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🎓 COMPLETE LECTURE: Biochemistry - Metabolism (Pages 79-87)

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PAGE 79 - SORBITOL, LACTASE DEFICIENCY, AMINO ACIDS

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📌 TOPIC 1: SORBITOL

What is sorbitol and why does it matter?

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• Simple explanation: When there is too much glucose floating inside a cell, an enzyme called aldose reductase converts it into sorbitol.
• Sorbitol = a sugar-alcohol (like the sweetener in sugar-free gum). It's the same chemical, actually!
• Aldose reductase = the enzyme (think of it as a "converter machine") that does this job.
• Why "trapping"? Because once glucose becomes sorbitol, it cannot easily leave the cell. Sorbitol is stuck inside - this is the problem.

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• In some tissues, there is a second enzyme called sorbitol dehydrogenase that converts sorbitol further into fructose (another type of sugar).
• So the pathway is: Glucose → Sorbitol → Fructose
• The diagram in your book shows: Glucose --NADPH--> Sorbitol --NAD+--> Fructose

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• Intracellular = inside the cell
• If a tissue does NOT have enough sorbitol dehydrogenase (the second converting enzyme), sorbitol keeps building up inside the cell. It can't leave, and it can't be converted further.
• Osmotic damage = when something accumulates inside a cell, it draws water into the cell (like how salt draws water). The cell swells up and gets damaged. Imagine a balloon being over-filled with water - it can burst or get damaged.

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• These are the REAL diseases that happen because of sorbitol accumulation in diabetics:
  • Cataracts = clouding of the lens of the eye. The lens accumulates sorbitol → swells → becomes cloudy → you can't see well.
  • Retinopathy = damage to the retina (the "screen" at the back of the eye that captures images). Sorbitol accumulates in retinal cells → they get damaged → vision loss.
  • Peripheral neuropathy = damage to nerves in hands and feet. Diabetics often feel numbness, tingling, or burning in feet - this is why.
  • Chronic hyperglycemia = chronically high blood sugar (chronic = long-term, hyper = high, glycemia = blood sugar). All of this is a complication of poorly controlled diabetes.

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• Galactose = another sugar (found in milk). If galactose builds up in the blood (like in the disease galactosemia), aldose reductase converts it into galactitol - another sugar-alcohol.
• Galactitol also accumulates in the lens of the eye → causes cataracts in babies with galactosemia.

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• Liver, ovaries, seminal vesicles = these organs have BOTH aldose reductase AND sorbitol dehydrogenase.
• So they can both make sorbitol AND then convert it to fructose → sorbitol does not accumulate here → they "lose" sorbitol (it passes through, not stuck).
• The mnemonic "they LOSE sorbitol" helps remember that sorbitol doesn't pile up in these organs.

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• LARKS = Lens, Aldose reductase, Retina, Kidneys, Schwann cells
• These tissues have ONLY the first enzyme (aldose reductase), NOT the second one.
• So they convert glucose → sorbitol, but they CANNOT convert sorbitol → fructose.
• Result: sorbitol accumulates in these tissues → osmotic damage → that's why diabetics get cataracts (lens), retinopathy (retina), nephropathy (kidneys), and peripheral neuropathy (Schwann cells are the cells that wrap around nerves).
• Schwann cells = cells that form a protective "insulation layer" (called myelin) around nerve fibers. When they are damaged by sorbitol, nerves malfunction → neuropathy.

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📌 TOPIC 2: LACTASE DEFICIENCY

What is lactase and why does its deficiency matter?

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• If you don't have enough lactase scissors, lactose in your milk cannot be cut and absorbed → it causes problems → lactose intolerance.

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• Intestinal brush border = the inner lining of your small intestine has tiny finger-like projections called villi, and on the surface of these villi are even tinier projections called microvilli. Together they look like a brush under a microscope, hence "brush border." This is where lactase sits and works.
• Lactase cuts lactose → glucose + galactose → both get absorbed into the blood.

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• Primary lactase deficiency is the most common form worldwide. As humans grow from babies to adults, the gene that keeps lactase active slowly "turns off" - this is completely normal from an evolutionary standpoint (originally, humans drank milk only as infants).
• Some humans have a genetic variant called the "lactase-persistent allele" that keeps the gene ON even in adulthood - this is more common in Europeans and certain African groups.
• If you lack this persistent allele → lactase activity falls after childhood → you become lactose intolerant as an adult.
• Allele = a version of a gene (like different models of the same car).

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• Secondary lactase deficiency = temporary loss of lactase because the brush border (the intestine's inner lining) gets DAMAGED by something like:
  • Rotavirus = a common virus causing diarrhea in children. It damages the intestinal lining.
  • Autoimmune disease = when the body's own immune system attacks the intestinal cells.
• Once the intestine heals, lactase activity often returns.

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• Congenital = present from birth. This is when the baby is born without a working lactase gene. Very rare. These babies can't tolerate milk from day one.

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• When undigested lactose reaches the large intestine (colon), bacteria there ferment (eat) it.
• Fermentation produces acid → stool pH drops (becomes more acidic → low pH = acidic).
• Fermentation also produces hydrogen gas → this hydrogen gets absorbed into the blood → travels to the lungs → you breathe it out → the lactose hydrogen breath test measures how much H2 is in your breath. More H2 = more fermentation = more undigested lactose = lactase deficiency.

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• Just re-emphasizing: the acid (H⁺ ions) come from bacterial fermentation of lactose in the colon.

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• Biopsy = taking a tiny piece of tissue to examine under the microscope.
• Mucosa = the lining of the intestine.
• In hereditary (primary) lactase deficiency, the intestinal lining LOOKS completely normal under the microscope - the problem is only at the enzyme level (not enough lactase activity), not structural damage. This helps distinguish it from conditions that cause actual intestinal damage (like Celiac disease).

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• Bloating = feeling of a swollen, full belly - from gas produced by bacteria fermenting lactose.
• Cramps = painful muscle spasms in the abdomen - from the gas and intestinal irritation.
• Flatulence = passing gas (farting) - the hydrogen and CO2 gas produced by bacteria need to go somewhere!
• Osmotic diarrhea = undigested lactose sitting in the intestine pulls water into it (osmosis = water follows particles). This extra water makes the stool loose/watery → diarrhea.

