Clinical Correlations

Vitamin A deficiency an early signs of this deficiency is night blindness. Prolonged deficiency leads to an irreversible loss in the number of visual cells. Severe vitamin A deficiency leads to xerophthalmia- a pathologic dryness of the conjunctiva and cornea. If untreated, it results in corneal ulceration and ultimately in blindness because of opaque scar tissue.

Abetalipoproteinemia (Hypobetalipoproteinemia) a rare genetic disorder with a recessive inheritance characterized by neurological symptoms, including ataxia and mental retardation. –Plasma triacylgycerol and cholesterol levels are decreased.—there is a complete absence of β lipoproteins (no chylomicrons or VLDLs, LDLs) –Absorption of fat is greatly reduced. –There is no effective treatment to prevent the neurological symptoms from appearing. It is caused by a defect in Microsomal Triacylglycerol Transfer Protein (MTP)-(normally responsible for loading of apoB with lipid or deficiency of apoB48 and apoB100. It could also be a deficiency acantcytosis in RBC. When characterized by malabsorption of diaetary lipid, steatorrhea (fatty stool), and accumulation of intestinal triglyceride (problem with apoB48). Patients exhibit membrane abnormalities in their erthrocytes with production of acantocytes (thorny appearing cells). This unusual red cell morphology results from malabsorption of dietary lipids including EFAs like linoleic acid which is required for membrane synthesis. Administration of fat soluble vitamins (particularly Vit E) can reduce severity of disorder.

Acetyl CoA deficiency could result in Respiratory distress syndrome due to decrease in DPPC synthesis.

Acyl-CoA Dehydrogenases A group of inherited diseases that impair β-oxidation result from deficiencies in acyl-CoA dehydrogenases. The enzymes affected may belong to Very long chain acyl-CoA dehydrogenase (VLCAD), Long-chain acyl-CoA dehydrogenase (LCAD), medium chain acyl-CoA dehydrogenase (MCAD) and short-chain acyl-CoA dehydrogenase (SCAD)

MCAD most common. In first years of life this deficiency will become apparent following a prolonged fasting period. Symptoms include vomiting, lethargy and frequently coma. Excessive urinary excretion of medium chain dicarboxylic acids as well as their glycine and carnitine esters is diagnostic of this condition. In case of deficiency taking care to avoid prolonged fasting is sufficient to prevent clinical problems.10 % of infants who die from SIDS have a deficiency of MCAD

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--Jamaican vomiting sickness from eating unripe akee fruit which contains hypoglycin A, an unusual amino acid that is metabolized to an intermediate, a suicide inhibitor of MCAD

Adenosine Deaminase (ADA) deficiency deoxyadenosine accumulates. Causes defects in DNA synthesis in bothe T cells and B cells resulting in immature T and B cells. This defect leads to Severe Combined Immuodeficiency Syndrome (SCID), which affects both T and B cells.

Albinism defective tyrosinase; leading to poor formation of melanin. Lack pigmentation because without tyrosinase they cannot convert tyrosine to dopa and dopa to dopaquinone in melanocytes and , thus, cannot synthesize melanins

Alcoholic fatty liver Fatty liver occurs in alcoholics because of ethanol replaces fatty Acids as oxidizable substrate for mitochondria. After esterification of the fatty acids to triglycerides (TG), the TGs then accumulate in the liver. Also the acetyl-CoA produced form ethanol metabolism can be channeled to fatty acids. Also there is an overall increase in TG synthesis due to alcoholism

Alcoholic Hepatitis and liver Cirrhosis cirrhosis of the liver is characterized by extensive scarring or fibrosis and may result from the necrosis and inflammation associated with the alcoholic hepatitis

Alkaptonuria a genetic deficiency of Homogentisate Oxidase missing because the Tyrosine degradation pathway is defective. Homogentiisic acid accumulates and gets symptoms of black urine and arthritis. Characterized by brown-colored urine and abnormal pigmentation of connective tissue, caused by oxidation products of homogentisic acid

Amino aciduria any condition resulting in excessive excretion of amino acids in the urine

Andersen’s Genetic defect in defective glycogen branching enzyme causes type IV glycogen storage disease. Infants born with this disease suffer cirrhosis and failure of the liver as well as hepatosplenomegaly. Most affected infants die by 2 years of age.

APRT deficiency adenine is not utilized. Adenine is oxidized by xanthine dehydrogenase via 8-hydroxyadenine intermediate to 2,8 dihydroxyadenine (2,8-DHA) 2,8-DHA is extremely insoluble and its accumulation in the kidney can lead to crystalluria and the formation of urinary stones. Adenine and 2,8-DHA are secreted by the human kidney and 2,8-DHA are secreted by the human kidney and 2,8-DHA is protein bound in circulation. As such, toxicity in tissues other than the kidney is minimized.

Arsenate poisoning Inhibits the generation of glycolytic energy because, arsenate uncouples ATP generation from glycolysis. Arsenate is a structural analog of phosphate and can act as a substrate for any reaction in which phosphate is a substrate. [Arsenate

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esters, unlike phosphate esters, are kinetically as well as thermodynamically unstable and hydrolyze almost instantaneously.

Arsenite poisoning Arsenite toxic because they bind to sulfhydryl compounds (including lipoamide) that can form bidentate adducts. The inactivation of lipoamide- containing enzymes by arsenite, especially the pyruvate dehydrogenase and the α-ketoglutarate dehydrogenase complexes, brings respiration to a halt.

Ataxia telangiectasia A DNA repair defect that is hereditary and shows a defect in the removal of cross links. Associated with lymphomas

Atherosclerosis due to an imbalance in uptake of LDL cholesterol. The endothelium of large and medium artery walls may become damaged by oxidized LDL, or other factors including normal turbulence of blood, high pressures on arterial walls of hypertensive patients, free radicals from cigarette smoking, diabetes (glycation of LDL) Endothelial damage or dysfunction increases adhesiveness and permeability of the endothelium for platelets and leukocytes. Monocytes and macrophages with scavenging receptors are recruited with subsequent production of reactive oxygen species. Excessive uptake of modified LDLs by macrophages which become laden with oxidized cholesterol form foam cells which accumulate and form fatty streaks. The fatty streak enlarges over time, necrotic tissue and free lipid accumulates, surrounded by epitheloid cells and smooth muscle cells, forming an advanced plaque with a fibrous cap. The plaque eventually begins to occlude the blood vessels, causing ischemia, and infarction in the heart, brain, or extremeties.

The long standing elevation of blood glucose is widely believed to cause the chronic complications of diabetes—premature atherosclerosis, retinopathy, nephropathy and neuropathy.

Beriberi deficiency in Vitamin B1. This is a sever Thiamine deficiency syndrome found in areas where polished rice is the major component of the diet. Signs of infantile beriberi include tachycardia, vomiting, convulsions, and, if not treated death. The deficiency syndrome can have a rapid onset in nursing infants whose mothers are deficient in thiamine. Adult beriberi is characterized by dry skin, irritability, disorderly thinking, and progressive paralysis

Bilirubin Gallstones similar to cholesterol gallstones except main component is calcium bilirubinate. It is due to increased bilirubin production as in chronic hemolytic anemias.

Bloom’s syndrome A DNA repair defect that is hereditary; is Autosomal recessive and is associated with leukemias

Carbon monoxide poisoning carbon monoxide is a very toxic gas because it binds with a higher affinity to heme than does oxygen. Since CO has a higher affinity than oxygen, oxygen cannot displace it. In this way, CO act much like a potent competitive inhibitor.

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There can be plenty of oxygen available, but the hemoglobin or myoglobin bound to CO will not carry it; therefore, the oxygen is nogt make available to tisues. CO effectively binds irreversible to the heme in myoglobin and hemoglobin.

