Treatment of glycogen accumulation disorder type Ia
Glycogen accumulation disorder type Ia (GSD Ia) is the most common type of glycogen accumulation disorder. The cause of this inherited endocrine metabolic disease is abnormal glucose-6-phosphatase activity due to mutations in the G6PC gene. The clinical presentation of patients varies depending on the age of onset, rate of progression and severity of the disease. In recent years, several new developments have been made in the study of GSD Ia. Genetic testing is beginning to be used in the clinical diagnosis of GSD Ia. Modified corn starch has been applied to the dietary treatment of GSD Ia patients in Europe and the United States.
Glycogen accumulation disorder (GSD) type Ia is a rare disease that results from insufficient glucose-6-phosphatase activity, leading to excessive accumulation of glycogen and fat in the liver, kidneys, and intestinal mucosa. typical symptoms in patients with GSD Ia are hypoglycemic episodes in infancy when the interval between feedings is extended to 3-4 h. Mutations in this disease have been identified in Caucasians, German-Jews, Hispanics and Asians, with an overall incidence of about 1/100,000. the disease has a higher incidence in German-Jews (1/20,000).
The diagnosis relies on non-invasive genetic sequencing techniques and liver aspiration pathology. In recent years, some new advances have been made in the clinical management of GSD Ia and new insights into the management of chronic complications in adult patients are reviewed in this paper.
1.Dietary treatment
Raw corn starch has been used in the treatment of GSD I since the early 1980s. There is no consensus on the age at which to start raw corn starch therapy, with some suggesting that it should be introduced between 6 months and 1 year of age. Raw cornstarch requires amylase for digestion, but amylase is not present or not fully present until 2 years of age. Adverse effects of raw corn starch include increased anal discharge, bloating, diarrhea, and in some cases, discomfort may resolve 2 weeks after initiation of treatment.
Therefore, gradual initiation of increasing the amount of raw corn starch until the target amount is reached can help improve patient tolerance.
A modified form of corn starch (Glycosade), has been used in Europe and the United States in 2011 for the treatment of patients with GSD Ia. Its usage is to be taken once a night at bedtime, which is more effective in preventing nocturnal hypoglycemia than the traditional raw corn starch. It is important to prepare raw corn starch with cool white water. When hot water is used, the starch is easily hydrolyzed by amylase, making its breakdown, absorption and excretion faster, which is not conducive to maintaining a constant blood glucose level.
The current latest GSD I treatment guidelines recommend raw corn starch dosage as follows: for young children, 1.6 g raw corn starch per kg body weight (ideal body weight) once every 3-4h; for older children, adolescents and adults, 1.7-2.5 g raw corn starch per kg body weight (ideal body weight) once every 4-5h (can be extended to 6h in some cases).
2. Treatment of chronic complications in adult patients
Despite adherence to diet therapy, some GSD Ia patients still develop chronic complications including growth retardation, hepatomegaly, intermittent hypoglycemic episodes, hyperlactatemia, hyperlipidemia, gout with hyperuricemia, proteinuria, kidney stones, progressive nephropathy, osteoporosis, and bleeding tendencies.
2.1 Liver-related complications Of greatest concern for patients with GSD Ia are recurrent hepatic adenomas, which are accompanied by a significantly higher risk of developing hepatocellular carcinoma. Some domestic studies have reported that liver adenomas are mostly found at follow-up around adolescence. Foreign studies have found that some GSD Ia patients with hepatic adenomas have abnormalities on chromosome 6, manifested by the acquisition of 6p with concomitant deletion of 6q.
The expression of 2 candidate oncogenes located on the long arm of chromosome 6: insulin-like growth factor 2 receptor gene and large tumor suppressor gene 1 was decreased by more than 50%, suggesting that the deletion of these genes may be associated with the early development of liver tumors. In addition, chronic inflammatory responses may be associated with liver tumorigenesis, and subclinical abnormalities in neutrophil metabolism were found in G6Pase(-/-) mice. Moreover, it has been noted that there is a persistent inflammatory response in the liver of GSD Ia patients with neutrophil infiltration and elevated interleukin 8 levels.
