Inborn Errors 1 & 2: Hypoglycemia and Disorders of Fat Utilization Flashcards
Clinical definition of hypoglycemia
glucose level less than 50 mg/dl
Clinical signs and symptoms of hypoglycemia
Irritability, tremor, seizures, decreased level of consciousness or coma
In infants and small children the symptoms may be non-specific and include “fussiness”, lethargy, tremor, trouble feeding.
Glucose-6–phosphatase deficiency
glycogen storage disease I
Most severe glycogen storage disease
Glucose that enters the liver can form glycogen but cannot leave the liver as glucose. Liver becomes very enlarged with normal glycogen which can injure the liver over time.
The excess glucose “trapped” in the liver follows all possible pathways in a concentration driven attempt to get out:
Increased production of lactate (causes lactic acidosis) Increased fatty acid synthesis (hypertriglyceridemia) Increased uric acid due to shunting and decreased renal excretion.
Presentation of glucose-6-phosphatase deficiency
Affected infants present early in life usually within the first year of life with severe fasting hypoglycemia occurring within 3-4 hours after a meal.
Treatment involves providing a constant supply of oral glucose to avoid hypoglycemia. In older individuals, raw corn starch allows more widely spaced feedings of 5-6 times/day.
Long term complications in poorly controlled individuals include complications of chronic lactic acidosis, hepatic cancer, renal dysfunction, and osteoporosis.
Hepatic Glycogen Synthase Deficiency
Glycogen synthesis disorder (GSD 0)
Cannot make glycogen and so have nowhere to store glucose after a meal and rely solely on gluconeogenesis for glucose production.
Hyperglycemia after a meal, followed by fasting hypoglycemia, increased lactate, and severe ketotic hypoglycemia (because of low insulin and high counter-regulatory hormones)
Only GSD without hepatomegaly!
Branching enzyme deficiency
Glycogen synthesis disorder (GSD IV, Anderson Disease)
Very rare (less than 0.5% of reported glycogen synthesis disorders)
Very abnormal glycogen that is not branched accumulates in the liver and skeletal muscle.
Hypoglycemia is not a prominent symptom, as straight-chain glycogen can still be cleaved
WEAKNESS due to myopathy induced by the abnormal glycogen and HEPATOMEGALY are the most obvious clinical symptoms.
Liver injury from abnormal glycogen can be severe and lead to liver injury, cirrhosis and death before the age of 6 years.
Phosphorylase deficiency (GSD VI) and phosphorylase kinase deficiency (GSD IX)
Glycogen breakdown disorders
Together account for 25-30 % of GSD cases
Milder than G-6-phosphatase deficiency as gluconeogenesis, lipolysis, fatty acid oxidation and ketogenesis are intact
Hepatomegaly, short stature, and mild muscle weakness may be the only findings.
Ketotic hypoglycemia occurs and may resolve over time. This is because fat oxidation and ketogenesis are normal.
Adults can often fast 18-24 hours although treatment with raw cornstarch may improve energy levels.
Debranching enzyme deficiency
(GSD III, Cori Disease)
Glycogen breakdown disorder
Accumulation of abnormal glycogen in liver and muscle
Hepatomegaly and hypoglycemia (NORMAL lactate and uric acid levels), delayed growth/short stature, myopathy
Later in early life, symptoms are milder than G-6-phsophatase deficiency as glucose can be derived from the outer glycogen branches as well as gluconeogenesis.
Increased ketones are present during hypoglycemia because fat oxidation is preserved.
Some forms of the disease affect both the liver and muscle while others only affect the liver.
The condition seems to improve clinically by adulthood.
Fructose 1-6 bisphosphatase deficiency
Gluconeogenic disorder
Late hypoglycemia following fasting for 18-24 hours (glycogen formation and breakdown are normal).
NO HEPATOMEGALY but there is SEVER LACTIC ACIDOSIS and increased levels of pyruvate because of convergence of gluconeogenic precursors at this level.
The lactic acidosis results in a compensatory respiratory alkalosis that appears clinically as marked hyperventilation. Large amounts of fructose ingestion may precipitate an episode. During hypoglycemia ketones are elevated as would be expected since there is no defect in fat oxidation
Hereditary fructose intolerance
Disorder of fructose metabolism
Fructose is metabolized by fructokinase to fructose 1 phosphate and then by aldolase B which splits the F1P into 3 carbon compounds that enter the pathways of glycolysis/gluconeogenesis below the key steps between F-6-P and F-1-P.
