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MPPC Disease Terms Part 1
Terms in this set (122)
-When TCA cycle or respiration is blocked, such as under anaerobic conditions, pyruvate accumulates, leading to excess lactate, which results in acidosis. (Lactate is negatively charged, so when transported out in blood, protons are released from other sources in order to balance the charge).
-Associated (anaerobic) conditions/disorders: physical exercise, severe lung disease, high altitude, drowning, severe anemia, sickle cell crisis, carbon monoxide poisoning, cyanide poisoning, Von Gierke disease, Pyruvate dehydrogenase deficiency, Leukemia/metastatic carcinoma
Two different forms:
1. Aresenate = structural analog of phosphate; normally glyceraldehyde3-P generates 1,3bis-phosphoglycerate- with aresanate, can replace phosphate and put on bisphosphoglycerate, gets hydrolyzed & decouples ATP synthesis from glycolysis
*Aresenite = more severe than aresenate; not an analog, but anion form - binds (inhibits) lipid acid cofactor part of pyruvate dehydrogenase enzyme, which converts pyruvate into Acetyl CoA. First step relies on thymine cofactor and 2 thiol form } arsenite binds to this & halts reaction; citric acid cycle backs up, so much more serious condition
Pyruvate kinase deficiency
-Enzyme converts PEP to pyruvate & generates ATP in the process
-Affected isozyme only present in red blood cells (lack of energy problem only in RBCs since glycolysis is only pathway of ATP production)
-Lack of ATP form glycolysis impairs Na+/K+ ATPase -> loss of intracellular K+ & increase of intracellular Na+ ; cellular swelling causes rigidity of RBC and splenic hemolysis
-Results in chronic hemolytic anemia
-Treatment = splenectomy, blood transfusions, iron chelation
Pyruvate caboxylase deficiency
-Loss of PC enzyme: build up of pyruvate, lactic acid, alanine, lactic acidosis, hypoglycemia (lack of gluconeogenesis), neurological dysfunction (TCA defects). Also affects myelin sheath and neurotransmitters.
Symptoms: developmental delay, buildup of lactic acid (vomiting, abdominal pain, fatigue) triggered by illness or fasting.
Rare, recessive (1:250,000 births worldwide); most mutations are sporadic arising in parents' germ cells
Type A: infantile, North American (Algonquin Indians)
Type B: severe, neonatal, Europe (France)
Type C: mild, intermittent / benign
Treatment: no effective treatment. Although if less severe form, can supply biotin cofactor to less active enzyme
Pyruvate dehydrogenase deficiency
Mutations in PDH enzyme limit conversion of pyruvate to acetyl-CoA. => ATP is reduced, lactate accumulates.
Metaboloic form (severe): presents with overwhelming lactic acidosis at birth, with death in the neonatal period.
Chronic neurological form (less severe): lactic academia moderate, but there is profound psychomotor retardation.
X-linked (E1alpha subunit): presents differently in males and females.
*Neurological symptoms arise because brain depends on glucose oxidation for energy supply.
Treatment: high fat / low-carb (ketogenic) diet, thiamin cofactor supplement
Acute cyanide poisoning
*Cyanide (CN-) blocks electron transport chain by binding ferric (Fe3+) iron in cytochrome oxidase
=> Results in hyperventilation from massive lactic acidosis due to switch to anaerobic glycolysis.
*Acid form HCN (prussic acid) highly diffusible, can cause death instantly. Bitter almond smell.
*Treatment: Nitrite used to oxidize hemoglobin to methemoglobin (Fe3+), which binds cyanide tightly, removing it from cytochrome oxidase.
Note: cyanide from dietary sources (almonds, nuts, amygdalin) or medicine (nitroprusside) is detoxified by enzyme rhodanase in the liver, reacts cyanide with thiosulfate to form harmless thiocyanate
MERRF: Myoclonic Epilepsy and Ragged-Red Fiber disease
-Caused by point mutation in the mtDNA gene MT-TK, which encodes tRNA(lys).
-Onset of symptoms: Late childhood to adult.
-Progressive myoclonic epilepsy (neurodegeneration)
-Clumps of diseased mitochondria appear in muscle fibers (stain red); destruction of muscle due to high energy demand
-Slowly progressive dementia.
-Treatment: none effective, but
Coenzyme Q-10 and L-carnitine
have been attempted
Leber's hereditary optic neuropathy
-Sudden onset of blindness in young adults caused by degeneration of optic nerve.
-Most common mutation is in NADH-Q reductase (Complex I); or other mutations that impair respiratory chain (NADH-Q reductase, QH2-cytochrome c reductase, cytochrome oxidase).
-Optic nerve has high energy demand and relies entirely on oxphos for ATP supply.
-Prevalence: 1 in 9000 in Northern Europe, 1 in 30,000 in Europe
Leigh syndrome: subacute necrotizing encephalopathy
-Progressive neurodegenerative disorder the presents in early childhood and often results in death within two years, distinctive neuropathology.
-Frequent mutations in respiratory complex I or IV.
-Also, an X-linked form: mutation of mitochondrial encoded pyruvate dehydrogenase complex.
-Affects central nervous system; movement disorders, dystonia, cystic cavitation, breathing abnormalities.
-Patients who survive are mentally retarded.
Defect in medium chain acyl-CoA dehydrogenase impairs ability to break down MCFA.
Prevalence: 1:15,000 (1:100 carrier frequency). 80% of patients have a common A985G transition (Lys to Glu); yet there is clinical heterogeneity.
Manifestation: intermittent hypoketotic hypoglycemia triggered by prolonged fasting, exercise, or illness.
Treatment: high-carbohydrate/low fat diet, avoidance of fasting (mainly preventative).
Prognosis: excellent if caught early, but can be suddenly fatal if undetected, frequently underlying cause in cases of sudden infant death syndrome (SIDS).
