Disease Signs and Symptoms Deficiency/Problem Notes Amyloidosis

BIOCHEMISTRY BLOCK 1 - Madhav Patel
Disease Signs and Symptoms Deficiency/Problem Notes

Amyloidosis ĐŚĂŶŐĞŝŶĐŽŶĨŽƌŵĂƚŝŽŶƚŽĂŵǇůŽŝĚƌĞƉĞĂƚĞĚɴƐŚĞĞƚƐƚƌƵĐƵƌĞ;ƐĞĐŽŶĚĂƌǇƐƚƌƵĐƚƵƌĞͿ͘ĞƉŽƐŝƚŝŽŶŽĨĂŵǇůŽŝĚƐƉĞĞĚƐƵƉƚŚĞƉƌŽĐĞƐƐŽĨĐŽŶǀĞƌƐŝŽŶĂŶĚĚĞƉŽƐŝƚŝŽŶ;ƐĞĞĚŝŶŐͿ͘tŚĞŶƐƚĂŝŶĞĚǁŝƚŚŽŶŐŽƌĞĚĚǇĞ͕ƚŚĞǇĂƉƉĞĂƌ
red with normal light microscopy and exhibit apple-‐green birefringence when viewed in polarized light
Creutzfeld-‐jakob disease (CJD, prion disease) trasmissible spongiform encephalopathies characterized by spongiform degeneration and astrocytic Sporadic CJD (85% of all cases) due to somatic cell Famillial CDJ typically manifests in fourth decade of life.
gliosis in the CNS. Frequently, prion aggregates and amyloid plaques are seen which are resistant to mutation or rare spontaneous refolding of PrPc to Astrocytes proliferate in response to injury and this is nown
proteolytic degredation. PrPsc). Famillial CDJ due to autosomal dominnant as gliosis. Macrophages (microglial cells?) in the CNS ct as
inherited mutation. scavenger cells and remove dead and dying astrocytes
Alzheimer Disease ĂŐĞͲƌĞůĂƚĞĚŶĞƵƌŽĚĞŐĞŶĞƌĂƚŝǀĞĚŝƐŽƌĚĞƌ͘ŵǇůŽŝĚƉůĂƋƵĞƚŚĂƚĂĐĐƵŵƵůĂƚĞƐŝƐĂŵǇůŽŝĚɴŚĂǀŝŶŐ ǆĐĞƐƐŝǀĞƉƌŽĚƵĐƚŝŽŶŽĨɴϰϮ͕ĂĚĞŐƌĂĚĂƚŝŽŶƉƌŽĚƵĐƚ

ĐŚĂƌĂĐƚĞƌŝƐƚŝĐɴͲƉůĞĂƚĞĚƐŚĞĞƚ͘ůƐŽĂŶĂĐĐƵŵƵůĂƚŝŽŶŽĨŶĞƵŽĨŝďƌŝůůĂƌǇƚĂŶŐůĞƐ͕ŝŶƐŝĚĞƚŚĞŶĞƵƌŽŶƐ͕ƚŚĞ of amyloid precuror protein (APP), is a key
key component of the tangle is hyperphosphorylated tau proteins. component of amyloid plaue, normal cellular
defense mechanism against leads to neuronal
damage
Parkinson's disease Dopamine epletion in the neostriatum due to degeneration of dopaminergic nigrostriatal neurons in alterations in the ubiquitin-‐roteasome pathway of protein degradation which leads to abnormal accumulation of
substantia nigra pars compacta. This insoluble protein acumulates inside neurons forming inclusions ƚŚĞƉƌŽƚĞŝŶɲͲƐǇŶƵĐůĞŝŶďŽƵŶĚƚŽƵďŝƋƵŝƚŝŶŝŶƚŚĞĚĂŵĂŐĞĚĐĞůůƐ͘KƚŚĞƌĞůůͲĚĞĂƚŚŵĞĐŚĂŶŝƐŵƐŝŶĐůƵĚĞŽǆŝĚĂƚŝǀĞ
called lewy bodies. Early in the course of the disease, the most obvious symptoms are movement-‐ stress due to increased reactive oxygen species, defect in complex I of electron transport chain in mitochondria
related; these include tremors, rigidity, slowness of movement and difficulty with walking and gait. leading to decrease in ATP production which again affects the ubiquitin-‐proteasome protein egradation pathway
HEMOGLOBINOPATHIES
Sickle Cell Anemia (Hb SS) Vaso-‐occlusive pain crisis episodes usually arise sudenly, precipitated by low-‐oxygenation states Autosomal recessive single amino acid substitution glu > val replacement increases hydrophobic forces within
(extreme exercise/fatigue) or cold temperature. Symptoms include deep pain in the extremities and ;ɴϲŐůƵхǀĂůͿǁŝƚŚŝŶƚŚĞŚĞŵŽŐůŽďŝŶ;,ďͿŐĞŶĞ͕ hemoglobin molecules leaing to polymerization in DEOXY
spine and occasionally the abdomen and chest. Episodes may be accompanied by fever, malaise, creating the abnormal Hb SS. Patients who are state. HbS polymerizes reversibly when deoxygenate to
reticulocytois and leukocytosis. Chronic anemia as a result of constant hemolysis is seen in most homozygous recessive for Hb SS mutation are said to form a gelatinous network of fibrous polymers that stiffen
patients. Hb levels are commonly decreased (baseline levels below 10g/dL) yet well tolerated y have sickle cell anmeia, while eterozygotes (one the RBC membrane, increase viscosity, and cause
patients. Increased HB degredation will lead to elevated levels of bilirubin B23(jaundice) which is mutated and one normal copy) are said to have dehydration due to potassium leakage and calcium influx.
concentrated in gallbladder and precipitate in the presence of calcium to form calcium bilirubinate sickle cell trait (Hb AS) and have ssignificantly less Repeated polymerization/depolymerization of the HB SS
gallstones. Patients are also at increased risk for infection with parvovirus B19, which causes an acute clinical manifestations of disease. truncates the RBC lifespan from 120 to 10-‐20 days.
aplastic anemia secondary to suppression of erythrogenesis. This can be devastating because of High (proposed this has remained in the gene pool to protect
hemoysis. The spleen enlargess during the first year of life in sickle cell anemia, as it becomes against malaria). Hemolytic anemia. Path: microvascular
congested with trapped slow-‐flowing sickld cells within the splenic sinuses and reticuloendothelial occlusions > ischemia > coagulatory necrosis > denaturation
system. Microvascular occlusions produce chronic tissue hypoxia and microinfarctions. Over time,
fibrosis incduces autosplenectomy. With functional asplenia, patients are particularly susceptible to
infecction by the encapsulated organisms Streptococcus pneumoniae and Haemophilus influenzae.
Vacination and prophylactic daily penicillin throughout childhood are mainstays of treatment to
prevent spesis and meningitis. Treatment focuses on hhydration, oxygenn therapy analgesia, and
sometimes transfusion. Hydroxurea, and antitumor rug, is therapeutically useful because it increases
circulating levels of HB F, which decreases RBC sickling. This leades to deccreased frequency of painful
crises and reduces mortality.
Hemoglobin C trait (Hb AC) No splenomegaly or vaso-‐occlusive crisis lysine is substituted for glutamic acid in the 6th
ƉŽƐŝƚŝŽŶŝŶɴĐŚĂŝŶ͕ɴϲŐůƵхůǇƐ͘
Hemoglobin SC disease (Hb SC) Hb S and Hb C are found in equal amounts, splenomegaly and vaso-‐occlusive crisis is seen ĐŽŵƉŽƵŶĚŚĞƚĞƌŽǌǇŐŽƐŝƚǇ͕ŽŶĞɴͲŐůŽďŝŶŚĂƐƐŝĐŬůĞ
cell mutation, while the other is mutant for HbC.
^ŝĐŬůĞďĞƚĂ;ŽͿƚŚĂůĂƐƐĞŵŝĂ;^ɴΣƚŚĂůĂƐƐĞŵŝĂͿ ŽŶĞƐŝĐŬůĞďĞƚĂͲŐůŽďŝŶĂŶŽƚŚĞƌɴͲŐůŽďŝŶŝƐĂďƐĞŶƚ͕хϵϬй,ď^
^ŝĐŬůĞďĞƚĂ;нͿƚŚĂůĂƐƐĞŵŝĂ;^ɴнƚŚĂůĂƐƐĞŵŝĂͿ ŽŶĞƐŝĐŬůĞďĞƚĂͲŐůŽďŝŶĂŶĚĂŶŽƚŚĞƌɴͲŐůŽďŝŶŝƐŝŶĚĞĐƌĞĂƐĞĚĂŵŽƵŶƚƐ͕хϲϬй,ď^͕ƐƉůĞŶŽŵĞŐĂůǇĂŶĚ
vaso-‐occlusive crisis seen.
ɲƚŚĂůĂƐƐĞŵŝĂƐ ǁŚĞŶƚŚĞƌĞĂƌĞĚĞůĞƚŝŽŶƐŝŶĂƚůĞĂƐƚŽŶĞŽĨĨŽƵƌɲ
globin genes on chromosome 16
ɲͲƚŚĂůĂƐƐĞŵŝĂͲϮƚƌĂŝƚ individuals with this type of defect are called as silent carriers of a-‐thalassemia because no clinical ŽŶĞŽĨĨŽƵƌɲͲŐůŽďŝŶůŽĐŝĚĞůĞƚĞĚ
manifestations are noted
ɲͲƚŚĂůĂƐƐĞŵŝĂͲϭƚƌĂŝƚ mild symptoms two deleted loci
,ď,ĚŝƐĞĂƐĞ;ɴϰĚŝƐĞĂƐĞͿ mild to moderate hemolytic anemia. In HbH disease, Hb A production is only 25-‐30% normal Fetuses three loci deleted
ĂĐĐƵŵƵůĂƚĞƐŽŵĞƵŶƉĂŝƌĞĚɴĐŚĂŝŶƐƚŽĨŽƌŵŚŽŵŽƚĞƚƌĂŵĞƌŽĨɴĐŚĂŝŶƐ;,ďĂƌƚƐ͖ɴϰͲĐŚĂŝŶƚĞƚƌĂŵĞƌƐͿ͘
/ŶĂĚƵůƚƐ͕ƵŶƉĂŝƌĞĚĐŚĂŝŶƐĂĐĐƵŵƵůĂƚĞĂŶĚĂƌĞƐŽůƵďůĞĞŶŽƵŐŚƚŽĨŽƌŵɴϰƚĞƚƌĂŵĞƌƐĐĂůůĞĚ,ď,͘,ď,
forms new inclusions in erythroblasts an precipitates in circulated RBC. Patients with HbH disease
have thalassemia intermedia characterized by moderately severe hemolytic anemia, but milder
ineffective erythropoiesis Survival into mid-‐adult life without transfusions is common
,ǇĚƌŽƉƐĨĞƚĂůŝƐǁŝƚŚ,ďĂƌƚƐ;ɶϰͿ ĨĞƚĂůĚĞĂƚŚŽĐĐƵƌƐƐŝŶĐĞɲͲŐůŽďŝŶƐĂƌĞƌĞƋƵŝƌĞĚĨŽƌ,ď&ƐǇŶƚŚĞƐŝƐ͕ŵŽƐƚƐĞǀĞƌĞĂŶĚůĞƚŚĂůĚŝƐĞĂƐĞdŚĞ all four loci deleted

ŵŽŶŽǌǇŐŽƵƐƐƚĂƚĞĨŽƌƚŚĞɲͲƚŚĂůĂƐƐĞŵŝĂ;ŚǇĚƌŽƉƐĨĞƚĂůŝƐͿĐĂƵƐĞƐƚŽƚĂůĂďƐĞŶĐĞŽĨɲͲŐůŽďŝŶƐǇŶƚŚĞƐŝƐ͘
EŽƉŚǇƐŝŽůŽŐŝĐĂůůǇƵƐĞĨƵůŚĞŵŽŐůŽďŝŶŝƐƉƌŽĚƵĐĞĚďĞǇŽŶĚƚŚĞĞŵďƌǇŽŶŝĐƐƚĂŐĞ͘ǆĐĞƐƐɶͲŐůŽďŝŶĨŽƌŵƐ
ƚĞƚƌĂŵĞƌƐĐĂůůĞĚ,ďďĂƌƚƐ;ɶϰͿǁŚŝĐŚŚĂƐĂǀĞƌǇŚŝŐŚŽǆǇŐĞŶĂĨĨŝŶŝƚǇ͘/ƚĚĞůŝǀĞƌƐĂůŵŽƐƚŶŽKϮƚŽĨĞƚĂů
tissues, causing tissue asphyxia, edema (hydrops fetals), congestive heart failure, and death in utero.
