = Avoid dairy products or add lactase pills to diet; lactose-free milk.
Hyperammonemia
Can be acquired (liver disease) or hereditary (urea cycle enzyme deficiencies)
results in excess NH4 which depletes alpha-ketoglutarate, leading to inhibition of TCA cycle.
Tx = limit protein in diet. Lactulose to acidify GI tract and trap NH4 for excretion.
Rifaximin to lower colonic ammoniagenic bacteria.
Benzoate or phenylbutyrate (both of which bind amino acid and lead to excretion) may be given to lower ammonia levels.
Ammonia intox = tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision
N-acetylglutamate synthase deficiency
Required cofactor for carbamoyl phosphate synthetase I. Absence of it leads to hyperammonemia
Presents in neonates as poorly regulated respiration and body temp, poor feeding, developmental delay, intellectual disability (identical to presentation of carbamoyl phosphate synthetase I deficiency)
Ornithine transcarbamylase deficiency
Most common urea cycle disorder. X-recessive (vs other urea cycle enzyme deficiencies, which are auto recessive)
Interferes with body’s ability to eliminate ammonia. Often evident in the first few days of life, but may present later. Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway)
Findings: High orotic acid in blood and urine. Low BUN. Symptoms of hyperammonemia. No megaloblastic anemia (vs orotic aciduria)
Phenylketonuria
Due to low phenylalanine hydroxylase or low tetrahydrobiopterin cofactor (malignant PKU). Tyrosine becomes essential!!!
High phenylalanine leads to excess phenylketones in urine
Phenylketones = phenylacetate, phenyllactate, phenylpyruvate
Findings: Intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor
Disorder of aromatic amino acid metabolism leads to musty body odor.
Autosomal recessive. 1:10,000
Screening occurs 2-3 days after birth (normal at birth bc of maternal enzyme during fetal life)
PKU patients MUST avoid aspartame
Tx = lower phenylalanine and raise tyrosine in diet, tetrahydrobiopterin supplementation
Maternal PKU: Lack of proper dietary therapy during pregnancy. Findings = microcephaly, intellectual disability, growth retardation, congenital heart defects.
Maple Syrup Urine Disease
Blocked degradation of branched amino acids (Isoleucine, Leucine, Valine) due to low alpha-ketoacid dehydrogenase (B1).
Causes high alpha-ketoacids in the blood, esp those of leucine.
Causes severe CNS defects, intellectual disability and death
Tx = restriction of isoleucine, leucine, valine in diet. Thiamine supplementation
Autosomal recessive
Urine smells like maple syrup/burnt sugar
Alkaptonuria (Ochronosis)
Congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate leading to pigment forming homogentisic acid accumulation in tissue.
Auto recessive
Usually benign
Dark connective tissue, brown pigmented sclerae, urine turns black on prolonged exposure to air. May have debilitating arthralgias (homogentisic acid toxic to cartilage)
Homocystinuria
All auto recessive. All types result in excess homocysteine.