Accumulation of F-1-P inhibits glycogenolysis and gluconeogenesis and and so produces hypoglycemia.
Symptoms arise following the introduction of fructose into the diet and worsen with periods of high fructose intake.
Symptoms include nausea vomiting pallor, and in some cases coma. Typically these symptoms arise following the introduction of fruit into the diet.
Laboratory studies demonstrate elevated liver function tests. If untreated affected individuals may develop progressive liver and kidney problems. Treatment primarily involved dietary fructose restriction
Galactosemia
Disorder of galactose metabolism
Galactose (in milk and mild products) is broken down to glucose and lactose.
Normally galactose is metabolized galactose-1-phosphate then to UDP-galactose which can then be converted to UDP glucose with then can enter traditional glucose metabolic pathways.
Galactosemia occurs when there is a deficiency in the enzyme that produces UDP galactose. The enzyme is galactose-1-phosphate uridyltransferase (GALT).
Unable to metabolize galactose when milk is introduced in the diet. As a result of the buildup of galactose and its metabolites there is progressive liver injury leading to JAUNDICE and COAGULATION DISTURBANCES as well as CATARACTS due to the buildup of a galactose metabolite in the lens of the eye.
Nausea and vomiting may follow ingestion of milk products. Neurologic problems including ataxia, tremor or speech impairment may also be present.
Treatment: dietary lactose restriction.
Medium Chain Acyl CoA Dehydrogenase deficiency
MCAD
Most common disorder of fat oxidation
Unable to complete beta-oxidation for medium chain fatty acids (C-6-C-10). As a result tissues like skeletal muscle have increased reliance on glucose as a fuel and so peripheral glucose utilization is increased.
Also, without the energy provided by fat oxidation gluconeogenesis is reduced in the liver leading to an accumulation of carbon skeletons from gluconeogenic precursors that appear as urinary organic acids.
Reduced production of acetyl CoA by beta-oxidation causes a failure to produce ketone bodies.
Presents in infancy to early childhood as moderately severe hypoglycemia after 12-18 hours of fasting especially in the presence of a viral illness. This is because glycogenolysis is preserved and so there is not early hypoglycemia as is seen in G-6-Pase deficiency.
When have hypoglycemia, ketones are low and insulin is low. Blood will demonstrate increased levels of medium chain acyl carnitines.
Long term outcomes are good and treatment involves frequent carbohydrate-rich feedings.
Very Long Chain Acyl CoA Dehydrogenase deficiency
VLCAD
This disorder is similar to MCAD deficiency but involved the metabolism of fatty acids of longer chain length C-12-C-16).
The phenotype of the disorder is similar to MCAD deficiency but may be milder and appear later in life.
Affected individuals may develop muscle soreness or even rhabdomyolysis following exercise.
CPT-1 Deficiency
CPT-1 is required to carry fatty acids into the mitochondria where beta-oxidation takes place.
Individuals who do not have CPT1 have a defect in fat oxidation and as a result develop fasting hypoglycemia with low levels of ketones.
Typically present in infancy following a viral illness
Serum shows increased levels of free carnitine but low levels of acyl-carnitines.
Ammonia levels are also elevated (result of accumulation of nitrogen that has been removed from amino acids during the recruitment of substrate for gluconeogenesis).
Treatment relies on the constant delivery of dietary carbohydrate to prevent hypoglycemia.
What are the other medical causes of hypoglycemia (not an inborn metabolic disorder)?
Deficient counter-regulatory hormones: ex. hypopituitarism or adrenal insufficiency
Hyperinsulinism: maternal diabetes and IV glucose given to the mother during labor and delivery. Perinatal stress (low birth weight infants, birth asphyxia, maternal eclampsia or pre-eclampsia, prematurity)
Infants of Diabetic Mothers: see next card
Ketotic Hypoglycemia: most common cause of hypoglycemia in childhood (15 months to age 5 years), especially if thin and/or undernourished. Limited stores of muscle protein, and cannot sustain normoglycemia from gluconeogenesis during periods of acute illness accompanied by reduced food intake. HIGH KETONES and KETONE BODIES
Insulinoma
Insulin overdose
Sufonylurea ingestion
Ethanol ingestion: In alcoholics not eating many carbs. The metabolism of ethanol produces of high levels of NADH, inhibiting gluconeogenesis by driving pyruvate towards lactate to regenerate NAD and by driving oxaloacetate towards malate making it unavailable for gluconeogenesis.