Carnitine deficiency Deficiencies in carnitine lead to an inability to transport fatty acids into the mitochondria for oxidation may be limited to only muscles. This can occur in newborns and particularly in preterm infants. Deficiency is also found in patients undergoing hemodialysis or exhibiting organic aciduria. May manifest symptoms can range form mild occasional muscle cramping to severe weakness or even death. Treatment is by oral carnitine administration.

Carnitine Palmitoyltransferas I (CPTI) Deficiency Deficiencies in this enzyme affect primarily the liver and lead to reduced fatty acid oxidation and ketogenesis.

Carnitine Palmitoyltransferase II (CPTII) deficiency result in recurrent muscle pain and fatigue and myoglobinuria following strenuous exercise. Carnitine acyltransferases may also be inhibited by sulfonylurea drugs such as tolbutamide and glyburide.

Cholesterol Gallstones (cholelithiasis) occurs when the bile salts to cholesterol ratio decreases because of a defective 7α hydroxylase. This causes cholesterol to precipitate. A cholesterol gallstone is defined as being at least 75% cholesterol by weight.

Chronic Alcoholic could be ketotic. Will frequently see folate deficiency with chronic alcoholics. There is inadequate dietary intake of folate, direct damage to intestinal cells and brush border enzymes, which interferes with absorption of dietary folate; a defect in the enterohepatic circulation, which reduces the absorption of folate; liver damage causing decreased hepatic production of plasma proteins’ and interference with kidney resorption of folate.

Cockayne’s syndrome (CS) In humans, defects in (NER) nucleotide-excision repair can lead to this, Trochothiodystrophy (TTD) and Xeroderma pigmentosum (XP) but CS and TTD patients are not predisposed to cancer as is XP patients. CS is due to defects in XPB and XPD genes. Characteristics include Dwarfism, Neutral retardation, Retinal Atrophy, Cataracts and Gait defects.

Con’s disease defective glycogen debranching enzyme

Cori’s disease/Forbes’ disease defective debranching enzyme. Type III glycogen storage disease. This disease also causes heart and lung problems, resulting in stunted growth, an enlarged liver, hypoglycemia, and acidosis.

Cyanocobabalamin (Vit B12) deficiency can be characterized by megaloblastic anemia. Which can be distinguished from pernicious anemia, which results from inability to absorb B12 due to failure of the stomach to produce intrinsic factor. Excretion of FIGLU, especially after a histidone load test, is common in both folate and B12 deficiency. This deficiency also shows progressive peripheral neuropathy (unlike folate deficiency) People used to do a shilling test to measure this deficiency

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The enzyme seen with Vit B12 is Homocysteine methyl transferase (Methionine, SAM) and Methylmalonyl CoA Mutase (Odd chain fatty acid oxidation Val, Met, Thr, Ile)

Cystathioninuria Cystathionase missing because the Methionine degradation pathway is defective. Cystathionine accumulates and symptoms are benign.

Produce unusual sulfur containing metabolites in the urine and may occasionally be improved by vitamin B6 pyridoxal administration

Cystic Fibrosis (CF) defects in the function of CFTR (cystic fibrosis transmembrane conductance regulator) protein. Major defect is in CI transport, but may affect other ions. CFTR gene is on chromosome #17

Cystinosis due to defective transport system in lysozomes and the efflux of cysteine in cytosol is inhibited

Cystinuria Dibasic amino acid defective. Specifically cystine, cysteine is poorly soluble in water and precipitates leading to kidney stones. Different from cystinosisDefect in renal transport of cysteine (also OM, Lys, and Arg). Stones are predominantly cystine stones

Diabetes many causative agents; two forms, insulin dependent ( no endogenous Insulin synthesized ) and insulin independent (usually a problem with the insulin receptor)

Diabetes ketoacidosis in IDDM individuals. Severe metabolic acidosis. Insulin deficiency has caused an abnormal metabolic pattern in which serum glucose is not utilized and excessive amounts of ketoacids have been produced and accumulate in the blood. This has lowered serum bicarbonate levels and decreased pH. Some may hyperventilate as an attempt by the lungs to correct the acidosis. Insulin treatment promotes glucose uptake and restoration of normal metabolism. When the hyperglycemia is corrected, the loss of water and electrolytes ceases.

Dysbetalipoproteinemia deficiency of apoE in VLDL

Ehlers-Danlos Syndrome (defects in collagen processing usually) This syndrome, which may be due to any disorder is a heterogeneous group of generalized connective tissue disorders that result from inheritable defects in the collagen molecule. This family of diseases is characterized by stretchy skin and loose joints and short stature. Many contortionists seen in circus side-shows suffer from this syndrome, which may be due to any one of several enzyme deficiencies.

Essential Fatty acid deficiency (linoleic acid) Flaky skin

Fabry’s (sphingolipidoses) accumulation of Ceramide trihexoside (Trihexosylceremide) because of a deficient α-Galactosidase affecting the kidneys. There is an increased

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globosides and has a reddish-purple skin rash, kidney and heart failure, pain in lower extremities and is an x linked recessive.

Fanconi’s anemia a DNA repair defect that is hereditary, Autosomal recessive and shows defects in Fragile chromosomes and is associated with Leukemias

Farber’s disease (spingolipidoses) Autosomal recessive disease where there is a ceramidase deficiency from which one gains an accumulation of Ceramide. This deficiency slows or inhibits the production of sphingosine and release of a fatty acid from Ceramide. Very painful and will have progressively deformed joints, can have skin nodules , Tissues show granulomas, and death within a few years.

Fasting hypoglycemia can be caused by toxin from unripe Jamaican akee fruit. The toxin inhibits acetyl CoA dehydrogenase of beta oxidation. Low blood glucose occurring during fasting. Fasting hypoglycemia tends to produce neuroglycopernia symptoms and may result from a reduction in the rate of glucose production by the liver. Thus, blood glucose levels are often seen in patients with hepatocellular damage or adrenal insufficiency or in fasting individuals who have consumed large quantities of ethanol. Could be due to an increase rate of glucose utilization by the peripheral tissues, most commonly due to elevated insulin resulting from a pancreatic beta cell tumor. If left untreated, a patient with fasting hypoglycemia may lose conciousness and experience convulsions and coma.

“Fatty Liver” occurs in conditions in which there is an imbalance between hepatic TGs and the secretion of VLDL. Diseases such as hepatitis, uncontrolled diabetes mellitus, and chronic ethanol ingestion can cause fatty liver.

Alcoholic fatty liver Fatty liver occurs in alcoholics because of ethanol replaces fatty Acids as oxidizable substrate for mitochondria. After esterification of the fatty acids to triglycerides (TG), the TGs then accumulate in the liver. Also the acetyl-CoA produced form ethanol metabolism can be channeled to fatty acids. Also there is overall increases in TG synthesis due to alcoholism

Fetal alcohol Syndrome (FAS) negative effects in development and impairment of brain functions due to alcohol consumption by pregnant women.

Fluoride toxication

Folate deficiency can also cause neural tube defects. Clinical symptoms of folic acid deficiency include: macrocytic anemia, megaloblastosis of bone marrow (megaloblastic anemia) and Gastronintestinal disturbances.

Folic acid deficiency probably the most common vitamin deficiency encountered in the U.S. It is seen particularly in alcoholics and in pregnancy. It is characterized by megaloblastic anemia (low hemoglobin level and large red blood cells), resulting from a lack of the tetrahydrofolate derivatives required for DNA synthesis.