Findings: High homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (down and in), thrombosis, and atherosclerosis (stroke and MI)
Types:
1) Cystathionine synthase deficiency
Tx = lower methionine, raise cysteine, raise B12 and folate in diet
2) Low affinity of cystathionine synthase for pyridoxal phosphate
Tx = increase B6 and cysteine in diet
3) Homocysteine methyltransferase (methionine synthase) deficiency
Tx = raise methionine in diet
Cystinuria
Hereditary defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of Cysteine, Ornithine, Lysine, and Arginine (COLA)
Excess cystine in the urine can lead to recurrent precipitation of hexagonal cystine stones
Tx = urine alkalinization (postassium citrate, acetazolamide) and chelating agents (penicillamine) increase the solubility of cystine stones; good hydration
Autosomal recessive - common (1:7000)
Urinary cyanide-nitroprusside test is diagnostic
Cystine = cysteine = cysteine connected by disulfide bond
Von Gierke Disease
Type I Glycogen storage disease
Deficient enzyme = Glucose-6-Phosphatase
Autosomal recessive
Severe fasting hypoglycemia, very high glycogen in liver, high blood lactate, high triglycerides, high uric acid, hepatomegaly
Tx = frequent oral glucose/cornstarch; avoidance of fructose and galactose
Pompe Disease
Type II Glycogen storage disease
Deficient enzyme = Lysosomal alpha-1,4-glucosidase (acid mutase)
Auto recessive
“Pompe trashes the pump” - heart, liver, muscle
Cardiomegaly, hypertrophic cardiomyopathy, exercise intolerance, and systemic findings leading to early death
Cori Disease
Type III Glycogen storage disease
Deficient enzyme = Debranching Enzyme (alpha-1,6-glucosidase)
Auto recessive
Gluconeogenesis is intact
Milder form of type I (Von Gierke) with normal blood lactate levels
McArdle Disease
Type V Glycogen storage disease
Deficient enzyme = Skeletal muscle glycogen phosphorylase (myophosphorylase)
Auto recessive
Blood glucose levels typically unaffected
Tx = B6 (cofactor)
Increased glycogen in muscle, but muscle cannot break it down leading to painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities.
List the Sphingolipidoses (6)
Fabry Disease Gaucher Disease Niemann-Pick Disease Tay-Sachs Disease Krabbe Disease Metachromatic Leukodystrophy
Fabry Disease
Lysosomal storage disorder (Sphingolipidosis)
Deficient enzyme = alpha-galactosidase A
Accumulated substance = Ceramide trihexoside
X-recessive
Peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease
Gaucher Disease
Lysosomal storage disorder (Sphingolipidosis)
Deficient enzyme = Glucocerebrosidase (Beta-glucosidase)
Accumulated substance = Glucocerebroside
Auto recessive
Most common one.
Hepatosplenomegaly, pancytopenia, osteoporosis, aseptic necrosis of femur, bone crises, Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper)
Tx = recombinant glucocerebrosidase
Niemann-Pick Disease
Lysosomal storage disorder (Sphingolipidosis)
Deficient enzyme = Sphingomyelinase
Accumulated substance = Spingomyelin
Auto recessive
Progressive neurodegeneration, hepatosplenomegaly, foam cells (lipid-laden macrophages), cherry red spots on macula***
Tay-Sachs Disease
Lysosomal storage disorder (Sphingolipidosis)
Deficient enzyme = Hexosaminidase A
Accumulated substance = GM2 ganglioside
Auto recessive
Progressive neurodegeneration, developmental delay, cherry red spot on macula, lysosomes with onion skin, no hepatosplenomegaly
Krabbe Disease
Lysosomal storage disorder (Sphingolipidosis)
Deficient enzyme = Galactocerebrosidase
Accumulated substance = Galactocerebroside, psychosine
Auto recessive
Peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Metachromatic leukodystrophy
Lysosomal storage disorder (Sphingolipidosis)
Deficient enzyme = Arysulfatase A
Accumulated substance = Cerebroside sulfate
Auto recessive
Central and peripheral demyelination with ataxia, dementia
List the Mucopolysaccharidoses (2)
Hurler Syndrome
Hunter Syndrome
Hurler Syndrome
Lysosomal storage disorder (Mucopolysaccharidosis)
Deficient enzyme = alpha-L-iduronidase
Accumulated substance = Heparan sulfate, dermatan sulfate
Auto recessive
Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
Hunter Syndrome
Lysosomal storage disorder (Mucopolysaccharidosis)
Deficient enzyme = Iduronate sulfatase
Accumulated substance = Heparan sulfate, dermatan sulfate
Mild Hurler + aggressive behavior, no corneal clouding
Systemic primary carnitine deficiency
Inherited defect in transport of LCFAs into the mitochondria leads to toxic accumulation
Causes weakness, hypotonia, and hypoketotic hypoglycemia
Medium chain acyl-CoA dehydrogenase deficiency
Minor illness can lead to sudden death. Treat by avoiding fasting.
