Inborn Errors of Metabolism

Inborn errors in metabolism are defects in what?

- Metabolic Pathwars

When do Inborn errors of metabolism often present?

- In newborn period

Inborn errors of metabolism: Non-Specific features

- Failure to thrive

- Hypotonia: Decreased muscle tone

Which lab findings suggest Dx of Inborn Errors of Metabolism?

- Hypoglycemia: ↓[Glucose]

- Ketosis:

- Hyperammonemia

- Lactic Acidosis

Ketosis

- Body uses fat for energy instead of glucose

Why do inborn errors of metabolism cause ketosis?

- Blocked glucose/energy metabolism → ↑ fat breakdown → ketones

Hyperammonemia

- Excess ammonia in the blood

Why do inborn errors of metabolism cause hyperammonemia?

- Impaired ammonia disposal/urea cycle → ↑ ammonia in blood

Lactic Acidosis

- Problem breaking down lactic acid. results in low blood pH

Why do inborn errors of metabolism cause lactic acidosis?

- Pyruvate can't be metabolized normally → ↑ pyruvate → lactate

What can cause Newborn Hypoglycemia?

Good Girls Hate Old Fat

- Glycogen storage disease

- Galactosemia

- Hereditary fructose intolerance

- Organic Acidemias

- Fatty acid metabolism disorders

Which Glycogen Storage Diseases DON'T cause hypoglycemia?

- McArdle's Disease

- Pompe's Disease

Which Glycogen Storage Diseases DO cause hypoglycemia?

- Von Gierke's Disease

- Cori's Disease

What is seen in glycogen storage diseases with hypoglycemia?

- Fasting hypoglycemia: hours after eating

- Ketosis: Absence of glucose during fasting → FA breakdown → ketone synthesis

- Hepatomegaly: Glycogen buildup in liver

Von Gierke's Disease

- Severe hypoglycemia

- Lactic acidosis

Cori's Disease

- Gluconeogenesis intact → mild hypoglycemia

- No lactic acidosis

Hereditary Fructose Intolerance: Deficiency and Accumulation

- D: Aldolase B

- A: Fructose-1-Phosphate

Hereditary Fructose Intolerance: MOA

- Buildup of F1P → Depletion of ATP → Loss of gluconeogenesis/glycolysis

Hereditary Fructose Intolerance: Labs

- Hypoglycemia

- Lactic Acidosis

- Ketosis

Hereditary Fructose Intolerance: Presentation

- Starts just after weaned from breast milk (no fructose in milk)

- "Reducing sugars" (Glucose, Fructose, Galactose) in urine

- Hepatomegaly

Classic Galactosemia: Deficiency and Accumulation

- D: Galactose 1-Phosphate Uridyltransferase

- A: Galactose-1-Phosphate

Classic Galactosemia: MOA

- Accumulation of Glucose-1-Phosphate → ↓ ATP → shuts down gluconeogenesis/glycolysis

Classic Galactosemia: Presentation

- In first few days of life

- Vomiting/diarrhea after feeding

- Hepatomegaly

Classic Galactosemia: Dx

- Reducing sugars in urine

Classic Galactosemia: Labs

- Hypoglycemia

- Lactic Acidosis

- Ketosis

Organic Acidemias: Defect and Accumulation

- D: Abnormal metabolism of organic acids (Propionic and Methylmalonic Acid)

- A: Buildup of organic acids in blood/urine

Organic Acidemias cause what?

- Hyperammonemia via shutdown of urea cycle

How does Succinyl-CoA relate to Organic Acidemias?

