Diseases – Biochem

 Adenosine Deaminase deficiency

o ADA required for AdenosineInosine (purine salvage)
o Inc dATP  Toxic to lymphocytes  AR SCID
 Lesch-Nyhan syndrome:
o Deficiency in HGPRT (purine salvage)
o Hyperuricemia, Gout, Pissed off (aggression), Retardation, DysTonia (HGPRT)
 Xeroderma pigmentosum
o Defect in nucleotide excision repair (G1)
o Prevents repair of pyrimidine dimers due to UV light exposure
 Lynch syndrome (Hereditary nonpolyposis colorectal cancer HNPCC)
o Defect in mismatch repair (G2)
 Ataxia telangiectasia
o Mutation in nonhomologous end joining (dsDNA repair)
 Fanconi anemia
o Mutation in Nonhomologous end joining (dsDNA repair)
 I-cell disease (Inclusion cell disease/mucolipidosis type II)
o Inherited lysosomal storage disease
o Golgi fails to add mannose-6-P to proteins for trafficking to lysosomes
o Proteins secreted extracellularly instead of delivered to lysosomes
o Coarse facial feats, clouded corneas, restricted joint move, Inc plasma lysosomal enzymes
 Kartagener syndrome (1* Ciliary Dyskinesia)
o Immotile cilia due to dynein arm defect
o Infertility, Inc risk of ectopic pregnancy, Inc risk of bronchiectasis & situs inversus
 Ehlers-Danlos syndrome
o Faulty collagen synthesis hyperextensible skin, bleeding, hypermobile joints
o Assc w/ joint dislocation, berry & aortic aneurysms, organ rupture
o Hypermobility type – most common
o Classical type (joint & skin) – Mutation in Type V collagen
o Vascular type (vascular & organ rupture) - Deficient in Type III collagen (ThreE D)
 Scurvy (Collagen synthesis)
o Vitamin C deficiencyCannot hydroxylate Pro & Lys residues
o Swollen gums, bruising, anemia, “corkscrew” hair
 Osteogenesis imperfecta (Brittle Bone disease)
o AD: gene defect in COL1A1 and COL1A2
o Dec production of otherwise normal type I collagen
o Fractures w/ minimal trauma, blue sclera (translucent CT), hearing loss (ossicles)
 Menkes disease (XL recessive CT disease)
o Caused by impaired Copper absorption/transport due to defective Menkes protein
(ATP7A)Dec activity of lysyl oxidase
o Brittle, “kinky” hair, growth retardation, hypotonia
 Marfan syndrome
o Defect in fibrillin, a glycoprotein that forms a sheath around elastin
 McCune-Albright syndrome
o Mut in G-protein signaling
o Unliateral café-au-lait spots, polyostotic fibrous dysplasia, precocious puberty, endocrine
o Lethal if mut before fertilization, survivable in patients with mosaicism (genetically distinct
cell lines in same individual)
 Prader-Willi syndrome
 o Maternal imprinting: Ch 15 from mom normally silent, Paternal gene is deleted/mutated
o Hyperphagia, obesity, retardation, hypogonadism, hypotonia
 AngelMan syndrome
o Paternal imprinting: Ch15 from dad normally silent, Maternal gene is deleted/mut
o Inappropriate laughter “happy puppet”, seizures, ataxia, severe retardation
 Cystic fibrosis
o AR defect in CFTR gene on Ch7, deletion of Phe508
o Encodes ATP-gated Cl- channel that secretes Cl- into lungs & GI & reabsorbs in sweat glands
o Inc Cl- in sweat is diagnostic, Inc immunoreactive trypsinogen (newborn screening)
 Duchenne muscular dystrophy
o XLR due to frameshift mutation (or nonsense)  deleted Dystrophin gene
o Dystrophin helps anchor muscle fibers
o Onset before 5 years old, death due to dilated cardiomyopathy
 Becker MD
o XLR due to non-frameshift insertion in dystrophin gene (partially functional)
 Myotonic Type 1 MD (AD)
o CTG repeat expansion in DMPK geneAbnormal expression of myotonin kinase
o My Tonia, My Testicles (atrophy), My Toupee, My Ticker (arrhythmia)
