Type XI Glycogen Storage Disease/Fanconi-Bickel Syndrome

Introduction:

Glucose is the main energy source for cells to carry out normal functions. When an excess of glucose is present, the glucose gets converted to glycogen and stored in the liver and muscles. Conversely, glycogen is broken down to produce glucose when glucose levels are reduced. Several enzymes aid in the formation and transport of glycogen. When damaged, an important transporter called GLUT2, the glucose transport has defects, resulting in Fanconi- Bickel syndrome.

What Are the Causes?

Fanconi- Bickel syndrome is known to be a congenital autosomal recessive condition. It occurs due to heterozygous (one gene may be mutated) or homozygous (both genes may be mutated) defects in the SLC2A2 gene that encodes the glucose transporter 2 (GLUT2). The GLUT2 is responsible for the uptake and release of glucose in the liver. GLUT2 is found in liver hepatocytes, pancreatic B-cells, enterocytes, renal tubular cells, and discrete regions of the brain. Therefore, defects in GLUT2 lead to dysfunctional metabolism and glycogen storage, mostly in the kidney and liver. In addition, defective expression of GLUT2 in the third trimester of pregnant women causes low birth weight and transient diabetes mellitus among infants.

What Is GLUT2 and Its Role in Various Organs?

GLUT2 maintains homeostasis by regulating glucose uptake in epithelial cells of organs. GLUT2 in pancreatic B- cells aid in glucose-stimulated insulin secretion. In the liver, the transporter aids in glycogen metabolism regulation. In the kidney, GLUT2 aids in the bulk of glucose reabsorption in the proximal tubule. In the intestine, the transport facilitates the transport of dephosphorylated glucose from enterocytes. In case of high glucose load in the intestine, it aids in absorbing glucose directly from basal cells. Other energy sources like galactose, mannose, glucosamine, and fructose are also absorbed. In the brain, the transporter facilitates glucose transfer to astrocytes and plays the glucose sensor role. Damage to GLUT2 can impact feeding behavior as the brain cannot sense glucose levels in the body.

What Is the Incidence of the Disease?

The disease is most commonly seen in newborns and infants up to two years of age. According to some studies, the incidence is higher in the middle east or families where inbreeding is common. However, the true incidence still needs to be determined due to the need for more sample size and studies.

What Are the Clinical Features?

• The classic feature of Fanconi- Bickel syndrome includes fasting hypoglycemia, postprandial hyperglycemia, and glucose intolerance.

• Malabsorption of glucose and dairy products leads to diarrhea.

• Hypoglycemia is seen due to defective glucose transport from hepatocytes and GLUT2 expression.

• Decreased glucose absorption from the liver and less insulin secretion due to decreased pancreatic B cells sensitivity lead to post-prandial hyperglycemia.

• Accumulation of glycogen in hepatorenal cells leads to hepatorenomegaly and abdomen protrusion.

• Increased glucose in the blood can lead to ketosis.

• Demineralization of bone leads to rickets which can progress to osteoporosis. Other symptoms include bone pain and fracture.

• When ketosis, diarrhea, and proximal renal dysfunction are left untreated, it results in chronic acidosis.

• Hepatomegaly and splenomegaly due to glycogen accumulation in the liver can be seen.

• Galactose intolerance and non-insulin-dependent diabetes mellitus.

• In untreated cases of renal Fanconi, tubular nephropathy may be seen.

• The child's difficulty thriving, short stature, and stunted growth are also common.

• Wrist widening.

• Other characteristic symptoms include a “doll” shaped face, fat deposition in the shoulder and abdomen, delayed dentition, dental caries, delay in puberty, increased fracture risk, and pancreatitis.

• Symptoms of renal Fanconi, such as low phosphorus and potassium level in the blood, more amino acids, protein urine, polyuria, and dehydration, can be seen.

• Hepatomegaly reduces in size as the child reaches puberty.

Rare complications include:

• Hepatocellular carcinoma- liver cancer is most common among other glycogen storage diseases.

• Acquired growth hormone deficiency can occur secondary to the syndrome.

• Craniosynostosis (increased intracranial pressure).

What Is the Diagnostic Feature?

• No specific imaging studies are available prenatally. However, genetic counseling and amniotic fluid analysis may aid in detection.

• Most cases are postnatally detected with a positive blood glucose screening. However, absent glucose rules out the disease as it is a characteristic feature for detecting the syndrome.

• Biopsies are not a preferred diagnostic test. However, certain instances have seen increased glycogen deposition in hepatocytes and steatosis (fatty liver disease).

• Renal biopsy shows glycogen deposition in renal and tubular cells.

• An abdominal ultrasound scan can detect hepatomegaly.

• A blood glucose test to detect hypo and hyperglycemia is done.

What Is the Differential Diagnosis?

The only differential diagnosis of Fanconi syndrome is Von Gierke disease (glycogen storage disease type 1a) due to similar characteristics like hepatomegaly, renomegaly, and a “doll-like” face. The differentiating features are the absence of rickets and tubular dysfunction in Von Gierke's disease.

What Are the Treatment Options?

There is no specific treatment for the disease. Instead, symptoms are managed by various means.

Dietary modification is the most important step in treating the syndrome.

• Glucose and galactose are removed from the diet.

• Small doses of uncooked cornstarch at night can stabilize glucose concentration in the blood during the long interval between meals as it is difficult to digest and release glucose slowly.

• Fasting hypoglycemia is avoided by consuming small meals at regular intervals.

• Achieving good metabolic control can reduce liver size.

• Supplements of electrolytes and water are given to balance renal tubulopathy.

• Supplements of vitamin D and phosphatase for hypophosphatemic rickets are given.

• Bicarbonate supplement reduces the risk of severe acidosis and improves growth.

• Citrate is also given to achieve electrolyte balance.

What Is the Prognosis of the Disease?

• The prognosis is good when detected early and provided with adequate treatment, and survival to adulthood is also favorable.

• Late detection of Fanconi- Bickel syndrome increases the risk of liver failure, respiratory distress, and other health complications.

• Suitable dietary changes can reduce liver size and glycogen accumulated even after a late diagnosis. Thus, preventing the need for liver transplantation.

• Early treatment of children can help them meet developmental milestones, maintain adequate height and weight and improve cognitive function.

• Long-term benefits of early treatment include improved fertility among both genders.

Conclusion:

The exact mechanism of GLUT2 dysfunction and treatment of patients with Fanconi-Bickel Syndrome is unknown. However, dysfunctional GLUT2 is known to cause impaired glucose control due to improper functioning of various organs like the liver, kidney, pancreas, intestines, and brain. Thus leading to dysglycemia, rickets and renal Fanconi condition, and diabetes mellitus-like conditions among newborns. Therefore, adequate studies must be carried out for its effective management and to provide a better quality of life.