Von Gierke disease (GSD 1)


Introduction

Glycogen storage disease type I, also called Von-Gierke’s disease, is a genetic disorder caused by a mutation in the glucose 6 phosphatase gene on chromosome 17. The end result is that glycogen can’t be broken down into glucose in liver cells, so glucose metabolism goes awry, resulting in symptoms like low blood sugar, weakness and poor growth.

Glycogen storage disease (GSDI) due to glucose-6-phosphatase (G6P) deficiency characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver.

  • Also known as or hepatorenal glycogenosis or Von Gierke disease
  • Autosomal recessive inheritance (chromosome 17)
  • M/C GSD

History:

GSDI was first described by von Gierke in 1929. In 1952, Cori and Cori showed that the disease (called GSDIa) was caused by a deficit in G6Pase, an enzyme expressed mainly in the liver and kidney and, to a lesser degree, in the intestine. Subsequently, it was found that some patients are not deficient in G6Pase, even though a number of functional tests demonstrated their inability to degrade G6P in vivo: this condition was called GSDIb. To explain this defect, Arion et al hypothesized that G6P hydrolysis required the participation of several proteins located in the endoplasmic reticulum (ER) membrane: a catalytic unit (G6Pase) capable of hydrolyzing several phosphate esters (G6P, mannose-6-phosphate, carbamylphosphate and pyrophosphate) and a G6P-specific bidirectional translocase (G6PT), which would assure its entry into the lumen of the endoplasmic reticulum, where G6Pase exerts its action. Unlike G6Pase, G6PT is expressed ubiquitously. G6Pase and G6PT were found to be co-dependent as G6Pase activity is required for efficient transport of G6P into the ER lumen.


Pathophysiology

Glycogen storage diseases (GSD):

Inherited metabolic disorders of glycogen metabolism
Simplified pathway of glycogen synthesis and degradation. | Ozen H. (2007). Glycogen storage diseases: new perspectives. World journal of gastroenterology, 13(18), 2541–2553. https://doi.org/10.3748/wjg.v13.i18.2541
Schematic of the pathways linked to glycogen metabolism. Glycogen breakdown produces glucose-1-phosphate (via glycogenolysis) and glucose (via glycophagy and debranching enzyme activity). Both products enter into the glycolytic pathway giving rise to pyruvate which acts as a key precursor for the TCA cycle, fatty acid synthesis and gluconeogenesis. The interconversion of pyruvate to lactate and alanine further integrate the metabolism of the liver and muscle tissues. Additionally, fructose-6-phosphate generated in glycolysis can also shunt to the pentose phosphate pathway for nucleotide synthesis. | Ellingwood, S. S., & Cheng, A. (2018). Biochemical and clinical aspects of glycogen storage diseases. The Journal of endocrinology, 238(3), R131–R141. https://doi.org/10.1530/JOE-18-0120

Glucose-6 phosphatase (G6Pase)

Dysfunction in the G6P system causes GSD-I
  • G6Pase: M/important role of which is to provide glucose during starvation, is found mainly in the liver and the kidneys.
  • Both glycogenolysis and gluconeogenesis are affected.

Subtypes:

Depending on the abnormality in G6Pase system
  • GSDIa: Catalytic subunit G6P-α defect (expression in liver, kidney and intestine only)
  • GSDIb: G6P transporter defect (ubiquitously expressed)
  • GSD type Ic and Id: Liver microsomal transport of phosphate and glucose is deficient in GSD-Ic and Id (GSD-Ic and GSD-Id), respectively. Not clinically found.

Clinical features

GSDI patients may present with fast-induced hypoglycemia (sometimes occurring rapidly in about 2-2½ hours after a meal) and hyperlactacidemia in the neonatal period. More commonly, the first symptom is the presence of a protruded abdomen due to marked hepatomegaly around 3 months of age, though in some cases the liver may already be enlarged at birth

  • Hypoglycemia (tremors, seizures, cyanosis, apnea)
  • Poor tolerance to fasting
  • Marked hepatomegaly
  • Growth retardation (small stature and delayed puberty), generally improved by appropriate diet
  • Osteopenia and sometimes osteoporosis
  • Full-cheeked round face
  • Enlarged kidneys (PATHOGNOMIC)
  • Platelet dysfunctions leading to frequent epistaxis
Image showing an infant having characteristic features of Von Gierke’s Disease, a rounded doll’s face, fatty cheeks and protuberant abdomen | Raza, M., Arif, F., Giyanwani, P. R., Azizullah, S., & Kumari, S. (2017). Dietary Therapy for Von Gierke’s Disease: A Case Report. Cureus, 9(8), e1548. https://doi.org/10.7759/cureus.1548

Complications

Late complications:

  • Hepatic complications: Adenomas → hepatocellular adenomas (HCA)
  • Renal complications: Silent glomerular hyperfiltration before the development of microalbuminuria then proteinuria, which can lead to renal failure
  • Hyperuricemia → Gout
  • Hyperuricemia + hypocitraturia → Stones, nephrocalcinosis and renal failure
  • Severe hypertriglyceridemia → Pancreatitis, arterial dysfunction
  • Pulmonary hypertension (rare, serious): Due to abnormalities in the platelet metabolism of serotonin have been suspected [32].

GSDIb subtype:

Neutrophils and/or monocytes are functionally abnormal, showing decreases in respiratory burst and motility in response to stimuli
  • Recurrent infections
  • Relapsing aphthous gingivostomatitis
  • Inflammatory bowel disease

Diagnosis

Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon.

Fasting blood analyses:

Poor fasting tolerance
  • Hypoglycemia
  • Hyperlactacidemia
  • Hypertriglyceridemia: Milky white plasma
  • Hypercholesterolemia
  • Lactic acidosis
  • Hyperuricemia

Antenatal diagnosis:

  • Molecular analysis of amniocytes or chorionic villous cells
  • Pre-implantatory genetic diagnosis discussed with families with confirmed history

G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis:

More commonly used confirmatory test

Liver biopsy:

Sufficiently large sample required to enable analysis of the different constituents of the G6Pase system.
Glycogen storage disease type I. Liver biopsy showing mosaic pattern, prominent cell membranes and rare nuclear hyperglycogenation (HE stain). | Ozen H. (2007). Glycogen storage diseases: new perspectives. World journal of gastroenterology, 13(18), 2541–2553. https://doi.org/10.3748/wjg.v13.i18.2541

Differential diagnoses:

  • GSDIII: Glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I)
  • Primary liver tumors
  • Pepper syndrome (hepatic metastases of neuroblastoma)

Management

Genetic counseling:

Disease is transmitted as an autosomal recessive trait. Both parents of an affected child are heterozygotes. The risk of recurrence is 25%, at each pregnancy. Identification of both mutations in the patient enables the diagnosis of potential heterozygotes in the family.

Dietary managemetn:

The mainstay of treatment is to prevent hypoglycemia either by continuously providing a dietary supply of glucose, or by frequent ingestion of UCCS during day and night or nocturnal intragastric feeding
  • Management of hypoglycemia:
    • Frequent meals
    • Nocturnal enteral feeding through nasogastric tube
    • Oral addition of uncooked starch (later stages)
  • Management of acisdosis:
    • Restricted fructose and galactose intake

Liver transplantation:

Performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib.

Kidney transplantation:.

Severe renal insufficiency
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