Type Ia Glycogen Storage Disease 

Updated: Jul 07, 2021
Author: Kathleen R Ruddiman, DO; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

A glycogen storage disease (GSD) is the result of an enzymatic defect among various reactions that produce glucose, either by glycogenolysis or gluconeogenesis. Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences, but in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.[1]

The diagram below illustrates metabolic pathways of carbohydrates.

Metabolic pathways of carbohydrates Metabolic pathways of carbohydrates

Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity. The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, GSD type 0, which is due to defective glycogen synthase, also is recognized.

These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms. In general, GSDs are inherited as autosomal-recessive conditions. Several different mutations have been reported for each disorder.

Diagnosis

The diagnosis may be suspected based on the patient history, physical examination, and laboratory findings. Biochemical assay for enzyme activity and gene sequencing is the method of definitive diagnosis.  

Specifically, GSD type Ia is characterized by deficiency in the glucose-6-phosphatase (G6Pase) enzyme. GSD type Ib is a similar condition that has active G6Pase enzyme activity but with a defect in the glucose-6-phosphate transporter protein. A newly described form, GSD type Ic, does not appear to be related to mutations within the transporter protein.

Management

Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations. In some cases, liver transplantation may abolish biochemical abnormalities, and active research continues to investigate the possibility of genetic therapy in the future.

Pathophysiology

With GSDs, carbohydrate metabolic pathways are blocked at various levels and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect. As noted above, G6Pase, which is found mainly in the liver and kidneys, is affected in GSD-Ia. G6Pase hydrolyzes glucose-6-phosphate (G6P), an end-product of both glycogenolysis and gluconeogenesis, into glucose before it can be released into circulation. G6Pase is present in the lumen of the endoplasmic reticulum (ER) in the aforementioned tissues and requires G6P transport into the ER in order to function. In GSD Ib, G6P transport into the ER is defective and prevents normal G6Pase from converting G6P into glucose. In GSD Ia, the transport complex is functional, but the G6Pase enzyme activity is decreased or absent.

GSD type I, also known as Von Gierke disease, is an autosomal-recessive condition and has several subtypes. GSD Ia may be explained by mutations of the catalytic unit gene of the G6Pase complex, unlike GSD type Ib and GSD type Ic.  The G6PC gene that codes for G6Pase is located on chromosome 17q21, and various mutations have been identified that lead to its abnormal function in GSD Ia.[2]

Direct metabolic effects

GSD Ia leads to fasting hypoglycemia owing to the inability to convert G6P into glucose. If undiagnosed or untreated, this condition can cause hypoglycemic seizures, with significant risk for morbidity and mortality. Accumulation of G6P substrate leads to increased utilization of the glycolysis pathway for energy production, resulting in lactic acidosis.[3]  Increased use of the glycolytic pathway also increases lipogenesis, leading to hypercholesterolemia and hypertriglyceridemia, which can result in hepatic steatosis and pancreatitis.[4]  Atherosclerotic risk in relation to the hyperlipidemia of GSD Ia is still unclear.[5] Additional excesses of G6P are shunted down the pentose phosphate pathway, leading to excess production of purines. The purines are then broken down into uric acid, resulting in hyperuricemia, which can cause gout and kidney stones. 

Indirect/chronic effects 

Often, GSD Ia is diagnosed early and can be managed with dietary interventions.  In this case, immediate mortality from hypoglycemic seizures becomes less common, and patients more often deal with long-term effects of the disease. For example, chronic hypoglycemia and resulting chronic hypo-insulinemia result in growth defects and delayed puberty. Accumulation of glycogen in the liver and kidneys causes hepatomegaly and nephromegaly, and may lead to chronic kidney disease and hepatic adenomas, with some patients developing hepatocellular carcinoma.[6]   Chronic kidney disease can in turn result in anemia of chronic disease and hypertension.[7]

Epidemiology

GSD Ia is seen in 1/100,000 births, with notably increased prevalence in the Ashkenazi Jewish population (1/20,000). [8]

Sex- and age-related demographics

GSDs are autosomal-recessive conditions, with an equal number of males and females being affected.

In general, GSDs present in childhood. In a retrospective analysis by Rake et al, median age of presentation for GSD I was 6 months.[9]

Prognosis

Von Gierke disease is not curable.

Morbidity/mortality

Immediate morbidity arises from hypoglycemic seizures. Serious long-term complications resulting in morbidity and mortality include nephropathy and hepatic adenoma.[6]

Complications

Complications include the following:

  • Hypoglycemic seizures

  • Nephropathy with renal failure

  • Hepatic adenoma with potential malignant transformation

  • Osteoporosis 

Patient Education

Educate patients in the recognition of hypoglycemia and its appropriate treatment. For patient education resources on hypoglycemia, see the following:

 

Presentation

History

The initial presentation is most often characterized by abdominal distension and failure to thrive. Patients may present with hypoglycemic seizures or coma.[9]

Global muscle weakness is not a typical feature of von Gierke disease. Schwahn et al found height, weight, bone mass, and grip force decreased in one group of GSD 1a patients.[10]  Older patients may give a history of kidney stones, gout, or pancreatitis.