Autosomal recessive disorder of fatty acid oxidation. Lower ability to break down fatty acids into acetyl-CoA leads to accumulation of 8-10C fatty acyl carnitines in the blood and hypoketotic hypoglycemia. May present in infancy or early childhood with vomiting, lethargy, seizures, coma, and liver dysfunction
Hyper chylomicronemia
Type I familial dyslipidemia
Increased blood levels of chylomicrons, TG, and cholesterol
Auto recessive. Lipoprotein lipase deficiency or altered apolipoprotein C-II.
Causes pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas (no increased risk for atherosclerosis). Creamy layer in supernatant
Familial hypercholesterolemia
Type IIa familial dyslipidemia
Increased blood levels of LDL and cholesterol
Auto dominant. Absent or defective LDL receptors. Heterozygotes (1:500) have cholesterol = 300; homozygotes (very rare) have cholesterol = 700+.
Causes accelerated atherosclerosis (may have MI before 20), tendon (Achilles) xanthomas, and corneal arcus
Hypertriglyceridemia
Type IV familial dyslipidemia
Increased blood levels of VLDL and TG
Auto dominant. Hepatic overproduction of VLDL
Hypertriglyceridemia (>1000) can cause acute pancreatitis.
Autosomal Recessive diseases (12)
Albinism ARPKD Glycogen storage diseases Hemochromatosis Kartagener Syndrome Mucopolysaccharidoses (NOT Hunter) Phenylketonuria Sickle Cell Disease Sphingolipidoses (NOT Fabry) Thalassemias Wilson
Myotonic Type 1 MD
Auto Dom
Trinucleotide repeat CTG in DMPK gene
Abnormal expression of myotonin protein kinase
Myotonia, muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia
My Tonia, My Testicles, My Toupee, My Ticker
Becker MD
X recessive
Non-frameshift insertions in dystrophin gene - this makes it partially functional instead of shortened
Less severe than Duchenne
Onset in adolescence/ early adulthood
Deletions can cause each MD
Duchenne MD
X recessive
Deleted dystrophin gene (frameshift)
Inhibits muscle generation. Weakness starts low and progresses up.
Pseudohypertophy of calf muscles from fibrofatty replacement of muscle
Gower maneuver - use upper extremities to stand up
Waddling gait
Dilated cardiomyopathy = cause of death
Onset before 5 yrs old
X-linked recessive disorders (10)
Be Wise, Fool’s GOLD Heeds Silly HOpe
Bruton agammaglobulinemia Wiskott-Aldrich Syndrome Fabry Disease G6PD deficiency Ocular albinism Lesch-Nyhan Duchenne (and Becker) MD Hunter Syndrome Hemophilia (A & B) Ornithine transcarbamylase deficiency
Cystic Fibrosis
1 lethal genetic disease in whites
CFTR gene - Chromosome 7
Deletion of Phe508
CFTR encodes ATP-gated Cl- channel that secretes Cl in lungs/GI tract and reabsorbs Cl in sweat glands
Extra thick mucus secreted into lungs and GI tract
Recurrent pulmonary infections
Tx = N-acetylcysteine
Auto Recessive
Von Hippel-Lindau
Deletion of VHL tumor suppressor gene
Chromosome 3
Development of numerous tumors (benign and malignant)
Tuberous sclerosis
Neurocutaneous disorder - multi-organ system involvement
Numerous benign hamartomas
Incomplete penetrance - variable expression
Auto Dom
Neurofibromatosis Type 2
NF2 gene - Chromosome 22
Bilateral acoustic schwannomas
Juvenile cataracts
Meningiomas
Ependymomas (a type of brain tumor)
Auto Dom
Neurofibromatosis Type 1
“Von Recklinghausen Disease”
Mutations in NF1 gene - Chromosome 17
Neurocutaneous disorder - cafe-au-lait spots
Cutaneous neurofibrosis
Optic gliomas
Pheochromocytoma
Lisch nodules (pigmented iris hamartomas)
100% Penetrance, Variable expression
Auto Dom
Multiple Endocrine Neoplasias
MEN1 gene = MEN1
RET gene = MEN2A and MEN2B
Familial tumors of endocrine glands (pancreas, parathyroid, pituitary, thyroid, adrenal medulla)
Auto Dom
Marfan
FBN1 gene mutation on Chromosome 15
Defective fibrillin - connective tissue disorder affecting skeleton, heart, eyes
Tall with long extremities. Pectus excavatum. Hypermobile joints. Long, tapering fingers/toes (arachnodactyly)