2.2 Renal-related complications Adult GSD Ia patients have increased renin-angiotensin activity and renal hyperfiltration, which in turn results in progressive renal failure. Studies in animal models have found elevated angiotensinogen levels in the kidneys of G6Pase(-/-) mice at 2 weeks of age.
Subsequently, elevated levels of transforming growth factor beta and connective tissue growth factor were found in G6Pase(-/-) mice at higher weeks of age in combination with increased expression of angiotensinogen. This study also found that the development of nephropathy in G6Pase(-/-) mice was associated with increased expression of angiotensinogen, even without combined proteinuria. The renin-angiotensin system plays a key role in the development of renal insufficiency in GSD Ia patients.
Low doses of angiotensin-converting enzyme inhibitors (ACEIs) such as captopril and lenopril are effective in controlling microalbuminuria. At low doses, these drugs can improve renal perfusion. In a study including 95 patients with GSD I, the use of ACEI significantly improved the patients’ glomerular hyperfiltration status and slowed the progression of the kidney from hyperfiltration to microalbuminuria. However, in that study, ACEI did not prevent progression from the microalbuminuric phase to the massive albuminuric phase and the renal failure phase.
2.3 Hyperlipidemia
Hyperlipidemia in patients with GSD Ia can be treated with lipid-modifying drugs such as 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors and fibrates. Lipid-modifying drugs combined with ACEI and vitamin E can help to slow down the progression of renal disease in GSD Ia patients. One study showed a potential benefit of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in patients with GSD Ia compared to controls in that it increased triglyceride synthesis in patients. Lowering triglycerides may reduce the risk of pancreatitis in patients with poor metabolic control, but there is still no consensus on the recommendation of lipid-lowering agents.
2.4 Hyperuricemia
Hyperuricemia can be improved in patients with well-controlled metabolism with GSD Ia. There is no consensus on when to start the use of drugs for hyperuricemia. In some cases, however, persistent hyperuricemia can lead to gout attacks, gout stones and the development of kidney stones. Medications such as allopurinol and febuxostat may be considered to lower uric acid levels. Colchicine may be used to treat acute attacks of gout in patients. In cases where other drugs have failed, newer drugs such as pegloticase may be considered.
2.5 Bleeding tendency
Coagulation defects in GSD I patients are due to acquired platelet dysfunction with prolonged bleeding time and abnormal platelet adhesion and aggregation. Some GSD I patients have angiohemophilia-like manifestations with abnormal function of vascular hemophilia factor (von Willebrand Factor, vWF) and/or decreased vWF antigen levels. Bleeding manifestations include nosebleeds, subcutaneous bleeding, excessive menstruation, and excessive bleeding during surgical procedures. Therefore, you should inform your physician of your condition prior to surgery or delivery in adult women.
Although dietary interventions can improve bleeding tendencies, the exact etiology of bleeding tendencies remains unclear. Standardized treatment of platelet dysfunction in patients includes the use of antifibrinolytic agents and 1-desamino-8-D-arginine vasopressin to stimulate the promotion of vWF factor and factor VIII release from the endothelial cell storage pool. Caution is required when administering intravenous 1-desamino-8-D-arginine vasopressin with glucose to avoid volume overload and hyponatremia. In addition, fibrinolytic inhibitors such as ε-aminohexanoic acid (Amicar) may be used as adjunctive therapy for mucosa-associated bleeding.
ε-aminohexanoic acid should not be used in patients suspected of having renal or ureteral bleeding to avoid obstructive nephropathy and is contraindicated in the setting of disseminated intravascular coagulation.
3.Gene therapy and cell therapy
Gene therapy or cell therapy for GSD Ia has the potential to block the development of chronic complications due to recurrent episodes of hypoglycemia and associated metabolic abnormalities. Some preliminary studies of hepatocyte transplantation have demonstrated the durability of donor cell function, but the long-term efficacy of this approach needs to be further confirmed [[17]-[18]]. Given the experience gained with liver transplantation in patients with GSD Ia, the efficacy of liver-targeted gene therapy for this disease may be promising.