CPT II (carnitine palmitoyl transferase II) deficiency
-Most common inherited carnitine metabolism disorder is CPT II deficiency, which is characterized by recurrent episodes of acute myoglobinuria precipitated by prolonged exercise or fasting.
-CPT II: transfers FA from carnitine back to CoA once in mitochondrial matrix to proceed to B-oxidation
*Adult: mild, myopathic form. Symptoms include rhabdomyolysis (breakdown of muscle fibers, reslease of myoglobin), myoglobinuria, myalgia (muscle pain), weakness. Symptoms induced by exercise, fasting, high-fat diet, cold temperature, infection.
*Infantile: severe, multisystemic. Characterized by hypoketotic hypoglycemia (low levels of fat breakdown products and blood sugar), seizures, hepatomegaly, cardiomyopathy.
*Neonatal: lethal within 1-4 days. Respiratory failure, hypoglycemia, seizures, hepatomegaly, liver failure, cardiomegaly.
Avoidance of fasting, extensive exercise, lipid intake
Medium chain FA triheptanoin (tri-C7)
Less LCFA, more SCFA in diet
Jamaican vomiting sickness
Caused by the ingestion of hypoglycin, a toxin present in the unripe fruit of the akee tree.
Children who eat this unripe fruit develop a severe hypoglycemia which is often fatal.
*Hypoglycin acts by inhibiting short and medium chain acyl CoA dehydrogenases.
Because more glucose must be oxidized as fuel, blood glucose levels fall to extremely low levels.
Fatty acid levels rise, omega-oxidation increases, excess dicarboxylic acids are excreted in the urine.
Defect in propionyl-CoA carboxylase defect, which converts propionyl-CoA into methylmalonyl-CoA, leads to build up of priopionate and acidemia.
Diagnosis: usually diagnosed in infants by high levels of organic acids in urine.
Prevalence: 1:35,000 US live births. 1:3,000 in Saudi Arabia, also common in Amish and Mennonite.
Symptoms: frequent vomiting, protein intolerance, metabolic acidosis ketoacidosis, lethargy, developmental delay, mental retardation, hypoglycemia, hypotonia, hyperammonemia.
Treatment: Bicarbonate to correct the acidosis. Diet low in valine, methionine, isoleucine, and threonine to minimize propiogenic substances (low protein/high carbohydrate diet).
Defects in methylmalonyl CoA mutase (MCM) enzyme that converts methylmalonyl-CoA to succinyl-CoA, leads to buildup of methylmalonic acid, which is excreted at high levels in the urine.
Defects in the Vitamin B12 synthetic enzymes (or nutritional deficiency) can also lead to the same condition.
Symptoms: metabolic acidosis, failure to thrive, hypoglycemia, hypotonia, hyperammonemia, neurological symptoms,coma, seizures, mental retardation.
Treatment: diet low in branched amino acids, odd chain FA, Vitamin B12 (cobalamin) supplement, carnitine supplement.
Zellweger Spectrum Disorder
-Defect in peroxisome biogenesis due to mutations in several peoxin family genes
-Leads to accumultion of VLCFA (C26:0, C26:1) and branched FA (phytanic acid) in blood, which leads to disruption of myelin sheath resulting in neurological damage and progression to vegetative state.
Zellweger Spectrum Disorder: continuous spectrum of 3 disorders-
1. Zellweger Syndrome (ZS): Most severe, present as newborns or in childhood with hypotonia, faical dysmorphism, seizures, liver disfunction
2. Neonatal adrenoleukodystrophy (NALD): Less severe than ZS
3. Infantile Refsum disease (IRD): Least severe form, progressive loss of hearing, vision, smell & motor function
Defect in peroxisomal alpha-oxidation enzymes phytanoyl-CoA 2- hydroxylase (PAHX; type 1) or peroxin 7 (type 2) leads to build up of brached FA: phytanic acid (produced from microbial breakdown of chlorophyll a).
Clinical features include retinitis pigmentosa, blindness, anosmia, deafness, sensory neuropathy, and cerebral ataxia.
Late onset phenotype: onset is most commonly in childhood/adolescence.
Treatment: dietary restrictions. Avoid sources of phytanic acid, such as milk and meat from ruminants.
Defect in peroxisomal VLCFA transporter, leads to accumulation of VLCFA in blood.
Most common inborn error of peroxisomal metabolism (1 in 15,000).
Defect in ABCD1 gene, which encodes a protein (ALDP) that transports VLCFA into peroxisomes. VLCFA (C26:0; C24:0) accumulate and damage myelin sheath. Progressive motor disfunction.
X-linked: more prevalent in males, heterozygous females show some symptoms later in life.
Two main phenotypes:
Childhood cerebral ALD- most severe, death within 2 years of onset
Adrenomyeloneuropathy (AMN)- milder, gradually progressive.
Caused by the inability to synthesize body proteins due to the lack of some essential amino acids. Develops within weeks after older child is abruptly weaned from breast milk. Rapid progression of retarded growth and muscle wasting. High mortality.
Symptoms: fatigue, lethargy, edema due to low plasma proteins-increased interstitial fluid, changes in skin pigment, susceptible to infections, coma
Diagnosis: enlarged liver
Treatment: Calories in carbohydrates, simple sugars, fats, vitamins and minerals, then proteins.
Defect in the neutral and aromatic amino acid (tryptophan) transport systems.
Bacteria in the GI tract convert the unabsorbed amino acids to indoles, kynurenine and serotonin, which are absorbed and appear in the urine.
No synthesis of nicotinamide from tryptophan.
Symptoms resemble pellagra (Dermatitis, Diarrhea and Dementia), particularly the rash on parts of the body exposed to sun.
Diagnosis: tryptophan degradation products in the urine.
Treatment: Niacin supplementation.
