Von Gierke Disease

von Gierke Disease: Type 1
Glycogen Storage Disease

Kennedy Fitzgerald
NTRI 7530
Fall 2020
Background
• Discovered by Von Gierke in 1929: first
metabolic disorder in which an enzyme defect
was identified (2)
• Glycogen storage disease type 1-also known as
Von Gierke disease is an inherited disorder
caused by deficiencies of specific enzymes in the
glycogen metabolism pathway. (1)
• VG is caused by a deficiency in G6Pase. Results
in the inability to dephosphorylate G6P impairs
glucose release from the liver. As a consequence,
patient exhibit hypoglycemia between meals. (1)
(3)
Background Cont.
• Two major subtypes (1)
• GSD1a: deficiency of G6Pase
• GSD1b: have normal G6Pase enzyme activity but have a
deficiency of the transporter enzyme glucose 6P
transporter 1 (G6PT1)
• Patients present with hepatomegaly and
hypoglycemic seizures at 3-4 months of age. Children
typically have doll like features: excess subcutaneous
fat in cheeks, relatively thin extremities, short stature,
protruding abdomen. (2)
• Confirmed via genetic testing
(4)
Treatment/Management
• To maintain blood glucose concentrations, regular “round the clock”
feeding is required. (2)
• A nocturnal nasogastric drip can be used, along with the daytime
feeding of uncooked cornstarch (acts as a slow-release form of
glucose). (2)
• Those who are identified and treated carefully at a young age can live
into adulthood. (1)
Epidemiology
• Most common and most severe of GSD’s (2)
• The incidence of GSD I in the overall population is 1/100,000. (1)
• GSD Ia and Ib prevalent in 80% and 20% respectively. (1)
• Affect males and females equally within a given population. (2)
• The Ashkenazi Jewish population has a 5-times greater prevalence
compared to rest of the population. (1)
Biochemical Mechanism (5)
G6Pase is a regulatory enzyme in
both gluconeogenesis and
glycogenolysis.
Allows the release of newly

synthesized glucose into the blood
stream to maintain blood glucose
levels.
G6Pase is located in the ER and

requires G6P transporter to bring G6P
to into the ER lumen before it is
hydrolyzed.
(5) (5)
Metabolic Consequences of VG
(6)
Hypoglycemia (5)
• G6Pase deficiency causes
G6P to accumulate within
hepatocytes. (6)
• High levels of G6P increase

substrate availability for
PFK-2 which increases
F26BP.
• Hypoglycemia seen in von
Gierke patients is due to
active glycolysis and
inactive gluconeogenesis.
(5)
Lactic Acidemia (1)
• Due to an increase in lactate production
and a decrease in lactate excretion
• Pyruvate levels are increased due to
• Increased muscle breakdown
hyperalanemia deamination of alanine in
liver excess pyruvate levels
• Very active glycolysis increases pyruvate
production
• NADH levels are increased due to
• Very active glycolysis
Hyperlipidemia (1)
Increased production of VLDL’s
1. Increase in hepatic de novo lipogenesis
1. Increase glycolysis increase TCA cycle activity
and glycerol 3P synthesis increase in citrate
production increase de novo fatty acid
synthesis and lipogenesis  increase VLDLs (6)
2. Increase in hepatic repackaging into triacylglycerides
1. Hypoglycemia lower insulin levels increase
lipolysis increased FA CoA levels increased
resynthesis increased TAGs increased VLDLs
Decreased excretion of VLDLs

Hypoglycemia lower I/G ratio decreased adipose LPL
gene expression  decreased VLDL clearance
Hyperuricemia (1)
• Hyperuricemia
• Increase in production and
decrease excretion in serum urate
• Serum lactate competes with urate
for excretion by the kidney via the
renal organic anion pump.
Hyperalanemia (1)
• The very low insulin levels in VG patients causes muscle proteolysis to
be activated to a greater extent than in normal fasting.
• Muscle
• Hypoglycemia lower insulin levels increased muscle breakdown
catabolism of muscle BCAA formation and release of alanine into the
blood uptake into the liver
• Liver:
• Excess pyruvate is transaminated to alanine
Summary
• Von Gierke Disease aka Glycogen Storage Disease Type 1
• Deficiency in G6Paseimpairs glucose release from liver
• Requires regular feeding “round the clock”, nocturnal NG tube,
cornstarch
• Metabolic consequences
• Hypoglycemia
• Lactic acidemia
• Hyperlipidemia
• Hyperuricemia
• Hyperalanemia
References
1. Parikh NS, Ahlawat R. Glycogen Storage Disease Type I. [Updated 2020 Aug 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls
Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534196/
2. Ellingwood SS, Cheng A. Biochemical and clinical aspects of glycogen storage diseases. J Endocrinol. 2018 Sep;238(3):R131-R141. doi:
10.1530/JOE-18-0120. Epub 2018 Jun 6. PMID: 29875163; PMCID: PMC6050127.
3. [Internet]. 2020 [cited 2020 November 4]. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0344033819318709
4. [Internet]. 2019 [cited 2020 November 4]. Available from: https://healthjade.net/von-gierke-disease/
5. Ferrier DR. Biochemistry. 6th ed. Baltimore (MD): Lippincott Williams & Wilkins; 2014.
6. [Internet]. 2019 [Cited 2020 November 4]. Available from:
https://www.memorangapp.com/flashcards/69001/GS+Unit+5+Biochemistry+Workshop+8/

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Von Gierke Disease

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von Gierke Disease: Type 1

Glycogen Storage Disease

Allows the release of newly

G6Pase is located in the ER and

• High levels of G6P increase

Decreased excretion of VLDLs

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