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Inborn errors of folate metabolism in humans include congenital defect of folate absorption, dihydrofolate reductase deficiency, formiminotransferase deficiency. Various measurements are used to establish deficiency [folate level, the concentration of the folic acid-binding protein and the excretion of formiminoglutamic acid (FIGLU)]FIGLU is excretion in the urine is increased particularly after a histidine load, reflecting a decreased availability of THF as a one carbon trap in histidine catabolism Forbes’ disease/ Cori’s disease defective debranching enzyme. Type III glycogen storage disease. This disease also causes heart and lung problems, resulting in stunted growth, an enlarged liver, hypoglycemia, and acidosis.

Fructokinase deficiency A deficiency of on of the key enzymes required for the entry of fructose into intermediary metabolic pathways can result in either a benign condition (fructokinase deficiency) or in a severe disturbance of liver and kidney metabolism.

Fructose Intolerance- defects in fructose-1-phosphate aldolase

Fructosuria defect in fructokinase. This condition is not usually serious, since the excess fructose that accumulates in the urine.

(Classical) Galactosemia a uridyltransfrease deficiency or defect in galactokinase (Autosomal recessive) Cause galactosemia and galactosuria. There is and accumulation of galactose 1 phosphate and galactitol in nerve tissue, lens, liver, and kidney causing liver damage, severe mental retardation, and cataracts Treat with removal of galactose (therefore lactose) from the diet.

Gaucher’s disease most commonly observed sphingolipidosis. (Autosomal recessive) Patients are deficient in glucocerebrosidase which is needed to degrade glucocerebroside. Glucocerebroside is stored mostly in the liver, spleen and bone marrow. When not degraded it can’t be readily excreted because it is not very soluble in water or body fluids. It then accumulates in cells of spleen and liver (organ enlargement) also accumulates in bone marrow (osteoporosis). There is mental retardation in infantile form and frequently fatal.--enlarged spleen and liver destroys red blood cells leading to anemia, and white blood cells and platelets important in coagulation leads to bruising and bleeding.SS: hepatosplenomegaly, erosion of bones, crumpled paper inclusions (referring to macrophages)

Glucose-6-phosphate Dehydrogenase Deficiency may be a causative factor in drug induced hemolytic anemia

Gout (gouty arthritis) A disorder that occurs when uric acid crystallizes in joints of the body. Usually the great toe or large joints. It develops secondarily to hyperuricemia (elevated levels of uric acid) The formation and presence of sodium urate-crystals in

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joints of extremities is associated with extreme swelling and tenderness in those areas. There are elevated levels of uric acid in the blood and urine. Commonly associated with: Heavy alcoholism, Renal Impairment, Hypertension, Diuretic therapy. Can destroy skeletons and cause crippling. Commonly affects middle aged males.*feeding 15Nglycine to a patient who is an over producer will result in uric acid that is enriched in 15N at the N-7 of uric acid. Therapy:Colchicine and NSAIDS are superior to aspirin and paracetamol. Colchicine inhibits microtubule formation and prevents phagocytic cells from engulfing the urate crystals. Intracellular administration of corticosteroids terminate attack within 12-24 hours. Can promote renal excretion of urate by administering uricosuric agents such as citrosoda or by drinking lots of soda and liters of water per day. Also Allopurinol and its metabolite alloxanthine should be administered as they are effective inhibitors of xanthine Oxidase, and will cause a decrease in uric acid levels. Dietary control: Avoid purine rich foods, slow weight loss for obese people (sudden or rapid weight loss precipitates uric acid production), Avoidance of high fat and protein foods, Avoidance of alcohol (alcohol interferes with uric acid excretion. Acetaldehydes and acetates produced from alcohol metabolism compete against uric acid for excretion from the kidneys.

GM1 Gangliosidosis Autosomal recessive/ accumulation of Ganglioside GM1 because of deficiency of GM1 β-galactosidase. Mental retardation, liver enlargement, skeletal deformities. Get an accumulation of both gangliosides and mucopolysaccharides. Fatal Deficiency slows or inhibits formation of GM2 and release of Gal from GM1

Hartnup disease Neutral amino acid transport system defective. Chiefly tryptophan is the problem. An increase in tryptophan decreases bacterial enzyme which increases endoderivative in feces. Autosomal Recessive Won’t have significant absorption of tryptophan. Tryptophan is converted to endoderivative. Most pronounced in intestine and kidney (neutral amino aciduria) Transport system goes to enterocytes. Hyperaminoaciduria results from defects in the absorption of neutral amino acids by intestine and kidney.

Hemoglobin H disease a mildly to moderately severe hemolytic anemia; and if all four of the α-globin genes are defective, hydrops fetalis and fetal death result because α-globin chains are required for the synthesis of HbF.

Hemolytic anemia Most patients with a deficiency of a glycolytic enzyme exhibit this. Genetic deficiency of pyruvate kinase (PK) leads to Hemolytic anemia-excessive erythrocyte destruction. Hemolytic anemia in PK deficiency is a consequence of reduced rate of glycolysis and the rate of ATP synthesis being inadequate to meet energy needs of the cell and maintain the structural integrity of the Erythrocyte membrane. --Not getting ATP required by Na/K ATPase --Problems with iron transport --Can lead to lysis of RBC

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Some patients with Glycerol 6 phosphate dehydrogenase deficiency develop hemolytic anemia if they are treated with an oxidant drug (i.e., Antibiotics, Antimalarials, and Antipyretics), ingest fava beans or contract a severe infection.-- NADPH needed to reduce glutathione--Critical proteins in RBC membrane must be in reduced state

Hemosiderosis the cumulative effect iron overload

Her’s disease Type VI glycogen storage disease, deficiency in glucose-6-phosphatase. Is caused by a defect in the isozyme of glycogen phosphorylase that is present in the liver. Patients born with this disease consequently suffer hepatomegaly, moderate hypoglycemia, mild acidosis, and growth retardation.

Hereditary fructose intolerance deficiency in Aldolase B. It is characterized by vomiting, postprandial hypoglycemia, and damage to liver and kidney cells following ingestion of fructose or of fructose-containing foods, such as sucrose or sorbitol. It is due to a deficiency of the aldolase that cleaves fructose 1-phosphate, which is formed from fructose by fructokinase to dihydroxyacetone phosphate and D-glyceraldehyde. Fructose 1 phosphate accumulates in cells and is believed to underlie the hepatic and renal damage.

Hereditary hyperammonemia Failure to synthesize urea during the first week following birth. All inherited deficiencies of the urea cycle enzymes result in mental retardation.

Hexokinase deficiency ultimately reduces the amount of oxygen that is available for the tissues. Patients posses a genetic defect in the isoenzyme of hexokinase found in the erythrocyte. Because hexokinase is the first enzyme in glycolysis, the red blood cells of these patients contain low concentrations of the glycolytic intermediates, including 1,3,-BPG, the precursor of 2,3-BPG. 2,3-BPG binds to hemoglobin and lowers its affinity for oxygen. This normally allows hemoglobin to release oxygen in tissue capillaries. Consequently, the hemoglobin of these patients with low levels of 2,3-BPG has an abnormally high oxygen affinity. The oxygen saturation curves of red blood cells from a patient with hexokinase deficiency are shifted to the left, indicated that oxygen is less available for the tissues. This defect will also result in hemolytic anemia.

Homocysteinemia Cystathionine beta synthase missing because the Methionine degradation pathway is defective. Homocysteine accumulates and get cardiovascular complications and Neurological problems Elevated homocysteine associated with spinal tube birth defects.

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Homocystinuria multi-system disease. Cystathionine β synthase deficiency is most frequent cause. It is Autosomal recessive. Clinical abnormalities mainly affect the ocular, skeletal, central nervous and vascular systems, with possible involvements of other organs (including liver, hair and skin). Clinical features include dislocation of the optic lens, osteoporosis, thinning and lengthening of the long bones, mental retardation, and thromboembolism with varying extents. Patients have been treated with betain which is an oxidation product of choline and an independent source of methyl groups for methionine synthesis. The result of this treatment in some is a diminution of plasma homocysteine levels.