Niacin is used with diet changes (restriction of cholesterol and fat intake) to reduce the amount of cholesterol and certain fatty substances in your blood. Niacin is also used to prevent and treat pellagra (niacin deficiency), a disease caused by inadequate diet and other medical problems.
Defect in the absorption of arginine, lysine, ornithine, and cystine from the gut and the renal tubules.
Frequency: 1 in 7000 individuals
Symptoms: Cystine stones in the kidneys, ureter, and bladder. Infections due to cystine crystals.
Treatment: fluids, penicillamine forms a soluble cystine compound.
Deficiency in gamma-GGT; unable to transport amino acids into cells & does not resynthesize GSH (an antioxidant)
Symptoms: Hemolytic anemia, mental retardation, peripheral neuropathy, ataxia.
Diagnosis: Excess glutathione in urine and blood
Treatment: None, avoid hemolytic crises (phenobarbital, acetylsalicylic acid, sulfonamides).
-Defect in glutathione synthetase, glutamylcysteine synthetase, or 5-oxoprolinase.
-Frequency: Rare (40 cases worldwide)
-Consequences: Lower 5-oxoproline in urine
-Symptoms: Acidosis, hemolytic anemia, electrolyte imbalance, jaundice, CNS symptoms.
-Diagnosis: Mass-spec analysis of 5-oxoproline
-Treatment: Deliver Na-bicarbonate to the blood.
Vitamin B6 Deficiency
Pyridoxal phosphate (PLP) is cofactor for transamination reactions (removal of nitrogen). PLP is derived from vitamin B6.
Microcytic, hypochromic anemia
Diagnosis: Xanthurenic acid (a degradation product of tryptophan) appears in the urine
Mild, but common disease.
Histidinemia is caused by the shortage (deficiency) of the enzyme that breaks down histidine. Histidinemia typically causes no health problems, and most people with elevated histidine levels are unaware that they have this condition.
The combination of histidinemia and a medical complication during or soon after birth (such as a temporary lack of oxygen) might increase a person's chances of developing intellectual disability, behavioral problems, or learning disorders.
GSH= glutathione, a major cellular antioxidant. Complete deficiency is lethal.
Defect in liver function, failing to detoxify ammonia:
-Viral hepatitis, ischemia, hepatotoxins, or cirrhosis; mutations in any of the five enzymes in the urea cycle—1/30,000.
-Normal levels of ammonia in serum: 5-50 mmol/L. When liver function is compromised, >1 mmol/L.
Symptoms are neurological due to neurotoxicity:
Tremors, slurring of speech, somnolence, vomiting, cerebral edema, blurring vision, coma, or death.
Tests for the levels of organic acid, amino acids and orotic acids in the urine.
Restrict protein diet and prescribe sodium benzoate and sodium phenylacetate.
Citrullinemia type I
Defect mutation in argininosuccinate synthase gene.
Ammonia accumulate in blood
lethargy, seizures and ataxia.
Citrullinemia type II
Defect in solute carrier family 25 gene.
1/100,000, primarily affect east asians and those in middle east
dysfuntion in citrin synthesis, ammonia and other toxic material buildup
Defect in arginase.
Arginine and ammonia buildup in the body
Poor growth, spasticity, learning delays, vomiting, lethargy, can lead to seizures and coma.
Blood tests for ammonia and arginine, high levels of orotic acid in the urine.
Low protein diet.
Defect in argininosuccinate lysate.
Ammonia buildup in the blood
Vomiting, refusal to eat, progressive lethargy, and coma.
Measure ammonia levels in the blood.
Hemodialysis, intravenous arginine delivery to clear ammonia, restrict protein diet.
-Congenital heart disease is a commonly associated
-Hypothyroidism is a common complication (30% lifetime risk)
-Celiac disease is a common disorder
-Average age of death is 50 years
-Increased risk for obesity due to innate low muscle tone, & reduced exercise tolerance; type II diabetes due to obesity & autoimmune risk
-Obstructive sleep apnea due to midface hypoplasia (compromised airway)
-Risk for Alzheimer's disease
-Obsessive-compulsive disorder (also coping mechanism)
-Increased risk for acute myeloid & lymphocytic leukemias
-Adult patients do not have same risk for coronary artery disease & hypertension as general population
-Long term screening from birth recommended for: hypothyroidism at young age, echocardiogram regardless of clinical exam findings at birth
Lack phenylalanine hydroxylase enzyme; unable to convert Phe to Tyr. Therefore, the nonessential Tyr becomes essential.
Protein-calorie malnutrition mainly occurring in first year of life with more starved appearance than Kwashiorkor. The condition is also more gradual, developing over months/year. Growth retardation & wasting away of fat and muscle tissues, but mental alertness and appetite present. Mortality is usually low.
Essential fatty acid deficiency
Occurs when omega 3 & 6 polyunsaturated fatty acids are absent in the diet, usually in infants or children.