 Fragile X syndrome (XLd)
o CGG repeat in 5’ UTR of FMR1 gene methylationdec expression
o Fragile X = eXtra large testes, jaw, ears
o 2nd most common cause of mental retardation
 Edwards syndrome: Trisomy 18 (Election age 18)
o Small jaw, low set Ears, death before 1st year
o PAPP-A and free B-hCG DEC in 1st trimester
 Patau syndrome (Trisomy 13) “Puberty 13)
o Cleft Palate, holoProsencephaly, Polydactyl, dead in a year
 Cri-du-chat syndrome
o Microdeletion of short arm of Ch5
o Microcephaly, retardation, high pitched crying (mewing)
 Williams syndrome
o Microdeletion of long arm of Ch7 (includes elastin gene)
o “Elfin” face, retardation, hypercalcemia (Inc sens to VitD)
 DiGeorge syndrome (22q11 deletion)
o CATCH22: Cleft palate, Abnormal facies, Thymic aplasia (T cell deficiency), Cardiac defects,
Hypocalcemia (2* to parathyroid aplasia)
 Rickets
o Vit D deficiency  bone pain/deformity
 Glucose-6-P Dehydrogenase Deficiency (G6PD Def)
o Enzyme necessary to make NADPH from glucose-6-P
o NADPH is necessary to keep glutathione reduced, which detoxifies free radicals
o Dec NADPH in RBCHemolytic anemia
o XLR, most common human enzyme disorder, Inc in blacks (Inc Malaria resistance)
o Heinz bodies: denatured Hemoglobin precipitates in RBCs due to oxidative stress
o Bite cells: From phagocytic removal of Heinz bodies by splenic Macs
 Fructose Metabolism Disorders (AR)
o Essential Fructosuria: Defect in Fructokinase, benign b/c fructose not trapped in cells
o Fructose intolerance: Defect in Adolase B, Fructose-1-P accumulatesDec P availableInh
of glycogenolysis & gluconeogenesisHypoglycemia, jaundice, cirrhosis
  Reducing sugar detected in urine (nonspecific test for carbohydrate metab error)
 Galactose metabolism disorders (AR)
o Galactokinase deficiency: Galactitol accumulates, benign  infantile cataracts
o Classic Galactosemia: Galactose-1-P Uridyltransferase absence
 Damage from accumulation of toxic substances (Galactitol) in lens of eye
 Failure to thrive, infantile cataracts, retardation
 Treat with dietary lactose restrictions
 Urea Cycle Disorders
o N-acetylglutamate synthase deficiency: Cofactor for carbamoyl phosphate synthase I
 Leads to hyperammonemia, neonates, developmental problems, AR
o Ornithine Transcarbamylase deficiency: Most common urea cycle disorder, XLR
 Inc orotic acid in blood/urine, Dec BUN, Sx of hyperammonemia
 NO megaloblastic anemia (vs orotic aciduria)
 Catecholamine Synthesis PhenylalanineTyrosineDOPA (melanin)DopamineNEEpi
o Phenylketonuria (PKU):
 Due to Dec phenylalanine hydroxylase or Dec BH4 (malignant PKU)
 Tyrosine becomes essential, Inc phenylalanineInc phenylketones in urine
 Disorder of aromatic AA metabmusty body odor, retardation, fair skin, eczema
 Must avoid aspartame b/c it contains phenylalanine
o Alkaptonuria:
 Deficiency of homogentisate oxidase for degradation of TyrosineFumarate
 Accumulation of pigment-forming homogentisic acid in tissue
 Blueish-black CT and sclerae, urine turns black w/ exposure to air, toxic to cartilage
(may cause arthralgia)
 Maple Syrup Urine Disease
o Blocked degradation of branched AA (Isoleucine, Leucine, Valine) due to Dec (B1)
 I Love Vermont maple syrup from trees with (B1ranches)
o Leads to Inc alpha-ketoacids in blood, causes severe CNS defects
 Homocystinuria: Methionine(B12) Homocysteine (B6)CystathionineCysteine
o Can have defect in any step: Cystathionine synthase or Methionine synthase
o Inc homocysteine in urine, retardation, osteoporosis, marfanoid habitus, Inc kyphosis, lens