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• Self-explanatory. If you can't digest lactose, either avoid it OR take lactase enzyme supplements (sold as "Lactaid") OR drink lactose-free milk (where lactose has already been pre-digested by the manufacturer).

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📌 TOPIC 3: AMINO ACIDS

What are amino acids?

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• Amino acids can exist in two mirror-image forms: L (left-handed) and D (right-handed) - like your left hand and right hand.
• The human body ONLY uses L-amino acids to build proteins. D-amino acids exist in bacteria and some antibiotics but not in human proteins.

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Essential Amino Acids

• Essential = your body CANNOT make these on its own - you MUST eat them.
• PVT TIM HaLL is a mnemonic (memory trick):
  • Phenylalanine - found in meat, eggs, dairy
  • Valine - branched chain amino acid (BCAA)
  • Tryptophan - makes serotonin and melatonin (mood and sleep!)
  • Threonine
  • Isoleucine - another BCAA
  • Methionine - contains sulfur
  • Histidine - essential mainly in children
  • Leucine - BCAA (purely ketogenic)
  • Lysine - also purely ketogenic

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• Glucogenic amino acids can be converted into glucose when the body needs it (during fasting/starvation). This is like having a backup fuel source.
• The mnemonic "We met his valentine" = Methionine, histidine, valine.
• "So sweet (glucogenic)" = sweet = sugar = glucose → glucogenic.

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• These amino acids are BOTH glucogenic AND ketogenic - they can produce either glucose OR ketone bodies (fat-derived fuel), depending on the body's needs.
• Ketone bodies = alternative fuel made from fat breakdown. Used during fasting/starvation, especially by the brain.

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• Leucine and Lysine can ONLY produce ketone bodies - they cannot make glucose. This is unusual and important to know.
• Memory trick: "LeucyLysine are purely Ketogenic" - both start with L.

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Acidic Amino Acids

• Acidic amino acids = carry a NEGATIVE charge at the normal body pH (7.4).
• Think of them as having a tiny "negative magnet" on them.
• Aspartate and Glutamate are important - glutamate is the main excitatory neurotransmitter in the brain!

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Basic Amino Acids

• Basic amino acids = carry a POSITIVE charge at body pH.
• Arginine has the strongest positive charge (most basic).
• Histidine is special - it's listed as essential AND basic, but at normal body pH (7.4) it actually carries almost NO charge (its pKa is close to 7.4). This makes histidine great for enzymes that need to accept or donate protons at body pH.

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• Children need more arginine and histidine because their bodies are growing rapidly and these amino acids are needed in larger amounts. That's why histidine IS essential - especially in kids.

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• Histones = proteins around which DNA is wrapped (like thread around a spool). They have many positively charged arginine and lysine residues.
• DNA is negatively charged (from its phosphate backbone).
• Positive histones bind tightly to negative DNA - opposite charges attract! This is how DNA is packaged neatly inside the cell nucleus.

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• Memory trick: Histidine and Lysine are basic amino acids. "His lys lies" → they lie in the basic camp.

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PAGE 80 - UREA CYCLE, TRANSPORT OF AMMONIA, HYPERAMMONEMIA

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📌 TOPIC 4: UREA CYCLE

The Big Picture - Why do we need a Urea Cycle?

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• Catabolism = breaking down (opposite of building up).
• When amino acids are broken down, they don't just disappear - their carbon skeleton gets converted into molecules like pyruvate or acetyl-CoA that the body can burn for energy.
• Pyruvate and Acetyl-CoA = key fuel molecules. Acetyl-CoA feeds into the TCA cycle (the Krebs cycle) which produces energy (ATP).

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• The nitrogen part of amino acids becomes ammonia (NH3) → then gets converted to urea (a much less toxic molecule with formula: NH2-CO-NH2) → released into blood → filtered by kidneys → excreted in urine.
• BUN (Blood Urea Nitrogen) is a blood test that measures how much urea is in your blood, used to assess kidney and liver function.

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The mnemonic: "Ordinarily, Careless Crappers Are Also Frivolous About Urination"

• Ornithine
• Carbamoyl phosphate
• Citrulline
• Argininosuccinate
• Arginine
• Fumarate (leaves the cycle)
• Arginine → splits into
• Urea (leaves) + Ornithine (stays, cycle repeats)

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The Urea Cycle Steps (simplified):

1. In the mitochondria of liver cells:
   • CO2 + NH3 + 2 ATP → Carbamoyl phosphate (via enzyme Carbamoyl phosphate synthetase I, or CPS1)
   • This is the rate-limiting step (the slowest step, controls the whole cycle's speed)
   • N-acetylglutamate is an allosteric activator of CPS1 (it "turns on" the enzyme)
   • Carbamoyl phosphate + Ornithine → Citrulline
2. Citrulline exits the mitochondria into the cytoplasm (cytosol):
   • Citrulline + Aspartate → Argininosuccinate
   • Argininosuccinate → Arginine + Fumarate (fumarate exits - enters TCA cycle)
   • Arginine → Urea + Ornithine (via arginase)
   • Ornithine goes back into the mitochondria → cycle repeats
3. Urea is released into the blood → kidneys → excreted in urine.

• 1st NH2 = from NH3 (free ammonia, from amino acid breakdown)
• 2nd NH2 = from aspartate (an amino acid that donates its nitrogen)
• CO2 = from normal cellular respiration

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📌 TOPIC 5: TRANSPORT OF AMMONIA BY ALANINE (Cahill Cycle / Glucose-Alanine Cycle)

Why do muscles need to send ammonia to the liver?

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1. Amino acids are broken down → their nitrogen/amino group is transferred to alpha-ketoglutarate → forms glutamate (carries NH3)
2. Glutamate transfers its amino group to pyruvate → forms Alanine (carries NH3)
3. Alanine is released into the blood
4. Meanwhile, the pyruvate came from glucose breakdown (glycolysis)
5. The remaining carbon skeletons become alpha-ketoacids

1. Alanine's amino group is removed → forms pyruvate again
2. Pyruvate is used for gluconeogenesis (making new glucose in the liver)
3. The amino group is detoxified through the urea cycle → urea → excreted
4. The new glucose travels back to the muscle via blood → used for energy

• Muscle → lactate → liver → converted to glucose → back to muscle

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📌 TOPIC 6: HYPERAMMONEMIA

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• Acquired = something you develop during life (not born with). Liver disease (like cirrhosis from alcoholism) = liver can't run the urea cycle properly → ammonia builds up.
• Hereditary = born with a genetic defect in one of the urea cycle enzymes → can't process ammonia at all or efficiently.

