Carbohydrate Metabolism - Biochem Genetics

Carbohydrates

• Carbohydrate: (CH20)n → saccharide monomers

• Primary source for energy (ATP production)

  Complex carbohydrates: longer saccharide chaines —> bread, legues, veggies

  Simple carbohydrates: contain mono and disaccarhdires —>

Saccharide

• Single “sugar” molecules

• Ex: Glucose, Fructose, Galactose

• Ring shaped: size of ring, orenation of the OH group

Disaccharides

• Two linked sugar molecules

• Ex sucrose(glucosle+furctose), Lactose (glucose +galactose), Maltose (Gluclose +glucose)

• The common disaccharides (sucrose, lactose, maltose) are digested on the surface of the small insteintes—> enzymes excist: sucrase, Lactase, maltase

  • Break down into their mon saccharide comepents to allow for absortion through the GI wall and into the blood stream

• “LActose intolerance”: loss of lactase activity in the small intestine; unable to be abasorded leading to bloating and discofmrt

Polysaccharides

• Long chains of linked sugar molecules

• Ex: glycogen (Animals), Amalose, Amolopectin, Cellleose (Plants)

• Primary storage source for Gluclose in Animals and plants

• Can also have structural functions (cellulose +chtitin)

• Composed of diffrent monomeric units linked by different alpha+beta bonds

Starch

• Main storage of glucose in plants: as either Amylose or amylopectin

  • Amylose is unbranched polysaccharide chain: linked only by alpha 1,4 linkages → long, uninterrupted chain of glucose (HELICAL SHAPE)

  • Amylopectin: have 1,4 alpha linkages chain with additional 1,6-alpha linkages of glucose → creating a branched molecule, higher storage capacity

Digestion starts with chewing, but needs

• Salvitory gland → amylase

• Pancreas → Amylopectin

Glycogen

• Major storage form of glucose: highly branch a 1,4 and a 1,6 bonds

  Body need a constant supply of blood glucose: taken in through diet but then stored:

• Liver synthesizes and stores glycogen (glycogenesis): a repository for when glucose is low (between meals, sleep, fasting)

  • when blood glucose is low, liver glycogenolysis occurs

    • Glycogen → Glucose-6-Phostpaht (cannot leave liver)→ Glucose (CAN leave liver)

  • Glycogen storage= 8-10 hours of glucose → longer than that, switch to fat stores for days/weeks of energy (creates KETONE BODIES for energy)

• Muscle has glycoen but no glu-6-phospahtase: → muslces can absord, store and use glyocen but cannot RELEASE IT BACK

• Brain has no glycogen stores!! needs liver to provide a steady stream of gluclose

Gluconeogenesis

• the process of synthesis of glucose within cells

• this can use a number of different sources:

  • Amino Acids (call Glucogenic Amino Acids) : must be converted into substrates that can be metabolized to create glucose

  • Glycerol: created form fatty acid metabolism

Glycolysis

• process of metabolism glucose into energy intermediaries that can enter into Krebs cycle and oxidative phosphorylation for ATP production

  • Glu-6-phosphate → Pyruvate → Actyl CoA (which enter the krebs cycle)

Ketones (Ketoacids)

• Appear in hypoglycemic states, where the body shifts to Fatty Acid Beta-oxidations pathway to produce ACETYL -CoA

• Ketone bodies can freely cross cell membranes —> CAN BE RELEASED INTO THE BLOOD STREAM as an alternative energy source for brain and muscle

• Examples:

  • Acetoacetyl CoA

  • Acetone

  • B-OH butyrate

Galactose Metabolism

• Lactose (present in breast milk) → Galactose + Glucose [Small Intestine]

• Galactose → Galactose-1-phospahte via GALK → Gluclose-1-phosphae via GALT + co-factor UDP-glucose

  • UDP-glucose is converted to UDP-galactose and must be reconverted back to UDP glucose

• Blocks in this system =

  • build up the different pathway products

  • Excess accumulation of galactose = galactic acid + galactitol

3 Galactosemia

3 major IEM

• Galactokinase deficiency (GALK)

• GALT deficiency → CLASSIC Galactosemic

• GALE Deficiency

Autosomal Recessive

• Galactokinase deficiency: untreated leads to cataracts → Galatonic acid + galactical build up as deposits in the eye

• Gale Deficiency: Mild + Severe (rarer, galactosemia-like) → high gal-1-phosphate and galactose + UDP galactose

ALL treted with DIetary Galactose restiction: but glactose also naturally produces galactose on its own so not fully sufficeint

Classic Galactosemia

GALT Deficiency

Neonatal onset: when baby is introduced to breast milk: Glaonic acid/Galctocla buildup

• Lethargy, poor feeding, vomiting, diaheria, death (LPVDD)

• Liver Failure: jaundice, bleeding, liver swelling (hepatomegly from gal-1-p buildup)

• Renal dysfunction

• Cataracts (galactitol buildup)