Symptoms: Dermatitis, alopecia (loss of hair), thrombocytopenia (decrease in platelets), and growth retardation
Treatment: Linoleic acid (18:2 w6) can be used to treat EFA, which can be elongated and desaturated to produce arachidonic acid (20:4 w6). Order of importance of fatty acids for alleviating EFA: Linoleic > Linolenic > Arachidonic
Type 1 diabetes
-occurs during childhood/puberty
-symptoms develop rapidly
-frequently undernourished nutrition status
-10% of diagnosed diabetics
-moderate genetic predisposition
-insulin producing beta cells of pancreas are destroyed
-ketosis is common
-low to absent plasma insulin
Type 2 diabetes
-Frequently diagnosed after age 35
-symptoms develop gradually
-Obesity usually present
-90% of diagnosed diabetics
-very strong genetic predisposition
-Insulin resistance combined with inability of beta cells to produce appropriate quantities of insulin
-ketosis is rare
-Plasma insulin is high early in disease, low in disease of long duration
-respsonsive to oral hypoglycemic drugs
-Treatment: diet, exercise, oral hypoglycemic drugs, insulin may not be necessary
von Gierke disease (type I glycogen storage)
Deficient in glucose-6-phosphatase
Liver and kidney affected
Severe hepatomegaly, severe hypoglycemia, lactic acidosis, ketosis, hyperuricemia
Pompe disease (type II glycogen storage)
Deficient in alpha-1,4 glucosidase
Affects all organs
Death from cardiac failure in infants
Cori disease (type III glycogen storage)
Deficient in debranching enzyme
Affects muscle and liver
Milder than type I
Andersen disease (type IV glycogen storage)
Deficient in branching enzyme
Affects liver, myocardium
Death from liver cirrhosis usually before age 2 years
McArdle diseaes (type V glycogen storage)
Deficient in phosphorylase enzyme
muscle cramps and pain on exertion, easy fatigability, normal life expectancy
Hers disease (type VI glycogen storage)
Deficient in phosphorylase enzyme
Like type I but milder, with less severe hypoglycemia
Tauri disease (type VII glycogen storage)
Deficient in phosphofructokinase
affects muscle, RBCs
muscle cramps and pain on exertion, easy fatigability, normal life expectancy
type VIII glycogen storage disease
phosphorylase kinase deficiency
mild hepatomegaly and hypoglycemia
Caused by either deficiency in galactokinase or galactose 1-phosphate uridyl transferase
Galactose accumulates in the blood and tissues
In the lens of the eyes, galactose is reduced by aldolase reductase into galactitol, which contributes to development of cataracts
Treatment: galactose free diet
Beta galactosidase deficiency
Deficiency of lactose causes lactose intolerance, the inability to metabolize lactose into glucose & galactose
Treatment: lactose free diet
Osteogenesis Imperfecta Type I
Symptoms: Frequent fractures of long bones of arms and legs, the ribs, and small bones of the hands and feet; fractures heal normally and usually without deformity.
Pathology: Collagen is of normal quality but produced in insufficient quantities. Patients have only half of the normal amount of pro alpha1(I) chains of Type I collagen (null allele). Inherited in an autosomal dominant manner.
Osteogenesis Imperfecta Type II
Symptoms: Innumerable fractures present at birth and generally fatal in the first few weeks or months of life.
Pathology: Collagen is made completely, but improperly. Mutant collagen peptide is incorporated into nascent procollagen triple-helical molecule.; 3/4 of procollagen is abnormal
Symptoms: Growth retardation of longitudinal bones.
Autosomal dominant, GOF mutation in the fibroblast growth factor receptor (FGFR3) gene (80-90% de novo mutations).
Almost all cases are caused by a G380R mutation in the transmembrane domain that cause ligand-independent stabilization of FGFR3 dimers that activate downstream signaling.
Leads to defective differentiation of chondrocytes.
Note: De novo mutations exclusively in paternal germline. Increase with frequency with paternal age >35 years. Homozygous state is lethal
Normal dominant transmission proceeds once de novo mutation occurs.
Pathology: Autosomal dominant mutation - polyglutamine expansion (genetic anticipation). Average age of onset is 37 years; Penetrance is high (100% by age 80).
Death follows 10-20 years after onset (up to 30 yrs).
Symptoms: personality changes, memory loss, series of motor problems including chorea (involuntary movements of arms and legs).
Initial symptoms: muscle coordination is slightly impaired; forgetfulness, cognitive disorganization, personality changes
Middle stages: both involuntary and voluntary movements become uncontrolled with jerking and writhing, speech is slurred, thought processes diminish, and severe psychiatric conditions appear, including depression, paranoid delusions, and uncontrolled rage
Later stages: patients are mute, cognitively nonfunctional, and immobilized in contorted positions as a result of rigid joints and severe contractions
Spinal muscular atrophy (SMA)
Pathology: Autosomal recessive, LOF mutation of survival motor neuron 1 (SMN1) protein.
Details: Adjacent SMN2 gene has a single base change from SMN1 gene that 90% of the time prevents incorporation of exon 7 required for normal protein function. 95% of cases are deletions of SMN1 or gene conversion replacing SMN1 with SMN2; 5% are mutations that affect protein function or exon 7 splicing.
*SMA Severity is modified by copy number of SMN2 gene that produces low levels of functional SMN.
Symptoms: Motor neuron degenerative disease that results in muscle atrophy.
Type I (aka Werdnig-Hoffman disease):
born with very little muscle tone ("floppy"), weak muscles, and feeding and breathing problems; life expectancy of < 2 years
Type II - intermediate:
Patients can sit, but never stand; diagnosis by 2 years; childhood lethal
Type III/ IV - milder
Stands and walks; adult survival
Duchenne muscular dystrophy (DMD)
Most common X-linked disorder in man - mutations in the dystrophin gene. Inheritance is recessive.
2/3 of mutations are deletions/duplications; 1/3 are point mutations, insertions
1/3 = new mutations (Haldane hypothesis); 1:10,500 gametes/generation; highest known spontaneous mutation rate
No protein product is made.
delayed motor development (late walking)
proximal muscle weakness
classic microscopic myopathic changes and electromyographic changes
cycles of myofiber degeneration and regeneration
necrotic fibers, accompanied by gradual replacement of fibers with adipose and connective tissue (fibrosis).