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• Asterixis (flapping tremor) = a characteristic sign. Ask the patient to hold their hands out flat (like stopping traffic) → their hands will flap up and down, like a bird's wings. It's caused by ammonia messing up the brain's motor control. Very classic sign of liver failure/hyperammonemia.
• Slurring of speech = ammonia affects the brain → speech becomes slow, thick, unclear.
• Somnolence = abnormal drowsiness / sleepiness (from brain being poisoned by ammonia).
• Cerebral edema = brain swelling (explained below).
• Blurring of vision = vision problems from brain/optic nerve involvement.

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• The TCA cycle (Krebs cycle) = the main energy-producing cycle inside cells. It requires a molecule called alpha-ketoglutarate.
• When ammonia is high, the body tries to mop it up: alpha-ketoglutarate + NH3 → glutamate (via glutamate dehydrogenase).
• This consumes all the alpha-ketoglutarate → the TCA cycle CANNOT run → brain cells run out of energy (ATP) → malfunction and die.

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• Glutamate = the brain's main excitatory neurotransmitter (it activates neurons).
• When alpha-ketoglutarate is used up to detoxify ammonia, glutamate gets used up too (to make glutamine, next point).
• Less glutamate → less neurotransmission → brain becomes sluggish.

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• GABA (Gamma-aminobutyric acid) = the brain's main INHIBITORY neurotransmitter (it CALMS neurons down).
• Glutamate → GABA (via an enzyme). When ammonia is high, this pathway gets dysregulated → GABA increases.
• More GABA = more inhibition = MORE slowing of the brain → deeper drowsiness → coma.

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• Glutamine = glutamate + NH3 (via glutamine synthetase). The brain tries to mop up ammonia by making glutamine.
• But glutamine accumulates in astrocytes (brain support cells) → causes osmotic swelling.

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• Astrocytes = star-shaped brain support cells. When they convert glutamate to glutamine to try to remove ammonia, glutamine ACCUMULATES inside them.
• Glutamine is osmotically active (draws water in) → astrocytes swell up with water → brain swells → cerebral edema → increased pressure inside the skull → fatal if severe.

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TREATMENT of Hyperammonemia:

• Lactulose = a non-absorbable sugar syrup. It is fermented by gut bacteria → produces acid → lower GI pH.
• In an acidic environment, NH3 (ammonia) + H⁺ → NH4⁺ (ammonium ion). Ammonium can't be absorbed → it gets trapped in the gut → excreted in stool.

• Rifaximin = an antibiotic that stays in the GI tract (doesn't get absorbed into blood).
• It kills gut bacteria that produce ammonia from protein.
• Less bacteria = less ammonia made in the gut.

• These are drugs given to patients with urea cycle disorders.
• They "latch onto" amino acids (glycine, glutamine) that carry nitrogen → form a new harmless compound → excreted by kidneys.
• This is essentially a "back door" way to eliminate nitrogen without needing the urea cycle.

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PAGE 81 - ORNITHINE TRANSCARBAMYLASE DEFICIENCY + AMINO ACID DERIVATIVES + CATECHOLAMINE SYNTHESIS

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📌 TOPIC 7: ORNITHINE TRANSCARBAMYLASE (OTC) DEFICIENCY

• OTC deficiency = the #1 most common error in the urea cycle. The enzyme ornithine transcarbamylase (which joins carbamoyl phosphate + ornithine → citrulline, the second step of the urea cycle) is deficient.

• X-linked recessive = the defective gene is on the X chromosome.
• Boys have only ONE X chromosome (XY) → if their one X has the bad gene → they get the disease.
• Girls have TWO X chromosomes (XX) → usually the other X has a working copy → they are carriers but often milder/unaffected.
• All other urea cycle enzyme deficiencies are autosomal recessive = need two bad copies (from both parents) on non-sex chromosomes.

• No OTC = the urea cycle is blocked at an early step → ammonia cannot be converted to urea → ammonia accumulates in blood → hyperammonemia.

• Newborns with OTC deficiency have massive hyperammonemia → lethargy, vomiting, seizures, coma in first days.
• Some mild forms present in adulthood (after high-protein meal or illness).

• Normally, carbamoyl phosphate is used in the urea cycle. When the urea cycle is BLOCKED (as in OTC deficiency), carbamoyl phosphate backs up and overflows into another pathway: pyrimidine synthesis → makes orotic acid.
• So in OTC deficiency, orotic acid spills into urine.
• Carbamoyl phosphate synthetase I (CPS1) deficiency = another urea cycle disorder where the FIRST enzyme is missing → no carbamoyl phosphate is made at all → there's NOTHING to overflow → no orotic acid in urine. This is how you tell the two apart on an exam.

• ↑ Orotic acid = because it overflows from the blocked urea cycle.
• ↓ BUN (Blood Urea Nitrogen) = less urea is being made (cycle is broken) → less urea in blood → BUN goes DOWN.
• No megaloblastic anemia = orotic acid is produced here, but it doesn't accumulate enough to block DNA synthesis (megaloblastic anemia happens when pyrimidine synthesis is severely blocked). This distinguishes OTC deficiency from orotic aciduria (where the enzyme LATER in pyrimidine synthesis is deficient → much more orotic acid accumulates → DNA synthesis blocked → megaloblastic anemia).

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📌 TOPIC 8: AMINO ACID DERIVATIVES

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• Phenylalanine → Tyrosine: Enzyme = phenylalanine hydroxylase. Requires BH4 (tetrahydrobiopterin) as cofactor. Defect = PKU (Phenylketonuria).
• Tyrosine → Dopa: Enzyme = tyrosine hydroxylase. Requires BH4. Defect in this enzyme → no dopamine → Albinism (if going towards melanin) or Parkinson's-like state.
• Tyrosine → Melanin: Enzyme = tyrosinase. Defect → Albinism (no pigment).
• Tyrosine → Thyroxine (T4/T3): Thyroid hormones! Made from tyrosine.
• Dopa → Dopamine: Enzyme = DOPA decarboxylase. Requires B6 (pyridoxal phosphate). Carbidopa blocks this enzyme and is used in Parkinson's disease treatment (to keep L-DOPA in brain).
• Dopamine → Norepinephrine (NE): Enzyme = dopamine beta-hydroxylase. Requires Vitamin C.
• Norepinephrine → Epinephrine (Epi): Enzyme = PNMT (phenylethanolamine-N-methyltransferase). Requires SAM (S-adenosylmethionine) as methyl donor. Cortisol induces this enzyme (which is why stress from the adrenal medulla requires cortisol from the adrenal cortex - the cortex bathes the medulla).
• NE and Epi are catecholamines = stress hormones ("fight or flight"). Epinephrine = adrenaline.