Produce unusual sulfur containing metabolites in the urine and may occasionally be improved by vitamin B6 pyridoxal administration

Hurler’s syndrome a mucopolysaccharidoses resulting from a deficiency of enzymes required for degradation of heparin sulfate and dermatan sulfate affected. More specifically it is an α-L-Iduronidase deficiency. There is corneal clouding, mental retardation, dwarfing, coarse facial features. There is deposition in coronary artery that leads to ischemia and early death.

Hunter’s syndrome a mucopolysaccharidoses resulting from a deficiency of enzymes required for degradation of heparin sulfate and dermatan sulfate affected. More specifically it is an iduronate sulfatase deficiency (X-linked) there is wide range of severity. Severe: dysostosis multiplex, organomegaly, no corneal clouding, but physical deformity, and mental retardation are mild to severe, death by 15.

Hyperammonemia type I defective CSPI (carbomoyl phosphate synthetase I)Ammonia, glutamine and alanine accumulateSymptoms: Hyperammonemiea (can result from complications of excessive alcohol consumption because of decreased liver function), mild hyperglycinemia, and hyperglycinuria, increased plasma glutamine, protein intoleranceurea synthesized in the liver diffuses from the blood into the intestine and is cleaved to CO2 and NH3 by bacterial urease. This ammonia is partly lost in the feces and is partly reabsorbed into the blood. In patients with kidney failure, plasma urea levels are elevated, promoting a greater transfer of urea from blood into the gut. The intestinal action of urease on this urea becomes a clinically important source of ammonia, contributing to the hyperammonemia

Hyperammonemia type II defective ornithine transcarbamoylase and ammonia, glutamine, orotic acid and sometimes uracil pyrimadase accumulatesSymptoms: Ammonia intoxication, generalWhen OTC is deficient, the carbamoyl phosphate that normally would enter the urea cycle accumulates and floods the pathway for pyrimidine biosynthesis. Under these conditions, excess orotic acid (orotate?) an intermediate in pyrimidine biosynthesis, is excreted in the urine. It produces no ill effects, but is indicative of a problem in the urea cycle.

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urea synthesized in the liver diffuses from the blood into the intestine and is cleaved to CO2 and NH3 by bacterial urease. This ammonia is partly lost in the feces and is partly reabsorbed into the blood. In patients with kidney failure, plasma urea levels are elevated, promoting a greater transfer of urea from blood into the gut. The intestinal action of urease on this urea becomes a clinically important source of ammonia, contributing to the hyperammonemia

Hypercholesterolemia (familial Hypercholesterolemia) an inherited disorder comprising of 4 classes of mutation in the LDL receptor gene.

defect (most common) results in a complete loss of receptor defect results in the synthesis of a receptor protein that is not properly processed

in the golgi apparatus and therefore is not transported to the plasma membrane defect results in an LDL receptor that is incapable of binding LDLs defect results in receptors that bind LDLs but do not cluster in coated pits and are

therefore not internalized

Can be heterozygous or homologous for a mutation in the receptor gene. Homozygotes exhibit grossly elevated serum cholesterol (primarily LDLs). The elevated LDL level results in their phagocytosis or macrophages. These lipidladen phagocytic cells tend to deposit within the skin and tendons leading to Xanthomas. A greater complication results from cholesterol deposition within the arteries leading to atherosclerosis (plaques)—major contributing factor of all cardiovascular diseasesIncreased LDL and cholesterol because of abnormal LDL receptor.

The combined drug treatment is more effective than a single drug gefcause each affects a different aspect of lipid metabolism. Lovastatin blocks endogenous cholesterol synthesis by inhibiting HMG CoA reductase, a key enzyme for cholesterol synthesis. Colestipos is an insoluble resin that binds bile acids, thus preventing their reabsorption by the intestines. Niacin is believed to inhibit the synthesis or secretion of VLDL. Together, the combined effects of these drugs can lower the total serum cholesterol.

Hyperglyceridemia (Type I) rare genetic absence of lipoprotein lipase. Results in excess triglyceride in the blood of several tissues, including liver, skin, and pancreas. There are Orange-red eruptive Xanthomas (visible subcutaneous lipid deposits within plasma tissue macrophages) over mucous membranes and skin may be seen. Fasting chylomicronemia produces a milky turbidity in the serum or plasma.

Hyperglyceridemia (Type II) Dominant genetic disease affecting 1/500 (heterogenous) individuals in the U.S. It is characterized by elevated LDL cholesterol and increased risk for the atherosclerosis and coronary artery disease. Cholesterol deposits or Xanthomas may be seen as:

Tendinous Xanthomas found around extensor or tendons or ligaments of the hands, feet, and Achilles tendons

Subcutaneous Tuberous Xanthomas firm, painless red-yellow nodules which develop in pressure areas like the elbows, knees, and the behind

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Xanthelasmas soft yellow nodules around the eyelids

Arcus Corneal arc-shaped cholesterol deposit in corneous of the eye

Hyperlipidemias represent an abnormally high level of one or more of the plasma lipoproteins. These disorders are classified on the basis of electrophoretic patterns. The most serious consequence of hyperlipidemias is the increased of atherosclerosis, an arterial disease that causes heart attacks and stroke.

Hyperphenlalaninemias phenylketonuria (PKU) caused by a deficiency of phenylalanine hydroxylase, is the most common clinically encountered inborn error of amino acid metabolism. Hyperphenylalaninemia may also be caused by deficiencies in the enzymes that synthesize or reduce the coenzyme tetrahydrobiopterin (BH4) It is frequently important to distinguish among these various forms of hyperphenylalaninemia, because their clinical management is different.

Hypertriglycerinemia a type of hyperlipidemia (type IV); deficiency apoC-II, or LPL, eruptive Xanthomas; get an increascerolse in VLDL and triacylglycerol.

Hyperuricemia uric acid levels are high. It is a risk factor for gout but uric acid accumulation has to continue for years without treatment before gouty arthritis develops.

Hypolipidemias caused by a deficiency of one or more of the plasma lipoproteins. Hypobetalipoproteinemia (partial deficiency of apoB) a rare genetic disorder

with a recessive inheritance characterized by neurological symptoms, including ataxia and mental retardation. –Plasma triacylgycerol and cholesterol levels are decreased.—there is a complete absence of β lipoproteins (no chylomicrons or VLDLs) –Absorption of fat is greatly reduced. –There is no effective treatment to prevent the neurological symptoms from appearing.

Abetalipoproteinemia absence of apo B HDL deficiency (Tangier disease) a rare familial disorder characterized by

recurrent polyneuropathy, lymphadenopathy, tonsillar hyperplasia (have orange tonsils and blood smear contain amorphous acanthocytes), and hepatosplenomegaly (from storage of cholesterol in reticuloendothelial cells) Patients serum displays inability to activate LCAT because of Apo A1 deficiency.Deficiency in HDL, leading to low levels of Apo A1 and Apo A III.

--Plasma cholesterol levels are low; triacylglycerols are normal or increased. –There is a marked decrease in plasma HDLs. –There is no known treatment

Hypothrombinemia Vitamin K deficiency

Hypothyroidism In areas of the world where the soil is deficient in iodide. Hypothyroidism is prevalent. The thyroid gland enlarges (forms a goiter) in an attempt to

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produce more thyroid hormone. In the United States table salt enriched with iodide is used to prevent hypothyroidism caused by iodine deficiency.