- Common pathway to TCA cycle

In Organic Acidemias, one of the steps is disrupted due to an enzyme deficiency

Organic Acidemias: Presentation

- Newborns (weeks/months)

- Poor feeding, vomiting, hypotonia, lethargy

Organic Acidemias: Labs

- Hypoglycemia

- Ketosis

- Hyperammonemia

- Elevated urine/plasma [organic acids]

Propionic Acidemia: Deficiency and Accumulation

- D: Propionyl-CoA Carboxylase

- A: Propionyl-CoA → Propionic Acid

Propionic Acidemia: MOA

- Enzyme utilized to convert Propionyl-CoA → Methylmalonyl-CoA is deficient →→ Accumulation of Propionyl-CoA as it cannot be processed

Methylmalonic Acidemia: Deficiency and Accumulation

- D: Methylmalonyl-CoA Mutase

- A: Methymalonyl-CoA → Methylmalonic acid

Methylmalonic Acidemia: MOA

- Enzyme utilized to convert Methylmalonyl-CoA → Succinyl-CoA is deficient →→ Accumulation of Methylmalonyl-CoA as it cannot be processed

Maple Syrup Urine Disease: Type of Disorder, Deficiency, Accumulation

- T: Branched chain AA disorder

- D: α-Ketoacid Dehydrogenase

- A: AAs and α-Ketoacids in plasma/urine

Maple Syrup Urine Disease: Why does the urine smell sweet?

- AAs and α-Ketoacids accumulate in plasma/urine → α-Ketoacid of isoleucine gives urine sweet smell

Common Fatty Acid Disorders

- Carnitine deficiency

- MCAD (medium-chain-acyl-coA dehydrogenase) deficiency

Carnitine and MCAD deficiencies both cause what?

- Hypoketotic Hypoglycemia when fasting

Why do Carnitine and MCAD deficiencies both Hypoketotic Hypoglycemia?

1. Lack of FA breakdown → low [ketone bodies]

2. Overutilization of glucose → hypoglycemia

3. Lack of Acetyl-CoA for Gluconeogenesis

Carnitine and MCAD Deficiencies: Symptoms

- 3 months → 2 yrs // symptoms w/ fasting or illness

- Failure to thrive, altered consciousness

- Hypotonia

- Hepato and Cardiomegaly

- Hypoketotic hypoglycemia****

Primary Carnitine Deficiency: MOA and Presentation

- Normally moves FAs → mitochondria for metabolism

- Muscle weakness, cardiomyopathy

Primary Carnitine Deficiency: Labs

- ↓ Carnitine

- ↓ Acylcarnitine

MCAD Deficiency: MOA

- Poor oxidation of 6-10 carbon FAs → Dicarboxylic acids (6-10C) in urine

MCAD Deficiency: Labs

- Dicarboxylic acids (6-10C) in urine

- ↑ Acylcarnitine levels

Urea Cycle Disorders: General Characteristics

- Onset in newborn period (24-48hrs) after feeding

- Feeding causes protein load → symptoms

- Poor feeding, vomiting, lethargy, seizures

Urea Cycle Disorders: Labs

Isolated Severe Hyperammonemia:

- Normal: < 50 mgc/dl

- Urea disorder: > 1000 mgc/dl

Key finding*

Most common urea cycle deficiency

- Ornithine transcarbamylase deficiency

OTC Deficiency: Deficiency and Accumulation

- D: Ornithine Transcarbamylase (used for urea cycle)

- A: ↑ Carbamoyl Phosphate // ↑ Orotic Acid // ↑ Ammonia

Orotic Aciduria: Type of disorder

- Disorder of pyrimidine synthesis

Orotic Aciduria: Major features

- Megaloblastic Anemia

- Poor growth

Orotic Aciduria: Ammonia levels

- No issues with urea cycle → normal [ammonia]

Mitochondrial Disorders: General Characteristics

- Loss of ability to metabolize pyruvate → acetyl-CoA

- All cause severe lactic acidosis and elevated alanine

What is one of the most common mitochondrial disorders?

- Pyruvate Dehydrogenase complex deficiency

Why is hypoglycemia not common in mitochondrial disorders?

- The main issue is blocking Pyruvate → Acetyl CoA → Shunts towards Alanine/Lactate

- Although limited, pyruvate can still be metabolized into gluconeogenesis (less w/out acetyl coa) → no hypoglycemia

PDH Complex Deficiency: Deficiency and Accumulation

- D: PDH

- A: Alanine/Lactate

PDH Complex Deficiency: Key Findings

- Poor feeding

- Growth failure

- Developmental delays

PDH Complex Deficiency: Labs

- Elevated alanine

- Lactic acidosis

- NO hypoglycemia