ɴƚŚĂůĂƐƐĞŵŝĂ Hypochromia and microcytoisis (resemble RBCs found in severe Iron deficiency anemia) characterize ɴͲŐůŽďŝŶŐĞŶĞŚĂƐƚǁŽĐŽƉŝĞƐ͕ŽŶĞŽŶĞĂĐŚ ^ŝŶĐĞɴͲŐůŽďŝŶŝƐƌĞƋƵŝƌĞĚĨŽƌ,ď͕ŝƚŵĂŶŝĨĞƐƚƐĐůŝŶŝĐĂůůǇ
ĂůůĨŽƌŵƐŽĨɴͲƚŚĂůĂƐƐĞŵŝĂďĞĐĂƵƐĞŽĨƚŚĞƌĞĚƵĐĞĚĂŵŽƵŶƚƐŽĨŚĞŵŽŐůŽďŝŶƚĞƚƌĂŵĞƌƐ͘DĂŶǇĞůůŝƉƚŝĐĂů chromosome 11. If one gene is defective, it leads to several months after birth.
ĂŶĚƚĞĂƌĚƌŽƉͲƐŚĂƉĞĚZƐĂƌĞĂůƐŽŶŽƚĞĚ͘/ŶŚĞƚĞƌŽǌǇŐŽƚĞƐ;ɴͲƚŚĂůĂƐƐĞŵŝĂƚƌĂŝƚͿ͕ƚŚŝƐŝƐŽŶůǇ ɴͲƚŚĂůĂƐƐĞŵŝĂƚƌĂŝƚͬŵŝŶŽƌ͘/ĨďŽƚŚŐĞŶĞƐĂƌĞ
ĂďŶŽƌŵĂůŝƚǇƐĞĞŶ͕ĂŶĚĂŶĞŵŝĂŝƐŵŝŶŝŵĂů͘/ŶɴͲƚŚĂůĂƐƐĞŵŝĂŵĂũŽƌ͕ƵŶƉĂŝƌĞĚĂůƉŚĂŐůŽďŝŶƐĂĐĐƵŵƵůĂƚĞ defective, it leads to ɴͲƚŚĂůĂƐƐĞŵŝĂŵĂũŽƌ;ŽŽůĞǇ
and form toxic inclusion bodies. Toxic inclusion bodies kill proerythroblasts and reduces RBC life span anemia)
producing severe hemolytic anemia. Massive bone marrow expansion deranges growth an
development. Increased erythropoietin leads to extramedullary erythropoiesis (spleen an liver)
leading to "chipmunk" facies and pathological fractures (kidney senses tissue hypoxia > kidney
stimulates erythropoietin > increased RBC synthesis > doesn't allow RBC's enough time to mature >
increased reticulocytes in blood > bone marrow becomes overactive > widening of bone marrow >
thinner cortical bone > pathological fractures). Hemolytic anemia causes hepatosplenomegaly, leg
ulcers, gallstones, an high output congestive heart failure. The conscription of caloric resources to
support the erythropoiesis leads to inanition, susceptibility to infection, endocrine dysfunction and in
most severe cases death in first decade of life. Chronic transfusions with RBCs improve oxygen
delivery, suppress the excessive ineffective erythropoiesis, and prolong life, but the inevitable side
effects, notably iron overload, usually prove fatal by age 30 :(.
Methemogobinemia Methemoglobinemias are characterized by "chocolate cyanosis" and chocolate-‐colored blood. Oxidation of Fe2+ (ferrous) of heme component of left shift on oxygen dissociation curve.
Symptoms are related to tissue hypoxia-‐anxiety, headache, dyspnea in rare cases coma and death. Hemoglobin to Fe3+ (ferric) state, which cannot bind
Treatment is use of methylene blue which reduces Fe3+ to Fe2+. oxygen. Oxidation may be caused by certain drugs
such as nitrates or endogenous products like reactive
oxygen species(increased by various stress).
Oxidation may also be because of inherited defect in
NADPH-‐cytochrome b5 reductase which is
responsible for the conversion of methemoglobin
(Fe3+) to hemoglobin (Fe2+)
DISORDERS OF FIBROUS PROTEINS

collagen synthesis (OVERVIEW) ZŝďŽƐŽŵĞƐŽŶZZƐǇŶƚŚĞƐŝǌĞƉƌĞͲƉƌŽͲɲͲĐŚĂŝŶǁŝƚŚƐŝŐŶĂůƐĞƋƵĞŶĐĞ͘WƌĞͲƉƌŽͲɲͲĐŚĂŝŶĞŶƚĞƌƐŝŶƚŽůƵŵĞŶŽĨZZǁŚĞƌĞƐŝŐŶĂůƐĞƋƵĞŶĐĞŝƐĐůŝƉƉĞĚ;ƉƌŽͲɲͲĐŚĂŝŶͿ͕ƐŽŵĞŽĨƚŚĞƉƌŽůŝŶĞĂŶĚůǇƐŝŶĞŚǇĚƌŽǆǇůĂƚŝŽŶŽĐĐƵƌƐ;ƉƌŽůǇů
ĂŶĚůǇƐǇůŚǇĚƌŽǆǇůĂƐĞŶĞĞĚǀŝƚĐͿ͘^Ͳ^ĚŝƐƵůĨŝĚĞďŽŶĚĨŽƌŵĂƚŝŽŶďĞƚǁĞĞŶƚŚĞƉƌŽͲɲͲĐŚĂŝŶƐƚĂƌƚƐĨƌŽŵƚŚĞĐͲƚĞƌŵŝŶƵƐƚŽǁĂƌĚƐŶͲƚĞƌŵŝŶƵƐ;ǁŚŝĐŚŝŶŝƚŝĂƚĞƐƚŚĞǁŝŶĚŝŶŐƉƌŽĐĞƐƐŽĨƚƌŝƉůĞŚĞůŝǆĨŽƌŵĂƚŝŽŶͿƚŽƉƌŽĚƵĐĞ
procollagen. Procollagen moves to golgi (processing of oligosaccharide chains). Procollagen loaded into vesicles and are exocytosed into extracellular matrix. Amino-‐and carboy-‐terminal propeptidases cleave n and c-‐
terminal propetides converting procollagen to tropocollagen. Tropocollagen undergo cross-‐linking (schiff base formation and aldol condensation) to form mature collagen (lysyl oxidase cross links, needs copper)
Osteogenesis imperfecta (OI), brittle bone Collagen-‐containing helix mutations can form insoluble aggregates in the ER that are degraded ŵƵƚĂƚŝŽŶƐŝŶĞŝƚŚĞƌƉƌŽɲϮĐŚĂŝŶŐĞŶĞŽĨƚǇƉĞϭ Substitution of an amino acid with a bulky side chain for one
disease, lobstein syndrome ('protein suicide'). The central feature of OI is a severe decrease in bone mass that makes bones procollagen (COL1A1 and COL1A2 genes), most of the glycine residues that appear as every third amino acid
brittle. The appearance of "popcorn-‐like" deposits of mineral in x-‐rays of the ends of long bones is an commonly single base substitutions. in triple helix (more steric hindrance that creates a bulge in
ominous sign. the disorder is frequently associated with blue sclerae. Dentinogenesis imerfecta, the collagen complex). These mutations compromise the
teeth may have characteristic amber, yellowish brown, or translucent bluish gray color because of a structural integrity of the triple helix, causing disruption to
deficiency of dentin that is rich in type one collagen. Progressive hearing loss, the loss can be helix folding, retention of the mutant trimers in the ER.
conductive, sensorineural or mixed, and varies in severity. positive family history.
Elhers-‐Danlos syndrome (EDS) EDS most typically affects the joints skin, and blood vessels. EDS is characterized by hyperelasticity of Classic (EDS I-‐ severe and EDS II-‐mild); mutation in
the skin and hypermobile joints (more prone for dislocation). Ligament and joint changes: Laity and COL5A and COLD5A2(type 5 collagen), COL1A1 and
hypermobility of joints vary from mild to unreducible dislocations of hips and other large joints. Skin: COL1A2 (type 1 collagen). Hypermobile (EDS III):
Skin changes vary from thin and velvety to skin that is either dramatically hyperextensible(rubber mutation in TNXB gene which encodes tenascin X
person syndrome) or easily torn or scarred. Patients with classical EDS develop characteristic (minor component of connective tissue that appears
"cigarette-‐paper" scars. easy bruisability occurs in several types EDS. Mitral valve prolapse and to regulate the assembly of collagen fibers).
hernias, mild to moderate scoliosis, and degenerative arthritis is also seen in EDS. Vascular (type III) is Vascular (EDS IV): mutation in COL3A1 (type III
considered one of the more serious forms because blood vessels and organs are more prone for collagen).
tearing. Many Patients with EDS type IV express a characteristic facial appearance (large eyes, small
chin, thin nose and lips, lobeless ears), have a small stature with a slim build, an typically have thin,
pale, translucent skin (veins visible in chest and abdomen)
Scurvy skin changes with roughness, easy bruising and petechia (small hemorrhage beneath skin), gum Ascorbic acid deficiency (vit C) Ascorbic acid is required as coenzyme for prolyl hydroxylase
bleeding, loosening of teeth poor wound healing. Defective collagen fibrillogenesis impairss wound and lysyl hydroxylase in collagen formation. Hydroxyproline
healing fragile capillaries, resulting in abnormal bleeding. and hydroxylysine are important for stabilizing collagen b
cross linking the propeptides in collagen.
Menkes, copper transport disease, steely hair Low serum Cu levels with deposition of Cu in intestinal cells. Decreased activity of Cu dependent lysyl X linked defect in copper binding P type ATPase
disease, kinky hair disease oxidase leads to defective collagen cross linking. Characterized by sparse and coarse brittle hair, (ATP7A mutation) in intestinal cells.
growth failure, and deterioration of the nervous system.
Alpha1 Antitrypsin (A1AT) efficiency Severe A1AT deficiency causes panacinar emphysema or COPD in adult life in may people, especially autosomal recessive , decreased A1AT activity in the A1AT binds to target proteases (e.g. elastase) by binding the
those exposed to cigarette smoke. Cigarette smoke directly inactivates A1AT by oxidizing essential blood and lungs and deposition of excessive methionine residue.
methionine residues to sulfoxide forms, decreasing the enzyme activity by a factor of 2000. A1AT also abnormal A1AT protein in liver cells.
causes impaired liver function in some patients andd may lead to cirrhosis and liver failure. Symptoms
include shortness of breath, wheezing, and rhonchi. Patients may develop emphysema during their
thirties/forties even without a history of significant smoking. Treatment is avoiding damaging
inhalants, IV infusions of A1AT, liver and lung transplantations. A1AT deficiency is the leading cause of
liver transplantation in newborns.