subluxation, thrombosis, atherosclerosis
 Cystinuria
o Defect in renal PCT & intestinal AA transporter: no reabsorption of Cysteine, Ornithine,
Lysine, and Arginine (COLA)
o Excess cysteine in urinerecurrent precipitation of hexagonal cysteine stones
o Tx: Alkalinize urine (Potassium citrate, acetazolamine) & chelating agents (penicillamine)
 Glycogen Storage Disease “Very Poor Carbohydrate Metabolism”
o Von Gierke disease (type I)
 Dec Glucose-6-phosphataseInc Glycogen in liver, Inc lactate, Inc TG, Inc uric acid
(Gout), severe fasting hypoglycemia, hepatomegaly
o Pompe disease (type II)
 Dec lysosomal acid maltaseCardiomegaly, hypertrophic cardiomyopathy
 “Pompe trashes the Pump” (heart, liver, and muscle)
o Cori disease (type III)
 Dec debranching enzymemilder form of Von Gierke disease (normal lactate level)
 Gluconeogenesis is intact
o McArdle disease (type V) “McArdle=Muscle”
 Dec Skeletal muscle glycogen phosphorylase (Myophosphorylase)
  Inc glycogen in Muscle but cannot break it downMuscle cramps, Myoglobinurea
(red urine) w/ exercise, arrhythmia, blood glucose NOT affected
 Lysosomal Storage Diseases – Sphingolipidoses
o Fabry disease (XLR)
 Lack alpha-galactosidase AInc Ceramide trihexoside
 Early: Triad of peripheral neuropathy, angiokeratomas*, hypohidrosis
 Late: Renal failure, CV disease
o Gaucher disease (most common)
 Lack Glucocerebrosidase (B-glucosidase)Inc Glucocerebroside
 Hepatosplenomegaly, pancytopenia, osteoporosis, aseptic necrosis of femur
 Gaucher cells* lipid-laden Macs resembling crumpled tissue paper
o Niemann-Pick disease (Jews)
 Lack SpingomyelinaseInc Sphingomyelin
 Neurodegeneration, hepatosplenomegaly, foam cells*, “cherry red” spot on macula
o Tay-Sachs disease (Jews) (AR)
 Lack HeXosaminidase A (HEXA) Inc GM2 ganglioside
 Neurodegeneration, develop delay, startle response, “cherry red” spot on macula,
onion skin lysosomes, NO hepatosplenomegaly (vs Neimann-Pick)
o Krabbe disease
 Lack GalactocerebrosidaseInc Galactocerebroside, psychosine
 Peripheral neuropathy, develop delay, optic atrophy, globoid cells
o Metachromatic leukodystrophy
 Lack Arylsulfatase AInc Cerebroside sulfate
 Central & peripheral demyelination w/ ataxia, dementia
 Lysosomal Storage Diseases – Mucopolysaccharidoses
o Hurler & Hunter (mild) syndrome
 Lack iduronidase/Iduronate sulfateInc heparin sulfate & dermatan sulfate
 Developmental delay, gargoylism, airway obstruction, corneal clouding (only
Hurler), hepatosplenomegaly
 Fatty acid metabolism diseases
o Carnitine deficiency “CARnitine=CARnage of FAs”
 Cannot transport LCFA into MTAtoxic accumulationweakness, hypotonia
o Long-chain Acyl-CoA dehydrogenase (LCAD) deficiency
 B-oxidation of medium chain FAsacetyl CoA (Decreased)
 Accumulation fatty acyl carnitines in bloodhypoketonemia, hypoglycemia
 Lethargy, seizures, coma, liver dysfunction, muscle weakness, cardiomyopathy
 Cardiac & skeletal muscle use FAs & ketones as primary energy source
 Cholesterol disorders
o Hyperchylomicronemia (type I): AR
 Dec Lipoprotein lipase or apolipoprotein C-II  Inc Chylomicrons, TG, cholesterol
 Pancreatitis, hetatosplenomegaly, eruptive xanthomas (NO Inc risk atherosclerosis)
o Familial Hypercholesterolemia (type IIa): AD
 Absent/defective LDL receptorsInc LDL, cholesterol
 Accelerated atherosclerosis, tendon (Achilles) xanthomas, corneal arcus
o Hypertriglyceridemia (type IV): AD
 Hepatic overproduction of VLDLInc VLDL & TG
 Hypertriglyceridemia <1000, can cause acute pancreatitis