Inborn Errors of Metabolism Flashcards
Definition of hypoglycemia
Whipple’s triad: classic symptoms–> BG resolution w/ glucose ingestion
ANS sx in hypoglycemia
Sweating Shaky, trembling Tachycardia Anxiety Weakness Hunger Nausea/vomiting
Neuroglycopenic sx in hypoglycemia
Irritable, restless Headache Confusion Visual changes Slurred speech/concentration Behavior changes Somnolence Coma/seizures
hypoglycemia in kids: why ID and treat?
hypoglycemia can injure the developing brain and result in permanent neurodevelopmental problems
Hypoglycemia and timing:
Glucose 6 phosphatase deficiency
Milder Glycogen Storage Diseases in infants and children
Hyperinsulinism
Cortisol and GH deficiency in infants
> 6-8 hrs
Cortisol deficiency and fatty acid oxidation disorders in infants
Milder glycogen storage and gluconeogenic diseases
Cortisol and GH deficiency in children and adults
> 10-12
Fatty acid oxidation disorders in older children and adults
Mild disorders of GSD in adults
> 12-24 hrs
ketotic hypoglycemia
Fatty acid oxidation disorders in older children and adults
Most common cause of hypoglycemia in kids
-ketotic hypoglycemia
(don’t have enough aa or fat)
-not an inborn error
inborn errors of carb and fat metab
- many present as hypoglycemia
- May present with accumulation of abnormal amounts of substrate behind block: glycogen, galactose, fructose, lactate, triglycerides
Precipitating factors: fasting, illness, exercise, ingestion of dietary galactose or fructose.
Presence of ketones separates defects in fat oxidation from glucose disorders
(don’t burn fat? you don’t make ketones)
Names of inborn errors of carb metabolism
Glycogen storage diseases:
Glycogen synthase, branching enzyme
Glycogen phosphorylase, phosphorylase kinase
Gluconeogenic Defect: F1,6 bisphosphatase deficiency
Glucose 6 phosphatase deficiency
Hereditary Fructose Intolerance
Galactosemia
glucose 6 phoshphatase deficiency
- presents as buildup of glycogen
- liver can’t release glucose from glycogenolysis and gluconeogenesis
- hepatomegaly
- hypoglycemic
- lactic acidosis
- Hypertriglyceridemia and hypercholesterolemia
- Hyperuricemia
- Short stature, doll-like face
Glucose 6 phosphatase deficiency (GSD-I)
Constant glucose supply! Frequent feeding Nasogastric drip feeding Uncooked cornstarch: Slow release CHO, lasts 6 h, slow start
Any possible hypoglycemia needs prompt iv glucose treatment
Results: Normalization of growth Maintaining glucose > need for gluconeogenesis Decrease cholesterol and triglycerides Still hepatomegaly but less pronounced
Glycogen synthase deficiency
Clinical presentation: hyperglycemia after a meal, followed by low blood sugar later, increased lactate, and severe ketotic hypoglycemia
No liver enlargement unlike other GSDs
Treatment: high protein diet to provide gluconeogenesis substrates and low glycemic index complex carbs to minimize post-prandial hyperglycemia and hyperlactacidemia
Branching enzyme deficiency
Abnormal glycogen: associated with tissue damage
Symptoms:
Progressive liver cirrhosis (transplant by age 4 – 6 YRS)
Hepatosplenomegaly, failure to thrive
Nonprogressive form: mild mutations
Cardiomyopathy
Muscle:
Neonatal severe hypotonia and muscle weakness
Childhood muscle weakness
Neuropathy
Diagnosis: pathology on muscle biopsy, enzyme assay in liver or fibroblasts, mutation analysis
Prognosis: mutation analysis can aid
Treatment: supportive
Disorders of glycogen breakdown
Glycogen Phosphorylase (GSD VI)
Glycogen Phosphorylase kinase (GSD IX) Debranching Enzyme (GSD III)
Debranching enzyme deficiency
Debranching enzyme: a-1,6-glucosidase
GSD-IIIA: deficiency in liver and muscle (85%)
GSD-IIIB: deficiency in liver only (15%)
Initial presentation:
Similar to GSD-I: hypoglycemia, hepatomegaly, growth retardation, mildly elevated cholesterol
lactate and uric acid normal
Elevation of liver enzymes, fasting ketosis
Late presentation:
Cardiomyopathy
Myopathy (3-4th decade)
Polyneuropathy
Cirrhosis
Abnormal glycogen causes tissue
(Liver, heart, muscle) damage
Treatment:
Continuous glucose, raw cornstarch, to keep BG >70
High protein diet may help myopathy and growth failure
Gluconeogenic enzyme deficiencies
Pyruvate Carboxylase and PEP Carboxykinase: rare- probably lethal
Fructose-1,6-bisPO4ase deficiency
Fructose 1,6 bisophosphatase
- will hypoglycemia, but slower onset
- accumulate pyruvate
- comes out as lactate
Hypoglycemia: late and mild
Metabolic acidosis: severe lactic acidosis
Normal lactate/pyruvate ratio
Often acidosis with Kussmaul breathing primary symptom
Ketones present and appropriate
Mildly elevated liver enzymes, no ammonia
TREATMENT:
Acute: give glucose -> will correct lactate
Give bicarbonate sparingly, acidosis corrects with glucose
Prevention: avoid long fasting, uncooked cornstarch at night
Prompt treatment of hypoglycemia
Hereditary fructose intolerance
Due to deficiency in Aldolase B which splits Fructose 1 P into 3 carbon intermediates that can enter glycolysis.
