16 - Clinical Aspects of Energy and Metabolism 2

What are glycogen storage diseases (GSDs), and how do they differ by organ involvement? Do all GSDs show low ketones?

GSDs are inherited enzyme defects in glycogen metabolism, causing glycogen buildup.

• Liver GSDs → hypoglycemia, hepatomegaly, ketosis

• Muscle GSDs → weakness, cramps, no hypoglycemia

• Mixed (e.g., Type III) → both liver and muscle signs
  Hepatomegaly is due to glycogen and fat buildup.
  Ketones are not always low—they're low in GSD I, but usually present in others.

What is the basic defect in GSD type I (Von Gierke disease)?

GSD I is caused by a deficiency of glucose-6-phosphatase, which prevents the liver from converting glucose-6-phosphate into free glucose, leading to metabolic imbalance.

What are the metabolic changes in GSD I?

• Glucose level: ___, because ___

• Lactic acid level: ___, because ___

• Uric acid level: ___, because ___

• Triglyceride level: ___, because ___

• Ketone level: ___, because ___

• Glucose level: Hypoglycemia, because glucose-6-phosphate cannot be converted into glucose during fasting.

• Lactic acid level: Acidosis, because excess G6P enters glycolysis, increasing pyruvate and NADH, which drives lactate formation via lactate dehydrogenase.

• Uric acid level: Elevated, because lactic acidosis reduces renal uric acid excretion and AMP degradation increases purine turnover.

• Triglyceride level: Elevated, because excess acetyl-CoA and NADPH from glycolysis and the PPP are diverted into lipogenesis.

• Ketone level: Low or absent, because hypoglycemia doesn't fully activate fat oxidation and ketogenesis is suppressed.

What is the mechanism behind low ketone levels in GSD type I despite hypoglycemia?

In GSD I, excess G6P increases glycolysis → more pyruvate → more acetyl-CoA → citrate accumulates and exits the mitochondria.
In the cytosol, citrate is converted to acetyl-CoA → then to malonyl-CoA, which inhibits CPT1, the enzyme that imports fatty acids into mitochondria.
As a result, fatty acid oxidation and ketogenesis are suppressed, so ketone levels stay low despite hypoglycemia.

Why is shortening fasting intervals an important treatment strategy in GSD type I?

In GSD I, the liver cannot release glucose due to glucose-6-phosphatase deficiency.
Short fasting intervals prevent severe hypoglycemia by providing a steady external glucose source, bypassing the defective glycogenolysis and gluconeogenesis pathways.

How does muscle necrosis lead to dark urine in glycogen storage diseases?

In muscle GSDs (e.g. Type V), energy failure during exercise causes muscle necrosis.
This releases myoglobin into the blood, which is filtered into urine → causing dark (cola-colored) urine due to myoglobinuria.

What is MCAD deficiency and what does it impair?

MCAD deficiency is an autosomal recessive disorder caused by a defect in medium-chain acyl-CoA dehydrogenase, which blocks mitochondrial β-oxidation of medium-chain fatty acids.
This leads to hypoketotic hypoglycemia, accumulation of medium-chain acylcarnitines, and reliance on backup pathways like ω-oxidation.

What is ω-oxidation, and how does it produce octanoylcarnitine and suberic acid in MCAD deficiency?

ω-oxidation is a minor fatty acid pathway that becomes active when β-oxidation fails.
It adds an oxygen to the terminal (ω) methyl group of fatty acids → forms a dicarboxylic acid.
In MCAD deficiency:

• Medium-chain fatty acids like octanoic acid are shunted to ω-oxidation → producing suberic acid (a dicarboxylic acid seen in urine).

• Accumulated medium-chain acyl-CoAs are converted to acylcarnitines (like octanoylcarnitine) for detox and transport, which appear on blood acylcarnitine profile.

Why is long-chain acyl-CoA dehydrogenase (LCAD) deficiency typically more severe than MCAD deficiency?

LCAD deficiency blocks the first step of fatty acid oxidation, preventing any breakdown of long-chain fatty acids.
This results in complete loss of fat-derived energy and accumulation of toxic long-chain acylcarnitines.
In contrast, MCAD patients can still partially metabolize long-chain fats until medium chains accumulate, providing some residual energy.

How does frequent feeding and medium-chain triglyceride (MCT) supplementation help in fatty acid oxidation disorders?

Frequent feeding prevents catabolic fasting states, reducing the need for fatty acid oxidation.
In long-chain FAO disorders (e.g., LCAD, CPT II), MCFAs bypass the carnitine shuttle and directly enter mitochondria for oxidation.
This allows energy production without relying on defective long-chain pathways.

Why are carnitine supplements used in FAO disorders, and what is secondary carnitine deficiency?

In FAO disorders, accumulating fatty acyl-CoAs are detoxified by forming acylcarnitines, which are excreted in urine.
This leads to loss of free carnitine stores over time → called secondary carnitine deficiency.
Supplementing carnitine helps replenish intracellular stores, support fatty acid transport, and reduce toxic acyl-CoA buildup.