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• Tryptophan → Niacin (Vitamin B3): This is why if you eat enough protein (tryptophan), you can partially make your own niacin. Niacin → NAD+/NADP+ (electron carriers in energy metabolism).
• Tryptophan → Serotonin: Requires BH4 and B6. Serotonin = "feel good" neurotransmitter. Antidepressants (SSRIs like fluoxetine) work by increasing serotonin.
• Serotonin → Melatonin: Melatonin = sleep hormone, made in the pineal gland at night. This is why tryptophan (in turkey!) might make you sleepy - though the effect is mild.

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• Histidine → Histamine: Requires B6. Histamine = allergic response molecule. Released in allergic reactions → itching, sneezing, runny nose. Antihistamines (like Benadryl/cetirizine) block histamine receptors.

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• Glycine is used to make porphyrin (the ring structure), which then becomes heme (the iron-containing part of hemoglobin that carries oxygen). Requires B6.
• Defect in this pathway → porphyrias (diseases with porphyrin accumulation).

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• Glutamate → GABA: Requires B6 (via glutamate decarboxylase). This is important because:
  • B6 deficiency → can't make GABA → seizures in newborns!
  • GABA = inhibitory neurotransmitter. Benzodiazepines (Valium) enhance GABA's effect to calm anxiety/seizures.

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• Glutathione = the body's master antioxidant (made from glutamate + cysteine + glycine). Protects cells from oxidative damage.

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• Arginine → Creatine: Creatine is stored in muscles and provides quick energy for muscle contraction.
• Arginine → Urea: As we discussed, in the urea cycle.
• Arginine → Nitric Oxide (NO): BH4 is required. NO = vasodilator (makes blood vessels relax and widen). Nitroglycerin (heart medication) works by releasing NO → dilates coronary arteries.

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Catecholamine Synthesis/Tyrosine Catabolism (detailed pathway on page 81):

• Phenylketonuria (PKU): Phenylalanine hydroxylase deficient → can't convert phenylalanine to tyrosine → phenylalanine accumulates → "phenyl ketones" in urine → musty odor.
• Alkaptonuria: Homogentisate oxidase deficient → homogentisic acid accumulates → dark urine, black cartilage.
• Albinism: Tyrosinase deficient → can't make melanin → no skin/hair/eye pigment.

• Norepinephrine/Epinephrine are broken down by:
  • MAO (Monoamine oxidase) = enzyme
  • COMT (Catechol-O-methyltransferase) = another enzyme
• NE → Normetanephrine (via COMT) → Vanillylmandelic acid (VMA) (via MAO)
• Epi → Metanephrine (via COMT) → VMA (via MAO) → Homovanillic acid (HVA)
• VMA and metanephrines are measured in urine to diagnose pheochromocytoma (tumor of the adrenal medulla that secretes too much epinephrine/norepinephrine).

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PAGE 82 - PKU, MAPLE SYRUP URINE DISEASE, ALKAPTONURIA

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📌 TOPIC 9: PHENYLKETONURIA (PKU)

• The enzyme phenylalanine hydroxylase (PAH) converts phenylalanine → tyrosine.
• If PAH is deficient or absent → phenylalanine CANNOT be converted → it piles up in the blood.

• Normally, tyrosine is a non-essential amino acid (the body can make it from phenylalanine).
• But if PAH doesn't work → tyrosine can't be made → must come entirely from the diet → tyrosine becomes conditionally essential in PKU patients.

• Excess phenylalanine gets converted into phenyl ketones (like phenylpyruvate, phenylacetate, phenyllactate) via alternative pathways.
• These phenyl ketones spill into urine → musty/mousy body odor (classic exam finding).

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• BH4 (Tetrahydrobiopterin) = the cofactor (helper molecule) that PAH needs to function.
• Even if you HAVE the PAH enzyme, without BH4 it doesn't work → same effect as PKU.
• BH4 deficiency is a PKU variant - often WORSE because BH4 is also needed for other enzymes (making dopamine, serotonin) → severe neurological disease.
• Without treatment, these infants die in infancy.

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• Embryopathy = damage to the embryo/fetus.
• If a WOMAN with PKU becomes pregnant and has uncontrolled high phenylalanine → the baby (even if the baby itself doesn't have PKU) is exposed to toxic phenylalanine through the placenta → devastating fetal defects.
• Microcephaly = abnormally small head (and brain) → intellectual disability.
• Prevention: The mother must follow a strict low-phenylalanine diet BEFORE and THROUGHOUT pregnancy.

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• Intellectual disability = brain damage from high phenylalanine.
• Microcephaly = small head = small brain = developmental problems.
• Seizures = high phenylalanine disrupts neurotransmitter balance.
• Hypopigmented skin = pale skin, fair hair, light eyes. WHY? Because tyrosine (which makes melanin pigment) is deficient in PKU → less melanin → lighter appearance. This is especially noticeable in a child of dark-complexioned parents.
• Eczema = skin rash, mechanism not fully clear.
• Musty body odor = from phenylketones in sweat and urine.

• Babies with PKU appear normal at birth because the MOTHER's normal enzymes cleared the phenylalanine during pregnancy.
• After birth, without the mother's enzymes, phenylalanine starts building up → screen at 2-3 days.
• This is the standard newborn screening test (heel prick blood test).

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• Eat foods LOW in phenylalanine. Avoid meat with high phenylalanine. Use special PKU formulas.
• Supplement tyrosine (since they can't make it).
• BH4 supplementation helps some PKU patients (those with mild forms responsive to cofactor).

• Aspartame = popular artificial sweetener (found in Diet Coke, Equal, sugar-free products). In the body, aspartame breaks down into phenylalanine + aspartate → dangerous for PKU patients.
• That's why Diet Coke cans say "CONTAINS PHENYLALANINE" - it's a legal warning for PKU patients.