• E Coli (gram negative) sepsis": flourishes in environment w high galactose

Labs

• Elevated liver enzymes and bilirubin

• Coagualopathy (liver dysfunction)

• Positive reducing substance in urine

Urine Galactose

• All monosaccharides are reducing sugars → Will reduce inorganic ions such as copper via Fehling’s reagent

• Urine testing will detect presence of reducing sugars in urine (normally DOES NOT HAPPEN)

  • thin layer chromatography (TLC) can distinguish between different sugars that are present

Blood Glucose and GALT

• Newborn screening relies on the blood spot measurement of Galactose and Gal-1-P levels

  • CAN DETECT ALL 3 Galactosemias

  • But false negative: infants on lactose-free formulas → wont accumulate enough

• Alternative strategy: Detection of GALT activity

  • Prost-transfusion false negative

  • Detects Galatsemia classic, but misses the other two

• Galt activity vs measuring Galactose and Gal-1-P levels

Galactosemia Treatment

• Lifelong Galactose free diet: No breast milk, No Soy

  Outcome with Treatment

  • Life threating disease resolves quickly

  • Long term issues: we will endogenously produce galactose even if it is fully removed from the diet

    • reduced IQ + growth,

    • ataxia,

    • ovarian dysfunction

GALT Mutation

• Q188R in Caucasian 70% of classical cases

• S135L in 65% of African AMerican “Clinical variant”

  • can have better outcomes: better ovarian function

  • harder to detect: better GALT function

• N314D (Durate variants) → 50% GALT activity reduction

  • two Duartes mutations = GALT 50% activity, are just ‘carriers’

Fructose Metabolism

• Fructose mainly produced via the breakdown of Sucrose:

Fructose Disorder

3 Main Disorders of Fructose Metabolism

• Fructokinase Deficiency (Fructosurea)

• Hereditary Fructose Intolerance (Fructosemia)

• Fructose 1,6-Biphosphatase Defcieny

All autosomal recessive

Fructokinase Deficiency (Fructosurea)

• Benign condition

• Usually detected indinally

• Urine reducing substance: Fructose

• No treatment necessary

Hereditary Fructose intolerance

Etiology: Gene for Fructose-1-P Aldolase B (ALDOB gene) → a deficiency

Symptoms: only once diet includes fructose → sigfnicant reactions

• vomiting, lethargy, irritability, seizures

• Postprandial hypoglycemia, liver/kidney Dz

• Liver failure, acidosis, growth failure, death

Diagnosis

• Suspect with urine reducing substance for fructose:

  • Fructose + fructose-1-phosphae (toxic for body + decrease glycolysis)

• confirm with enzyme activity + mutation analysis

Treatment

• Eliminating fructose prevents and reverses further symptoms

• So patients will remain resistant despite elimination of fructose

Fructose 1,6-Biphosphatase

Symptoms: sudden, early life-threatening episodes of:

• Fasting hypoglycemia with lactic acidosis (***so even when Fructose has been eliminated***) → inability to shunt over Gly-3-P into the glycogensis pathway

• hyperventilation, vomiting, lethargy

• may be lethal

Fructose 1,6-Bisphosphatase → Glyceryalhyd-3-Phosphate (usable for glycognesisa) via 1,6-Bisphosphatase activity

Diagnosis

• NO URINE FRUCTOSE

• Check enzyme on liver biopsy

• Urine glycerol-3-phosphateleves

• Molecular testing

Treatment

• Acute: correct hypoglycemia and acidosis, IV

• Chronic: Avoid fasting with frequent glucose feeding, limit fructose

• Good outcomes once treatment initiated

Glycogen Storage Disorders

• When glycogen cannot be broken down, it accumulates in the cells they are stored in:

  • Liver involvement: causing hypoglycemia (inability to liberate glucose from glycogen) and swelling of the liver

  • Muscle involvement: causing muscle breakdown and weakness

Almost all are Recessive, but one if X-linked

• Type 1 Von Gerike Diease

• Type 2 Pompe Diease

• Type 5 McArdle Disease

Von Gierke Disease (GSD1) Metaboism

• Gluclose-6-phosphatase deficiency in Liver, Kidney and intestinal mucosa

  • Type1a: the glucose-6-phsopatase enzyme is defective

  • Type 1b: membrane transport protein for gluclose-6-phosphate

• When fasting, Body needs Glu-6-phosphate to be converted to glucose

  • GSD1 Both type susceptible to Hypoglycemia when fasting

Von Gierke (GSD1) Symptoms

• Usually not present early on: WELL FED = protection from fasting and therefore hypoglycemia

• Sometimes hypoglycemia and lactic acidosis

• Usually present at 3-4 months of age

  • Hepatomegaly

  • Hypoglycemia

  • Hyperuricemnia

  • Hyperlipidemia (fats are broken down more and end up in the blood)

