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Glycogen accumulation in hepatocytes → foreign body reaction and hepatocyte injury → progressive cirrhosis
7 types.
Mnemonic: Von Gierke Put Coors And McDonalds in Her Taurus. (Imagine Von Gierke loading up his girlfriend's Ford Taurus with Coors and McDonalds for a picnic)
• Type 1: Von Gierke
• Type 2: Pompe
• Type 3: Cori
• Type 4: Andersen
• Type 5: McArdle
• Type 6: Hers
• Type 7: Tarui
# Type 1 glycogen storage
(von Gierke's): deficient glucose-6-phosphatase (liver, kidney) → defective glycogenolysis and gluconeogenesis → severe hypoglycemiamia* (seizures, hypoxic brain damage), increased lactate
• Hepatorenomegalyy* - glycogen accumulates in liver and kidney because excess G-6-P stimulates glycogen synthesis and inhibits glycogenolysis .... Causes large abdomen
Hyperlipidemia *→ skin xanthomas and ↑ VLDL
Hyperuricemia --* ↓ free phosphate due to G6-Pase defect → ↑ AMP → AMP degraded to uric acid → ↑ uric acid → predisposes to gout
Fasting lactic acidosis --* ↑ lactate → ↓ uric acid excretion by kidneys
Ingestion of galactose or fructose → no increase in blood glucoseose*
Administration of glucagon, epinephrine, or other gluconeogenic stimulus → no increase in blood glucose
#glycogen storage deficiency 2
Type II (Pompe's): defective lysosomal α-1,4-glucosidase AKA acid a-glucosidase→ enzyme is responsible for digesting glycogen → glycogen deposits accumulate in lysosomes
• Lysosomal α-1,4-glucosidase is responsible for only ~3% of glycogenolysis, so defects don't cause hypoglycemia
• Organs most affected are those that store glycogen (liver, heart, skeletal muscle)
• Left ventricular hypertrophy leads to outflow tract obstruction and cardiac failure
• Mortality in infantile form due to cardiac failure from massive cardiomegaly *→ death before age 2
Mnemonic: Pompe's trashes the Pump (heart)
#Pompe ECG and blood
Short PR, giant QRS...... blood shows elevated CK, decreased leukocyte acid maltase.
#Glycogen storage deficiency 3
(Cori's): defective α-1,6-glucosidase (glycogen debrancher enzyme)* →

Presents with both liver and muscle involvement, there is
-hypoglycemia
- hepatomegaly
- ketoacidosis
- muscle weakness/hypotonia (not seen in Von Gierke)
milder than Type I (von Gierke's), normal blood lactate levels
Assumulation of glycogen, but the molecules have shorter outer branches → single glucose residue
• Glycogenolysis is defective but gluconeogenesis is still functional.
#glycogen storage deficiency 4
Type IV (Andersen's): defective α-4,6-glucosidase (glycogen branching enzyme)
• Inability to form branches → accumulation of long, insoluble glycogen chains → hepatosplenomegaly and cirrhosis
• Causes infantile cirrhosis, failure to thrive and hypotonia → usually fatal
#glycogen storage deficiency 5
Type V (McArdle's):
defective skeletal muscle glycogen phosphorylase → unable to break down glycogen *→ ↑ glycogen in muscle → muscle cramps/weakness with exercise → can lead to myoglobinuria (myoglobin in urine)
• Still form normal glycogen molecules
• McArdle's = Muscle phosphorylase
#glycogen storage deficiency 6
Type VI (Hers'): deficient Hepatic glycogen phosphorylase* → gluconeogenesis but no glycogenolysis → fasting hypoglycemia (mild) and hepatomegaly/cirrhosis
• Hers' = Hepatic phosphorylase
• As with Type V (McArdle's), glycogen structure is normal
• Early childhood presentation of hepatomegaly and growth retardation → hepatomegaly may improve with ↑ age
#glycogen storage deficiency 7
(Tarui's): defective muscle phosphofructokinase. Tarui's presents with:
• exercise-induced muscle cramps and weakness
• growth retardation
...
...
lipoproteinemias
...
# type 1 dyslipoproteinemia manifestations
• The clinical findings include chylomicron-induced acute pancreatitis, hepatosplenomegaly, and eruptive/pruritic skin xanthomas
• There is no increased risk of atherosclerosiss*. !!!!!
type 2a dislipoproteinemia/familial hypercholesterol findings
"Due to defective LDL receptor, LDL cannot be cleared from the blood. More IDL is converted into LDL.