95% of patients have dilated cardiomyopathy later in the course of disease
variable mental retardation
usually wheelchair bound by age of 12
death in late teens or early 20's (cardiac or respiratory failure)
Becker muscular dystrophy (BMD)
Pathology: Caused by mutations (X-linked, recessive) in the dystrophin gene, leading to reduced or truncated BMD protein that is still functional
Symptoms: Milder and have later onset compared to DMD
1. Leber hereditary optic neuropathy (blurring, loss of central vision)
2. MERRF (myoclonic epilepsy, ragged red fibers)
3. MELAS (myopathy, encephalopathy, lactic acidosis, stroke-like episodes)
*Maternal transmission only (may resemble x-linked dominant)
*Greatest effect on highly aerobic tissues
*Complicated by mixed population of normal/abnormal mitochondrial genomes in each cell (i.e. heteroplasmy)
*Disease expression influenced by dosage of abnormal genomes within cell or tissue
*Some disorders may be caused by mutations in the nuclear genome
Due to deletion of paternal 15q (imprinting):
small hands and feet
Due to deletion of maternal 15q (imprinting):
Silver Russell syndrome
Growth retardation and asymmetry due to imprinting of region 11p15.5
Somatic overgrowth due to imprinting of region 11p15.5
Adenosine deaminase deficiency
*ADA deficiency leads to the accumulation of deoxyadenosine which is converted to dATP -dATP inhibits ribonucleotide reductase, which inhibits the formation of deoxyribonucleotides and DNA replication (particularly in T and B lymphocytes).
*Result is severe combined immunodeficiency (SCID)
Purine nucleoside phosphorylase deficiency
Immunodeficiency with T-cell defect
Familial Orotic Aciduria
Pathology: Accumulation of orotic acid in blood and urine, failure to thrive. Caused by defects in the pyrimidine de novo biosynthesis, thus inhibition of RNA and DNA synthesis. Deficiency in either orotate phosphoribosyl-transferase (step 5) or orotidylate decarboxylase (step 6) } enzymes in pyrimidine biosynthesis
-megaloblastic anemia: erythrocytes are larger & have higher nuclear-to-cytoplasmic ratios & neutrophils have hyper segmented nuclei
-orotic acid crystals in urine, and poor growth
Note: Lack of UMP will also lead to lack of pyrimidine nucleotides
*Caused by HGPRT deficiency which affects salvage of purines and leads to
-increased degradation of purine bases and increased uric acid -purine deficiency
*Symptoms: hyperuricemia, gout, urinary tract stones, mental retardation, spasticity, and self-mutilation.
Uric acid crystals formed in joints & kidneys
Hyperuricemia (increased uric acid in serum); *Reasons mainly unknown for growth malformation; but in some patients, caused by PRPP synthase over activation that increases purine production and degradation; or partial HGPRT deficiency
*Allopurinol, a purine analog (looks like hypoxanthine), treats gout -metabolized in cells & binds to and inhibits xanthine oxidase (which oxidizes hypoxanthine -> xanthine -> uric acid) -blocks uric acid formation
As a result, patient excretes a mix of uric acid, xanthine, and hypoxanthine that is more soluble than uric acid alone
Note: allopurinol binds irreversibly
Weight loss or improper growth
Maintenance of body weight <85% of that expected,
extreme fear of weight-gain, irrational perception of figure/weight status, amenorrhea (in women)
Often accompanied by depression, obsessive-compulsive tendencies, anxiety
Restricting type, binge-eating-purging type
Repeated binge eating
followed by inappropriate compensatory behavior (e.g. vomiting, fasting, laxative-use, excessive exercise)
over at least a 3 month period at least twice a week, irrational perception of figure/weight status
Often accompanied by depression
Purging type, non-purging type
Muscle Dysmorphia or Big-orexia
Repeated obsesion w/ appearance/muscle size
Followed by inappropriate compensatory behavior viewing self frequently in mirror; excessive exercise and dieting in controlled manner to obtain perfect physiequ
Irrational perception of figure/weight status
Use of other drugs (steroids)
Eating Disorders Not Otherwise Specified (EDNOS)
Diagnostic criteria: Any eating disorder that does not completely fit the criteria of a specific eating disorder (Example: Woman who exhibits all criteria of anorexia nervosa but has regular menses).
Binge Eating Disorder:
Characterized by repeated, uncontrollable binges without the compensatory behaviors of bulimia nervosa; sufferers are typically either overweight or obese
Eating unusual substances (e.g. dirt, toilet tissue, etc)
-abnormal retention of lipids within a cell (accumulate in vesicles that displace cytoplasm)
-The mechanism is one of altered metabolism involving the uptake of FAAs and converted into triglycerides and stored.
-The accumulation of triglycerides is commonly seen in hepatocytes, e.g. steatosis (fatty change), but can also occur in the heart, kidneys & skeletal muscle
-There are multiple etiologies for the increase in FAAs in the blood stream: starvation, diabetes, steroid use, total parenteral nutrition (TPN), obesity & pregnancy.
-ethanol toxicity and hypoxia injury cause increased acetate formation that increases the synthesis of FAAs resulting from impaired protein synthesis associated with toxins and malnutrition.
Arise in patients with hyperlipidemia and may be seen as yellowish nodules in tendons of the heel & knee. In epidermis, have foamy macrophages due to accumulation of cholesterol.
Accumulation of cholesterol in both macrophages & smooth muscle cells that yields a foamy appearnace. Rupturing of these cells results in an extracellular accumulation of crystalline cholesterol, which can have a needle-like appearance. This stimulates a giant reaction where multiple macrophages come together to try to digest it.
Lysosomal Storage Disease / Niemann-Pick Disease type C
Mutation of the NPC1 or NPC2 genes that give rise to a protein transporter in the endosomal-lysosomal system rather than the enzyme sphingomyelinase associates with Types A & B. This defect leads to an accumulation of cholesterol and glycolipids within lysosomes, forming foamy macrophages.
These cells can be found in the spleen, liver, lymph nodes, bone marrow, tonsils, gastrointestinal tract, and lungs of these patients.
Alpha 1-Anti-trypsin Deficiency
Autosomal recessive disease involving the PiZ gene (ZZ)
The protein is synthesized in hepatocytes but the genes mutation leads to misfolding of the protein that leads to increased destruction and accumulation in hepatocytes (large eosinophilic globules)
-Excessive accumulation of hemosiderin with parenchymal cells of the liver, pancreas, heart and skin that leads to cell injury.