Cystic medial necrosis of aorta leads to aortic incompetence and dissecting aneurysms
Floppy mitral valve
Subluxation of lenses (up and temporal)
Auto Dom
Li-Fraumeni Syndrome
Abnormal TP53 - multiple malignancies at early age
AKA SBLA Cancer Syndrome (Sarcoma, Breast, Leukemia, Adrenal gland)
Auto Dom
Huntington Disease
Trinucleotide repeat - CAG on Chromosome 4
Depression, progressive dementia, choreiform movements, caudate atrophy
High dopamine, low GABA, low ACh
Demonstrates anticipation
Auto Dom
Hereditary spherocytosis
Spheroid RBCs due to spectrin/ankyrin defect
Hemolytic anemia
High MCHC
High RDW
Tx = splenectomy
Auto Dom
Hereditary hemorrhagic telangiectasia
Inherited disorder of blood vessels
“Osler-Weber-Rendu”
Branching skin lesions (telangiectasia) Recurrent epistaxis Skin discolorations Arteriovenous malformations GI bleeding Hematuria
Auto Dom
Familial hypercholesterolemia
High LDL due to defective/absent LDL receptor
Severe atherosclerotic disease early in life
Corneal arcus
Tendon xanthoma (Achilles)
Auto Dom
Familial adenomatous polyposis
Mutations on chromosome 5q - APC gene
Colon becomes covered with polyps after puberty
Progresses to colon cancer unless resected
Auto Dom
ADPKD
Autosomal Dominant Polycystic Kidney Disease
Mutation in PKD1 - chromosome 16 (85% of cases)
Mutation in PKD2 - chromosome 4
Bilateral, large multiple cysts. Kidney enlargement
Angelman Syndrome
Mutation/deletion on Chromosome 15
Paternal imprinting - Maternal gene deleted/mutated
5% from paternal uniparental disomy
Inappropriate laughter** (happy puppet), seizures, ataxia, severe intellectual disability
Prader-Willi Syndrome
Mutation/deletion of genes on chromosome 15
Maternal imprinting (gene from mom is normally silent - paternal** gene is deleted/mutated)
Hyperphagia, obesity, intellectual disability, hypogonad, hypotonia
25% due to maternal uniparental disomy
Menkes Disease
X recessive
Connective tissue disease caused by impaired copper absorption and transport leads to defective Menkes protein -ATP7A
Leads to lower activity of lysyl oxidase (Cu is cofactor)
Brittle, kinky hair. Growth retardation. Hypotonia.
Ehlers-Danlos Syndrome
Faulty collagen synthesis
Hyperextensible skin, tendency to bleed (easy bruising), hypermobile joints
Multiple types - can be linked with joint dislocation, organ rupture, berry and aortic aneurysm
Hypermobility Type (joint instability) = most common
Classical Type (joint + skin) = Type V collagen
Vascular Type (vascular and organ rupture) = Type III
Osteogenesis Imperfecta
Brittle bone disease - mistaken for child abuse
Most common is Auto Dom
Lower production of otherwise normal* Type 1 collagen
Multiple fractures with minimal trauma - may occur during birth
Blue sclerae
Hearing loss
Dental imperfections (lack of dentin)
Collagen types
I = Most common (90%) - Bone, skin, tendon, dentin, fascia, cornea, late wound repair
Osteogenesis Imperfecta type I
II = Cartilage (hyaline too), vitreous body nucleus pulposus
III = Reticulin - skin, blood vessels, uterus, fetal tissue
Ehlers-Danlos Vascular Type
IV = Basement membrane, lens, basal lamina
Alport Syndrome
Goodpasture Syndrome
Kartagener Syndrome
“Primary Ciliary Dyskinesia”
Immotile cilia due to dynein arm defect
Male/female infertility bc of immotile sperm and dysfunctional fallopian tube cilia
Bronchiectasis, Recurrent Sinusitis, Situs Inversus
Drugs that act on microtubules
Microtubules Get Constructed Very Poorly
Mebendazole - anti-helminth Griseofulvin - anti-fungal Colchicine - antigout Vincristine/Vinblastine - anticancer Paclitaxel - anticancer
I-cell Disease
“Inclusion Cell Disease” - lysosomal storage disorder
N-acetylglucosaminyl-phosphotransferase is defective
- Golgi can’t phosphorylate manose residues
- Low manose-6-phosphate on glycoproteins
- Proteins secreted extracellularly instead of being delivered to lysosomes
Coarse facial features. Cloudy cornea. Restricted joint movements. high levels of lysosomal enzymes.