Marfans Syndrome Triad of long limbs, dislocated lenses and aortic root dilation is generally sufficient to make diagnosis. inherited as a dominant trait, by a gene called FBN1, The fibrillin-‐1 protein is essential for the proper formation of
Skeletal system: arachnodactyly, disproportionate long limbs, scoliosis, pectus excavatum and which encodes a connective protein called fibrillin-‐1. the extracellular matrix including the biogenesis and
carinatum, joint flexibility, unexplained stretch marks. Eyes: superotemporal subluxation of the mainenance of elastic fibers. Fibrillin-‐1 directly binds a laten
crystalline lens in one or both eyes (ectopia lentis) in 80% of patients. Cardiovascular: the signs of form of TGFɴ keeping it sequestered and unable to exert its
regurgitation from prolapse of the mitral or aortic valves (which control the flow of blood through the biological activity. Reduced levels of fibrillin-‐1 thus affects normal
heart) result from cystic medial degeneration of the valves. Lungs: Marfans syndrome is a risk factor ĨƵŶĐƚŝŽŶŽĨĞůĂƐƚŝŶĂŶĚĂůůŽǁd'&ɴůĞǀĞůƐƚŽƌŝƐĞ͘ůƚŚŽƵŐŚŝƚŝƐŶŽƚ
for spontaneous pneumothorax (air in pleural cavity). The most serious signs and symptoms ƉƌŽǀĞŶŚŽǁĞůĞǀĂƚĞĚd'&ɴůĞǀĞůƐĂƌĞƌĞƐƉŽŶƐŝďůĞĨŽƌƚŚĞƐƉĞĐŝĨŝĐ
pathology seen with the disease, an inflammatory reaction releasing
associated with Marfan syndrome involve the CV system. Undue fatigue, SOB, heart palpitations,
proteases that slowly degrade the elastin fibers and other
racing heartbeats, or Angina Pectoris with pain radiating to the back, shoulder, or arm. Cold arms,
components of ECM is known to occur.
hands and feet can also be linked to Marfan's because of inadequate circulation. A heart murmur,
abnormal ECG, and symptoms of angina can lead to further investigation. Patients may be at risk of
Aortic dissection, which may be fatal even if rapidly treated.
VITAMIN / DEFICIENCIES
Fat Soluble vitamins: A, D, E, K > lipophilic > stays in the body for a long time. Anything that interrupts absorption of fats will affect these guys too, think cystic fibrosis, abetalipoproteinemia, gall stones, biliary insufficiency, etal. Since they stay in the body for a long
time, deficiencies arise when there is a chronic issue, and also will get toxicity with excess. Water soluble vitamins: B's and C. Toxicity is very uncommon because they are water soluble > excess is lost in urination.
ŐŽƚƚĂĂĚĚǀŝƚĚĞĨŝĐŝĞŶĐŝĞƐ͙
Arsenate poisoning competes with inorganic phosphate in glycolysis. 0 net ATP gain.
Pyruvate Kinase Deficiency 2nd most common enzyme deficiency leading to hemolytic anemia.
Pyruvate Dehydrogenase Deficiency (E1) although rare, but is the most common cause of congenital lactic acidosis. The brain is deprived of x linked PDH deficiency(E1 subunit, thiamine can't make Acetyl CoA > low ATP production > therefore
energy because lack of acetyl CoA, sensitive to acidosis, neurodegeneration, muscle spasticity, and cofactor). excess pyruvate is converted into lactate > lactic acidosis etc
early death (lack of ATP = no breaking of actin/myosin cross bridges = rigor mortis)
Leigh Syndrome subacute necrotizing encephalomyelopathy, causes congenital lactic acidosis, neurodegeneration, mutation in the PDH complex, ETC, or ATP synthase defect in the mitochondrial ATP production, brain deprived
muscle spasticity and early death(rigors mortis) of energy because of lack of acetyl CoA, sensitive to acidosis
which increases the conversion of pyruvate to lactic acid,
Xlinked condition (found in mostly males than females)
Niacin/ Thiamine deficiency causes serious central nervous system problems (wernicke-‐karsakoff syndrome/dementia) PDH complex is inactive Brain is unable to produce sufficient ATP
Glucose-‐6-‐phosphate dehydrogenase Persons with G6DGH deficiency are normally asymptomatic unless triggered by (oxidants) ingestion of x linked recessive deficiency of G6PDH, commonly NADPH is not synthesized, hence will not maintain
(G6PDH) deficiency -‐ (favism) drugs like antimalarial drugs, sulfonamides, certain analgesics, few non-‐sulfa antibiotics, chemicals like manifested in males. Commonly seen in regions of glutathione in reduced state (GSH, antioxidant). H202
thiazolesulfone, methylene blue, and naphthalene. RBC's are more susceptible to oxidative damage Africa, middle east, and south Asia (commonly (hydrogen peroxide) will increase and generate ROS >
because they contain large amount of oxygen, and hence generate more ROS. RBC lysis occurs referred to as Mediterranean region) damage to RBC membranes. G6PDH deficiency protects
because of lipid peroxidation and membrane damage, leading to chronic hemolytic anemia, increased against malaria b/c of decreased RBC lifespan (heterozygote
bilirubin and jaundice, presence of Heinz bodies and bite cells, normal levels of 2,3-‐BPG. May see advantage in females). increased ROS in RBC's damage
ƉƌŽůŽŶŐĞĚŶĞŽŶĂƚĂůũĂƵŶĚŝĐĞ;хϭϬĚĂǇƐͿ͕ƉŽƐƐŝďůĞůĞĂĚŝŶŐƚŽŬĞƌŶŝĐƚĞƌƵƐ;шϮϱŵŐͬĚ>͕ŶĞƵƌŽůŽŐŝĐĂů plasmodium (parasite in malaria). Tests for diagnosis
probs). Hemolytic crises in response to, illness/infections, drugs or chemicals (some listed above), include: blood and reticulocyte counts (look for increased
foods like broad/fava beans, and diabetic ketoacidosis. Very Severe crisis can cause acute renal reticulocytes), liver enzymes to exclude other causes of
failure. jaundice, LDH (elevated in hemolysis and marker of
hemolytic severity), FREE haptoglobin (decreased in
hemolysis. binds to Hb to prevent excretion = increased
BOUND haptoglobin), and a "direct antiglobullin test"
(coombs test)-‐ should be negative as hemolysis is not
immune-‐mediated. Beutler fluorescent spot test is a rapid
and inexpensive test that virtually IDs NADPH produced by
G6PDH under UV light. decreased fluorescence confirms
deficiency (+ve test). it can be falsely negative in patients
who are actively hemolysing, so test is done 2-‐3 weeks after
hemolytic episode.
Essential fructosuria asymptomatic -‐ Fructose in urine (fructosuria) fructokinase deficiency fructose cannot be converted to fructose-‐1-‐phosphate.
Benign condition, no renal threshold for fructose
Hereditary fructose intolerance symptoms appear when fruit juices are introduced for the first time (case stem when baby is weaned aldolase B deficiency. aldolase b normally converts deficiency decreases availability of inorganic phosphate
off milk, or when fructose/sucrose is introduced into diet). Decreased ATPs slow down glycogenolysis Fructose-‐1-‐P into glyceraldehyde and DHAP. (because fructokinase is uses ATP in previous step via
and gluconeogenesis leading to hypoglycemia and its signs. In the absence of Pi, AMP is degraded, fructokinase in metabolism) leads decreased ATP
causing hyperuricemia. Decreased oxidative phosphorylation diverts pyruvate toward lactate production.
formation leading to lactic acidosis.
Polyol Pathway Effect of hyperglycemia on polyol pathway. Insulin independent transport of glucose into cells of lens, reduction of sugar molecule into polyol. Glucose is sorbitol accumulates n uncontrolled diabetes mellitus and
retina, Schwann cells of peripheral nerves, liver, kidney,, placenta, RBC, and cells of ovaries an seminal oxidized into sorbitol (osmotically active) by aldose contributes to diabetes complications. The activity of
vesicles allows for the entry of large amounts of glucose. Accumulation of glucose and adequate reductase (NOT A DEFICIENCY). Aldose reductase aldose reductase can lead to major problems in the lens,
supply of NADPH causes aldolase reductase to convert glucose > sorbitol, and galactose > galactitol. (REQUIRES NADPH) is found in many tissues, nerves, kidney, retina where it is responsible for the
Excess sorbitol trapped inside the cell as it cannot efficiently pass through the membrane, exacerbated including the lens, retina, Schwann cells of peripheral production of sorbitol from glucose and galactitol from
in tissues where sorbitol dehydrogenase is low or absent, for example, in retina, lens, kidney, and nerves, liver, kidney, placenta, RBC and cells of galactose. When the concentration of glucose or galactose
nerve cells. Accumulation of sorbitol in these tissues causes osmotic swelling as a result of water ovaries and seminal vesicles. is elevated in the blood, their respective sugar alcohols are
retention. Some of the complications of diabetes are attributed, in part, to this phenomenon, synthesized in these tissues more rapidly than removed,
including cataract formation, peripheral neuropathy, and microvascular problems leading to resulting in increased osmotic pressure within these cells
nephropathy and retinopathy.
Non Classical Galactosemia accumulation of galactitol (via aldose reductase) in lens leads to development of cataracts. Mental galactokinase deficiency. Galactokinase uses ATP to galactitol is osmotically active (like sorbitol made via aldose
retardation is NOT seen. Treatment is dietary restriction of milk products. convert galactose into galactose-‐1-‐phosphate. reductase that needs NADPH)
Classical Galactosemia accumulation of galactitol in lense in lens leads to development of cataracts. Depletion of inorganic deficiency of galatose-‐1-‐phosphate uridyl transferase galactose and galactose-‐1-‐phosphate accumulates in cells.
phosphate leads to liver damage (hyperbilirubinemia, jaundice), and damage to central neurons enzyme(GALT). Galactose is converted to osmotically active galactitol by
(MENTAL RETARDATION) aldose reductase. Accumulation of galactose-‐1-‐P depletes
iP(inorganic phosphate in cells)
GLYCOGEN STORAGE DISEASES

Von Gierk's disease (Type 1 GSD) Doll-‐like face with fatty cheeks. Relatively thin extremities and short stature. A protuberant abdomen Most common of all glycogen storage diseases (GSD) clinical manifestations result from inability to maintain an
that is due to massive hepatomegaly (increased glycogen synthesis with decreased degradation). is due to a deficiency of glucose-‐6-‐phosphatase. GSD adequate blood glucose level during the post-‐absorptive
hepatocytes are distended by glycogen and fat with large and prominent lipid vacuoles. enlarged Ia results from mutations o G6PC (ER), the gene for ŚŽƵƌƐŽĨƚŚĞĚĂǇ͘ј'ϲWŵĞĂŶƐŵŽƌĞƐƵďƐƚƌĂƚĞĨŽƌWWWїј
kidneys, but normal spleen/heart size. lactic acidosis, hyperuricemia, hyperlipidemia, glucose-‐6-‐phosphatase. GSD Ib results from reductive biosynthesis and purine synthesis. Excess purine
hyperventilation, and seizures (severe fasting hypoglycemia). In GSD Ib, bleeding and infection risk mutations of the gene for T1 protein (translocase), ĚĞŐƌĂĚĂƚŝŽŶůĞĂĚƐƚŽŚǇƉĞƌƵƌŝĐŵŝĂ͘ј'ϲWŝŶŚŝďŝƚƐ>,с
from neutropenia and neutrophil dysfunction (neutrophils can use glucose from RER (T1 problem, G6P the G6P transporter in ER. more lactate and less pyruvate formation. hypoglycemia
not getting into RER from reduced gluconeogenesis causes more lactic acid
ĨŽƌŵĂƚŝŽŶƚŽŵĞĞƚĞŶĞƌŐǇŶĞĞĚƐ͘јŐůƵĐĂŐŽŶĨƌŽŵ
ŚǇƉŽŐůǇĐĞŵŝĂхĂĚŝƉŽƐĞĚĞŐƌĂĚĂƚŝŽŶĂŶĚјŬĞƚŽŶĞďŽĚǇ
ĨŽƌŵĂƚŝŽŶ͘KǀĞƌĂůůŵĞƚĂďŽůŝĐĂĐŝĚŽƐŝƐхјĐŽŵƉĞŶƐĂƚŽƌǇ
respiration. Lactate competes with uric acid for excretion in
renal tubules. (does this explain enlarged kidneys?)