-May be hereditary due to a mutation of the HFE genes or secondary in its origin.
-Can result in cirrhosis of the liver. Cirrhosis represents parenchymal fibrosis and regenerative nodules of hepatocytes.
-Hemochromatosis can also involve the pancreas causing diabetes, the skin leading to abnormal pigmentations, and the cardiac myocytes leading to heart failure.
-Visualize in cells with Prussian blue staining
Damage to portions of the hypothalamus or amygdala responsible for integrating metabolic information regarding nutrient stores leading to hyperphagia.
Can be caused by trauma, tumor, inflammatory disease, or elevated ICP and is associated with a wide variety of symptoms.
Progressive centripetal obesity with classic findings.
Variable in adults but >90% of children with Cushing's syndrome have generalized obesity, accompanied by a decrease in linear growth.
Modest weight gain due to slowed metabolic activity and associated with lipid abnormalities.
There is some evidence that increasing serum TSH within the normal range is associated with a modest increase in body weight in adults but treatment of subclinical hypothyroidism does not appear to be associated with weight loss.
Polycystic ovary syndrome
~50% of women with PCOS are obese. Poorly understood but appears to be related to hyper androgenism and insulin resistance leading to ectopic fat deposition.
Growth hormone deficiency
Associated with an increase in both subcutaneous and visceral fat in both adults and children.
Psychiatric disorders associated with obesity
Depression, Schizoaffective, SAD
Obesity or increased waist circumference
40 inches men
36 inches women
Impaired lipid metabolism
Elevated triglycerides (≥150 mg/dL)
<40 mg/dL men
<50 mg/dL women
HTN (hypertension) (≥130/85)
Hyperglycemia (FPG ≥100mg/dL)
Non-alcoholic liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH)
Early on elevated liver enzymes
One of the leading causes of liver cirrhosis
(Associated with obesity)
Obstructive sleep apnea
Snoring at night
Fall asleep during activities
(Associated with obesity)
Vitamin A deficiency
Early signs: skin lesions (such as hyperkeratosis), and night blindness Depletion can result in drying of the conjunctiva, corneal ulcers, and destruction of the eye.
Vitamin A toxicity
skin erythema, increased liver size, affects the liver lysosomal fragility. Huge doses during pregnancy can result in birth defects.
Vitamin D deficiency
Rickets is a deficiency condition due to inadequate intake and poor calcification of bones. Children look plump, have retarded growth, and are bow legged. Rickets can be corrected by supplement therapy.
Osteomalacia is an adult version of rickets. Multiple pregnancies, long periods of lactation with low intake and low exposure to sunlight are conditions that can lead to of osteomalacia. It is a condition of demineralization of the adult skeleton due to inadequate levels.
Vitamin D toxicity
Excess intake is accompanied by anorexia, excessive thirst, vomiting, weight low, high blood Ca2+ levels, and Ca2+ deposit in tissues causing calcification of tissues common to very young children. Chronic over-consumption is a contributing factor to the development of artherosclerosis. Cardiac myopathy, atherosclerotic lesions of vasculature with calcium deposits caused by calcification of elastic tissue.
Vitamin K deficiency
-For humans, 50% of vitamin K comes from the diet and the other 50% comes from bacterial synthesis in the intestine.
-Infants have a limited placental transfer of the vitamin, and the gut of an infant is sterile. Thus, newborns are deficient in vitamin K.
-Individuals with no bacterial intestinal flora or who are on long-term antibiotic therapy may develop a deficiency.
Vitamin E deficiency
Deficiency caused reproductive failure in animals. A pure dietary deficiency is rare, usually associated with a malabsorption syndrome.
Symptoms: hemolytic anemia, muscular dystrophy, nerve damage (membrane damage results from PUFA oxidation).
Vitamin C deficiency
Poor nutrition or diet is the major cause. Factors that increase our requirements for it include smoking, the use of oral contraceptives, and wound healing.
Deficiency leads to scurvy: swollen legs, loose teeth, swollen and bleeding gums, bleeding problems, and poor wound healing.
Beri beri disease
Due to vitamin B1 (Thiamin) deficiency
Symptoms: mental confusion, anorexia, muscle weakness, peripheral paralysis, edema (wet
beri beri), muscle-wasting (dry beri beri), tachycardia, enlarged heart.
Wernicke-Korsakoff syndrome is usually found in chronic alcoholics.
Wernicke-Korsakoff syndrome results from thiamine deficiency.
It is generally agreed that Wernicke's encephalopathy results from severe acute deficiency of thiamine (vitamin B1), whilst Korsakoff's psychosis is a chronic neurologic sequela after Wernicke's encephalopathy.
Vitamin B2, Riboflavin deficiency
Glossitis (tongue) and dermatitis - lesions of mouth and skin, scrotum.
Cheilosis - cracked lips
Sebhorreic dermatitits - leisions of nasal-labial folds, eyelids and ears, vulva, anus, and free
border of prepuce.
-Chronic wasting disease: associated with Dermatitis, Dementia, and Diarrhea (3 D's).
-Mental changes: fatigue, insomnia, apathy, confusion, hallucination, loss of memory.
Vitamin B6 (pyridoxine) deficiency
Dermatitits, cheilosis, glossitis; anemia.
Neurological changes (EEG abnormalities, epileptiform convulsions, premenstrual syndrome).
Vitamin B6 (pyridoxine) toxicity
nerve damage to the arms and legs due to high intake from supplements and is reversible when supplementation is stopped.
Vitamin B12 (cobalamin) deficiency
Deficiency (e.g. in strict vegetarians, long-term antibiotic usage):
Megaloblastic anemia - characterized by the presence of large, structurally and visually
abnormal, immature red blood cells (megaloblasts).
Pernicious anemia - caused by lacking of intrinsic factor.