• Aromatic amino acids = phenylalanine, tyrosine, tryptophan (they have a benzene ring structure). PKU affects this group.

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📌 TOPIC 10: MAPLE SYRUP URINE DISEASE (MSUD)

• Branched amino acids = isoleucine, leucine, valine = the BCAAs = "branched" because their side chains have a branch structure.
• The enzyme branched-chain alpha-ketoacid dehydrogenase (big name, just remember it's the enzyme that breaks them down) requires Vitamin B1 (thiamine) as a cofactor.
• If this enzyme is deficient → BCAAs can't be broken down → they pile up in blood/urine.

• The BCAAs are first converted to alpha-ketoacids (intermediate step), but since the next enzyme is deficient → alpha-ketoacids accumulate.
• Leucine's ketoacid (alpha-ketoisocaproate) is especially neurotoxic.

• The accumulated alpha-ketoacids have a characteristic sweet, caramel/burnt sugar smell - exactly like maple syrup!
• The smell is present in urine, sweat, and even ear wax. This is how the disease got its name.
• Babies present in the first week of life with poor feeding, vomiting, lethargy.

• Dystonia = abnormal muscle tone / involuntary muscle contractions.
• The accumulated ketoacids are toxic to the developing brain.

• Restrict the BCAAs so there's less to accumulate. Use special MSUD formulas (like PKU formulas, but different).
• Thiamine (B1) supplementation helps some mild forms.

• Memory trick: I = isoleucine, love = leucine, Vermont maple syrup = Maple Syrup Urine Disease, B1ranches = branched-chain enzyme requires B1 (thiamine).

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📌 TOPIC 11: ALKAPTONURIA

• Normal tyrosine catabolism: tyrosine → homogentisic acid → (via homogentisate oxidase) → maleylacetoacetate → TCA cycle.
• If homogentisate oxidase is missing → homogentisic acid cannot be broken down → accumulates.
• Homogentisic acid is a pigmented compound that binds to collagen.

• The disease is rare and usually not fatal. It reduces quality of life mainly through joint problems.

• Ochronosis = bluish-black discoloration of cartilage and connective tissue from homogentisic acid deposits.
• The ear cartilage turns dark (look at a patient's ears!), the whites of the eyes (sclerae) turn darkish.
• Sclerae = the white part of the eye.

• Homogentisic acid in urine oxidizes when it touches air → turns black. Classic sign: baby's diaper is black!

• Arthralgias = joint pain. The acid deposits in joint cartilage → degrades the cartilage → severe arthritis, especially in the spine and large joints.

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PAGE 83 - HOMOCYSTINURIA, CYSTINURIA, ORGANIC ACIDEMIAS

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📌 TOPIC 12: HOMOCYSTINURIA

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• Cystathionine synthase converts homocysteine → cystathionine (needs B6 as cofactor).
• If this enzyme fails → homocysteine CANNOT move forward → backs up → homocysteine piles up.
• Treatment: avoid methionine (since it makes homocysteine), supplement cysteine (which becomes essential), high-dose B6 (to try to stimulate whatever residual enzyme activity exists).

• Some people have a mutant enzyme that doesn't hold B6 (pyridoxal phosphate) tightly → enzyme works poorly → homocysteine backs up.
• Treatment: flood the system with LOTS of B6 → forces the enzyme to bind it → restores some activity.

• This enzyme converts homocysteine back to methionine (requires Methyl B12 and methylfolate).
• If deficient → homocysteine can't be recycled back → piles up.
• Treatment: supplement methionine (since it can't be made from homocysteine remethylation).

• MTHFR makes methylfolate (the donor of methyl group to convert homocysteine → methionine).
• If MTHFR is deficient → no methylfolate → homocysteine can't be recycled → builds up.
• MTHFR mutation is actually the most common inherited risk factor for elevated homocysteine levels in the general population!

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• Osteoporosis = weak, brittle bones (homocysteine interferes with collagen cross-linking → weak connective tissue).
• Marfanoid habitus = tall, thin body with long limbs, resembling Marfan syndrome. But NOT Marfan!
• Ocular changes - lens subluxation downward and inward: The lens of the eye is held in place by tiny fibers (zonular fibers, which are collagen). Homocysteine damages collagen → fibers break → lens drops. In homocystinuria it goes DOWN AND IN. Compare to Marfan syndrome where lens goes UP AND OUT ("Marfan up and fans out").
• Cardiovascular effects: Homocysteine damages the lining of blood vessels (endothelium) → promotes clot formation (thrombosis) and fatty plaque buildup (atherosclerosis) → stroke, heart attack (MI).
• Kyphosis = hunching/forward curvature of the upper spine (from bone weakness/osteoporosis).
• Intellectual disability = brain damage from homocysteine toxicity.
• Hypopigmented skin = less melanin (pale skin/hair) because cystathionine synthase deficiency reduces cysteine, which is needed for melanin production.

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📌 TOPIC 13: CYSTINURIA

• Renal PCT = Proximal Convoluted Tubule of the kidney. This is where amino acids are normally reabsorbed (pulled back) from the filtered urine into the blood.
• In cystinuria, the transporter that reabsorbs COLA amino acids is broken → these amino acids stay in the urine instead of being reabsorbed.
• COLA = Cystine, Ornithine, Lysine, Arginine
• Cystine = two cysteines joined by a disulfide bond (cysteine + cysteine = cystine).

• Cystine is poorly soluble in urine → it crystallizes → forms kidney stones (renal calculi).
• The stones are hexagonal shaped (6-sided) - unique to cystinuria. Classically tested on exams!
• Recurrent = comes back again and again because the defect is permanent.

• The nitroprusside test turns a characteristic color in the presence of cystine.

• Urinary alkalinization (eg, potassium citrate, acetazolamide) = making the urine more basic (higher pH). Cystine is more soluble in alkaline urine → less likely to crystallize → less stones.
• Chelating agents (eg, penicillamine) = penicillamine grabs cystine and makes it more soluble.
• Good hydration = dilutes urine → less concentration → less crystallization.
• Diet low in methionine = methionine → cysteine → cystine. Less methionine = less cystine made.