Pompe's Disease (Type II GSD) life threatening disease affecting all parts of the body. Forms: infantile, late onset, and adult form. mutation in the GAA gene which codes for acid alpha accumulation of glycogen in lysosomes of muscle and other
Infantile is most severe, death by age 1. Severe muscle weakness, resulting in an overall "floppy baby" ŐůƵĐŽƐŝĚĂƐĞ͘ĞĨŝĐŝĞŶĐǇŽĨůǇƐŽƐŽŵĂůĂĐŝĚɲͲϭ͕ϰŽƌɲͲ cells. Build up of glycogen causes lysosomes to expand until
appearance due to poor muscle tone. Head lag, legs fall outward into a "frog-‐like" position because of 1,6 glucosidase or both (acid maltase). they take up so much space that the muscle/cell is
weak muscles. Failure to meet developmental milestones such as rolling over, sitting up, crawling and damaged. Glycogen begins to leak out of lysosomes and
walking, or loss of abilities already achieved. Heart problems: severe cardiomegaly due to glycogen cause more damage to the surrounding muscle cells. this
accumulation, heart rhythm changes, heart failure, often results in early death. Breathing/Respiratory leads to muscle weakness that gets worse with time.
problems: difficulty breathing and respiratory infections due to weak diaphragm not contracting Currently no definitive therapy. Myozyme or Lumizyme
properly, difficult to breath deeply enough to clear mucus out of lungs. Infants eventually need to use (alglucosidase alfa) is a lysosomal glycogen-‐specific enzyme
a ventilator. Feeding and Digestion problems: enlarged and protruding tongue, muscle weakness, indicated for use in patients with Pompes Disease (enzyme
difficulty in feeding, low intestinal movements. Muscle biopsy: PAS positive (glycogen). EMG reveals replacement therapy).
myopathic features with irritability of muscle fibers and pseuomotonic discharges. Diagnosis by
ƌĞĚƵĐĞĚĂĐŝĚɲͲŐůƵĐŽƐŝĚĂƐĞĂĐƚŝǀŝƚǇŝŶŵƵƐĐůĞŽƌĐƵůƚƵƌĞĚĨŝďƌŽďůĂƐƚƐ͘
McArdles's disease two types of activity tend to cause symptoms (1) brief exercise of great intensity, such as sprinting or autosomal recessive, deficiency of muscle ŵƵƐĐůĞŐůǇĐŽŐĞŶĚŽĞƐŶ͛ƚďƌĞĂŬĚŽǁŶ͘DƵƐĐůĞŵĞŵďƌĂŶĞƐ
carrying heavy loads and (2) less intense but sustained activity such as climbing stairs or walking uphill. phosphorylase. Muscle energy disorder as the break when patient exercises > myoglobin + cellular
Most patients present with myoglobinuria after exercise (burgundy colored urine). Intense enzyme deficiency limits ATP generation by components escape > increased ammonia ions, inosine,
myoglobinuria may lea to acute renal failure (blocks glomerulus/filtration). serum creatine kinase (CK-‐ glycogenolysis and results in glycogen accumulation. hypoxanthine > uric acid (purine end product). Look at
MM) is usually elevated at rest, and increases after exercise. Exercise also increases blood ammonia, physio notes to add on stuffs*REMINDER
inosine, hypoxanthine, and uric acid. Diagnosis: Ischemic exercise test (squeezing the rubber ball with
P cuff tied to arm) -‐ lack of an increase in blood lactate and exaggerated blood ammonia elevations,
suggests a defect in the conversion of glycogen or glucose to lactate. definitive diagnosis by enzymatic
assay or mutation analysis of the myophosphorylase gene. Avoidance of strenuous exercise can
prevent major episodes of rhabdomyolysis (break down of skele muscle).
Hers' disease High glycogen content in liver, tendency toward (fasting) hypoglycemia. Hepatomegaly Deficiency of liver phosphorylase ůŝǀĞƌŐůǇĐŽŐĞŶĚĞŐƌĂĚĂƚŝŽŶĚŽĞƐŶ͛ƚŚĂƉƉĞŶ͘ĂŶΖƚŵĂŝŶƚĂŝŶ
fasting blood sugar > hypoglycemia
Tauri's Disease All the same symptoms as McArdle's with the addition of hemolysis and jaundice defect/deficiency of PFK-‐1 in muscle and the hemolysis will lead it to increased bilirubin levels
erythrocytes. Prevalent in Ashkenazi Jews and
Japanese populations
Anderson's Disease, Amyloplectinosis accumulation of glycogen with long outer branches with very few branch points. Failure to thrive, deficiency in branching enzyme 4:6 transferase
hypotonia, hepatomegaly, splenomegaly, progressive liver cirrhosis and failure. Death due to cardiac enzyme
or liver failure in first year of life
Cori's Disease, Forbes Disease, Limit accumulation of glycogen with short outer branches. Hepatomegaly, growth retardation, muscle debranching enzyme deficiency 1:6 alpha
Dextrinosis weakness, hypoglycemia. glucosidase, 4:4 transferase.
MUCOPOLYSACCHARIDOSES / LYSOSOMAL STORAGE DISEASES

Hurlers Syndrome (MPS I) progressive disorder, manifesting with multiple organ and tissue involvement (like other lysosomal a-‐L-‐iduronidase deficiency. Accumulation of HOW TO DIFFERENTIATE BETWEEN HURLERS AND HUNTERS.
storage diseases), leading to death in early childhood. Early symptoms: hepatosplenomegaly, coarse dermatan sulfate and heparan sulfate Hurlers has bilateral corneal clouding. Severe dementia or
facial features and an enlarged tongue (patient my keep mouth open because of this). Hearing loss learning difficulties/mental retardation (generally not seen
due to otitis media, caused by build up of GAGs in middle ear. Progressive learning difficulties and ŝŶŚƵƌůĞƌƐ͕ŽƌŵŝůĚĞƌŝŶĐŽŵƉĂƌŝƐŽŶͿ͘hƐƵĂůůǇĚŽŶ͛ƚƐĞĞ
corneal clouding. Most Hurlers infants succumb to cardiomyopathy. Umbilical hernia, depressed cardiomyopathy in Hunters.
nasal bridge, shortness of neck etc..
Hunters (MPS II) Severely affected patients share the same clinical signs and symptoms of patients, but cornea remains X-‐linked. Iduronate sulfatase deficiency,
clear. Only mild mental retardation if any, cardiomyopathy RARE. Prominent Mongolian blue spots accumulation of dermatan sulfate and heparan
(lower back), and character papular rash (interscapular space/area). sulfate.
Maroteaux-‐Lamy Disease (MPS VII) coarse facial features (dysmorphic) N-‐acetylgalactosamine sulfatase with the
accumulation of Dermatan sulfate
Sanfilippo Disorder (MPS III) physical defects are relatively mild, while the mental retardation is severe. (3) phases: (1) usually Accumulation of Heparan sulfate in blood and urine.
before diagnosis, consists of developmental delay alone, often primarily affecting speech. (2; age 3-‐11) there is four different types of sanfilippo disorders
the illness is dominated by a severe behavioral disturbance, characterized by hyperactivity, challenging and each one has a different enzyme deficiency
behavior and profound sleep disturbance. (3; usually after first decade) is associated with continuing ;ĚŽŶ͛ƚŶĞĞĚƚŽŬŶŽǁƐƉĞĐŝĨŝĐĞŶǌǇŵĞƐͿ
loss of skills and slow deterioration into a vegetative state, death usually occurring in the early third
decade
I-‐Cell Disease (inclusion cell disease) It presents with severe motor and cognitive retardation. Skeletal abnormalities (kyphoscoliosis, Mutation in cis-‐golgi located GLcNAc
dwarfism), hepatosplenomegaly, corneal clouding, repeated respiratory infection, death by first phosphotransferase. Can't attach mannose-‐6-‐p tag
decade. Stunted growth, small orbits, proptotic eyes, full and prominent mouth caused by gingival to target stuff to lysozomes. Default pathway will be
hypertrophy, short and broad hands, stiffening of small and joints, prominent abdomen with umbilical to send these enzymes outside of the cell = increase
hernia, and limited extension of hips and knee. EM of blood cells reveals large number of cytoplasmic levels of lysozomal enzymes in plasma
vacuoles, some of which have no visible content. Can stain these inclusion bodies with Sudan black B
for lipids and PAS for glycogen/glycoproteins.
Mucolipodosis Type I (sialidosis) L excessive swelling all over the body at birth, born with coarse facial features such as flat nasal bridge, Defect in the sialidase enzyme which is responsible sialic acid is accumulated in neurons, bone marrow and
puffy eyelids, enlargement of gums excessive tongue size (macroglossia). May have myoclonus, for the removal of sialic acid (NANA) in glycoprotein. various other cells.
hypotonia, ataxia, cherry red macula, hip dislocation, hepatosplenomegaly, tremors and seizures and
death occurs by 1 yr.
GPI LINKAGES
Acetylcholinesterase red cell membrane
Alkaline Phosphatase intestinal, placental
Decay-‐accelerating factor red cell membrane (DAF + CD59, stops complement from pwning RBCs)
5'-‐Nucleotidase T lymphocytes
Paroxysmal Nocturnal Hemoglobinuria Hemoglobinuria resulting from hemolysis of RBCs due to slight drop in pH during sleep (drop in PH defects of GPI anchors. Mutation in PIG-‐A gene of In this disease decay accelerating factor and CD59 are not
activates complement system). Diagnosis by Ham's test: Defective RBCs lyse at pH 6.2, but not normal certain hematopoietic cells. properly anchored to RBCs b/c of faulty GPI linkage.
RBCs Without these proteins linked to cell surface, complement
can lyse RBC's leading to hemoglobinuria.
Infant Respiratory Distress Syndrome (IRDS) tachypnea, tachycardia, chest wall retractions (recession), expiratory grunting, flaring of the nostrils Insufficiency of the surfactant production and surfactant helps prevent collapse of the terminal air-‐spaces
aka Neonatal RDS. and cyanosis during breathing efforts structural immaturity in the lungs. Dipamitoryl throughout the normal cycle of inhalation and exhalation.
lecithin (phosphatidyl choline) deficiency Surfactant tension is responsible for 2/3 of the elastic recoil.
