Inborn Errors of Metabolism (Exam Relevant)

Inborn errors in metabolism are defects in what?

- Metabolic pathways

When do inborn errors of metabolism often present?

- Newborn period/early childhood

Inborn Errors of Metabolism: Non-Specific Features

- Failure to thrive

- Hypotonia

- Poor feeding/lethargy

Which lab findings can suggest an inborn error of metabolism?

- Hypoglycemia

- Ketosis

- Hyperammonemia

- Lactic Acidosis

Ketosis

- Body uses fat for energy instead of glucose

Why do inborn error of metabolism cause ketosis?

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

Hyperammonemia

- Excess ammonia in blood

Why do inborn error of metabolism cause Hyperammonemia?

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

Lactic Acidosis

- Problem breaking down lactic acid → ↓ blood pH

Why do inborn error of metabolism cause Lactic acidosis?

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

Common Fatty Acid Oxidation Disorders

- MCAD Deficiency

- Carnitine Deficiency

What is a characteristic finding in fatty acid oxidation disorders?

- Hypoketotic Hypoglycemia

What do FA oxidation disorders cause hypoketotic hypoglycemia?

1. ↓ FA oxidation → ↓ Ketone production

2. ↑ Dependence on glucose → hypoglycemia

3. ↓ Acetyl-CoA → ↓ Stimulation of gluconeogenesis

When do fatty acid oxidation disorders commonly become symptomatic?

- During fasting or illness

Fatty Acid Oxidation Disorders: Common Presentation

- Lethargy/altered consciousness

- Hypotonia

- Failure to thrive

- Hypoketotic hypoglycemia

What is the normal function of carnitine?

- Transports long-chain FAs into mitochondria for β-oxidation

Primary Carnitine Deficiency: MOA

- ↓ Carnitine → impaired transport of LCFAs into mitochondria → ↓ β-Oxidation

Primary Carnitine Deficiency: Presentation

- Muscle weakness

- Cardiomyopathy

- Hypoketotic Hypoglycemia

Primary Carnitine Deficiency: Labs

- ↓ Carnitine and acylcarnitine

MCAD Deficiency: Deficiency and MOA

- D: Medium-chain acyl-CoA dehydrogenase

- Impaired β-Oxidation of medium-chain FAs → cannot generate adequate acetyl-CoA/ketones during fasting

MCAD Deficiency: Key finding

- Hypoketotic Hypoglycemia during fasting or illness

MCAD Deficiency: Labs

- ↑ Medium-chain acylcarnitines

- ↑ Dicarboxylic acids in urine

- Hypoketotic Hypoglycemia

Carnitine Deficiency vs MCAD Deficiency: Acylcarnitine

- Carnitine Def: ↓ Acyl Carnitine

- MCAD Deficiency: ↑ Medium-Chain Acylcarnitines

What is the major role of peroxisomes in fatty acid metabolism?

- Oxidation of very-long chain FAs

Mitochondria vs Peroxosomes: Fatty Acid Oxidation

- Mitochondria: Short/medium/long-chain FAs → β oxidation

- Peroxosomes: V long chains

What happens to VLCFAs after being shortened in peroxisomes?

- Shortened FAs are transferred to mitochondria → further β-Oxidation

What other type of FA metabolism occurs in peroxisomes?

- α-Oxidation of branched-chain FAs

Zellweger Syndrome: Defect

- Defective peroxisome synthesis

Zellweger Syndrome: MOA

- Failure to form functional peroxisomes → impaired metabolism of VLCFAs → VLCFA accumulation

Zellweger Syndrome: Labs

- ↑ Very-long-chain FAs

Zellweger Syndrome: Presentation

- Severe Hypotonia

- Seizures

- Liver Dysfunction

- Neurologic Abnormalities

- Presents in infancy

X-Linked Adrenoleukodystrophy: Defect and Accumulation

- D: Defective transport of VLCFAs into peroxosomes

- A: ↑ VLCFAs

X-Linked Adrenoleukodystrophy: Which organs are most affected?

- CNS/Myelin

- Adrenal Cortex

X-Linked Adrenoleukodystrophy: Presentation

- Progressive neurologic dysfunction

- Demyelination

- Adrenal insufficiency

Zellweger vs X-Linked Adrenoleukodystrophy

- Zellweger: Defective formation of peroxisomes

- X-ALD: Peroxisomes exist, but VLCFA transport defective

Both → ↑ VLCFAs

Refsum Disease: Defect and Accumulation

- D: α-Oxidation of Phytanic acid

- A: ↑ Phytanic Acid

Refsum Disease: Presentation

- Retinitis pigmentosa

- Peripheral neuropathy

- Ataxia

LYSOSOMAL STORAGE DISEASES MENTIONED IN THIS LECTURE, SEPARATE CARD DECK ALREADY MADE