  • Lactic acidosis

• “Doll-Like” faces with fat checks, relatively thin extrmeties, short statures and protrubent—> weird fat deposits

• Type Ib patients also have neutropenia

Von Gierke (GSD1) Diagnosis

Suspicion: usually infants more than new-born→ NOT ON NEWBORN SCREENING

• Hypoglycemia with minimal fasting

• Lactic acidosis, hyperuricemia, hyperlipidemia

Diagnosis

• Enzyme analysis: requires live biopsy

• Mutation Analysis

  • GSD1a: Glu-6-Phosphatase (G6PC) gene (94%)

    • Ashkenazi gene

  • GSD1b: Glu-6-Phosphate translocase (SLC37A4) gene (95%)

PRESENTS SIMILARLY TO GSDII: but diffrent genes, more milder and invovles MUSCLEs (myopathy)

Von Gierke (GSD1) Treatment

Avoid fasting/maintain blood glucose

• May need continuous nasogastric glucose

• Uncooked cornstarch: slow-release of glucose → when their salivatory gland mature enough to release amylase (complex carbohydrate breakdown)

  • Restrict Fructose and galactose (cannot be converted to free glucose)

• Dietary supplments

• Allopurinol for uric acid

• Statins for cholesterol

• Watch for hepatic adenomas

• G-CSF for neutropenic immunodeficiency

Pompes Disease (GSDII) Metabolism

Mechanism:

• Lysosomal Acid-alpha-Glucosidae (acid maltase) (GAA) Deficiency —> Lysosomal Glycogen Storage

Forms

• infantile: more severe → cardiomegaly, liver swelling

• Juvenile + Adult onset → less severe

Pompe’s Deasiae (GSDII)

Organs affected by glycogen accumulation

• Cardiac, skeletal and smooth muscle (primarily)

  • Muscle and Organ enlargement (due to Glycogen over-storage)

    • Tongue (macroglossia)

    • Heart (cardio Meagley)

    • Liver

    • Spleen

  • Progressive Muscle Breakdown and Weakness

    • Elevated CPK

    • Hypotonia

    • hypertrophic cardiomyopathy

    • Cardio-respiratory failure

Pompe’s Disease (GSDIII) Diagnosis

• Newborn screening: <10 days in IOPD (enzyme, DNA, CRIM, echo, CK)

• Muscle biopsy with glycogen staining, enzyme, and DNA

  • Pseudo-deficiency: low enzyme but asymptomatic → check DNA

Pompe’s disease (GSDIII) Treatment

Lysomal enzyme replacement therapy:

Outcomes:

• Without treatment: Death within on year

• With treatment: improvement of symptoms and delayed onset (in infantile)

  • Does not stop all symptoms

McArdle Disease (GSD V)

• No infantile onset + asymptomatic throughout infancy and childhood NT PROGRESSIVE, but EPIDOSIC → after prolonged periods of muscle excertion (pains + weakness after exercising)

Mutation in the muscle specific enzyme: Muscle Myophosphorylase (PYGM)

→ Decreased glycogenolysis by decreasing the cleavage of branches from the branched glycogen chain

• No hypoglycemia: Not important in the liver for the liberation of glucose from the branched glycogen molecule (other enzyme in the liver able to do that)

• But not the CASE IN MUSCLES

McArdle Disease (GSD V) Symptoms

Initial Presentation

• recurrent excersice induced muscle cramps and pain releaved by rest

• Recurrent epsidoic myoglobinurea → can lead to Renal Failure in severe cases

• Often lifelong history of poor escerise capacty

• Chronic proximal muscle weakness

McArdle Disease (GSD V) Diagnosis

Screening

• Elevated Creatine Kinase (CK) levels after exercise

• Urine myoglobin levels

Diagnosis

• Enzyme analysis: Myophopshalyase activity on muscle biopsy

• Molecular analysis: PYGM gene sequencing + del/dup analysis

Similar to GSD VII (Tarui’s Diease)

• But diffrent gen and intial slow growth and anemia not seen in GSD V

McArdle Disease (GSD V) Treatment

• Sub-maximal aerobic excercise: avoidn maximal aerobi or isometric excerise

• Avoid medicaitons that promote myopathy: statins, certina anesthetic

• Diet and supplments

  • Creatine monohydrte supplemnation

  • Carbohydrate rich diet

  • Pre-exercise simple sugars

Classic GLUT1 Defecieny

• Glucose Transport protein deficiency: diffuclty transporting gluclose acrossthe blood-brain barrier

  • Normal levels of glucose in the blood stream but low in CS fluid→ energy deficiency in the brain

AUTOSOMAL DOMINANT SLC2A1 gene mutation

Symptom

• Infaitlne seziures

• delveomntl delap,microcehpyl

• complex movement disorder

Treatment results in significant improvment:

• Ketogenic diet: allow for alternaive use for engery than GLUCLOSE

• L-Carnitine

• Avoid glucose intake