Nerve damage - in both hands and feet, which leads to a feeling of pins and needles, and
numbness; in severe cases, even neuropsychiatric disorders.
Folic acid deficiency
-most common deficiency particularly with pregnant women and alcoholics. Drugs (Dilantin, barbiturates, antimalarials, chemotherapeutics) can also cause deficiency.
- causing fetus development defect in neural tube development (first week).
- can also occur as a result of vitamin B12 deficiency (it is trapped as methyl THFA).
Deficiency: Infrequent, can occur when diet contain an unusual amount of raw egg (20 eggs/day). Egg white contains a biotin-binding protein, avidin. The binding of avidin will prevent the absorption of biotin. Deficiency may occur in pregnant woman, infants, alcoholics, elderly.
Deficiency disease: dry skin, dermatitis.
Keshan disease --- endemic cardiomyopathy Kashin-Beck disease --- endemic deforming arthritis
Myxodematous cretinism --- mental retardation
Deficiency is rare in U.S., however, deficiency can occur with severe gastrointestinal problems, such as Crohn's disease, or with surgical removal of part of the stomach, or in patients who rely on total parenteral nutrition (TPN).
People with iodine deficiency may also benefit from selenium supplementation. Iodine deficiency is rare in the U.S., but is still common in developing countries.
High blood Se levels (> 100 μg/dL) can result in a condition called selenosis.
Symptoms: gastrointestinal upsets, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage.
* Autosomal recessive inheritance pattern
* Disorder usually due to mutations within the phenylalanine hydroxylase (PAH) gene on chromosome 12 (conversion of Phe -> Tyr), though can also be caused by cofactor (Biopterin) deficiency.
*Cofactor deficiency has different neurological outcomes
* Characterized by elevated serum phenylalanine (PHE) level > 20mg% (nl<2) with concominant decrease in serum tyrosine (TYR).
*Newborn screening test is the major indicator
*Obtain fasting serum amino acid profile
*Perform urine and serum biopterin studies
*Phe becomes essential amino acid
*Mental retardation (too late to treat at this point)
* Treated with lifelong dietary restriction of PHE and supplementation with TYR, with goal of maintaining blood PHE level between 2-5mg%.
*Alternative therapies include using BH4 (bioptrin cofactor), large neutral amino acids, phenylalanine ammonia lyase injections, liver transplant and gene therapy.
*Defect is in conversion of Homocysteine to Cysteine (blocked enzyme)
-Homocysteine accumulates (blood accumulates; thrombogenic)
-Cys drops off until zero
Methionine metabolized by removing methyl group, creating homocysteine
Amino acid analysis:
-Elevated serum methionine
-multiple mixed disulfide peaks
Limit methionine in diet and supplement with cysteine for life
Maple syrup urine disease
aka - "brached chain ketoacid-dehydrogenase deficiency"
Elevated levels of branched chain amino acids (Leucine, Isoleucine, Valine) due to defect in common enzyme
Elevation of abnormal amino acid alloisoleucine = always present
urine smells like maple syrup
Ornithine transcarbamylase deficiency
Immediate, life threatening condition: Defect in early step of urea cycle.
Very high plasma ammonium
Elevations in many amino acids: Glutamine and Alanine are very high
Key to diagnosis: Citrulline level is zero (an intermeidate in urea cycle)
Display respiratory alkalosis (panting)
Genetically heterogenous group of disorders due to autosomal recessive mutations in the four genes encoding the glycine cleavage complex. Cannot degrade glycine - accumulates in CNS, occuring in utero.
P protein mutations (GLDC gene) account for about 70% of cases.
Biochemical diagnosis made by showing elevated CSF:serum glycine level.
-Classic infant onset cases are initially characterized by profound hypotonia and respiratory depression due to effect of high CSF glycine on spinal cord NMDA receptors.
-Structural brain abnormalities.
-Profound effects obsereved in utero.
-Infants later recover respiratory drive but develop intractable seizures and severe MR.
-High glycine levels can be treated by use of benzoate and dextromethorphan, but this does not alter the neurologic outcome.
-Treatment is non-effective; most patients are expired voluntarily.
Due to defective intestinal lipolysis or defective mucosal cell metabolism.
Results in fatty stools.
Can cause deficiency of fat soluble vitamins (A, D, E & K) due to loss in stool
Familial lipoprotein lipase deficiency (type I)
1. Deficiency of LPL
2. Production of abnormal LPL
3. Apo CII deficiency
Slow clearance of chylomicrons and VLDL.
Low levels of LDL and HDL.
No increased risk of coronary disease
Reduce fat and increase complex carbohydrates in diet.
Familial hypercholestrolemia (type II)
Type IIa - Defective LDL receptors or mutation in ligand region of apoB-100
Type IIb - Tendency for VLDL to be elevated, in addition
Reduced rate of LDL clearance leads to elevated LDL levels and hypercholesterolemia, resulting in atherosclerosis & coronary disease.
Note : mutations can occur in all domains of LDL receptor (most commonly in ligand binding domain).
Homozygous patients: blood cholesterol is 600-1200 mg/dl. Atherosclerosis at age 15-20 yrs.
Heterozygous patient: blood cholesterol is 280-500 mg/dl. Atherosclerosis by 40 years.
Familial hypertriacylglycerolemia (type IV)
Overproduction of VLDL often associated with glucose intolerance and hyperinsulinemia, which may be a cause of the overproduction
Cholesterol levels rise with VLDL concentration.
LDL and HDL tend to be subnormal.
Commonly associated with coronary heart disease, T2DM, obesity, alcoholism, and administration of progestational hormones.
Hepatic lipase deficiency
Deficiency of enzyme leads to accumulation of large triacylglycerol-rich HDL and VLDL remnants.
