Tegay - Carbohydrate Metabolsim Defects

Carbohydrates

• Carbohydrates (“Hydrated carbon”)

  • Empiric formula (CH₂O)_n

  • Smallest n = 3

• Primary source for energy and ATP production

Saccharide

• Saccharide = surgar

• Monosaccharides

  • Single sugar molecules

    • Eg. Glucose, fructose, galactose

• Disaccharides

  • 2 linked sugar molecules

    • Eg. Sucrose, lactose, maltose

• Polysaccharides

  • Long chains of linked sugar molecules

    • Eg. Glycogen, amylose, amlyopectin, cellulose

Common Disaccharrides

• Digestive enzymes (eg. sucrase, lactase, and maltase) exist on the surface of small intestinal cells to catalyze breakdown of disaccharides to monosaccharides for absorption

• Lactose intolerance is due to the loss of lactase activity in the small intestine

Polysaccharides

• Polysaccharides

  • Long chains of linked sugar molecules

    • Eg. Glycogen, amylose, amlyopectin, cellulose

Starch

• Amylose and Amylopectin

  • Major plant glucose storage polysaccharide

    • Amylose is unbranched with alpha-1,4 linkages

    • Amylopectin is branched with alpha-1,4 linkage (30X) attached to alpha-1,6 linkage

  • Mechanical breakdown of food by chewing starts digestion of starches but is insufficient alone

    • Amylase must be secreted by salivary glands and pancreas to hydrolyze amylose and amylopectin to glucose for absorption across intestine

Glycogen

• Major animal glucose storage polysaccharide

  • Highly branched alpha-1,4 and alpha-1,6 glycosidic bonds

• Body needs constant supply of blood glucose

  • Liver synthesizes and stores glycogen

  • When blood glucose is low, liver glycogenolysis occurs

    • Glycogen → Glucose-6-Phosphate → Glucose

      • Glucose can leave liver but not glucose-6-phosphate

    • Liver glycogen stores provide ~8 - 10 hours of glucose

      • Fat stores provide days to weeks of energy reserves

  • Muscle has glycogen but no glucose-6-phosphatase

    • Provides energy source but only within muscle cell

  • Brain has NO glycogen stores

Glycolysis

• Process of metabolizing glucose in energy intermediaries for ATP production

Gluconeogenesis

• Process of synthesis of glucose within cells

• Glucose can be synthesized from within cells from a variety of substrates

  • Glucogenic acids can be turned into glucose

  • Glycerol can enter into gluconeogenesis

Ketones

• Ketones

  • Under hypoglycemic states, fatty acid B-oxidation produces excess acetyl-CoA which is shunted from energy production to ketone body formation

    • Acetoacetyl CoA, Acetone, B-OH butyrate

  • Ketone bodies cross cell membranes and are an alternative energy source for brain and muscle

Galactose Metabolism

• Lactose is a disaccharide consisting of galactose and glucose

  • Must be broken down via galactase to be absorbed

• Galactose must be metabolized into usable glucose forms via Leloir pathway

  • When Leloir pathway is blocked, there will be accumulation of certain substrates and accumulation of alternative metabolic products

Galactose Metabolism Errors

• Autosomal recessive

• 3 inborn errors of Galactose Metabolism

  • Galactokinase Deficiency

    • Untreated leads to cataracts

    • Diagnosed via high galactose, red cell enzyme, mutation

  • GALT Deficinecy (Galactosemia)

    • Mild or severe

    • Diagnosed via high galactose-1-phosphate and uridine diphosphate galactose, red cell enzyme, mutation

  • GALE Deficiency

• Treatment

  • Life-threatening illnesses usually quickly resolved, although long term issues

    • Reduced IQ and growth, ataxia, ovarian dysfunction

  • Dietary galactose restriction

Classic Galactosemia (GALT Deficiency)

• Autosomal recessive

• Symptoms

  • Neonatal onset

    • Elevated liver enzymes and bilirubin, coagulopathy, gram negative bacteria

    • Lethargy, poor feeding, vomitting, diarrhea, death

    • Liver failure, jaundice, bleeding, hepatomegaly

    • Renal dysfunction

    • Cataracts

    • E-coli sepsis

• Mutation anaylsis allows PGD / Prenatal

• Treatment

  • Dietary galactose restriction

Urine / Blood Galactose Measurements

• Urine

  • All monosaccharides are reducing sugars that reduce inorganic ions such as Cu++

    • Called Fehling’s reagent

  • Urine testing detects presence of reducing sugars in urine (normally negative)

    • Thin layer chromatography (TLC) can distingusih specific sugars

• Blood

  • Newborn screening often measures blood spot Galactose and Gal-1-P levels

    • Detect all 3 galactose metabolsim defects but false negatives if on lactose-free formulas

  • NY state measures GALT blood spot

    • Detects only Galactosemia

    • Transfusiosn cause false negatives

Fructose Disorders

• Autosomal recessive

• 3 Main Disorders

  • Fructokinase Deficiency (Fructosurea)

  • Hereditary Fructose Intolerence (Fructosemia)

  • Fructose 1,6-Biphosphatase Deficiency

Fructokinase Deficiency (Fructosurea)

• Autosomal recessive

• Symptoms

  • Benign condition

  • Usually detected incidentally

  • Elevated urine reducing substance: fructose

• NO treatments necessary

Hereditary Fructose Intolerance (Fructosemia)