Fatal in childhood
Actinomycin D
Alpha-amanitin
Rifampin
Inhibit RNA Polymerases
Actinomycin D: inhibits prokaryotes and eukaryotes
Alpha-amanitin: From death cap mushroom
- inhibits RNA Pol II
- Severe hepatotoxicity if ingested
Rifampin: Inhibits RNA Pol in Prokaryotes
Ataxia telangiectasia
Fanconi Anemia
Mutations in nonhomologous end joining (ds repair)
Hereditary nonpolyposis colorectal cancer
Defect in mismatch repair
Pt is about 40 or so before something is noticed
Fluoroquinolones
Inhibit prokaryotic topoisomerase II (DNA Gyrase)
and topoisomerase IV
Bacteria unable to divide
Xeroderma Pigmentosum
Defect in nucleotide excision repair
Rarely live past 20 - usually die of SCC or Melanoma
Prevents repair of pyrimidine dimers bc of UV exposure
Lesch-Nyhan Syndrome
Defective Purine Salvage - absent HGPRT
Causes excess uric acid. Excess de novo purine synthesis
X recessive
Tx = allopurinol
Hyperuricemia Gout Pissed off (aggression, self-mutilating - nail biting) Retardation dysTonia (choreoathetosis)
Adenosine deaminase deficiency
Involved in Purine salvage
Too much ATP and dATP imbalances nucleotide pool through feedback inhibition of ribonucleotide reductase. This stops DNA synthesis and lowers lymphocyte count
Major cause of autosomal recessive Severe Combined Immunodeficiency
“Alymphocytosis”
“Glanzmann-Riniker Syndrome”
Allopurinol
Febuxostat
Xanthine oxidase inhibitors
When given with 6-MP, you need less of 6-MP. XO normally metabolizes 6-MP.
6-mercaptopurine
Inhibits de-novo purine synthesis
Its prodrug is azathioprine (also inhibits same thing)
Hypoxanthine is a precursor in purine synthesis. When taking an XO inhibiter like allopurinol you need a lower dose of 6-MP.
Inhibits PRPP to IMP
Methotrexate
Trimethoprim
Pyrimethamine
Inhibit dihydrofolate reductase (lowers dTMP)
Humans = MTX Bacteria = TMP Protozoa = Pyrimethamine
This is in pyrimidine synthesis pathway
Give folate with MTX to reduce its side effects
5-fluorouracil
Inhibits thymidylate synthase (lowers dTMP production)
In pyrimidine synthesis pathway
Anti-cancer. Give folate with 5-FU to increase its potency.
Hydroxyurea
Inhibits ribonucleotide reductase
used in cancer, Sickle Cell
Ribonucleotide reductase is how ribonucleotides are converted to deoxyribonucleotides.
In pyrimidine synthesis pathway
Mycophenolate
Ribavirin
Inhibits IMP dehydrogenase
Purine synthesis pathway
Mycophenolate: Prevents rejection in organ transplants
Ribavirin: Viral infections (flu, Hep C)
Leflunomide
Inhibits dihydrooratate dehydrogenase (Carbamoyl phosphate to orotic acid)
Used in RA
In pyrimidine synthesis pathway