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📌 TOPIC 14: ORGANIC ACIDEMIAS

• Organic acidemias = diseases where organic acids (breakdown products of amino acids) accumulate because of enzyme deficiencies.
• Hypotonia = floppy muscle tone ("floppy baby").
• High anion gap metabolic acidosis = the accumulated organic acids cause acid buildup in the blood. The "anion gap" is a formula that detects hidden acids in blood - when organic acids accumulate, the gap goes high.
• Hepatomegaly = enlarged liver (the liver is overloaded trying to process these organic acids).

• Organic acids interfere with the liver's ability to make glucose → hypoglycemia when fasting.
• They also drive ketone body production → ketoacidosis (acid crisis).

• The same organic acids also poison the urea cycle enzymes → ammonia builds up → brain damage.

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• Normally: Propionate → Propionyl-CoA → (propionyl-CoA carboxylase + Biotin) → Methylmalonyl-CoA → (methylmalonyl-CoA mutase + B12) → Succinyl-CoA → TCA cycle
• In propionic acidemia, the FIRST enzyme (propionyl-CoA carboxylase) is missing → propionyl-CoA builds up.
• Treatment: low-protein diet, avoid VOMIT foods = Valine, Odd-chain fatty acids, Methionine, Isoleucine, Threonine (all feed into propionyl-CoA).

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• The SECOND enzyme in the pathway (methylmalonyl-CoA mutase) is deficient, OR there is a B12 deficiency (B12 is the cofactor).
• Methylmalonyl-CoA accumulates.
• Treatment: similar to propionic acidemia + B12 supplementation (if B12-responsive form).

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PAGE 84 - GLYCOGEN REGULATION + GLYCOGEN STORAGE

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📌 TOPIC 15: GLYCOGEN REGULATION BY INSULIN AND GLUCAGON/EPINEPHRINE

• Glycogen = the storage form of glucose in the body. Like a bank account - when you have excess glucose, you store it as glycogen. When you need energy, you break down glycogen to get glucose back.
• Main storage sites: Liver (glycogen maintains blood glucose) and Skeletal Muscle (glycogen fuels muscle contraction during exercise).

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When EPINEPHRINE (adrenaline) and GLUCAGON are high (starvation, stress, exercise):

• Glucagon = hormone from pancreas (released when blood sugar is LOW) → tells liver to break down glycogen.
• Epinephrine = stress hormone (adrenaline) → tells liver AND muscle to break down glycogen.

1. Epinephrine binds beta receptor (on muscle, liver) or alpha2 receptor (liver)
2. → Activates adenylate cyclase (enzyme) → converts ATP to cAMP (cyclic AMP = a "messenger molecule inside the cell")
3. cAMP → activates Protein Kinase A (PKA)
4. PKA → activates glycogen phosphorylase kinase
5. Glycogen phosphorylase kinase → activates glycogen phosphorylase (the enzyme that breaks down glycogen)
6. RESULT: glycogen breaks down → releases glucose

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When INSULIN is high (after a meal, blood sugar is HIGH):

• Insulin = hormone from pancreas released when blood sugar is HIGH → tells liver and muscle to STORE glucose as glycogen.

1. Insulin binds its receptor (a tyrosine kinase dimer receptor)
2. → Activates a signaling cascade → activates Protein Phosphatase
3. Protein phosphatase removes phosphate groups from glycogen synthase → ACTIVATES glycogen synthase → glycogen SYNTHESIS happens.
4. Protein phosphatase also deactivates glycogen phosphorylase → stops glycogen breakdown.

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Glycogen Structure:

• Glycogen is like a tree: the trunk and branches are made of glucose units.
• Alpha-1,4 bonds = linear chain bonds (connecting glucose units in a straight line)
• Alpha-1,6 bonds = branch points (where a branch sprouts off the main chain)
• Having many branches means glycogen can be mobilized very QUICKLY - you can break off glucose from many branch points simultaneously.

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Glycogen in Skeletal Muscle:

• Glycogenolysis = breakdown of glycogen (lysis = break).
• Muscle glycogen → Glucose-1-phosphate → Glucose-6-phosphate → glycolysis → ATP for muscle work.
• KEY POINT: Muscle lacks glucose-6-phosphatase, so glucose-6-phosphate CANNOT be released from muscle into blood. Muscle glycogen is only for the muscle's OWN use!

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Glycogen in Hepatocytes (Liver cells):

• Liver CAN release glucose into blood (it has glucose-6-phosphatase) → maintains blood sugar between meals.

• Glycogen phosphorylase chews off glucose-1-phosphate units from the ends of chains, one by one, but it STOPS when it reaches 4 glucose units away from a branch point. At that point it cannot go further.

• The debranching enzyme (which has TWO activities) does two things:
  1. Transferase activity: Moves 3 glucose units from the branch tip to the end of the main chain.
  2. Glucosidase activity (alpha-1,6-glucosidase [enzyme 7]): Cleaves off the last remaining glucose unit at the branch point → releases FREE glucose (not phosphorylated!).

• Limit dextrin = the stubby branch that remains after phosphorylase has done all it can (before debranching enzyme acts). This is relevant in Cori and McArdle diseases.

• Lysosomes = the cell's recycling/garbage bins. They have their own enzymes to degrade glycogen.
• Acid maltase (enzyme 8) in lysosomes handles a small portion of glycogen degradation.
• Deficiency → Pompe disease (Type II glycogen storage disease).

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PAGE 85 - GLYCOGEN STORAGE DISEASES

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📌 TOPIC 16: GLYCOGEN STORAGE DISEASES (GSDs)

• Think of these as "traffic jams" in the glycogen breakdown pathway - depending on where the blockage is, a different disease results.

• PAS stain = a special stain used in pathology. Glycogen turns magenta/pink. Used to identify which cells have glycogen accumulation.

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VON GIERKE DISEASE (Type I) - Glucose-6-phosphatase deficient

• Glucose-6-phosphatase = the enzyme that converts glucose-6-phosphate → free glucose (so it can be released from the liver into blood).
• Without it: glucose cannot be released from the liver → severe low blood sugar (hypoglycemia) when fasting.
• Glucose-6-phosphate builds up → diverted to other pathways → ↑ lactate (from glycolysis), ↑ triglycerides (lipid synthesis), ↑ uric acid (from purines).
• Gout = painful joint disease from uric acid crystals depositing in joints.
• Hepatomegaly = enlarged liver (stuffed with glycogen). Renomegaly = enlarged kidneys.
• "Liver does not regulate blood glucose" = because without glucose-6-phosphatase, the liver can't export glucose.
• "Impaired gluconeogenesis and glycogenolysis" = both pathways end at glucose-6-phosphate, and neither can push past to make free glucose.