• Autosomal recessive

  • ALDOB gene

  • Fructose-1-P Aldolase B Deficiency

• Symptoms

  • On consuming fructose

    • Vomitting, lethargy, irritability, seizures

    • Postprandial hypoglycemia, liver/kidney disease

    • Liver failure, acidosis, growth failure, death

• Diagnosed via suspect with elevated urine reducing substance for fructose

  • Confirm with enzyme activity and/ or mutation analysis

• Treatment

  • Eliminating fructose typically prevents further symptoms

Fructose 1,6-Bisphosphatase Deficiency

• Autosomal recessive

• Symptoms

  • Sudden early life-threatening episodes of

    • Fasting hypoglycemia with lactic acidosis

    • Hyperventilation, vomiting, lethargy

    • May be lethal

• Diagnosed via no urine fructose, can check enzyme on liver biopsy, urine glycerol-3-phosphate level, molecular testing

• Treatment

  • Acute: correct hypoglycemia and acidosis, IV glucose

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

  • Good outcomes once treatment is initiated

Glycogen Storage Disease

• Almost all autosomal recessive

• Primarily effect liver and/or muscle

  • Liver involvement

    • Hepatomegaly and hypoglycemia

  • Muscle involvement

    • Muscle breakdown and weakness

Von Gierke (GSD 1)

• Autosomal recessive

  • Type 1a

    • Glucose-6-phosphatase enzyme is defective

    • GSD1a: Glucose-6-phosphate translocase (SLC37a4) gene

  • Type 1b

    • Translocase that transports glucose-6-phosphate across the microsomal membrane is defective

  • Both types mess up glucose-6-phosphate conversion to glucose and make individuals susceptible to fasting hypoglycemia

• Symptoms

  • Sometimes hypoglycemia and lactic acidosis during neonatal period

  • Usually present at 3 - 4 months of age with hepatomegaly, hypoglycemia, hyperuricemnia, hyperlipidemia, and lactic acidosis developing after short fasting

    • Often “doll-like” faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen

  • Type 1b also have neutropenia

• Diagnosed after suspicious signs of:

  • Hypoglycemia with minimal fasting

  • Lactic acidosis, hyperuricemia, hyperlipidemia

  • Confirmed via

    • Enzyme analysis (requires liver biopsy)

    • Mutation analysis

      • GSD1a: Glucose-6-phosphate translocase (SLC37a4) gene

  • Similar to GSD III but different gene, myopathy, milder

• Treatment

  • Avoid fasting, maintain blood glucose

  • May need continuous nasogastric glucose

  • Uncooked cornstarch = slow release glucose every 4 hours for infants younger than 2 years

    • With age can go to every 6 hours by mouth as a liquid

  • Restricted fructose and galactose

  • Dietary supplemenets

  • Allopurinol and uric acid, stains for cholesterol

  • Watch for hepatic adenomas

  • G-CSF for neutropenic immunodeficiency

Pompe Disease

• Autosomal recessive

  • Lysosomal Acid-akpha-Glucosidase (Acid maltase)

  • GAA Deficiency → Lysosomal Glycogen Storage

• Forms

  • Infantile, Juvenile, Adult onset

• Symptoms

  • Organs affected by glycogen accumulation

    • Cardiac, skeletal and smooth muscle

  • Muscle and organ enlargement via glycogen storage

    • Tongue (macroglossia), Heart (cardiomegaly), Liver and spleen

  • Progressive muscle breakdown and weakness

    • Elevated CPK, hypotonia, hypertrophic cardiomyopathy, cardio-respiratory failures

• Diagnosed via muscle biopsy with glycogen staining, enzyme, and DNA

  • Pseudodeficiency = low enzyme but asymptomatic → check DNA

  • New born screening = <10 days in IOPD

• Treatments

  • Without treatment → Death by 1 year / variable death

  • With treatment outcomes are variable but significant improvement

  • Administer acid alpha-glucosidase algucosidas alfa

    • Treatment depends on infantile onset or later onset

McArdle Disease (GSD V)

• Autosomal recessive

  • Mutation of muscle myophosphorylase (PYGM)

    • Decreased glycogenolysis

• Symptoms

  • Initially recurrent exercise induced muscle cramps and pain that is relieved by rest

  • Recurrent episodic myoglinurea that can lead to renal failure

  • Lifelong poor exercise capacity, fatigue, stamina

  • Chronic proximal muscle weakness

• Diagnosed

  • Elevated serum muscle creatine kinase (CK) level post exercise

  • Urine myoglobin levels

  • Confirmed via:

    • Enzyme analysis (Myophosphorylase activity on muscle biopsy)

    • Molecular analysis (PYGM gene sequencing and deletion / duplication)

• Similar to GSD VII (Tarui’s)

• Treatment

  • Sub-maximal aerobic exercise

  • Avoid medications that promote myopathy

  • Diet and supplements

GLUT1 Deficiency

• Autosomal dominant

• Disorders of glucose transporters

• Classic Symptoms

  • Seizures (before 2 years in 90%), DD, acquired microcephaly, complex movement disorder and cognitive impairment

  • Symptoms increase with fasting fever, and infection

• Diagnosed via low CSF glucose with normal blood glucose

• Treatment

  • Results in significant improvement

  • Keto diet, L-Carnitine, avoid glucose intake