Hypoxanthine-Guanine Posphoribosyl-Transferase (HGPRT) deficiency a inherited X-linked recessive condition. The entire HGPRT gene cloned and sequenced, and at least 200 mutations characterized. HGPRT handles both guanines and hypoxanthines. More efficient and more active than APRT. Lack of HGPRT leads to inability or reduced ability to salvage guanine and hypoxanthine as nucleotides. Defect affects cells ability to salvage adenine, guanine and hypoxanthine as nucleotides. Uric acid excreted in large amounts in urine or build in tissues. Accumulation of uric acid in cells causes urate crystals of sodium and or Calcium to form stones in tissues including kidneys and soft tissues including toes and ear lobes.

I cell disease or mucolipidosis II result because patients are deficient in a large number of lysosomal enzymes. Accordingly, their lysosomes contain a large amount of undegraded glycolipids and glycosaminoglycans, since they cannot be hydrolyzed. This results in severe neurologic damage and bone deformities. People affected by this disease are deficient in the golgi complex enzyme activity that is responsible for phosphorylating the mannose residue of glycoproteins to mannose 6-phosphate, which is necessary to direct lysosomal-targeted enzymes to lysosomes instead of to extracellular secretion. Enzymes absent in cell but present in serum.

Iron poisoning effect heme and ATP production-cytochromes of ETC. High tissue levels of iron correlate with increased risk of myocardial infarction. It has been suggested that unbound inorganic iron can promote the formation of reactive oxygen radicals, particularly the conversion of H2O2 to highly reactive hydroxyl radicals. The enhanced formation of oxygen radicals favors the oxidation of LDL.

Jamaican vomiting sickness from eating unripe akee fruit which contains hypoglycin A, an unusual amino acid that is metabolized to an intermediate, a suicide inhibitor of MCAD

Jaundice aka (icterus) refers to the yellow color of skin and sclerae caused by deposition of bilirubin secondary to increased bilirubin levels in the blood. Not a disease but usually a symptom of an underlying disorder. Can result as a complication of Excessive alcohol consumption which causes a decrease in liver function

Jaundice in Newborns newborns often accumulate bilirubin because of hepatic bilirubin glucuronyl transferase being low at birth and reaching adult levels in a couple weeks. Elevated bilirubin can diffuse into basal ganglia and cause toxic encephalopathy

Hemolytic jaundice (prehepatic jaundice)- the liver has the capacity to conjugate and excrete over 3000 mg bilirubin per day, whereas the normal production of bilirubin is only 300 mg/day. This excess capacity allows liver to respond to increase heme degradation with corresponding increase in conjugation

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and secretion of bilirubin diglucuronide. More bilirubin is excreted into bile and the amount of urobilinogin entering the enterohepatic circulation increases and urinary urobilinogen increases, unconjugated bilirubin is elevated in the blood.

o Acute hemolytic anemiao Neonatal physiologic jaundiceo Chronic hemolytic anemia

Hepatic jaundice1) conjugation failure

a. Neonatal physiologic jaundiceb. Crigler-Najjar disease

2) Bilirubin transport disturbancesa. Preconjugation transport failure (Gilbert’s disease)b. Postconjugation transport failure (Dubin-Johnson disease)

3) Diffuse hepatocellular damage or necrosisa. Hepatocellular jaundice- damage to liver cells causes a decrease

in both bilirubin uptake and production of conjugated bilirubin. Unconjugated bilirubin occurs in the blood and increased urobilinogen in the urine. The urine is dark in color and stools are a pale clay color. Plasma levels of AST (SGOT) and ALT (SGPT) are elevated and patient experiences nausea and anorexia.

b. Viral hepatitisc. Toxic hepatitisd. Cirrhosis

4) Intrahapatic obstruction (edema)

Posthepatic jaundice obstruction of the common bile duct Obstructive jaundice- not due to overproduction of bilirubin but

from obstruction of the bile duct. Patients experience GI pain, nausea, and produce stools that are pale, clay color. The liver regurgitates conjugated bilirubin into the blood which is excreted in the urine.

o by stoneso by neoplasmso by spasms or strictures

Krabbe’s disease (sphingolipidosis) Autosomal recessive; accumulation of Galactocerebroside because of a deficient galactocerebrosidase (beta-galactosidase) which affects the brain, liver and spleen. Mental retardation, blindness, deafness, one can see paralysis, convulsions and there is almost total absence of myelin. Globoid bodies in white matter of brain and disease. Is fatal early in life, death by age 2. Deficiency slows or inhibits formation of Ceramide and release of galactose from Gal-Cer.

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Kwashiorkor due to inadequate intake of good quality protein and diet consisting of mainly high starch foods. (Consuming a calorie adequate diet that is deficient in proteins) Victims have a decreased mass and function of heart and kidneys there is a decrease in blood volume, hematocrit, and serum albumin concentration. There is atrophy of the pancreas and intestines and the clinical symptoms include: edema, growth failure, apathy, skin rash, desquamation, pigment changes and ulceration, loss of hair, liver enlargement (hepatomegaly) anorexia and diarrhea

Lactose intolerance deficiency in intestinal beta Galactosidase (lactose) often a result to glucose and galactose. This disorder may be genetic or acquired. In infants, this has serious consequences since affected infants are not able to tolerate milk, which is normally their primary food. The condition is treated by substituting milk with lactose-free formula. In adults the condition is less serious and is treated by avoided milk products.

Lathyrism caused by regular ingestion of the seeds from the sweet Lathrus odoratus, which contain a compound that specifically inactivates lysyl Oxidase. The resulting reduced cross-linked of collagen fibers produces serious abnormalities of the bones, joints, and large blood vessels.

LCAT deficiency low levels of lecithin; cholesterol acyltransferase. This enzyme makes cholesterol esters in the blood. LCAT transfers cholesterol esters to VLDL and LDL in exchange for triacylglycerol and carrying cholesteryl esters to the liver, where the HDL is degraded and cholesterol released.

Leber’s disease (Leber’s optic atrophy) X-linked disease characterized by progressive bilateral atrophy of the optic nerve, leading to rapid loss of vision and permanent central blindess. Leber’s disease is due to genetic defect of NADH-CoQ reductase of complex I.

Leigh’s Encephalomyelopathy a lack of pyruvate carboxylase activity

Lesch-Nyhan Syndrome hypoxanthine-guanine phosphoribosyl transferase(HPGRT) Deficiency (a purine salvage enzyme also can recycle hypoxanthine and guanine). X- linked and affects only males.Exhibit gout-like symptoms and have similar clinical lab results and symptoms. Their pains and uric acid level respond to allopurinol. However, their neurological symptoms are not treatable with allopurinol.HPGRT deficiency leads to excessive uric acid (hyperuricemia)Clinical features: overproduction of uric acid and its consequences, neurobehavioral manifestations indicative of CNS dysfunction and miscellaneous symptoms that includes growth retardation and (megablastic) anemiaHallmark symptom is compulsory self mutilation. Biting being most common (lips, fingers, arms, shoulders or toes) Other forms include banging head against wheel chair supports, injuring hands or feet on sharp parts of wheelchairs and poking eyes with fingers.

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Treatment: properly designed wheelchair, administration of allopurinol to inhibit the catabolism of xanthine and hypoxanthine into uric acid by xanthine Oxidase. Allopurinol is effective in reducing hyperuricemia and the associated nephrotoxicity but appears to have no effect on the neurobehavioral aspects.

Lipoprotein (a)/LP(a) is a variant of LDL with high content of sialic acid, it contains Apo A which shares high sequence homology with plasminogen, and as such, it is thought that LP(a) interferes with fibrinolysis and thus promote thrombosis.