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POMPE DISEASE (Type II) - Lysosomal acid α-1,4-glucosidase (acid maltase) deficient

• Cardiomyopathy = heart muscle disease. Glycogen accumulates in heart muscle → heart becomes big and weak → heart failure.
• Hypotonia = floppy muscles (glycogen accumulates in skeletal muscle too).
• Enlarged tongue = macroglossia (glycogen accumulation).
• Infants die within the first year without treatment.
• TREATMENT: Enzyme replacement therapy with recombinant acid glucosidase (Alglucosidase alfa = Myozyme) - this is a real treatment available today!

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CORI DISEASE (Type III) - Debranching enzymes deficient

• Like Von Gierke BUT: gluconeogenesis IS intact (debranching enzyme deficiency does not affect gluconeogenesis), so blood lactate is normal.
• Why? Because in Von Gierke, glucose-6-phosphatase is missing → gluconeogenesis products (glucose-6-phosphate) pile up → lactate increases. In Cori, the block is BEFORE that step, and gluconeogenesis can still funnel glucose out.

• Without debranching enzyme, glycogen breakdown stops at the branch points → shortened, stubby glycogen chains (limit dextrin-like structures) pile up in cells.
• Cirrhosis = liver scarring from chronic glycogen overload. Hepatic adenomas = benign liver tumors.

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ANDERSEN DISEASE (Type IV) - Branching enzyme deficient

• Branching enzyme makes the branch points in glycogen. Without it, you make long UNBRANCHED glycogen chains (like amylose instead of amylopectin).
• These long, abnormal chains are poorly soluble → deposit in cells → treated as "foreign" → triggers immune reaction → liver inflammation → cirrhosis.

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McARDLE DISEASE (Type V) - Skeletal muscle glycogen phosphorylase (myophosphorylase) deficient

• Myophosphorylase = glycogen phosphorylase specifically in muscle.
• Without it, muscle CANNOT break down its own glycogen for energy during exercise.
• During intense exercise, muscles need rapid glucose → can't get it from glycogen → run out of fuel → cramps and pain.
• Myoglobinuria = myoglobin (muscle protein) leaks into blood and urine → urine turns red/brown (similar to blood in urine but different). This happens because muscle fibers literally break down (rhabdomyolysis) from lack of energy.
• Electrolyte disturbances from muscle breakdown → cardiac arrhythmia.

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PAGE 86 - LYSOSOMAL STORAGE DISEASES (LSD)

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📌 TOPIC 17: LYSOSOMAL STORAGE DISEASES

• Lysosomes = the cell's "stomach" / garbage disposal system. They contain enzymes (called lysosomal hydrolases) that break down large molecules (lipids, sugars, proteins).
• If any of these enzymes are missing → the substance that enzyme normally breaks down ACCUMULATES inside lysosomes → lysosomes swell → cells become dysfunctional.

• These three diseases are much more common in people of Ashkenazi (Eastern European) Jewish descent. This is due to genetic founder effects (a small ancestral population carried these mutations, which spread within the community).

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SPHINGOLIPIDOSES (diseases of sphingolipid breakdown):

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TAY-SACHS DISEASE

• Neurodegeneration = progressive destruction of neurons (nerve cells).
• Developmental regression = baby reaches milestones (can sit, grasp) then LOSES them.
• Hyperreflexia = exaggerated reflexes (the motor system is affected).
• Hyperacusis = exaggerated response to sounds (startles easily to loud sounds) = classic feature.
• Cherry-red spot on macula = the macula is the central part of the retina. In Tay-Sachs, ganglion cells around the macula accumulate lipid → appear whitish/opaque. But the fovea (center of macula) has no ganglion cells → it appears RED against the white background → "cherry-red spot." Seen on fundoscopic (eye) examination.
• Lysosomes with onion skin = under electron microscope, the lysosomes look like concentric rings (onion-like) from the accumulated ganglioside layers.
• No hepatosplenomegaly = unlike Gaucher and Niemann-Pick, Tay-Sachs does NOT enlarge the liver or spleen (the ganglioside accumulates mainly in neurons, not in liver/spleen macrophages).

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FABRY DISEASE

• Peripheral neuropathy = burning pain in hands/feet (the accumulated lipid damages peripheral nerves).
• Angiokeratomas = dark red/purple tiny skin lesions (raised), especially on the lower trunk/groin area. These are dilated blood vessels with overlying thickened skin.
• Hypohidrosis = reduced sweating (autonomic nerve damage from lipid accumulation).

• Ceramide trihexoside accumulates in kidney blood vessel walls → renal failure. Also accumulates in heart.

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METACHROMATIC LEUKODYSTROPHY

• Demyelination = destruction of the myelin sheath (the fatty insulation around nerve fibers). Without myelin, nerve signals slow down or fail.
• Ataxia = loss of coordination (can't walk steadily, balance problems).
• Dementia = progressive loss of cognitive (thinking) ability.
• Both central (brain, spinal cord) and peripheral (body) nerves are affected.

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KRABBE DISEASE

• Oligodendrocytes = cells in the brain that make myelin (the insulation). When they are destroyed → demyelination.
• CN II atrophy = optic nerve (Cranial Nerve II) degenerates → vision loss.
• Globoid cells = characteristic large macrophages stuffed with undigested material, seen on brain biopsy.
• Psychosine = an especially toxic intermediate that kills oligodendrocytes.

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GAUCHER DISEASE

• Hepatosplenomegaly = liver AND spleen enlarged (macrophages in these organs fill up with glucocerebroside).
• Pancytopenia = low counts of ALL blood cell types (red cells, white cells, platelets) - because the spleen is so enlarged it destroys blood cells (hypersplenism) and bone marrow is infiltrated.
• Osteoporosis = weak bones. Gaucher cells infiltrate bone marrow → destroy bone.
• Avascular necrosis of femur = the head of the thigh bone (femur) loses its blood supply and dies → severe hip pain, limping. Classic!
• Bone crises = episodes of severe bone pain (like a sickle cell crisis but from Gaucher cells).
• Gaucher cells = macrophages stuffed with glucocerebroside, appearing like "crumpled tissue paper" under microscope.

