Inborn Errors: Hypoglycemia & Disorders of Fat Utilization Flashcards
Major glycogen storage diseases
- G6Phosphatase Deficiency
- Debranching enzyme deficiency
- Branching enzyme deficiency
- Phosphorylase deficiency
- Phosphorylase kinase deficiency
Biochemical mechanisms of G6Phosphatase Deficiency
- Profound defect in hepatic glucose production during fasting
- Liver is dramatically enlarged with glycogen
- Lactic acidosis
- Increased fatty acid synthesis → hypertriglyceridemia
- Elevated ketones from fat oxidation
Clinical presenation of G6P deficiency
- Infants present within 1st year of life
- Increased risk of infections
- Growth retardation
- Improves in adulthood
Characteristics of debranching enzyme deficiency
- Present later in early life with moderate hypoglycemia, hepatomegaly, delayed growth and short stature
- Increased ketones from fat oxidation
- Can affect liver + muscles or just liver
- Improves clinically by adulthood
Characteristics of branching enzyme deficiency
- Abnormal glycogen accumulates in liver and skeletal muscle
- Tissue damage most prominent symptoms
- Also get hepatomegaly and weakness due to myopathy, cardiomyopathy
- Severe liver injury → cirrhosis + death < 6 years old
Characteristics of phosphorylase deficiency
- Mild phenotype
- Hepatomegaly + mild muscle weakness during exercise
- Hypoglycemia mild 12-15 hours after meal
- Avoid long fasting
Characteristics of phosphorylase kinase deficiency
- More severe
- Liver fibrosis
- Moderate to severe hypoglycemia
- Can progress to cirrhosis
Cause of Hereditary fructose intolerance
- Aldolase B deficiency
- causes build up of fructose-1-phosphate which inhibits glycolysis & gluconeogenesis
Clinical features of hereditary fructose intolerance
- Occurs when fruit is introduced into diet
- Hypoglycemia
- N/V
- Palor
- Coma
- Progressive Liver and kidney failure → elevated LFTs
- Symptoms worsen with high fructose
- Treat with fructose restriction
Cause of galactosemia
- Galactosemia occurs when there is a deficiency in the enzyme that produces UDP galactose.
- The enzyme is galactose-1-phosphate uridyltransferase (GALT)
Clinical presentation of Galactosemia
- Occurs when milk introduced into diet
- Buildup of galactose and its metabolites → liver damage and jaundice
- Coagulation disturbances
- Cataract formation
- N/V after ingestion of milk
- Neuro problems including ataxia, tremor, speech impairment
- Treatment is dietary lactose restriction
Common disorders of fat metabolism
- CoA Dehydrogenase deficiency (MCAD)Medium chain acyl
- Very long chain acyl CoA dehydrogenase deficiency (VLCAD)
- CPT-1 deficiency
Clinical features of CoA Dehydrogenase deficiency (MCAD)Medium chain acyl
- Can’t β oxidize medium chain fatty acids
- Increased peripheral glucose utilization
- Gluconeogenic precursors end up as organic acids in urine
- Failure to produce ketone bodies
- Presents in infancy → childhood after prolonged fasting, esp during viral illness
- Low insulin
- High medium chain acyl carnitines
Clinical features of Very long chain acyl CoA dehydrogenase deficiency (VLCAD)
- Similar to MCAD but milder and appears later in life
- Muscle soreness and rhabdomyolysis after exercise
Clinical features of CPT-1 deficiency
- CPT1 carries fatty acids into mitochondria → defect in fat oxidation
- Fasting hypoglycemia
- Present in infancy after illness
- Increased serum carnitine, low levels of acyl carnitines
- Elevated ammonia
- Treatment = constant carbs to prevent hypoglycemia
Common non-inborn causes of hypoglycemia
Large for gestational age newborn → high serum insulin + hypoglycemia post birth
Ketogenic hypoglycemia → elevated ketones, reduced muscle protein
Insulinoma → Adults as part of MEN-1. Surgical removal
Cortisol deficiency → Adrenal/pituitary gland failure. Low insulin + cortisol when hypoglycemic.
Insulin overdose → child abuse, homicide. No extra C-peptide present
Sulfonylurea ingestion → increased insulin, C-peptide, screen + for sulfonylurea
Ethanol ingestion → inhibits gluconeogenesis. Happens in alcoholics who drink a lot without eating carbs
Too little lean and fat mass
Key blood tests in hypoglycemia dx
- Confirmatory glucose concentration
- Insulin
- cortisol, growth hormone
- Ketones (acetoacetate - urine/β-OH butyrate - blood)
- Lactate and pyruvate in suspected glycogen storage disease (Sufonylurea screen)
- C-peptide
Key Urine tests in hypoglycemia
Ketones
Urine reducing substances (“non-glucose”) in newborns suspected of galactosemia