LP(x) is an abnormal lipoprotein, occurs in patients with obstructive liver disease of LCAT deficiency. The lipid content of LP(x) is unesterified cholesterol, the major apoproteins of LP(x) isolated from patients with LCAT deficiency are albumin, apoC, and apoA, and patients with obstructive liver disease lack apoA-1, the activator of LCAT

Lynch Syndrome defects in genes for base mismatch repair

Manic depression multifactorial disease not inherited in a simple mendelian pattern.Li+ admin-PIP2-IP3

Maple Syrup Urine Disease (MSUD) Autosomal recessive the alpha keto acid dehydrogenase (an absence or decrease in activity) that oxidatively decarboxylates the branch chain amino acids is defective. As a result, the branched chain amino acids and their alpha keto analogues (produced by transamination) accumulate. They appear in the urine, giving it the odor of maple syrup or burned sugar. Symptoms include vomiting, lethargy, mental retardation and severe brain damage, Symptoms occurs in infancy and if not treated, death often occurs by first year.

Marasmus (symptoms tend to overlap Kwashiorkor)Due to deficiency of protein and energy intake, as in starvation, and it results in generalized wasting (atrophy of muscles and subcutaneous tissues, emaciation and loss of adipose tissue) Edema, Hepatomegaly, and depigmentation occurs in Kwashiorkor but not in marasmus yet distinction between two disorders is not always clear

Marian Syndrome sometimes (but not always) defects in fibrillin characterized by tall, thin phenotype and fragile blood vessels. Patients have been known to die of aortic aneurysm.

Maroteaux-Lamy- N acetyl-galactosamine-4-sulfatase deficiency

MCAD deficiency most common. In first years of life this deficiency will become apparent following a prolonged fasting period. Symptoms include vomiting, lethargy and frequently coma. Excessive urinary excretion of medium chain dicarboxylic acids as well as their glycine and carnitine esters is diagnostic of this condition. In case of deficiency taking care to avoid prolonged fasting is sufficient to prevent clinical problems.

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*Jamaican vomiting sickness from eating unripe akee fruit which contains hypoglycin A, an unusual amino acid that is metabolized to an intermediate, a suicide inhibitor of MCAD 10 % of infants who die from SIDS have a deficiency of MCAD

McArdle’s syndrome Type V glycogen storage disease (skeletal muscle glycogen phosphorylase deficiency) Skeletal muscle affected, liver enzyme normal. Temporary weakness and cramping of skeletal muscle after exercise. No rise in blood lactate during strenuous exercise. Normal mental development. Myoglobinuria in later life. Fair to good prognosis and have a high level of glycogen with normal structure in muscle.

Medium-chain fatty acyl CoA dehydrogenase deficiency it is found in approximately 1 in 10,000 births and is therefore more prevalent than phenylketonuria. It causes a decrease in fatty acid oxidation and severe hypoglycemia, and is the cause of up to 10% of cases of sudden infant death syndrome (SIDS)

Megablastic anemia deficiency of Vit B12 or Folate

Can be found occasionally in Lesch-Nyhan Patients. Adenine supplements are found to effective in reversing the anemia suggesting that purine limitation may be the cause of the anemia. It has been suggested that bone marrow stem cells are particularly dependent on HPRT mediated purine salvage to maintain cell purine levels

Menke’s disease due to an inability to absorb copper from the intestine.

Metabolic acidosis A pH imbalance caused by HCO3-; HCO3- decreases and pH decreases

Metabolic alkalosis A pH imbalance caused by HCO3-; HCO3- increases and pH increases

Metachromatic leukodystrophy (sphingolipidoses) autosomal recessive. Accumulation of β- Sulfogalactocerebroside because of a deficient sulfatide sulfatase (arylsulfatase A) affecting the Brain. There is an accumulation of sulfatides. Mental retardation, Demyelination, progressive paralysis and dementia. Nerves stain yellowish-brown with cresyl violet (metachromasia) Fatal in first decade, Deficiency of enzyme slows or inhibits formation of Gal-Cer with release of SO3H2 from SO3H-Gal-Cer

Methylmalonic academia defect in the transferase that forms adenosylcobalamin. Individuals with this defect are usually recognized early in life and found to be acidotic (blood pH at 7 rather 7.4) and found excreting large quantities of methylmalonic acid. Individuals improve upon administration of large doses of cobalamin. Others have acidosis and excrete methylmalonic acid but do not respond to cobalamin these individuals often have a lethal lack of the methylmalonyl CoA mutase enzyme.

Methylmatonic academia disorders of methylmalonyl-CoA and B12 metabolism

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Methylmalonic aciduria patients also exhibit hyperammonemia. Results in metabolic acidosis and developmental retardation.

Microcytic hypochromic anemia Iron or vitamin B6 deficiency Small RBC (hyperchromic low levels of hemoglobin)

Morquio A galactose or N-acetyl-galactosamine-4-sulfate sulfatase deficiency (deficiency of β Galactosidase) (inability to degrade keratin sulfate GAG chains) It has a distinctive skeletal abnormalities, corneal clouding, odontoid hypoplasia;

Morquio’s galactose or N-acetyl-galactosamine-4-sulfate sulfatase deficiency inability to degrade keratin sulfate GAG chains)

Niacin (B3) deficiency Causes pellagra, a disease involving the skin, GI tract, and central nervous system. The symptoms of pellagra progress through the three Ds: Dermatitis, Diarrhea, Dementia and if untreated Death. Pellagra may be related to deficiency of Trp which supplies a portion of the niacin requirement)

Coenzyme: NAD (H), NADP (H) Enzyme including: Glyceraldehyde 3 phosphate dehydrogenase (Glycolysis) Pyruvate dehydrogenase (TCA), Alcohol dehydrogenase (Alcohol dehydrogenase), G6Pdehydrogenase [NADP] (PPP or HMP shunt)Group transferred: Hydride atom

Niemann-Pick B(a spingolipidoses)Autosomal recessive disease resulting in an accumulation of sphingomyelin because of a deficient sphingomyelinase which affects the brain (mental retardation), liver and spleen (enlargement of both) This is fatal in early life. The enzyme deficiency effects the production of Ceramide and release of phospocholine (choline-P) from phosphorylcholine-Cer (sphingomyelin)SS: zebra bodies

Orotic aciduria Orate phosphoribosyl transferase and OMP decarboxylase are separate domains of a single polypeptide. Low activities of orotidine phosphate decarboxylase and orate phosphoribosyltransferase result in abnormal growth, megablastic anemia, and the excretion of large amounts of oratate in the urine. Feeding a diet rich in uridine results in improvement of the anemia and decreased excretion of orotate.

Osteogenesis imperfecta (various defects in type I collagen)This disease, also known as brittle bone syndrome, is also a heterogeneous group of inherited disorders that is distinguished by bones that easily bend and fracture. Retarded wound healing and a rotated and twisted spine leading to a hump-back appearance are common features of the disease.

Pellagra defective kynurenine hydroxylase and or Vitamin 6 deficiency. Leads to pellegra

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Pentosuria L-xylose reductase deficiency

Pernicious anemia HCL production fails. Pepsin-peptide complex does not dissociate and remains inactive. Results from inability to absorb B12 due to failure of the stomach to produce intrinsic factor. The disease is most commonly due to an autoimmune destruction of the gastric parietal cells that are responsible for the synthesis of intrinsic factor. Consequences include macrocytic anemia, megaloblastosis of bone marrow, degeneration of axis cylinders of spinal cord neurons, lesions of mucous surfaces, glossitis, and methylmalonic aciduria. A long term, strict vegetarian diet may also lead to a deficiency of vitamin B12

Phenylketonuria deficiency in the phenylalanine hydroxylase enzyme system, resulting in mental retardation, if not treated by dietary restrictions early in life. PKU patients should avoid aspartame.phenylalanine is present in elevated concentrations in tissues, plasma, and urine. Phenyllactate, pheylacetate, and phenylpyruvate, which are not normally produced in significant amounts in the presence of functional phenylalanine hydroxylase, are also elevated in PKU. Mental retardation, failure to walk or talk, seizures, hyperactivity, tremor, microcephally, and failure to grow are characteristic findings in PKU. Patients show a deficiency of pigmentation.