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NIEMANN-PICK DISEASE

• Like Tay-Sachs BUT has hepatosplenomegaly (unlike Tay-Sachs).
• Foam cells = macrophages stuffed with lipid look "foamy" under the microscope (vs. "crumpled tissue paper" in Gaucher).
• Also has the cherry-red spot (lipid accumulation in retinal ganglion cells).

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MUCOPOLYSACCHARIDOSES (MPS) - diseases of glycosaminoglycan breakdown:

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HURLER SYNDROME (MPS type I)

• Hirsutism = excess body hair.
• Clouded cornea = GAG deposits in the cornea → vision loss.
• Coarse facial features ("gargoyle" facies).
• Progressive and severe.

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HUNTER SYNDROME (MPS type II)

• Milder than Hurler.
• No corneal clouding (key distinguishing feature from Hurler).
• Aggressive behavior / hyperactivity = behavioral problems.
• Affects mainly boys (X-linked).

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The Sphingolipid Breakdown Pathway Diagram:

• GM2 ganglioside → (Hexosaminidase A, blocked in Tay-Sachs) → GM3
• Ceramide trihexoside → (α-galactosidase A, blocked in Fabry)
• Glucocerebroside → (Glucocerebrosidase, blocked in Gaucher) → Ceramide
• Galactocerebroside → (Galactocerebrosidase, blocked in Krabbe) → Ceramide
• Sphingomyelin → (Sphingomyelinase, blocked in Niemann-Pick) → Ceramide
• Cerebroside sulfate (sulfatide) → (Arylsulfatase A, blocked in Metachromatic leukodystrophy) → Galactocerebroside

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PAGE 87 - FATTY ACID METABOLISM

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📌 TOPIC 18: FATTY ACID METABOLISM - SYNTHESIS AND DEGRADATION

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FATTY ACID SYNTHESIS (making fat):

• Where does FA synthesis happen? In the cytoplasm (cytosol) of cells - mainly liver, fat tissue, and nursing breast tissue.
• The Problem: The starting material (Acetyl-CoA) is inside the mitochondria (the cell's power plant), but fatty acid synthesis needs it OUTSIDE (in the cytosol).
• Solution: Acetyl-CoA is combined with oxaloacetate → forms citrate (inside mitochondria). Citrate can exit the mitochondria. Once in the cytosol, ATP citrate lyase cleaves it back into Acetyl-CoA + oxaloacetate. Now Acetyl-CoA is in the cytosol and ready for fat synthesis.

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1. Acetyl-CoA → Malonyl-CoA: The enzyme is acetyl-CoA carboxylase. Requires CO2 and Biotin (vitamin B7) as cofactor.
   • This is the rate-limiting step of fatty acid synthesis.
   • Insulin activates acetyl-CoA carboxylase → promotes fat synthesis (when you've eaten and blood sugar is high, insulin tells the body "store fat").
   • Glucagon inhibits it → no fat synthesis when you're fasting (makes sense - don't store fat when you're hungry!).
2. Malonyl-CoA → Fatty acid chain: Done by Fatty Acid Synthase (FAS) enzyme complex. Each cycle adds 2 carbons to the growing chain.
3. The product: Primarily palmitate (a 16-carbon fatty acid) = palmitate is the main product of de novo (new) fatty acid synthesis.
4. "Sytrate" = synthesis (memory trick for citrate being used in synthesis) "Carnitine = carnage of fatty acids" (memory trick for carnitine being used in fatty acid DEGRADATION - see below)

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FATTY ACID DEGRADATION (burning fat - Beta-Oxidation):

• Where does FA degradation happen? INSIDE the mitochondria (the power plant).
• The Problem: Long-chain fatty acids are too large to cross the inner mitochondrial membrane on their own.
• Solution: A molecule called carnitine acts as a "taxi cab" to carry them in.
• Carnitine shuttle:
  • In the cytosol: Fatty acid + CoA → Fatty acyl-CoA (via Fatty acyl-CoA synthetase)
  • Carnitine palmitoyltransferase I (CPT I) transfers the fatty acid from CoA to carnitine → forms fatty acyl-carnitine
  • Fatty acyl-carnitine crosses the inner mitochondrial membrane (via carnitine shuttle)
  • Carnitine palmitoyltransferase II (CPT II) transfers it back to CoA inside the matrix
  • Now Fatty acyl-CoA is inside the mitochondria → undergoes beta-oxidation

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• Fatty acyl-CoA is repeatedly chopped → each cycle removes 2 carbons as Acetyl-CoA (via acyl-CoA dehydrogenases).
• Acetyl-CoA → TCA cycle → produces energy (ATP, NADH, FADH2).
• During fasting, Acetyl-CoA → Ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone) → fuel for brain and other tissues.

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SYSTEMIC PRIMARY CARNITINE DEFICIENCY:

• Can't bring fatty acids into mitochondria → can't burn them for energy → fatty acids pile up in cytosol → toxic.
• Hypoketotic hypoglycemia = low blood sugar WITHOUT ketones. Why? Because ketone bodies come from fatty acid breakdown. If fatty acids can't be broken down → no ketones. AND without fatty acid fuel, the body burns through all its glucose → hypoglycemia. Normally in fasting/hypoglycemia, ketones rise - their absence here is a clue!
• Dilated cardiomyopathy = heart muscle runs mostly on fat for fuel. If fat can't be burned → heart muscle starves → dilates and weakens.
• Treatment: L-carnitine supplementation.

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MEDIUM-CHAIN ACYL-COA DEHYDROGENASE (MCAD) DEFICIENCY:

• MCAD = the enzyme that oxidizes medium-chain (6-12 carbon) fatty acids.
• If MCAD is deficient → medium-chain fatty acids cannot be broken down → pile up in blood.
• Again: Hypoketotic hypoglycemia = no ketones + low blood sugar (same reasoning as above).
• Dicarboxylic acids = unusual breakdown products that appear when the normal pathway is blocked.

• MCAD deficiency is one of the most important causes of sudden unexplained death in infants/children.
• During fasting (when fat is needed for fuel), MCAD-deficient patients cannot mobilize fat → energy crisis → liver failure, brain damage, death.
• Many countries now include MCAD deficiency in newborn screening (urine acylcarnitine profile).
• TREATMENT: Simply avoid fasting! Never skip meals. If sick (and not eating), give IV glucose immediately.

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📋 QUICK SUMMARY TABLE - All Topics Covered

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