Inborn Errors of Glucose and Fat Metabolism

Question 1

Mitochondrial defects usually present how?

Answer 1

The most energy using tissues are neural and muscle;

Usually present with muscle weakness or neurologic deficits

Question 2

When a baby eats fruit and ends up with a fructose metabolism error, which enzyme is missing?

Answer 2

Aldolase B

Question 3

Enzymes that go up during fasting

Answer 3

1. Catecholamines are high, insulin is low
2. Increased HSL (to break down TAG to DAG and release fat)
3. Increase CPT-1 and CPT-2 (If you are missing CPT-1 or carnitine, get hypoglycemia without ketones)

Question 4

If you can’t do beta-oxidation, what happens?

Answer 4

Can’t burn fat, muscle becomes dependent upon glucose and liver has no power for gluconeogenesis –> hypoglycemia

TG deposits in liver

Question 5

Any defects in glycolysis?

Answer 5

No, you would be dead.

Question 6

Baby get milk, baby gets sick, what is the answer?

Answer 6

GALT

Question 7

Clinical hypoglycemia

Answer 7

Clinical Hypoglycemia:
classic symptoms (Whipple's Triad)--> BG  resolution with glucose ingestion

Adults mean glucose in 50s after fasting for 84 hrs (if you fast people for long enough, then blood sugar will gradually go down… brain tolerates lower sugars because of ketogenesis)

• babies deal with low blood sugars better than an adult

Question 8

Symptoms of hypoglycemia

Answer 8

ANS vs. Neuroglycopenic

ANS:

• Sweating
• Shaky, trembling
• Tachycardia
• Anxiety
• Weakness
• Hunger
• N/V

Neuroglycopenic Sxs:

• Irritable, restless
• Headache
• Confusion
• Visual changes
• Slurred speech/concentration
• Behavior changes
• Somnolence
• Coma/seizures

ANS usually happen first, then neural.

Question 9

Order of glucose homeostasis during fasting

Answer 9

Absorption of meal –> Glycogenolysis –> Gluconeogenesis –> Fatty acid oxidation

Question 10

Hypoglycemia and timing

Answer 10

6-8 hours:

• Cortisol deficiency and fatty acid oxidation disorders
• milder glycogen storage and gluconeogenic diseases
• cortisol and GH deficiency

> 10-12 hrs:

• Fatty acid oxidation disorders
• Mild disorders of GSD

> 12-24 hrs:

• ketotic hypoglycemia (the most common in kids)
• fatty acid oxidation disorders

How big the person is determines how quickly they get the hypoglycemia

Question 11

Precipitating factors for inborn errors of carbohydrate and fat metabolism

Answer 11

• fasting
• illness
• exercise
• ingestion of dietary galactose or fructose

Question 12

Glycogen storage diseases

Answer 12

• Glycogen synthase, branching enzyme (can’t make it or you can make it, but maybe it’s weird)
• Glycogen phosphorylase, phosphorylase kinase (make it but can’t break it down)

Question 13

Large liver = indication for issues with what metabolite?

Answer 13

Glycogen

Question 14

Von Gierke (G-6-Pase Deficiency)

Answer 14

• Hepatomegaly
• Hypoglycemia (early)
• Lactic acidosis
• Hypertriglyceridemia
• Hypercholesteremia
• Hyperuricemia
• Doll-like face with short stature

Need to get glucose from diet because cannot convert from G-6-P

Question 15

Glycogen Synthase Deficiency

Answer 15

• Hyperglycemia after a meal, followed by a low blood sugar later, increased lactate, and severe ketotic hypoglycemia
• No liver enlargement
• Tx: high protein diet to provide gluconeogenesis substrates and low glycemic index complex carbs to minimize post-prandial hyperglycemia and hyperlacacidemia

Question 16

Branching enzyme deficiency

Answer 16

• Abnormal glycogen which is assoc. with tissue damage
• Sx:
  
  • Progressive liver cirrhosis
  • Hepatosplenomegaly, failure to thrive
  • Cardiomyopathy
  • Neuropathy
• Diagnosis: pathology on muscle biopsy, enzyme assay in liver or fibroblasts, mutation analysis
• Prognosis: mutation analysis
• Tx: supportive

Question 17

Debranching enzyme deficiency

Answer 17

• Some in liver and muscle, some in liver only
• Initial presentation similar to GSD-1; elevation of liver enzymes, fasting ketosis
• Late presentation: cardiomyopathy, myopathy, polyneuropathy, cirrhosis, abnormal glycogen causes tissue damage
• Tx: continuous glucose, raw cornstarch, to keep BG > 70; high protein diet may help myopathy

Question 18

Gluconeogenic Enzyme Defects

Answer 18

1. Pyruvate carboxylase and PEP carboxykinase: rare - probably lethal
2. Fructose - 1,6 - bisphosphatase deficiency

Question 19

F-1,6-BP deficiency

Answer 19

1. Hypoglycemia: late and mild
2. Metabolic acidosis, severe lactic acidosis (Kussmaul breathing response)
   
   • Normal lactate/pyruvate ratio
3. Ketones present and appropriate
4. Mildly elevated liver enzymes, no ammonia

Tx:

• Give glucose –> will correct lactate
• Avoid long fasting

Question 20

What enzyme gets you from fructose into glycolysis?

Answer 20

Aldolase B

Question 21

Hereditary Fructose Intolerance

Answer 21

• Deficiency in Aldolase B
• Effect is accumulation of fructose 1P which has toxic effects on liver, kidney and brain
• Sx a few months after birth (n/v, sweating, lethargy, hypoglycemia, hepatomegaly)
• Increased liver function tests, may progress to severe liver injury
• Tx: avoid fructose

Question 22

Galactosemia

Answer 22

Galactokinase converts galactose -> Galactose 1-P in order to eventuallly end up in glycolysis

Sx:

• Hypoglycemia
• Early failure to thrive (vomiting with milk)
• Hepatomegaly and cirrhosis
• Cataracts and visual impairment (metabolite accumulates in eye)
• Mental retardation

Diagnosis: newborn screening with a non-glucose reducing substance in the urine while on lactose-containing diet

Tx: lactose-free diet

Question 23

Errors of fat metabolism

Answer 23

Hypoglycemia, no big liver, no ketones

• Carnitine problems
• Acyl CoA dehydrogenase deficiencies
• HMG-CoA Synthase/Lyase

Question 24

Hormonal dysregulation

Answer 24

Counterregulatory hormone defects

• hypopituitarism
• GH deficiency
• ACTH or cortisol deficiency
• Beta-blocker (results in lack of epi)

Defects in insulin suppression

• Congenital hyperinsulinism
• Infant of a diabetic mother (most common)
• Iatrogenic
• Insulinoma

Question 25

Confirm hypoglycemia?

Answer 25

Critical sample; ensure