Membrane will become like hyaline because of production
of surfactant (aka -‐ hyaline membrane disease). The
incidence decreases with advancing gestational age 50% at
26-‐28 weeks to about 25% at 30-‐31 weeks
Cholesterol Gallstones ( cholelithiasis) other than high cholesterol two other factors are important in causing gallstones 1. how often and increased levels of hormone estrogen as a result of too much cholesterol and not enough bile salts to solubilize
how well the gallbladder contracts 2. presence of proteins in the bile which forms "the nidus" which pregnancy, hormone therapy, or the use of them, cholesterol becomes precipitate and forms gallstones.
initiates gallstone formation. Increased risk factors are female sex, overweight, age near or above 40 combined (estrogen containing) forms of hormonal Small material will become nidus where the cholesterol will
(fatty female at forty) LARGELY ASYMPTOMATIC. feeling of abdominal fullness (distention), flatulence, contraceptives, these may increase levels of build and this will form stones.
decreased satiety, and some non-‐specific abdominal symptoms, acute cholecytitis -‐ causes fever cholesterol in bile and also decrease gallbladder
(inflammatory condition characterized by retention of bile in the gallbladder and often secondary movement resulting in gallstone formation
infection by intestinal microorganisms, predominantly Escherichia coli and Bacteroides species).
choledocholithiasis presence of stones in bile duct which may lead to lipid malabsorption leading to
deficiency of essential fatty acids and vit ADKE. (this may lead to jaundice because bilirubin build up
and will be excreted in the feces)
Pyruvate carboxylase deficiency hypoglycemia, convulsions pyruvate carboxylase enzyme (ABC enzyme, needs important for gluconeogenesis.
ATP, biotin, CO2, and Mg). Normally reversibly
converts pyruvate into Oxaloacetate
Inhibitors Site of Action Type

Rotenone complex 1 electron transport
Antimycin A complex 3 electron transport
Cyanide complex 4 electron transport can get cyanide from consuming bitter almonds
Carbon Monoxide complex 4 electron transport
Azide complex 4 electron transport
Thermogenin Proton carrier Uncoupler
2,4 Dinitrophenol Proton carrier Uncoupler
Thyroid hormone Uncoupler
Aspirin (and other sialcylates?) Uncoupler
Oligomycin ATP synthase ATP synthase inhibitor
Arsenic binds lipoic acid in PDH and alpha ketoglutarate slowing down TCA (blocks E2 subunit). Also competes
with inorganic phosphate in glycolysis (rbc's sole source of ATP)
stuff that stops electron transport really damages the cell. Cellswill run out of ATP. Start doing anerobic glycolysis. Pyurvate > Lactate. Build up of lactic acid > acidosis. Cant maintain Na/K ATPase > ion
inbalance. Gonna have more sodium and water in the cell, causing swelling. Calcium also builds up in the cell. Calcium activates lysozomal enzymes > making the membrane leaky> mitocondrion leak
some cytochrome C > apoptosis.
ETC uncouplers > poke a hole in your inner mitochondrial membrane > protons leak out. Proton gradient is needed to capture free energy/make ATP, via ATP synthase. Still generate ATP, but uncouplers
will lose energy in the form of heat. TCA will speed up

DISORDERS OF LIPOPROTEIN METABOLISM (add a cell for lipid digestion/absorption? Maybe a cell for chylomicrons and other lipoproteins)
Abetalipoproteinemia Usually presents in early childhood with diarrhea and failure to thrive due to lipid malabsorption. Autosomal Recessive, loss-‐of-‐function mutation in Plasma levels of cholesterol and triglycerides are extremely
Most clinical manifestations result from defects in the absorption and transport of fat-‐soluble the gene coding for MTP (microsomal transfer low. Chilomicrons, VLDLs, and apoB are undetectable in
vitamins. Markedly deficient in Vit E, with moderate deficiency in Vit A and K. Characterized by (1) protein). A protein that transfers lipids to nascent plasma. Low levels of Fat soluble vitamins.
Spinocerebellar degeneration: loss of deep tendon reflexes, decreases distal lower extremity vibratory chylomicrons(intestine) and VLDLs (liver)
and proprioceptive sense, dysmetria, ataxia and development of spastic gait. (2) Progressive
pigmented retinopathy: decreased night and color vision followed by reductions in daytime visual
acuity and ultimately progressing to near blindness. (3) Acanthocytosis: refers to increase in the form
of red blood cells that have a spiked membrane, due to abnormal thorny projections.
Abetalipoproteinemia is often misdiagnosed as Friedrich's ataxia.
Familial hypobetalipoproteinemia (NOT FOR some patients show increased hepatic fat nonsense mutations in apoB100 low levels of plasma LDL-‐C, patients may be protected from
BLOCK EXAM) the development of atherosclerotic vascular diseases.
Familial Lipoprotein Lipase (LPL) deficiency Manifests in childhood with recurrent episodes of severe abdominal pain due to acute pancreatitis. deficiency of LPL, abnormal LPL, or apo C-‐II slow clearance of chylomicrons and VLDL leading to
(chylomicronemia syndromes) The fasting plasma is turbid, and if left at 4°C for a few hours, the chylomicrons float to the top and deficiency causing inactive LPL elevation of chylomicrons (predominantly) and VLDL. See
form a creamy supernatant. Fasting TAG levels are almost invariable > 1000 mg/dL. Physical ŝŶĐƌĞĂƐĞĚůĞǀĞůƐŽĨd'Ɛ͕ďĞĐĂƵƐĞƚŚĂƚ͛ƐǁŚĂƚĐŚǇůŽŵŝĐƌŽŶƐ
examination: lipemia retinalis (opalescent retinal blood vessels), eruptive xanthomas, and and VLDLs carry predominantly. (would we see a slight
hepatosplenomegaly resulting from the uptake of circulating chylomicrons by reiculoendothelial cells increase in cholesterol as well from VLDL?)
in the liver and spleen. For unknown reasons, some patients don't develop symptoms. Premature
atherosclerotic cardiovascular disease is not a general feature of familial chylomicronemia syndrome.
Familial hypercholesterolemia (FH) presents in childhood with cutaneous xanthomas. xanthomas can be found around the eyelids Autosomal codiminant disorder, caused by a large Total LDL-‐C levels are usually >500mg/dL, and can be higher
HOMOZYGOUS (xanthelasma palpebrarum), the outer margin of the iris (arcus senilis cornea), the buttochs, or form number of mutations (>900) in the LDL receptor than 1000mg/dL. Elevated levels of LDL-‐C are due to an
lumps in the tendons of hands, wrists, elbows, knees, or heels. Devastating complication of gene. Gene dose effect: Homozygotes show a more increase in the production of LDL from IDL, and a delayed
homozygous FH is accelerated atherosclerosis, which can reuslt in disability and death in childhood. severe phenotype than Heterozygotes. Higher catabolism of LDL from the blood. Patients with
Untreated, receptor-‐negative patients rarely survive past 2nd decade; patients with receptor-‐defective incidence in founder populations such as: Afrikaners, homozygous FH can be classified into two groups based on
LDL receptor have better prognosis but usually dev atherosclerotic vascular disease by age 30. Christian Lebanese, and French Canadians. A careful amount of LDL receptor activity measured in their skin
Combination therapy with an HMG-‐CoA reductase inhibitor, and a cholesterol absorption inhibitor family history should be taken, to help diagnosis. fibroblasts. receptor negative if <2% normal LDL receptor
sometimes results in relatively modest reductions in plasma LDL-‐C, but usually require additional lipid-‐ activity. receptor defective if 2-‐25% normal LDL receptor
lowering therapy. Since the liver is quantitatively the most important tissue for removing circulating activity
LDLs via the LDL receptor, liver transplantation is effective in decreasing plasma LDL-‐C levels.
Familial Hypercholesterolemia (FH) hypercholesterolemia from birth, although the disease is often not detected until adulthood. Family caused by the inheritance of one mutant LDL elevated levels of LDL-‐C, usually 200-‐400 mg/dL with normal
HETEROZYGOTE history is frequently positive for premature coronary atherosclerotic disease (CAD) on one side of the receptor gene. 1/500 persons worldwide. Mutations levels of triglyceride. Elevated because defective LDL
family. Corneal arcus, tendon xanthomas are present in 75% of patients, age of onset of coronary found in the LDL receptor can be in the signal receptor, can't internalize LDL and they accumulate in
atherosclerotic disease is highly variable. No definitive diagnostic test for heterozygous FH is sequence, or any region of the Receptor itself (ligand circulation.
available. Patients should be aggressively treated to lower plasma levels of LDL-‐C. Initiation of low-‐ binding, EGF precursor homology, O-‐linked sugars,
cholesterol, low fat diet is recommended, but almost all heterozygous FH patients require lipid-‐ Membrane spanning, and Cytoplasmic region).
lowering drug therapy. Statins, cholesterol absorption inhibitors, bile acid sequestrants, or nicotinic Mutations are found to be more common in the
acid are used as treatment. Patients who cannot be adequately controlled on combination drug ligand binding region, particularly on exon 4. 2nd
therapy are candidates for LDL apheresis. Untreated men have a ~50% chance of having a myocardial most common is the EGF precursor homology.
infarction before age 60.
Sitosterolemia Patients show elevated plasma levels of LDL cholesterol. they develop tendon xanthomas as well as autosomal recessive disease, due to mutations in ABCG5 and ABCG8 normally pump plant sterols into gut
premature athersclerosis. Also see episodes of hemolysis (how to differentiate from FH) due to ATP Binding Cassette (ABC) transporter family lumen, and bile. increased absorption of plan sterols in
incorporation of plant sterols in RBC membranes (hemolysis, expect to see jaundice). Diagnosis is (ABCG5 and ABCG8) intestine (normally usually <5%) and reduced transport of
confirmed by demonstrating and increase in the plasma level of sitosterol using gas chromatography. sterols into bile by the liver. This results in increased plasma
Reducing cholesterol in diet helps reduce symptoms and tissue levels of sitosterol and other plant sterols. The
trafficking of cholesterol is also impaired in sitosterolemia.
Familial Dysbetalipoproteinemia (FDBL) NOT usually presents in adulthood with xanthomas, premature coronary disease, and peripheral vascular due to genetic variations in apoE (E2, E3, E4) that mixed hyperlipidemia due to the accumulation of REMNANT
FOR BLOCK EXAM disease. Two distinctive types of xanthomsas; tuberoeruptive and palmar are seen in patients. interfere with its ability to bind lipoprotein lipoprotein particles. Elevated cholesterol and TAGs.
Patients with apoE4 have an increased incidence of late-‐onset Alzheimer's disease. in FDBL, the receptors. Majority with this disease are
plasma levels of cholesterol and TAGs are often elevated to a similar degree, the directly measured homozygous for the E2 allele
LDL-‐C is low, and the HDL-‐C is usually normal (in contrast to the low HDL-‐C usually seen in patients
with elevated TAG levels). Tx similar to FH. Alcohol consumption should be curtailed, HMG-‐CoA
reductase inhibitors, fibrates, niacin are generally effective.
Familial hypertriacylglycerolemia (FHTG) characterized by moderately elevated plasma triglycerides accompanied by more modest elevations in autosomal dominant disorder of unknown etiology. Elevated plasma levels of VLDL are due to increased
cholesterol (elevated VLDLs, and chylomicrons in severe cases). Increased intake of simple (~1 in 500). Like other Autosomal dominant production of VLDL, impaired catabolism of VLDL or a
carbohydrates, obesity, insulin resistance, alcohol use, and estrogen treatment, all increase VLDL diseases, identification of other first-‐degree relatives combination of these mechanisms.
synthesis, can exacerbate this syndrome. Diagnosis is made based on the history, triad of elevated with hypertriglyceridemia is useful in making the
plasma TAGs (250-‐1000 mg/dL), normal or slightly elevated cholesterol (<250 mg/dL), and reduced diagnosis.
