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Flashcards in Biochemistry/Genetics Deck (150):

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)
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
cleft lip/palate
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-)

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


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


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.



Drug for severe acne

Vit A derivative

Get neg pregnancy test and ensure reliable contraception before prescribing since it's teratogenic


B1 deficiency


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


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


Component of flavins FAD and FMN, used as cofactors in redox reactions (succinate dehydrogenase rxn in TCA)


B2 deficiency


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

Corneal vascularization


B3 deficiency



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


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


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




B6 deficiency


Convulsions, hyperirritability, peripheral neuropathy (deficiency inducible by isoniazid and oral contraceptives), sideroblastic anemias due to impaired Hb synth and Fe excess.


B6 function


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


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


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


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


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


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


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



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



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


(+) ATP, acetyl-CoA

(-) AMP, fructose-2,6-bisphosphate


TCA rde and regulators

Isocitrate dehydrogenase

(+) ADP



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


(+) NADP+



De novo pyrimidine synth rde and regulators

Carbomoyl phosphate synthetase II

(+) ATP

(-) UTP


De novo purine synth rde and regulators

Glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase



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

Antimycin A

Directly inhibit electron transport, causing a lower proton gradient and blockage of ATP synthesis


ATP Synthase inhibitors


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.



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)



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)



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)


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



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


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



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)

Glycogen storage diseases
Kartagener Syndrome
Mucopolysaccharidoses (NOT Hunter)
Sickle Cell Disease
Sphingolipidoses (NOT Fabry)


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
Duchenne (and Becker) MD
Hunter Syndrome
Hemophilia (A & B)
Ornithine transcarbamylase deficiency


Cystic Fibrosis

CFTR gene - Chromosome 7

Deletion of Phe508

#1 lethal genetic disease in whites

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
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
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



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 RDW

Tx = splenectomy

Auto Dom


Hereditary hemorrhagic telangiectasia

Inherited disorder of blood vessels


Branching skin lesions (telangiectasia)
Recurrent epistaxis
Skin discolorations
Arteriovenous malformations
GI bleeding

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



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

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



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

Pissed off (aggression, self-mutilating - nail biting)
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
"Glanzmann-Riniker Syndrome"



Xanthine oxidase inhibitors

When given with 6-MP, you need less of 6-MP. XO normally metabolizes 6-MP.



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



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



Inhibits thymidylate synthase (lowers dTMP production)

In pyrimidine synthesis pathway

Anti-cancer. Give folate with 5-FU to increase its potency.



Inhibits ribonucleotide reductase

used in cancer, Sickle Cell

Ribonucleotide reductase is how ribonucleotides are converted to deoxyribonucleotides.

In pyrimidine synthesis pathway



Inhibits IMP dehydrogenase

Purine synthesis pathway

Mycophenolate: Prevents rejection in organ transplants

Ribavirin: Viral infections (flu, Hep C)



Inhibits dihydrooratate dehydrogenase (Carbamoyl phosphate to orotic acid)

Used in RA

In pyrimidine synthesis pathway