findings include:

- increased serum LDL AND increased serum cholesterol leading to increased risk of atherosclerosis and coronary artery disease.
# type 2b dislipoproetinemia aka familial combined hyperlipidemia
characterized by decreased LDL receptor and increased ApoB (think of it as a negative feecback!!)

The inheritance pattern is autosomal dominant.
The function of ApoB-100 is to uptake the LDL particle in the liver!!
Due to decreased LDL receptor and increased ApoB, the characteristics lab findings are increased serum LDL, VLDL, and triglycerides
# type 2 dyslipoproteinemia/ familial hypercholesterolemia
is characterized by an absence of or a decrease in competent LDL receptors. The inheritance pattern is autosomal dominant.
# Type IV dyslipoproteinemia aka hypertriglyceridemia
"AD inherited.... • Due to hepatic overproduction of VLDL, the characteristic lab findings are increased serum VLDL and triglycerides.
• Patients present with pancreatitis.
facial flushing (induced by prostaglandins, NOT histamine)....
# Abetalipoproteinemia (also known as Bassen-Kornzweig syndrome)
characterized by microsomal triglyceride transfer protein (MTTP) deficiency. MTTP is essential for synthesis and secretion of beta-type apolipoproteins (e.g., ApoB-48 and ApoB-100). The inheritance pattern is autosomal recessive.

• Due to ineffective MTTP, there is reduced chylomicron and VLDL synthesis and secretion.
• Reduced chylomicron and VLDL synthesis leads to severely reduced absorption of dietary fats and fat-soluble vitaminss*. Accumulation of lipids within enterocytes can be seen on intestinal biopsy. (!!!)
# Abetalipoproteinemia findings
Clinical findings present in the first few months of life and include:
- failure to gain weight and grow
- steatorrhea, large, bulky,foul smelling stools
- abnormal star-shaped red blood cells (acanthocytes) due to deficiency of fat soluble vitamins (esp vitamin E)
- ataxia, and night blindness.
#

Vitamin A deficiency leads to
night blindness

- squamous metaplasia leading to skin abnormalities (follicular hyperkeratosis) !!!
eye abnormalities (Bitot's spots → buildup of keratin debris in conjuctiva),

lung abnormalities (bronchitis, pneumonia)

immune suppression
# Vitamin A eye metaplasia
When Vit A deficient, thin squamous lining of the conjunctiva covering the When Vit A deficient, thin squamous lining of the conjunctiva covering the eye undergoes metaplasia into stratified squamous epithelium, change called keratomalacia (thickening of eye).
# Vitamin A excess
Excess (result of eating bear liver or isotretinoin therapy for skin conditions):
increased intracranial pressure (papilledema, convulsions),
liver toxicity (vitamin A is stored in the liver)

splenomegaly, bone pain
# Vitamin A in pregnancy as teratogen
high doses of Vitamin A are highly teratogenic because it is lipid soluble it accumulates.... causes (birth defects include cleft palate, cardiac abnormalities, low IQ scores and extremely high risk for spontaneous abortions)
# Vitamin A uses
isotretinoin (all-trans retinoic acid, acid form of vitamin A), which is a topical medication used for mild acne and psoriasis !!!
Vitamin A can be useful in measles !!!

All vitamin A medications work by binding to eukaryotic nuclear receptors (retoinoic acid receptors). Then then act as ligand-activated transcription factors.
# b1 deficiency
Thiamine deficiency may lead to beriberi ("Ber1Ber1") and Wernicke-Korsakoff syndrome. In the United States, thiamine deficiency is most common in alcoholics (due to poor nutrition and that excess alcohol limits the body's ability to absorb and store thiamine.) ...
it also caused impaired ATP breakdown and ATP depletion which is WORSENED by glucose infusion (!!!!) and damages highly aerobic tissues (brain, heart).!!!