HDL. Plasma LDL-‐C levels are generally not increased, and often reduced due to the defective
metabolism of TAG rich particles.
Familial Combined Hyperlipidemia(FCHL) NOT The presense of small, dense LDL particles (distinct from mature LDL-‐C). It is associated with most common inherited lipid disorder (1 in 200), moderate elevations in plasma triglycerides (VLDL) and
FOR THE BLOCK EXAM metabolic syndrome (insulin resistance, obesity, hypertension), and patients do NOT develop Autosomal Dominant cholesterol (LDL) and reduced plasma levels of HDL-‐C.
xanthomas. Approxmately 20% of patients who develop CHD under age 60 have FCHL. Can manifest Patients almost always have significantly elevated levels of
in childhood but is usually not fully expressed until adulthood. Treatment is similar to other apoB-‐100
hyperlipidemias (statins, cholestrol absorptions inhibitors, niacin etc)
ApoA-‐1 Deficiency NOT FOR THE BLOCK EXAM Development of corneal opacities and planar xanthomas. Premature CHD is generally seen in the deletion of ApoA-‐I results in the virtual absence of ApoA-‐I is required for LCAT function. Thus plasma and
apoA-‐I deficient patients. HDL tissue levels of free cholesterol are increased in this disease
Tangier Disease Cholesterol accumulation in the reticuloendothelial system, resulting in hepatosplenomegaly and Autosomal codominant. mutations in the gene HDL is rapidly cleared from the circulation. Low plasma HDL-‐
pathognomonic enlarged, grayish yellow or orange tonsils. Tangier disease is associated with encoding ABCA1 a cellular transporter that facilitates C levels (<5mg/dL) and extrememly low circulating levels of
increased risk of premature atherosclerotic disease. An intermittent peripheral neuropathy eflux of enesterified cholesterol and phospholipids apoA-‐1. ABCA1 plays a critical role in the generation and
(mononeuritis multiplex) or a sphingomyelia-‐like neurologic disorder can also be seen. Associated from cells to apoA-‐1. stabilization of mature HDL particles. Obligate
with increased risk of premature atherosclerotic disease, although not as great as might be heterozygotes for ABCA1 mutations have moderately
anticipated from decreased HDL. Patients also have low LDL-‐C, which may attenuate atherosclerotic reduced plasma HDL-‐C levels (15-‐30 mg/dL) and are also at
risk. Obligate heterozygotes. risk for premature CHD.
Familial lecithin:cholesterol acyltransferase plasma concentrations of cholesteryl esters and lysolecithin are low. Abnormal LDL (lipoprotin X) and Autosomal recessive mutations in the gene encoding the proportion of free cholesterol in circulating lipoproteins
(LCAT) deficiency ༢Ͳs>>ŝƐĨŽƵŶĚŝŶĐŝƌĐƵůĂƚŝŽŶ͘WƌŽŐƌĞƐƐŝǀĞĐŽƌŶĞĂůŽƉĂĐŝĨŝĐĂƚŝŽŶĚƵĞƚŽĚĞƉŽƐŝƚŝŽŶŽĨĨƌĞĞĐŚŽůĞƐƚĞƌŽů the plasma enzyme LCAT. Complete deficiency = in greatly increased (from 25% to over 70% of total plasma
in the lens, very low plasma levels of HDL-‐C (usually <10mg/dL), and variable hypertriglyceridemia. classical LCAT deficiency. Partial deficiency = fish-‐eye cholesterol. Lack of normal cholesterol esterification
These can all be seen in partial LCAT deficiency. In contrast complete LCAT deficiency is characterized disease impairs the formation of mature HDL particles and therefor
by hemolytic anemia and progressive renal insufficiency that leads to end-‐stage renal disease (ESRD). results in rapid catabolism of circulating apoA-‐1.
Remarkably, despite the extremely low plasma levels of HDL-‐C and ApoA-‐1, premature atherosclerotic
cardiovacular disease is not common.
CETP Deficiency NOT FOR THE BLOCK EXAM Familial Hyperalphalipoproteinemia: outside of japan is unlikely be due to CETP deficiency. Plasma autosomal recessive, LOF, mutation in the gene increased plasma concentrations of large, cholesterol ester-‐
HDL-‐C level above 90th percentile. Reduced risk of CHD and increased longevity. coding for CETP (cholesterol ester transfer protein?). rich HDL3 particles. The absence of CETP results in reduced
Almost exclusively in Japanese descent. catabolism of HDL.
DISORDERS OF FATTY ACID OXIDATION

Medium-‐chain fatty acyl CoA dehydrogenase (1) Profound fasting hypoglycemia (due to decreased gluconeogenesis). (2) low or absent ketone autosomal recessive, MCAD deficiency impairs oxidation or medium chain fatty acids. C8-‐C12 FA's
(MCAD) Deficiency bodies(low or absent acetyl CoA formed as there is low or absent beta-‐oxidation). (3) Increase in C8-‐ accumulate in tissues to cause toxicity. Decreased fatty acid
C12acyl carnitines in the blood (very specific for diagnosis). Episodes may be provoked by overnight oxidation decreased acetyl CoA which decreases pyruvate
fast in an infant or flu in older child. Lethargy, coma and death if untreated. Primary treatment: IV carboxylase activity (decreased gluconeogenesis).
glucose. Prevention: frequent feeding, high carbohydrate diet, low-‐fat diet. Decreased acetyl CoA limits ketone body formation. Hypo
or non-‐ketoic hypoglycemia should be strongly associated
with a block in hepatic beta oxidation
Carnitine Deficiency Accumulation of LCFAs in tissues, and wasting of acyl-‐carnitine in urine can produ+B62ce (1)Genetic: autosomal recessive mutation in genes Carnitine deficiency leads to impaired carnitine shuttle
cardiomyopathy, skeletal muscle myopathy, encephalopathy, and impaired liver function (decreased for transport enzymes(a) Carnitine palmitoyl activity; the resulting decreased LCFA metabolism.
GFR?). Muscle specific CPT-‐II deficiency is more common. Hallmarks of this disease include: Muscle transferase I deficiency (b) Carnitine palmitoyl decreased beta-‐oxidation, decreased ketone body
ache; mild to moderate muscle weakness. Rhabdomyolosis and myoglobinuria upon exercise. Severe transferease II deficiency. (2) Acquired cause: formation, increased proteolysis. Decreased ATP means you
cases lead to hypoketoic hypoglycemia, hyperammonemia, and death. episodes provoked by dietary protein deficiency, impaired synthesis of can't maintain your membranes = Rhabdomyolosis
prolonged exercise, especially after fasting, cold, or stress. Symptoms may be exacerbated by high fat, carnitine in liver disease, or loss of carnitine during
low carbohydrate diet. Muscle biopsy shows elevated muscle TAGs detected as lipid droplets in homodialysis.
cytoplasm. Primary Tx: IV glucose and cease muscle activity.
Zellweger Syndrome Patients exhibit a broad spectrum of abnormalities, including liver and kidney dysfunction with autosomal recessive mutation in PEX genes that accumulation of VLCFAs and BCFAs that are normally
hepatomegaly, high levels of copper and iron in the blood, severe neurologic defects, encode peroxins, proteins required for the normal degraded in peroxisomes. The accumulation of these lipids
hypomyelination(decreased plasmalogens which are a component of myelin, and accumulation of assembly of peroxisomes can impair the normal function of multiple organ systems.
BCFAs interfere with myelination process. ooh snap! does more BCFA means methylmalonyl CoA is Patients show decreased biogenesis of plasmalogens (cell
accumulating), craniofacial and skeletal malformations. Such patients have high incidence of perinatal membrane component.
morality and rarely survive beyond 1 year.
Refsum Disease Severe symptoms related to brain (cerebellar ataxia), eyes (retinitis pigmentosa), and nerves (chronic autosomal recessive deficiency of peroxisomal impaired a-‐oxidation of phytanic acid resulting in buildup of
polyneuropathy). Tx: low-‐phytanic acid diet (restriction of dairy products, and avoid consumption of phytanic acid hydroxylase phytanic acid and its derivatives in the plasma and tissues
ruminant meat -‐ plant phytol fermented to phytanic acid and stored in fat) results in marked
improvement in signs and symptoms.
Jamaican vomiting sickness Ingestion of unripe Ackee fruit leads to sudden vomiting 2-‐6 hours after ingestion, followed by severe Ingestion of unripe Ackee fruit (Jamaica and West Hypoglycin A is metabolized to produce
hypoglycemia leading to convulsions(usually seen in severe hypoglycemia yo), coma, and death Africa), contains hypoglicin A methylenecyclopropylacetic acid (MCPA). MCPA interferes
with the transport of LCFAs into the mitochondria, and it
also inhibits acyl-‐CoA dehydrogenases involved in beta-‐
oxidation of fatty acids. Inhibition of beta-‐oxidation leads to
decrease in ATPs and hence decreases gluconeogenesis.
SPHINGOLIPIDOSIS
Tay-‐Sachs disease three forms; infantile (first 6months, usually fatal), juvenile (2-‐10 years), adult onset (3rd and 4th Hexosaminidase A, defective alpha subunit. Eastern accumulation of GM2 gangliosides. B-‐subunit forms active
decade). Causes progressive destruction of nerve cells in the brain and spinal cord (accumulation of Europeans, and Ashkenazi Jews tetramers
GM2 ganglioside). The child becomes blind, deaf, and unable to swallow. Muscles begin to atrophy
and paralysis sets in. Cherry red spot seen on retinoscopy.
Sandhoff disease Same clinical course of Tay-‐Sachs but accelerated Hexosaminidase B. Defective B-‐subunit leads to inactivation of both HexA and B
activity. Accumulation of BOTH globosides and GM2
gangliosides
Sandhoff Activator Disease Similar signs and Sx to Tay-‐Sachs. *Distinguish by Decreased HexA ACTIVITY. (tay sachs has a mutation in Sandhoff activator protein gene Defect or absence in Sandhoff activator protein leads to
decreased concentration of HexA? double check this ish) decreased Hexosaminidase A ACTIVITY. GM2 gangliosides
accumulate in the lysosomes.
Fabry's disease *Kidney complications are a common and serious effect of disease; renal insufficiency and renal X-‐linked recessive deficiency of alpha-‐Galactosidase ceramide trihexose, also called globotriaosylceramide,
failure may worsen throughout life. Cardiac complications occur when glycolipids build up in different A accumulate within the blood vessels, and other
heart cells. Hypertension and cardiomyopathy are commonly observed. Pain is one of the more tissues/organs.
common symptoms, and is often one of the first seen. "Fabry Crises" are usually experienced as
episodes of intense, excruciating burning pain, felt initially in the hands and feet and radiating to other
parts of the body. Angiokeratoas (blood vessels rising to the surface of skin) are
common(pathognomonicesque) painless papules that can appear on any region of the body, but are
predominant on the thighs, around the belly-‐button, buttocks, lower abdomen, and groin
Gaucherer's disease Hepatosplenomegaly is commonly seen. Spleen enlargement and bone marrow replaced by B-‐Glucosidase (B-‐glucocerebrosidase), carrier state Glucocerebroside (clucosylceramide) accumulates in white
glucocerebrosides cause anemia, thrombocytopenia, and leukopenia(less wbc's = more infections). and incidence is high in Ashkenazi Jews blood cells, spleen, liver, kidneys, lungs, brain, and bone
Patients usually bruise easily due to low levels of platelets, and experience fatigue due to low nubers marrow
of red blood cells. Neurological symptoms include: serious convulsions, hypertonia, myoclonus,
dementia, ocular muscle apraxia. A definitive diagnosis is made with genetic testing. Gaucher cells
have a distinct appearance: cytoplasm is blue-‐gray with striations or "wrinked tissue paper" quality.