Animal models of GSD Ia have demonstrated that adeno-associated virus (AAV) vectors containing a human glucose-6-phosphatase regulatory cassette/promoter are effective for the treatment of GSD Ia. Small genomic, double-stranded AAV2/8 vectors containing a small fragment of the human glucose-6-phosphatase gene are also effective for the treatment of GSDIa in G6Pase(-/-) mice and canine models. Single-stranded AAV vectors containing a larger human glucose-6-phosphatase regulatory cassette have likewise been shown to be significantly efficacious in the treatment of G6Pase(-/-) mice.
Other vectors that have been applied to the treatment of G6Pase(-/-) mice include the helper-dependent-adenovirus vector encoding canine glucose-6-phosphatase and the feline immunodeficiency virus vector encoding mouse glucose-6-phosphatase. Although survival was prolonged and hypoglycemic episodes were prevented in all mice treated with such vectors, observation of potential toxic effects remains limited because the AAV vector genomes remain largely episomal and
Because the AAV vector genomes remain largely episomal and are lost after cell division, the duration of efficacy of AAV vectors is limited. are lost after cell division in therapeutic experiments in the GSD Ia mouse model. However, between 7 and 12 months of age, the expression of glucose-6-phosphatase in these vectors was progressively diminished.
Gene therapy of G6Pase(-/-) mice using single-stranded AAV vectors containing larger glucose-6-phosphatase fragments completely corrects hepatic glucose-6-phosphatase deficiency at 6 months of age, but at 18 months of age, vector expression decreases by 90%. These studies suggest that while AAV vectors have a significantly longer duration of expression than other common free type gene therapy vectors (e.g. viral, adenoviral or plasmid DNA vectors), the effect decreases over time.
Some studies have found that initial AAV vector treatment induces the production of antibodies that affect efficacy and that treatment can be resumed by switching to another type of AAV vector. AAV vectors were also found to partially reverse the reduced insulin-like growth factor-1 levels and growth retardation in G6Pase(-/-) mice caused by reduced growth factor signaling.
Therefore, additional preclinical trials are still needed to assess the efficacy and safety of gene therapy. Such future experiments will use new animal models, including mouse models of liver-specific G6Pase(-/-) and adenoma and hepatocellular carcinoma modeling by feeding a high-fat diet.
Mice with liver-specific G6Pase(-/-) lack glucose-6-phosphatase only at the liver site and are more likely to survive long-term than non-specific G6Pase(-/-) mice, facilitating long-term experiments to evaluate new AAV therapeutic vectors for GSD Ia. Despite the obvious limitations of gene therapy for GSD Ia at present, the development of AAV vector-mediated therapy will continue in the future.
4. Liver transplantation
Liver transplantation is the end-of-life treatment for metabolic liver disease. More than 100 pediatric and adult patients with GSD I have received liver transplantation in North America. The 1-, 5-, and 10-year survival rates are 82%, 76%, and 64%, respectively. Metabolic disorders such as hypoglycemia, lactic acidosis, hyperuricemia and hyperlipidemia were corrected in these patients after liver transplantation. In China, there have also been recent successful cases of hepatic glycogen accumulation disorder treated with liver transplantation using donor organs for cardiac death in children.
In patients with GSD Ia, there is no possibility of recurrence of the original lesion in the transplanted liver after surgery because of the autonomic defect in hepatocyte function caused by a monogenic disease before transplantation.
The most common indication for liver transplantation in GSD Ia patients is the removal of hepatic adenomas with underlying precancerous lesions. Other indications are growth disturbance and poor metabolic control. Good metabolic control therapy can correct growth disturbances and minimize the risk of liver adenoma.
A single hepatic adenoma is recommended for surgical resection rather than receiving a liver transplant. Patients with GSD Ia are not routinely recommended to undergo liver transplantation because of the risk of mortality associated with liver transplantation and the high incidence of postoperative complications. However, liver transplantation should still be considered for patients with rapidly increasing size and number of hepatic adenomas, recurrence of hepatic adenomas after surgical resection, and those at high risk of liver malignancy.
In conclusion, the available treatments cannot achieve a cure for patients with GSD Ia, but diet with drug therapy can improve the quality of life and control the development of chronic complications to some extent. Patients with indications for liver transplantation may be considered for liver transplantation. Gene therapy is still in the exploratory stage and many questions remain to be addressed regarding long-term safety and efficacy, but gene therapy remains the most promising treatment for GSD Ia in the future.