Note: when you give glucose to a b1 deficient patient you MUST include b1 aka thiamine!!!!!
# beriberi
Beriberi has a dry (muscle wasting, sensory neuropathy, motor impairment, peripheral neuropathy)

- wet (congestive high pressure heart failure marked by peripheral edema, cardiomegaly, dilated cardiomyopathy) component !! )
# Wernicke-Korsakoff syndrome
composed of Wernicke's encephalopathy and Korsakoff's psychosis (memory loss, confabulation and personality change).... This is ususally permanent (!!!!)
Alpha-ketoglutarate is NOT able to be converted to succinyl CoA !!!! This enzyme requires B1 as a cofactor!!
# Wernicke's encephalopathy (!!)
triad of:

1) confusion, apathy, inattentiveness

2) horizontal nystagmus, bilateral abducens palsy, complete opthalmoplegia

3) ataxia
# Where does Wernicke-Korsakoff affect the brain causing memory loss?
This is due to damage of the medial dorsal nucleus of the thalamus AND the mammillary bodies. (!!!!!) Results in a phenomenon called "confabulation", where they are unsure of a gap in something, they fill it in with what they believe to be true!!

Also anterograde amnesia. These are usually permanent!

# what enzyme is diagnostic for Wernicke's encephalopathy and thiamine deficiency?
An increase in erythrocyte transketolase levels AFTER thiamine infusion.
# B1 is a coenzyme for what enzymes? (!!!)
", thiamine pyrophosphate (TPP), is an important coenzyme for several reactions, notably:
• dehydrogenase enzymes (e.g. pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase complex, and branched-chain ketoacid dehydrogenase).
• transketolase, an enzyme of the non-oxidative portion of the pentose phosphate pathway.
arginine derivatives
creatine, urea, and nitric oxide (!!!!)
• Creatine phosphate is a short term energy reservoir primarily used during the early stages of muscular exercise.
• NO is an important vasodilator, synthesized from arginine via nitric oxide synthase (NOS).
• urea
# What B vitamins do NOT wash out quickly?
Folate (B9) and Cobalamin (B12)
# arginase deficiency
Arginase is the enzyme which converts arginine into urea and ornithine.

presents as spasticity
# vitamin B2 deficiency
riboflavin deficiency causes:
- angular cheilitis (cracked angles of the mouth)
- glossitis with magenta-colored tongue
- corneal vascularization.
# Vitamin B2
"Riboflavin.
key component of FAD (used in succinate dehydrogenase of the TCA cycle, aka complex II of the electron transport chain) and FMN (used in NADH dehydrogenase, aka complex I of the electron transport chain), which are used as cofactors for redox reactions.
Think B2=FAD (2 ATP)"
# Vitamin B3
"(niacin): precursor for NADH and NADPH. (B3= NADH = 3ATP's)
• niacin may be administered in the form of nicotinic acid to raise HDL and lower LDL.
# Niacin excess
is associated with facial flushing
, hyperuricemia, and hyperglycemia. (acanthosis nigricans).... The insulin resistance is problematic for diabetics !!!
# Vitamin B5
"pantothenic acid:... aka ""pent-o-thenic"" acid.... needed to form coenzyme-A (CoA).

CoA is very important in early TCA cycle, it binds to oxaloacetate and enhances the conversion to citrate.
# niacin and cholesterol
Niacin decreases synthesis of hepatic tryglycerides and VLDL. !!!!!!!!! (!!!)
It also decreases VLDL conversion to LDL, thus, decreasing LDL.
Also increases HDL. (Niacin is the most effective antilipid for elevating serum HDL levels)
# Vitamin B6
"active form is pyridoxal phosphate (PLP). This is a cofactor in:
• transamination reactions (AST/ALT)
• deamination reactions
• decarboxylation (example: glycine + succinyl-CoA → aminolevulinic acid)
# Vitamin B3 deficiency (!!!!!!)
Niacin deficiency leads to glossitis and may lead to pellagra in severe deficiency (diarrhea, dermatitis, dementia). "The three D's of B3 deficiency"....