(enlarged, elongated lysosomes filled with glucocerebrosides.
Niemann-‐Pick Disease Hepatosplenomegally, unsteady gait(ataxia), slurring of speech(dysarthria), and discoordinated Complete absence of Sphingomyelinase Sphingomyelin accumulates in lysosomes of liver, spleen,
swallowing(dysphagia). Basal ganglia dysfunction causes abnormal posturing of the limbs, trunk and central nervous system including cerebellum
face (dystonia). Upper brainstem involvement results in impaired voluntary rapid eye movements
(supranuclear gaze palsy). More widespread disease involving the cerebral cortex and subcortical
structures is responsible for gradual loss of intellectual abilities causing dementia and seizures.
Characteristic foam cells present in bone marrow aspirates and macrophages and monocytes.
Retinoscopy reveals cherry red spots.
Farber's Disease (faber's lipogranulomatosis) dermatitis -‐ subcutaneous nodules and tissue granulomas (accumulation of ceramide). Joint pain, Ceremidase Ceramide accumulates in various tissues; joints, central
swollen joints, contracture of arthritis. Hoarseness of voice and hoarse cry due to ceramide nervous system, throat, liver, and other tissues.
accumulation in throat.
Metachromatic Leukodystrophy (not for mental retardation, psychological disturbances. Arysulfatase A Demylination
exam)
DIGESTION AND ABSORPTION OF AMINO ACIDS (maybe add a cell with the digestion process)
Cystic Fibrosis pancreas can't effectively release digestive enzymes. This includes enzymes for digesting proteins, deltaF508 deletion
carbohydrates, fats (including fat soluble vitamins)
Hartnup disease will see a symptoms of neutral essential amino acid deficiencies. tryptophan deficiency = serotonin, Autosomal recessive defect in transport of neutral decreased absorption in intestine and reabsorption in renal
melatonin, and niacin deficiency. Niacin deficiency > pellegra. 3 D's dementia, diarrhea, dermatitis. amino acids across both intestinal and renal tubules leads to deficiency manifestation of essential amino
(B6 deficiency can also lead to B3 deficiency) epithelial cells acids.
Cystinuria The most serious problem is insolubility of cystine, which can form kidney stone and its consequences. defect in the transport of cystine and the basic no deficiency manifestations are noted since cystine is
amino acids (arginine, lysine, ornithine) across both oxidized form of cysteine, arginine is semi-‐essential,
intestinal and renal epithelial cells ornithine is intermediary in urea cycle and re-‐synthesized.
DISORDERS OF UREA CYCLE

Ammonia Toxicity increased levels of ammonium and glutimine. Decreased a-‐ketoglutarate leads to decrease in TCA messed up enzymes in the urea cycle primarily (listed Ammonia is toxic to the nervous system and normally fixed
cycle = decreased ATP generation. When the urea cycle is defective, the cycle is interrupted which below). increased protein degradation can increase into a-‐ketoglutarate or glutamate
leads to accumulation of urea-‐cycle intermediaries before the block. Elevated ammonia leads to ammonia levels.
neurotoxic effects. Swelling of astrocytes because glutimine is osmotically active. Decreased
glutamate -‐ reduced glutaminergic neurotransmission (lethargy and reduced NS activity). High levels
of glutimine alters the permeability of the mitochondrial membrane, leading to a permeability
transition pore, which leads to cell death.
Hereditary Hyperammonemias. build up of ammonia (most severe). the severe decreases as you go down the list of urea cycle Carbamoyl phosophate synthetase I (rate limiting
Hyperammonemia Type 1 enzymes. enzyme of urea cycle) found in mitochondria
Hyperammonemia Type 2 (most common) Carbamoyl Phosphate accumulates in the mitochondrion. mental retardation seen in untreated x linked, ornithine transcarbamoylase deficiency.
individuals. Elevated levels of orotic acid (does NOT cause megaloblastic anemia). mitochondrial enzyme
Citrullinemia Citrulline accumulates argininosuccinate synthetase deficiency. cytosolic

enzyme
Argininosuccinicaciduria Argininesuccinate accumulates argininosuccinate lyase deficiency. cytosolic enzyme
Hyperargininemia Arganine accumulates arginase defficiency. cytosolic enzyme
Acquired hyperammonemia The hepatic changes in acute cases may be because of metabolic dysfunction of hepatocyte leading to liver disease, acute viral hepatitis, ischemia,
decreased urea cycle, and increased accumulation of ammonia and its consequences. The hepatic hepatotoxins, alcoholism, hepatitis, biliary
changes in chronic cases may be due to shunting of portal blood directly into systemic circulation, and obstruction.
does not have access to the liver. The detoxification of ammonia is therefore, severely impaired
leading to elevated levels of circulatory ammonia and hence its concsequences.
AMINO ACID METABOLISM

Classic Phenylketonuria (PKU) Irreversible mental retardation if not diagnosed or treated within the first month of life. Along with autosomal recessive, defective PAH gene (codes for Accumulation of phenylalanine in the blood that is well
mental retardation (IQ <50), baby develops tremors, seizures, and hyperactivity. Albanism signs Phenylalanine Hydroxylase). Treatment: all PKU above it's normal concentration (decreased tyrosine). PAH
(excessively fair hair and skin, hypopigmentation, eczema), and a "musty or mousy odor" of baby's patients must adhere to a special low phenylalanine activity is <1% in PKU patients. Mental retardation is due to
sweat and urine (due to phenylketone bodies produced from accumulated Phenylalanine). Early (Phe) diet for atleast the first decade of life. the build up of phenylalanine. It competes with other
detection and treatment is key: prevents devlopment of neurological problems, seizures, retardations. Lofenalac or PKU aid are semisynthetic preparations LNAA's (tyrosine, leucine, isoleucine, and valine) for
Guthrie test is doen 6-‐7 days after birth (takes time for the enzyme to develop in baby liver). In this used in the US (expensive?). Phe containing foods = transport across the blood brain barrier. other LNAA's are
assay, spores of Bacillus subtilis are plated on an agar plate containing B2 thienylalanine (inhibitor of meat, chicken, eggs, nuts, cheese, legumes, cow necessary for NT synthesis, myelin synthesis, hence the
bacillus growth). If the phenylalanine content of the blood is > 2 to 4mg/dL, the phenylalanine will milk, dairy, and aspartame (daaaayum whats a neuronal signs seen in PKU
counteract the effects of B2 thienylalanine and bacterial growth will occur (+ test). normal adult phe brother gonna eat?). wanna maintain levels of Phe
is <1-‐2mg/dL. newborn is 2-‐4mg/dL. classical PKU patients have values > 16mg/dL in blood at 3-‐12mg/dL. Tyrosine needs to be
supplemented.
maternal PKU expectant mother having PKU must maintain low-‐phenylalanine levels before and during pregnancy.
Especially during early, 8-‐10 weeks of gestation when there is maximum neuronal growth. Failure to
maintain low phenylalanine levels will result in babies born with congenital heart disease, growth
retardation, microcephaly, and mental retardation.
Non-‐classic PKU More severe than classic PKU. Dietary therapy corrects the hyperphenylalaninemia. However, BH4 is defective dihydropteridine reductase (DHPR) cases
also a coenzyme for two other hydroxylations required for neurotransmitters in the brain (5-‐HT and L-‐ deficiency of BH4, a coenzyme for PAH, tyrosine
Dopa) Resulting deficiency of neurotransmitter activity is in part responsible for pregressive hydroxylase, and tryptophan hydroxylase. less
neurological manifestation and eventual death (usually first 2 years of life, even when on strict diet) commonly a defect in biosynthesis of BH4 from GTP.
Hereditary Tyrosemia type 2 (Oculocutaneous may lead to lesions of the eye and skin as well as neurological problems. Patients are treated with low-‐ due to genetic defect in tyrosine aminotransferase
tyrosinemia, Richner-‐Hanhart syndrome) tyrosine and low-‐phenylalanine diet. (needs PLP/B6) ecoded by TAT
Hereditary Tyrosinemia type 3 (neonatal frequently observed in newborn infants, especially those that are premature. For the most part, the deficiency of the enzyme 4-‐
condition appears benign, and dietary restriction of protein returns plasma tyrosine levels to normal. hydroxyphenylpyruvate(4HPP) dioxygenase (needs
Since the enzyme requires ascorbate, supplementation also aids in reducing circulating tyrosine levels Vitamin C and Copper) encoded by the gene HPD.
Herediatary Tyrosinemia type 1 (hepatorenal Most severe form of tyrosinemia. The acute form is associated with liver failure, a cabbbage like body fumarylacetoacetate (FAA) hydrolase
tyrosinemia or tyrosinosis) odor, and death within first year of life.
Alkaptonuria (black urine disease) Oxidized pgments are deposited in bones, connective tissue, sclera, skin, and anywhere with cartilage, autosomal recessive deficiency of homogentisate homogentisic acid accumulates in the body fluids and is auto
a condition called ochronosis. about half of the patients will be diagnosed for the presence of dark (HGA) oxidase (homogentisic acid 1,2-‐dioxygenase). oxidized to its quinone form. Quinone derivatie has affinity
urine prior to development of other signs until middle life. Foci of gray-‐brown scleral pigment and this enzyme needs Fe towards cartilaginous tissue and hence accumulates over
generalized darkening of ear develop after 30 years of age. low back pain usually starts between 30 the cartilage.
and 40 years of life. Ochronotic arthritis is heralded by pain, stiffness, and some limitations of motion
of the hips, knees, and shoulders (small joints are usually spared). Pigmentation of heart valves,
larynx, tympanic membranes, and skin occurs. occasionally patients develop pigmented renal or
prostatic calculi. degenerative cardiovascular disease is increased in older patients. Diagnosis should
be suspected in a patient whose urine darkens to blackness. Bamboo spine: oxidized quinone
accumulates over vertebral cartilage.
Albanism individuals suffer from a lack of pigment in the skin, hair, and eyese, and they are sensitive to sunlight either copper dependent tyrosine hydroxylase
(photosensitivity) (tyrosinase) or two other enzymes that convert
tyrosine to melanine may be defective.
clinical depression -‐ connected to tryptophan peripheral dopa decarboxylase normally converts 5-‐HTP to 5-‐HT (needs PLP). this is unfavorable since low serotonin levels can't give 5-‐HT as a drug, cant cross the BBB. need to give 5-‐
metabolism serotonin has no function in the periphery, and can't cross the BBB. Carbidopa is a peripheral HTP which can cross the blood brain barrier
decarboxylase inhibitor which will allow more 5-‐HTP cross the BBB and convert into 5-‐HT in the pineal
gland.