There is a blockage of conversion of phenylalanine to tyrosine in PKU patients(Phenyl Ketonuria)

PKU /Classical caused by defective phenylalanine hydroxylase (PAH) leading to inability to convert phenylalanine to tyrosine. Tyrosine becomes and essential amino acid needed from diet or a supplement. Restriction of phenylalanine and aspartamine from the diet is required to reduce level of phenylalanine toxicity because Phenylalanine will pile up leading to phenyl pyruvate, phenyl acetate, and phenyl lactate. The cofactor BH4/THB is present and available. Therefore the conversion of tyrosine to catecholamines as well as conversion of tryptophan to serotonin is not impaired. Disease symptoms of mental retardation

PKU /Atypical/Secondary inherited defect on dihydrobiopterin (DHB) reductase or deficiency of THB/BH4 (about 20% of infants born with PKU have atypical PKU. Treatment requires both the restriction of dietary phenylalanine and supplementation with dopamine and 5-hydroxytryptophan because both Phenylalanine Hydroxylase and tryptophan hydroxylase require BH4. The supplements provide intermediates in catecholamine and serotonin synthesis which is impaired in PKU patients with a defect in DHB reductase. Disease symptoms of Mental retardation

PKU /Maternal -occurs in unborn children of phenylketonic mothers whose diets are not restricted in phenylalanine. (During pregnancy mother should maintain blood

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phenylalanine level between 2 and 4 Mg/dl. Phenylketones generated in the mother readily cross the placenta, resulting in brain damage in the unborn child.

Pompe’s disease (also called lysosomal glycogen storage disease) deficiency in α glucosidase, leading to accumulation of glycogen in the lysosomes. The only storage disease of glycogen storage that has anything to do with lysosome.

Prion disease Prion proteins are believed to cause a neurodegenerative disease by acting as a template to misfold other cellular prion proteins into a form that cannot be degraded. The word prion stands for proteinaceous infectious agent. The prion diseases can be acquired either through infection (mad cow disease) or from sporadic or inherited mutations (ex: Creutzfeldt-Jakob disease). Have connection with growth hormone inoculations in the U.S and France, to ritualistic cannablism in the Fore tribespeople.

Propionic Acidemia proplonyl-CoA carboxylase deficiency

Proprionic aciduria

Proprotein lipase deficiency expect high triglyceride content in blood

Purine Nucleoside Phosphorylase (PNP) deficiency deoxyadenosin accumulates. It causes defects in DNA synthesis but only T cells are more sensitive to PNP defects. Therfore the immunodeficiency associated with PNP defects only affects T cells but not B cells.

Pyruvate Kinase deficient RBC Pyruvate kinase exists as isoenzymes, and genetic defects in isoenzyme subunits may selectively affect the glycolytic enzymes of the erythrocyte. Any defect in a glycolytic enzyme (PK) that does not allow adequate ATP production, and consequently reduces activity of the ATPase—ion pump, decreases the stability of erythrocytes and causes them to swell and lyse. Of defects in glycolysis that cause hemolytic anemia PK deficiency is the most common.

Rafsums disease – a rare inherited disorder in which patients lack the mitochondrial α oxidizing enzyme. Disease caused by inability to properly degrade phytanic acid, resulting in an accumulation of this lipid in plasma (serum) and tissues. This leads to severe symptoms, including cerebella ataxia, retinitis pigrnentosa, nerve deafness and peripheral neuropathy. The restriction of dairy products and ruminant meat from the diet can ameliorate the symptoms of this.

Respiratory acidosis a pH imbalance caused by a change in CO2 levels. PCO2 increases and pH decreases

Respiratory alkalosis a pH imbalance caused by a change in CO2 level PCO2 decreases and pH increases

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Respiratory distress syndrome (hyaline membrane disease) in infants is associated with insufficient surfactant production, and accounts for approximately 15% of all neonatal deaths in western countries. Respiratory failure due to an insufficient amount of surfactant can also occur in adults whose surfactant-producing pneumocytes have been damaged or destroyed, for example, as an adverse side effect of the use of immunosuppressive medication or chemotherapeutic drugs.

Riboflavin deficiency Mot associated with a major human disease, although it frequently accompanies other vitamin deficiencies. Symptoms include dermatitis, cheilosis (fissuring at the corners of the mouth), and glossitis (the tongue appearing smooth and purplish)

Sandhoff’s disease Autosomal recessive, accumulation of Ganglioside (GM2) and globoside from deficiency of Hexosaminidases A and B. Get Same symptoms of Tay-Sachs but disease progresses more rapidly [Mental retardation, blindness, cherry red macula, muscular weakness, seizures and fatal]Deficiency slows or inhibits formation of Gal-Gal-Glc-Cer with release of Gal NAc from GalNac-betaGal-alphaGal-beltGlc-betaCer (globoside)

Sanfilipo A- D (MPS III) Four enzymatic steps are necessary for removal of N-sulfated or N-acetylated glucosamine residues from heparan sulfate:

Type A: Heparan sulfamidase deficiency –see a profound mental deterioration, hyperactivity, relatively mild somatic manifestations.(deficiency in heparin N-sulfatase)

Type B: N-Acetyglucosaminidase deficiency Type C: N-Acetyltransferase deficiency Type D: N-Acetylglucosamine deficiency

Severe nervous sytem disorders result from all types as well as mental retardation

Scheie syndrome (MPS I S) α-L-Iduronidase deficiency (MPS I H and MPS I S are allelic disorders) Corneal clouding, stiff joints, aortic valve disease, normal intelligence and life span. Degradation of dermatan sulfate and heparin sulfate affected

Scurvy deficiency in L-Ascorbic acid (vitamin C). Scurvy causes impairment of wound healing and bone formation and a lessening of the integrity of blood vessels, which leads to a hemorrhagic diathesis. Anemia is often present.

Sellweger syndrome absence of or deficiency of perioxisomes, leading to inability to make plasmalogens and some platelet activating factor; also patients cannot oxidize very long-chain (above 22 C) fatty acids

Severe Combined Immunodeficiency (SCID) (genetic not acquired) SCID could also result from mutations affecting the expression of IL-2 receptor γ chain on stem cells, leading to lack of maturity of beta cells. (SCID) heterogenous group of inherited

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disorders characterized by a failure in the cellular maturation of lymphoid stem cells resulting in reduced numbers and function of both B and T lymphocytes and immunosuppression. Have a lack of immune response. About 15-30% of SCID patients suffer from deficiency of the enzyme Adenosine Deaminase (ADA), a zinc dependent enzyme, which normally catalyzes irreversible deamination of deoxyadenosine to deoxyinosine. Others suffer from deficiency of Purine Nucleoside Phosphrylase (PNP)Deoxyadenosine accumulates and is salvaged by a nucleoside kinase which concerts it to dAMP leading to accumulation of dATP, a potent feedback inhibitor of ribonuclotide reductase, key for biosynthesis of deoxyribonucleotides (dNTPs) precursors to DNA synthesis.

Sickle cell anemia (hemoglobin S disease) most common disorder resulting from the production of a variant hemoglobin. Homozygous recessive disorder occurring in individuals who have inherited two mutant genes that code for synthesis of the β-chains of the globin molecules. It is characterized by a lifelong hemolytic anemia, painful crises and increased susceptibility to infections and other indications of poor circulation.