Effect is accumulation of fructose 1P which has toxic effects on liver, kidney and brain
Symptoms occur with the introduction of fruits and other sources of fructose in the diet in the first year of life (not at birth or in the first few months)
Symptoms: nausea, vomiting, sweating, lethargy, hypoglycemia, hepatomegaly
Increased liver function tests, may progress to severe liver injury. Renal dysfunction may be present
Treatment is avoidance of fructose/sucrose/sorbitol in the diet.
Galactosemia
Signs and Symptoms*: Hypoglycemia Early Failure to Thrive (vomiting with milk) Hepatomegaly/Cirrhosis Cataracts/Visual Impairment Mental Retardation Diagnosis: Non-glucose reducing substance in the urine while on lactose-containing diet: breast milk or infant formula Treatment: Lactose-free diet
N.B.- Galactosemia is part of the Newborn Screening Program in most states
Inborn errors of fat metabolism
- won’t see large liver
- see hypoglycemia but NO KETONES
- decreased fat oxidation in liver deprives gluconeogenesis of a source of fuel
- most tissues become obligate glucose users
Carnitine problems: L-Carnitine- Primary or dietary Carnitine Palmitoyl-Transferase (CPT)-I Carnitine/Acylcarnitine Translocase Carnitine Palmitoyl-Transferase (CPT)-II
Acyl CoA dehydrogenase deficiencies
MCAD, LCAD, etc
HMG-CoA Synthase/Lyase
Decreased fatty acid oxidation and ketone formation features
Common clinical features include fasting hypoglycemia with low ketones, liver failure, hypotonia.
Lab features include hypoglycemia, low ketones, coagulopathy hyperammonemia, and elevated CK from exercise-induced rhabdomyolysis
Newborn screening has identified a combined incidence of 1:5000 for FAOD. Most are treatable with a good long term outcome.
AcylCoA dehydrogenase deficiencies
Medium Chain [MCAD]- most common (1:9000)
Detected on the Newborn Screening Tests
Short Chain [SCAD]- rare
Long Chain [LCAD]- rare
All are Autosomal Recessively Inherited
Common Laboratory Features
Hypoglycemia
Abnormal urinary organic acids (omega-oxidation)
Increase in acylCoA derivatives in blood and urine
Decreased carnitine/Increased acylcarnitines- blood
MCAD
Enzyme that catalyzes initial step in B-ox of C10-C6 straight chain acyl-CoAs
Clinical Features:
Vomiting, lethargy, hypotonia, +/- seizures
Hypoketotic hypoglycemia
Hepatomegaly, fatty liver
May resemble Reye syndrome (acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction)
Rhabdomyolysis or cardiac symptoms (V fib and cardiac arrest) have been observed
Dx:
MS/MS-based acylcarnitine analysis of plasma with increased C8 and C8/ C10/carnitine ratio
Treatment:
Avoid fasting and provide a carb-rich diet
In those
Hormonal dysregulation
Counterregulatory hormone Defects (insulin low):
Hypopituitarism
Growth Hormone Deficiency
ACTH or cortisol deficiency
Beta-blocker (results in lack of epinephrine)
Defects in Insulin Suppression (insulin high): Congenital Hyperinsulinism Infant of a diabetic mother Iatrogenic Insulinoma
Clinical features of hypopituitarism
Midline defects Micropenis, undescended testes Jaundice nystagmus Poor growth
Primary adrenal insufficiency
Clinical features: Poor growth/weight gain Decreased energy Nausea, vomiting, abdominal pain Hypotension Hyperpigmentation Salt craving Associated autoimmune diseases
Hyperinsulinism
Neonatal: Infants of Diabetic Mothers: “Transient” Congenital hyperinsulinism “permanent” Childhood: Islet Cell Adenoma Insulin O.D., Type 1 DM, Child Abuse Adolescents - as above and: Oral Hypoglycemic Agent Ingestion Factitious”- hypoglycemic symptoms only
Features of hyperinsulinism in the newborn
Large for Gestational Age
Glucose Infusion Rate >10mg/kg/min to sustain normoglycemia
Non-ketotic (may see slight ketonuria)
Non-suppressed serum insulin
Rise in blood glucose >40mg/dL after glucagon (reflects increased storage of liver glycogen)
Ketotic hypoglycemia
One of the most common causes of hypoglycemia in childhood
Diagnosis of exclusion
Lack of substrates for gluconeogenesis (small child, not much muscle, no body fat, not eating well)
Hypoglycemia after fasting 14-24 hours
Presents at 1-5 years old
Spontaneously remits at 8-9 years old
Low blood sugar high ketones
Critical sample is key to eval hypoglycemia
CONFIRM BG