Remember, tryptophan is precursor to niacin (!!!!)
# causes of niacin deficiency
"1. Hartnup disease
2. In carcinoid syndrome, excess tryptophan metabolism converts tryptophan to serotonin.
3. Prolonged isoniazid use decreases niacin levels by depletion of pyridoxal phosphate, B6, which is necessary for endogenous synthesis of niacin!!
# hartnup disease
is an autosomal-recessive defect in intestinal AND renal transporters for neutral amino acids. This causes tryptophan excretion in urine and leads to pellagra. (dementia, diarrhea, dermititis)

Leads to wasting of the neutral amino acids except proline, hydroxyproline and arginine!! (differentiate from Fanconi syndrome!!)

Patients can develop symptoms of niacin deficiency or pellagra because of wasting of tryptophan!!!

Eat more tryptophan/niacin!!!
# niacin overdose (!!)
Hyperglycemia, hyperuricemia.
# Vitamin B6 deficiency/toxicity
• Pyridoxine deficiency causes:
o peripheral neuropathy and convulsions (due to its role in neurotransmitter synthesis (serotonin, E, NE, dopamine, GABA)). !!!!!!!!!!!!!
o sideroblastic anemias due to defective heme synthesis and resulting iron excess.
• Pyridoxine toxicity is associated with peripheral neuropathy, presenting with burning, numbness and tingling of the hands and feet
# Vitamin B9 deficiency
"Folate
Folate is converted to tetrahydrafolate (THF), which is a carbon carrier critical for synthesis of nitrogenous bases (particularly thiamine, adenine, and guanine) in nucleic acids, especially in states of rapid cell division (pregnancy, erythropoiesis).
• Deficiency leads to neural tube defects & megaloblastic anemia..... NO neurological symptoms
# folate absorption
*Folate is obtained via green vegetables, and fruits, absorbed in the jejunum (!!!!). The enzyme intestinal conjugase (which is inhibited by phenytoin) is required for absorption.
# Erb's Palsy "waiter's tip"
Damages C5-C6 roots via trauma in adults or trauma during delivery in infants.

With the deltoid and rotator cuff muscles are paralyzed due to injury of C5 and C6, the action of latissimus dorsi on the shoulder (extension, adduction, medial rotation) is unopposed → the arm hangs by the side (adduction) and is internally (medially) rotated

Arm is adducted (by side), extended (straight down), medially rotated.
Forearm pronated and hand flexed.


Loss of abduction of shoulder (deltoid, supraspinatus)
Loss of lateral rotation of the shoulder (infraspinatus)
Loss of flexion/supination of forearm (biceps)
Use the mnemonic "Real Texans Drink Cold Beer" to remember the proximal-to-distal organization of the brachial plexus: Roots → Trunks → Divisions → Cords → Branchesranches*
• 5 Roots: ventral rami of C5, C6, C7, C8, T1
• 3 Trunks:
o Superior (upper) trunk (C5, C6)
o Middle trunk (C7)
o Inferior (lower) trunk (C8,T1)
• 6 Divisions: an anterior and posterior division for each of the 3 trunks
• 3 Cords (named according to their anatomic relationship to the axillary artery):
o Posterior cord → axillary nerve, radial nerve
o Lateral cord → raneous nerve, part of median nerve
o Medial cord → ulnar nerve, part of median nerve
• 5 terminal Branches: axillary, radial, musculocutaneous, median, ulnar nerves
# Klumpke palsy aka claw hand (!!!)
lesion of the lower trunk (C8-T1) of the brachial plexus!!!! ; extremely rare and can be caused by a forceful combination of arm traction and abduction during delivery.
Note: Although lower trunk lesions are typically presented as obstetrical complications, adults may sustain the injury by grasping for a ledge when falling from height!!!

Examples include grasping for the top rung of a ladder when falling or grabbing a tree branch when falling from above.
Anterior shoulder dislocation
Primary presentation: Arm is externally rotated and abducted
Anterior shoulder dislocation can result in axillary nerve injury.

• Axillary nerve injury presents with anesthesia of upper lateral arm and paralysis/paresis of the deltoid and teres minor muscles.
Flattening of the deltoid, protrusion of acromion.
# Anterior shoulder dislocation can also result in (!!!)
musculocutaneous nerve injury.