Sideroblastic Anemia decrease of heme production and increase in ferritinB6 deficiency; Required by Delta ALA synthetase in HEME synthesisUnderproduction of HEME (key characteristic)Underutilization of iron; Ferritin (iron storage protein) accumulation (key char.)Macrophages loaded with ferritin called sideroblasts

Sitosterolemia a rare inherited Autosomal sterol storage disorder due to defects in A TP binding cassette (ABC)/. Family transporters that mediate cholesterol efflux.

Steatorrhea- Pancreatic Lipase Deficiency- steatorrheaabnormal appearance of lipids caused by abnormalities in protein digestion. Seen in individuals with a deficiency in pancreatic secretion (ex: b/c of chronic pancreatitis, cystic fibrosis, or surgical removal of pancreas) the digestion and absorption of fat and protein is incomplete causes this and undigested protein in the feces.

Tangier disease (HDL deficiency) due to defect ABC-1 Transporter-protein that carries cholesterol to HDL so LCAT (activated by Apo-A1) can convert cholesterol to cholesterol estersmost cholesterol looks DISCOID because does not contain cholesterol esters to become spherical it is a rare familial disorder characterized by recurrent polyneuropathy, lymphadenopathy, tonsillar hyperplasia, and hepatosplenomegaly (from storage of cholesterol in reticuloendothelial cells)--Plasma cholesterol levels are low; triacylglycerols are normal or increased. –There is a marked decrease in plasma HDLs. –There is no known treatment

Tay-Sachs disease (spingolipidoses) Autosomal recessive/ get an accumulation of Ganglioside GM2 because of a deficient Hexosaminidase A which affects the brain.

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Increases gangliosides. See mental retardation, blindness, cherry red macula, muscular weakness, seizures and fatal (death by age 3)Deficiency of enzyme slows or inhibits formation of NANA-Gal-Glc-Cer (GM3) and release of GlcNAc from GM2Tay-Sachs variant- deficiency of both hexosaminidase A and hexosamindase B (B subunit) Sandhoff’s disease

Thalassemias (alpha silent, trait, HbH, hydrob fetalia, Beta minor and Beta major

Thalassemia hereditary hemolytic disease(s) in which an imbalance in the synthesis of globin chains occurs. As a group they are the most common single gene disorders in humans. Normally synthesis of the alpha and beta globin chains are coordinated so that each alpha globin chain has a beta globin chain partner. This leads to the formation of α2β2 or hemoglobin A. In the thalassemias, the synthesis of either α or β chain is defective. Can be caused by a variety of mutations, including gene deletions, substitutions or deletions of one to several nucleotides in the DNA.

α-Thalessemias defects in which the synthesis of alpha globin chains is decreased or absent. Because each individual’s genome contains four copies of the alpha globin gene there are several levels of alpha globin chain deficiencies. If one of the four genes is defective, the individual is termed a silent carrier of α-Thalessemia, because no physical manifestations of the disease occur. If 2 α-globin genes are defective, the individual is designated as having α-Thalessemia trait; if three are defective, the individual has hemoglobin H disease. Hydrops fetalis and fetal death result, because α-globin chains are required for the synthesis of HBF. Oxygen association curves are almost hyperbolic, indicating that these tetramers have very high oxygen affinities. This makes them essentially useless as oxygen deliverers to the tissues.

Hemoglobin H disease a mildly to moderately severe hemolytic anemia; and if all four of the α-globin genes are defective, hydrops fetalis and fetal death result because α-globin chains are required for the synthesis of HbF.

β thalessemias synthesis of β globin chains is decreased or absent, whereas α-globin chain synthesis is normal. α-globin chains cannot form stable tetramers and therefore precipitate, causing the premature death of cells initially destined to become mature red blood cells. Because there are only two copies of the β globin gene, individuals with gene defects have either β thalassemia trait (β thalassemia minor) if they have only one defective β globin gene, or β thalassemia major, if both genes are defective. Because the β globin gene is not expressed until late in fetal gestation, the physical manifestations of β thalassemia appear only after birth. Those individuals with β thalassemia minor make some β chains and usually do not require specific treatment. However, those infants born with β thalassemia major have the sad consequence of being seemingly healthy at birth, but becoming severly anemic, usually during the first or second year of life. These patients require regular transfusions of blood. Bone replacement has been a boon to these patients in the last decade or so.

Hemosiderosis the cumulative effect iron overload

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Trichothiodystrophy (TTD) In humans, defects in (NER) nucleotide-excision repair can lead to this, Cockayne’s Syndrome (CS) and Xeroderma pigmentosum (XP) but CS and TTD patients are not predisposed to cancer as is XP patients. Due to defects in XPB, XPD and XPG genes. Characteristics include: Brittle hair, Short stature, Scaly Skin, and Mental Underdevelopment.

Tyrosinemia I Fumarylacetoacetate hydroxylase missing because the Tyrosine degradation pathway is defective. Fumarylacetoacetate accumulates and get symptoms of Liver failure, death early in life

Tyrosinemia II Tyrosine aminotransferase missing because the Tyrosine degradation pathway is defective. Tyrosine accumulates and get in neurological defects.

Tyrosinosis renal complications, and excretion of hydroxphenyl pyruvate resulting from deficiency of p-hydroxyphenyl pyruvate Oxidase.

Von-Gierke’s disease Type 1 glycogen storage disease. Deficiency of glucose-6-phosphatase. This disease effects liver, kidney, and intestine. Fasting hypoglycemia is severe, and fatty liver (hepatomegaly). Hyperlacticacidemia and hyperuricemia and lactic academia due to enhancement of inability to release free glucose from the liver(and PPP). Normal glycogen structure and an increase in the glycogen stored. This disease leads to an increase in cellular levels of ribose phosphates, which increases levels of PRPP. These elevated levels result in increased de novo synthesis of purines.Type 1b results from deficiency of translocase. Expect hypoglycemia

Wernicke-Korsakoff Syndrome (WKS) neurological syndrome caused by long-term alcoholism. It is due to malnutrition in alcoholics specifically caused by Thiamine (Vit B12) deficiency as alcoholics take in far less thiamine due to malnutrition. Characterized by Encephalopathy, mental confusion, ataxia and polyneuropathy in addition to Psychosis and memory impairment. Treatment of Thiamine administration can reverse syndrome

Wolman’s disease lack of acid lipase; characterized by accumulation of excessive cholesterol esters in peripheral tissuess

Xeroderma Pigmentosum A skin cancer caused by defective repair of DNA. Clinical syndrome includes marked sensitivity to sunlight or UV light; dry skin and atrophy of the dermis, scarred eye lids, XP is an Autosomal recessive disease that occurs with a frequency of about 1 in 250,000, but it display substantial heterogeneity.

ZellWeger Disease/syndrome doesn’t have or have a deficiency with perioxisomes. Catalyzed by—Beta Oxidation of Very long chain fatty acid,--part of synthesis of bile acids take place,--Plasmologen formation-acts as platelet activator. There is an accumulation of very long chain fatty acid (›22C) * can have neurological defects

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Lipid Metabolism Disorders

Other inborn errors of ureogenisis

Some human cancers (e.g., teniposide)

STDs and UTIS (e.g., ciprofloxacin, nalidixic)

Notes and explainations taken from Lippincott’s illustrated reviews 2nd edition; The national medical series for independent study 3rd edition biochemistry; Smith, Marks, and Lieberman Basic Medical Biochemistry A clinical approach 2nd edition; Voet, Voet, Pratt, Fundamentals of biochemistry upgrade edition

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