Cheese effect (sympathomimetic effect?) Fermented food, and foods that have been stored for a long time contain tyramine (cheese, wine, MAO-‐I + tyramine = problems
pickled meats). When taking a MAO-‐inhibitor, the tyramine causes the release of catecholamines (ie
NE). Increases heart rate, vasoconstriction, BP, can lead to cardiac arrest
enzymes requiring ascorbate or copper enzymes that require copper and vit c: HGA oxidase (alkaptonuria), Dopamine B oxidase (dopamine > Menkes or Scurvy can lead to deficiency
norepinephrine. tyrosinase is a copper dependant enzyme in melanin synthesis
methylation reactions that use S-‐ Phenylethanolamine N methyl transferase (converts norpeinephrine to epinephrine). folate or methylcobalamine deficiency can slow
adenosylmethionine Methyltransferase (guanidinoacetate to creatine). Conversion of N-‐acetyl Serotonin to Melatonin down these reactions
uses SAM, not sure what the enzyme is (some random methyltransferase).
Carcinoid syndrome the most common systemic syndrome with carcinoid tumors is the carcinoid syndrome. Flushing and build up of 5-‐hydroxyindoleacetic acid (HIAA),
diarrhea are two most common symptoms. Diagnosis of carcinoid syndrome: measurement of urine catabolic product of serotonin
of plasma serotonin or its metabolite in urine. Carcinoid tumors are derived from the diffuse
neuroendocrine system of the GI tract. Forgut carcinoid generally have a low serotonin content.
Midgut carcinoids have a high serotonin content and most frequently cause the typical carcinoid
syndrome when the metastasize. Most common secretory products of carcinoid tumors involving
carcinoid syndrome is serotonin. 50% of dietary tryptophan is diverted towards serotonin formation
pathway which results in inadequate supply of tryptophan for niacin formation which leads to pellegra
like lesions. Patients show greatly elevated plasma serotonin or urinary 5-‐HIAA.
Classic Homocysteinuria Excessive blood clotting in the arteries and veins increase the risk of strokes and heart attack. There is reduced activity of cystathionine B synstase Elevated homocysteine and methionine
accelerated atherogenesis in them. It affects collagen assembly leading to connective tissue related (decreased affinity to PLP)
signs similar to Marfan's syndrome. It may also lead to rapid bone loss (osteoporosis). It may cause
retinal damage, damage to the neural network of the retina, and even loss of vision. Lens dislocation
inferomedially. Mental retardation is also seen in homocysteinuria, but not in marfans. An increase in
total plasma homocysteine represents and independent risk factor for coronary, cerebrovascular, and
peripheral arterial disease as well as for deep-‐vein thrombosis. Treatment involves a diet restricting
protein and methionine, while supplementing cysteine. In approximately half of patients, oral
pyridoxine produces a decrease in plasma methionine and homocystine concentration in body fluids.
Non-‐classic Homocysteinuria same symptoms and classic, but only see elevated Homocysteine levels. Folate and vitamin b12 deficiency in methionine synthase, folate, elevated homocysteine
deficiency should be prevented by adequate supplementation. Betaine is also effective in reducing methylcobalamin
homocysteine levels, by providing an alternate route to methionine.
Cystathioninuria accumulation of Cystathionine in urine. deficiency in cystathionase. Requires PLP cystathionase normally cleaves cystathionine to release
cysteine and a-‐ketobutyrate
Methylmalonic aciduria accumulation of methylmalonyl CoA. Increased methylmalonyl CoA interferes with the myelination inefficient functioning of methylmalonyl CoA mutase, methylmalonyl CoA can't form succinyl CoA, so is converted
process. This reaction happens in the oxidation of odd-‐chain fatty acids, and in methionine due to B12 deficiency (deoxyadenosylcobalamin). to Methylmalonic acid and excreted in urine
metabolism.
Maple syrup urine disease branched chain a-‐ketoacids and their byproducts appear in urine, giving it the odor of maple syrup or autosomal recessive defect in branched chain a-‐ build up of the branched chain amino acids (leucine,
burnt sugar. Infants with this disease seem healthy at birth, but if left untreated suffer severe brain ketoacid dehydrogenase (oxidative decarboxylation). isoleucine, and valine), and their byproducts in the blood
damage(mental retardation), and eventually die. This is the same mechanism seen in PKU; competing this is a complex enzyme like PDH. E1 (thiamine, and urine. BCAA's accumulate > undergo transaminiation
for LNAAT. From early infancy, symptoms of the condition include poor feeding, vomiting, most commonly mutated), E2 lipoic acid and vitB5 rxns> accumulation of their corresponding a-‐ketoacids >
dehydration, lethargy, hypotonia(skeletal muscle normally utilizes BCAA's, but are unable to here), (arsenate poisoning), E3 vit B2 + B3 acidosis.
seizures, ketoacidosis, coma, and neurological decline.
CATABOLIC END PRODUCTS

Tryptophan indole 3-‐acetic acid (IAA) and indole 3-‐pyruvic acid
Tyrosine Vanillactic acid
Dopamine Homovanillic acid
Norepinephrine + Epinephrine MHPG and vanillylmandelic acid
Serotonin 5-‐hydroxyindoleacetic acid (5-‐HIAA) accumulation in carcinoid syndrome
DIABETUS
Diabetic ketoacidosis (DKA) -‐ seen in type 1
Absolute or relative insulin deficiency(autoimmune destruction of beta cells) -‐ hyperglycemia and elevated ketone bodies leading to volume depletion and acid-‐base imbalance. Presents with nausea and vomiting are
DM (you better know this ish!) often prominent, and their presence in an individual with diabetes warrants laboratory evaluation for DKA. Abdominal pain may be severe and can resemble acute pancreatitis or ruptured viscus. Kussmaul respirations
and fruity odor of patients breath (secondary to metabolic acidosis and increased acetone) are classic signs of the disorder. Treatment for DKA: fluids, electrolytes, insulin therapy to decrease blood glucose GRADUALLY.
DKA results from relative or absolute insulin deficiency combined with counter-‐regulatory hormone excess (glucagon, catecholamines, cortisol, and growth hormone. Both insulin deficiency and glucagon excess, in
particular, are necessary for DKA to develop. The decreased insulin:glucagon ratio promotes gluconeogenesis, glycogenolysis, and ketone body formation in the liver, as well as increases in substrate delivery from fat
and muscle (free fatty acids, amino acids) to the liver. Hyperglucagonemia alters hepatic metabolism to favor ketone body formation, through activation of the enzyme CPT 1. This enzyme is crucial for regulating fatty
acid transport into the mitochondria, where beta oxidation and conversion to ketone bodies occur. Excess ketone body formation leads to metabolic acidosis. metabolic acidosis means hyperkalemia. Decreased
bicarbonate. Increased respiration to compensate for biuld up carbon dioxide formed from the buffering effect from bicarbonate. Hyperglycemia glycates proteins in the blood, sorbitol causes problems (osmotically
active, neuropathy etc), thinning of blood vessels. (add more stuff later)
DISORDERS OF PURINE AND PYRAMIDINE METABOLISM
Hyperuricemias: over pruduction(purine catabolism) or under secretion of uric acid. Causes of hyperuricemia falling under over producers are as follows: genetic defects in PRPP synthetase (elevated Vmax, increased affinity for ribose 5-‐
phosphate, or resistance to feedback inhibition) results in overproduction and over excretion of purine catabolites. Specific defects like hypoxanthine-‐guanine phosphoribosyl transferase, glucose-‐g-‐phosphatase.
Others are secondary to (hyperproliferative) diseases such as cancer, psoriasis, chemo or radiotherapy that enhance turnover. Goat is a metabolic disorder of purine catabolism seen in Hyperuricemias. When serum
urate (pKa = 5.4, so when urine pH dips below this uric acid precipitates forming crystals) levels exceed the solubility limit, monosodium urate crystalizes in soft tissues and joints and causes an inflammatory reaction,
gouty arthritis (first manifests in the first metatarsalphalangeal joint). Monosodium urate crystal accumulation in the joint fluid which show birefringence when observed under polarized light. Rx for gout: acute
conditions; Ibuprofen, diclofenac, colchicine (for its inhibitory effects on neutrophil motility and activity). Allopurinol for chronic gout. Allopurinol inhibits xanthine oxidase, reducing uric acid formation (xanthine back
tracks to nucleotide formation).
Lesch-‐Nyhan syndrome Bizarre syndrome of self-‐mutilation, decreased IQ, neuroligical signs. Frequent episodes of uric acid X linked recessive defect in hypoxanthine-‐guanine the accompanying rise in intracellular PRPP results in purine
lithiasis (stone formation) uric acid crystals (orange sand in urine). phosphoribosyl transferase (HGPRT), an enzyme of overproduction by de novo pathway. Increased energy
purine salvage spent by neurons to produce purines by de novo pathway
Von Gierke Disease Hypoglycemia, hyperuricemia, lactic acidosis, ketoacidosis, hyperlipidemia. Overall metabolic acidosis, Glucose-‐6-‐phosphatase purine overproduction and hyperuricemia occurs secondary
compensatory respiratory alkyosis, respiratory distress. to enhanced generation of the PRPP precursor ribose 5-‐
phospate. An associated lactic acidosis elevates renal
threshod for urate, elevating total body urates
Hypouricemias: (1)Purine nucleoside phosphorylase deficiency is associated with a severe deficiency of Tcells but (1)purine nucleoside phosphorylase deficiency,
apparently normal B cell function. Immune dysfunctions appear to result from accumulation dGTP (2)xanthine oxidase deficiency (3)ADA deficiency is
and dATP, which inhibit ribonucleotide reductase and there by deplete cells of DNA precursors. (2) described below
Hypouricemia and increased excretion of hypoxanthine and xanthine are associated with xanthine
oxidase deficiency due to a genetic defect or to severe liver damage. Patients with a severe enzyme
deficiency may exhibit xanthinuria and xanthine lithiasis.
Severe Combined Immunodeficiency Disease Patients suffer from devastating fungal, bacterial, and viral infections. In the absense of enzyme Autosomal recessive causes: mutation in ADA gene Adenosine deaminase (ADA) is expressed in the cytosol of all
replacement or bone marrow transplantation, infants often cuccumb to fatal infections. coding for adenosine deaminase (50% of cases), cells, but lymphocytes have the highest activity. Deficiency
Mutation in IL-‐7receptor alpha chain (IL7RA) gene, recults in accumulation of dATP which feedback inhibits
and RAG-‐1 and RAG-‐2 genes. X-‐linked inheritance ribonucleotide reductase. This results in deficiency of other
pattern: defective gene coding for gamma chain of deoxyribonucleotides dGTP, dTTP, dCTP. Decreased DNA
the receptors for IL-‐2,4,7,9,15 synthesis in Tcells(thymus) and Bcells (bonemarrow). B cells
and T cells are sparse and dysfunctional
Orotic Aciduria (commonly accompanies Patients typically have megaloblastic anemia which does not respond to administration of vitamin B Type 1 orotic aciduria reflects a deficiency of both Inability of severely damaged mitochondria to utilize
Reye's Syndrome) 12 or folic acid. Oral administration of uridine is used to treat this condition. Drugs may precipitate orotate phophoribosyltransferase and orotidylate carbamoyl phosphate produced for urea cycle. Carbamoyl
orotic aciduria. Allopurinol, an alternative substrate for orotate phosphoribosyltransferase, competes decarboxylase. Type II orotic aciduria is due to a phosphate then becomes available for cytosolic
with orotic acid. The resulting nucleotide product also inhibits orotidylate decarboxylase, resulting in deficiency of only orotidylate decarboxylase. overproduction of orotic acid in pyrimidine synthesis.
orotic aciduria and orotidinuria. 6-‐Azauridine, following conversion to 6-‐azauridylate, also
competitively inhibits orotidylate decarboxylase, enhancing excretion of orotic acid and orotidine.
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BIOCHEMISTRY BLOCK 1 - Madhav Patel