Patients have anthomas and coronary heart disease
Fragile X syndrome
Expansion of CGG repeat (normal, gray zone, premutation and full mutation levels of increasing repeats) & hypermethylation of the promoter of the FMR1 gene on the X chromosome.
Risk of full mutation increases when passed on to next generation (example of anticipation)
Intellectual disability in males (mild in females with full expansion + abnormal methylation)
Carrier can manifest specific features (tremor/ataxia, premature ovarian failure)
Acute chest syndrome
A life-threatening condition linked to sickle cell anemia. This syndrome is similar to pneumonia. An infection or sickle cells trapped in the lungs cause acute chest syndrome.
People who have this condition often have chest pain, shortness of breath, and fever. Often found to have low oxygen levels and abnormal chest x ray results.
Avascular necrosis of hip
Osteonecrosis (bone death caused by poor blood supply) that can be caused by sickle cell disease. It is most common in the hip and shoulder, but can affect other large joints such as knee, elbow, wrist and ankle. If this condition is not treated, the joint will deteriorate and this will become severe arthritis.
The presence of stones in the gallbladder.
Gallstones in children whit sickle cell disease are the result of elevated bilirubin excretion (crystallized) due to the increased hemolysis. Gallstones are found in about 30 to 50 percent of children with sickle cell anemia. They may be symptomatic or asymptomatic. Most physicians monitor the child with asyniptomatic gallstones and do not recommend a cholecystectomy (removal of the gallbladder) until symptoms occur, Elective cholecystectomy may be indicated when gallstones are symptomatic (chronic right upper quadrant pain, nausea, vomiting, and fullness after meals).
Severe pain in hand/feet bones is caused by blocked circulation often seen in sickle patients.
Ischemia and tissue hypoxia are the consequences and, in turn, worsen the sickling process. The eventual result is cell death.
They also may be clinically silent and discovered incidentally at radiography.
In infants and young children, infarction often occurs in the diaphyses of small tubular bones in the hands and feet. Infarction at these sites is termed "hand-foot" syndrome and results from the presence and persistence of red marrow in these regions.
Hemoglobin S beta thalassemia
Due to mutations in the HBB gene on chromosome 11 and inherited in an autosomal-recessive fashion. (>100 mutations noted). Mutations in promoters, splice jcts, missense coding.
Mutations are characterized as either βo or β thalassemia major if they prevent any formation of β chains, the most severe form of β thalassemia.
Also, they are characterized as β+ or β thalassemia intermedia if they allow some β chain formation to occur.
In either case, there is a relative excess of α chains, but these do not form tetramers: Rather, they bind to the red blood cell membranes, producing membrane damage, and at high concentrations they form toxic aggregates.
(Note: Delta thalassemia can occur in a similar fashion; albeit accounting for <3% of adult Hb).
Hemoglobin SC disease
Individuals have the gene for HbS inherited from one parent and the gene for HbC is inherited from the other parent. Hemoglobin C is an abnormal hemoglobin in which substitution of a glutamic acid residue with a lysine residue at the 6th position of the β-globin chain has occurred (E6K substitution).
Since HbC does not polymerize as readily as HbS, there is less sickling (fewer sickle cells). The peripheral smear demonstrates only a few sickle cells. There are fewer acute vaso-occlusive events. However, persons with hemoglobin SC disease (HbSC) have more significant retinopathy, ischemic necrosis of bone, and priapism than those with pure SS disease.
Males who have sickle cell anemia may have painful, unwanted erections. ). It happens because the sickle cells block blood flow out of an erect penis. Over time, can damage the penis and lead to impotence.
Damage to the small blood vessels in the lungs makes it hard for the heart to pump blood through the lungs. This causes blood pressure in the lungs to rise. Shortness of breath and fatigue are the main symptoms.
Sickle cell anemia
The most common form of sickle cell disease (SCD). Autosomal recessive inheritance of a mutation in the HBB gene (beta-globin) located on the short (p) arm of chromosome 11, where glutamic acid is replaced by valine.
Sickle cells contain abnormal hemoglobin called sickle hemoglobin or hemoglobin S. Sickle hemoglobin causes the cells to develop a sickle, or crescent, shape.
Sickle cells are stiff and sticky. They tend to block blood flow in the blood vessels of the limbs and organs. Blocked blood flow can cause pain, serious infections, and organ damage.
Sickle cell anemia has no widely available cure. However, treatments can help with the symptoms and complications of the disease. Blood and marrow stem cell transplantsmay offer a cure for a small number of people.
Hemoglobin S alpha thalassemia
The α thalassemias involve the genes HBA1 and HBA2, inherited in a Mendelian recessive fashion. Note there are two gene loci, and thus four alleles. The degree of impairment is based on which clinical phenotype is present (how many chains are affected).
Alpha thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns.
The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains), which have abnormal oxygen dissociation curves.
1 deleted copy: asymptomatic carrier
2 deleted copies: a-thalassemia trait (mild anemia)
3 deleted copies: Hemoblogin H disease; detectable levels of beta tetramers; anemia from birth (not lethal)
4 deleted copies: Hemoglobin Bart's; tetramer of gamma chains with no oxygen carrying capacity resulting in neonatal death
A group of inherited autosomal recessive blood disorders that originated in the Mediterranean region.
This genetic defect could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin.
This can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the characteristic presenting symptom. This is a quantitative problem of too few globins synthesized, whereas sickle-cell disease (a hemoglobinopathy) is a qualitative problem of synthesis of an incorrectly functioning globin.
Usually result in underproduction of normal globin proteins, often through mutations in regulatory genes. Hemoglobinopathies imply structural abnormalities in the globin proteins themselves. The two conditions may overlap, however, since some conditions that cause abnormalities in globin proteins (hemoglobinopathy) also affect their production.
THIS SET IS OFTEN IN FOLDERS WITH...
Bone & Muscle Block
MPCC Week 1: Myoglobin vs. Hemoglobin
Amino Acid Structures
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