The musculocutaneous nerve courses across the coracobrachialis in front of the shoulder joint, which renders the nerve prone to traction injury. It innervates the biceps and brachialis!!!

Musculocutaneous nerve injury presents with anesthesia of the anterolateral forearm and weakness in elbow flexion and forearm supination. !!!!
risks for coronary heart disease
...
# Classic galactosemia: (!!)
autosomal recessive deficiency in GALT (galactose-1-phosphate uridyltransferase) which converts galactose-1-phosphate, to glucose-1-phosphate and UDP galactose.
• Absence of GALT leads to galactose and galactose-1-phosphate accumulation which are converted to toxic substances such as galactitol, which damages the lens of the eye.
• All states mandate neonatal screening because lactose (i.e. milk) is metabolized to glucose and galactose.
# classic galactosemia presentation
Symptoms: vomiting, lethargy, poor growth, hepatic dysfunction (jaundice, coagulopathy, hepatomegaly), ascites, cataracts, mental retardation..... begins SOON after breastfeeding!


These infants also have an ↑ risk for E. coli septicemia
.
• Treatment: galactose-free diet (avoid milk)!!!!!!!
# Hereditary fructose intolerance:
autosomal recessive deficiency of aldolase B.


As a result, fructose-1-phosphate accumulates as a toxic metabolite, available phosphate levels drop, and glycogenolysis and gluconeogenesis are blocked, so there is profound hypoclycemia after eating sucrose or fructose!!!!

Typically presents once the baby is introduced to baby food and cereals, while taken off breast milk, because breast milk contains glucose and galactose (glucose+lactose). Baby food contains sucrose and fructose.
• Symptoms include vomiting, jaundice, convulsions, and severe cirrhosis.
• Treatment is avoiding intake of fructose or sucrose (combination of glucose and fructose).
# Essential fructosuria:
autosomal recessive, benign condition resulting from defect in hepatic fructokinase.
• Fructose can NOT be phosphorylated into fructose-1-phosphate, so it is unable to be sequestered in the cell and does NOT deplete the cell's phosphate. Fructosuria is an incidential finding (fructose in urine). Fructose is a reducing sugar!!!!!!!!!!!
Sugar will NOT be picked up on urine dipstick!!!
# why is essential fructosuria an incidental finding?
Normally in healthy individuals, only a very small amount of Fructose is phosphorylated into Fructose-6 phosphate.

In Essential fructosuria, the main fate of fructose IS phosphorylation to fructose-6 phosphate by the enzyme hexokinase.
Fructose-6-phosphate can then be further metabolized.
# Galactokinase deficiency:
autosomal recessive deficiency in galactokinase which phosphorylates galactose to make galactose-1-phosphate
• Accumulation of galactose → galactosemia (blood)→ galactosuria (urine)
• Galactosemia → cataracts (especially in infants) !!!!!!!!!!!!* because the lens of the eye contains aldose reductase, which converts galactose to galactitol, an osmotically active alcohol.
It is a mild condition
Shooting pain down the posterior thigh/leg... usually due to compession at L5 or S1!!!
Causes weakness of the hamstrings AND muscles below the knee!
There is diminished ankle reflex but NOT knee reflex.
...
# tibial nerve injury
• Knee trauma-Knee dislocation
• Can't invert or plantarflex (can't stand on toes) the foot ( so the right foot is stuck in dorsiflexion) !!!
cannot flex (curl) the toes due to loss of innervation to the interossei muscles.
• Sensory loss on the sole (plantar surface) of the foot !!!!
Common peroneal (fibular) nerve: (!!!)
This is the most commonly injured nerve in the leg due to its superficial location where it courses laterally around the neck of the fibula.
Patient is unable to evert or dorsiflex foot and can't extend toes . So foot is held in inversion, plantar flexed position.

Foot drop!!!!
• There is also a sensory loss in the anterolateral leg and dorsal aspect of foot (!!)
• Injury to common peroneal nerve presents with a drop foot

• Can be caused by:
- a direct blow to the lateral aspect of leg
- fibula neck fracture (!!!)
- cast that is too tight