Patients may have delayed puberty. Intellectual development may be diminished, especially in patients who have experienced coma.[9]

A prospective study by Melis et al found that GSD Ia patients had a higher prevalence of insulin resistance and metabolic syndrome.[11]

Physical Examination

Physical examination may reveal the following findings:

  • Hepatomegaly or abdominal distension

  • Tachypnea in infants as a respiratory mode of compensation for lactic acidosis 

  • Characteristic round facies

  • Xanthomas on the buttocks or extensor surfaces

  • Acute manifestations of gout

  • Hypertension or other manifestations of renal failure

  • Short stature[9]

 

DDx

 

Workup

Laboratory Studies

Diagnostics

The diagnosis can be established with genetic sequencing, and targeted mutation analysis is also available.[12]

A liver biopsy can be tested for G6Pase activity level, and liver histology usually reveals increased glycogen and lipid content. [13]

Additional assessment

Patients should have readily available glucometry to assess for hypoglycemia, a hallmark feature of GSD Ia.  Blood glucose levels should also be assessed during the initial workup.

The lactic acid level is often more elevated in GSD Ia than in other GSDs, which may help narrow down the diagnosis. Patients should have a complete metabolic panel to assess kidney function and liver function, given the prevalence of renal and hepatic pathology related with GSD Ia.

Hyperlipidemia is found in GSD Ia, although there is no clear evidence of increased atherosclerosis.[14]   A lipid panel should be assessed. Laboratory abnormalities also include hyperuricemia, hyperlactacidemia, hyperlipidemia, and hypercalciuria.

Vitamin D deficiency is a well known complication of GSD Ia and may also result in osteoporosis.[15] It is prudent to check vitamin D levels, and if suspected, assessment for osteoporosis may be indicated. 

Normochromic anemia has been documented as well; a complete blood cell count should be assessed. Measuring lipase and amylase may be justified in suspected cases of pancreatitis.

Imaging Studies and Histologic Findings

Imaging studies

Imaging often shows hepatomegaly and may reveal hepatic adenoma. Bone densitometry in older individuals may show low bone mass. Renal ultrasonography may show enlarged kidneys.

In a study to determine how well contrast-enhanced ultrasonographic scans can characterize focal liver lesions in patients with GSD type Ia, Nguyen et al examined images from 8 benign hepatic adenomas associated with the disease.[16]  The scans revealed marked hypervascularity in all of the lesions during the early arterial phase, with most of the lesions showing sustained enhancement in the portal and late phases.

Histologic findings

Biopsy of the kidney may reveal focal glomerulosclerosis. Liver histology usually reveals increased glycogen and lipid content.[13]

 

Treatment

Medical Care

Current treatment modalities

In general, no specific treatment exists to cure glycogen storage diseases (GSDs).

In most cases, the mainstay of management involves measures to reduce hypoglycemia, including frequent meals and consumption of uncooked cornstarch. Some patients require continuous nocturnal gastric drip feeding via nasogastric tube to prevent nocturnal hypoglycemia.[9]

Therapies to reduce comorbidities remain common. Ai et al utilized low molecular weight heparin, insulin, and fenofibrate to reduce hypertriglyceridemia, as well as orlistat and ezetimibe to reduce hyperlipemia, to manage a case of acute pancreatitis in a 23-year-old patient with GSD Ia.  Fenofibrate, orlistat, and ezetimibe were continued after hospital discharge for long-term preventive lipid-lowering therapy.[4]

Xanthine oxidase inhibitors are commonly used to treat hyperuricemia associated with GSD Ia.

Calcium and vitamin D supplementation has been used to slow development of osteoporosis associated with GSD Ia.

In patients who suffer significant progression of kidney disease, hemodialysis may be required.

Antihypertensive medications are commonly required. As demonstrated in a retrospective analysis, hypertension notably presents much earlier, at a median age of 17 years.[9]

Future prospects for treatment options 

Zingone et al demonstrated the abolition of the murine clinical manifestations of von Gierke disease with a recombinant adenoviral vector.[17]  These findings suggested that corrective gene therapy of GSDs may be possible for humans.

An encouraging study by Bijvoet et al provides evidence of successful enzyme replacement for the mouse model of Pompe disease, which may lead to therapies for other enzyme deficiencies.[18]

Other studies have shown the prevention of hepatic adenoma and carcinoma in mice when G6Pase hepatic activity was restored to >3%, and there is a current hypothesis that damage to the liver in GSD Ia may be precipitated by abnormalities in hepatic autophagy, a process for recycling and eliminating compromised organelles to maintain efficient cellular metabolism. G6Pase deficiency in GSD Ia has been associated with dysregulation of hepatic autophagy, a pathway that may lead to the development of hepatocellular carcinoma. A publication by Zhang et al postulates that  modulation of hepatic autophagy may be a viable target for future therapies. This group tested a recombinant adeno-associated virus (rAAV) vector that introduces an amino acid substitution into the existing G6PC gene sequence, which allowed G6PC -/- mice to survive long term.[19] This may translate into viable genetic therapy based on the rAAV vector for human patients in the future. 

A CRISPR/Cas-9 based genome editing therapy was tested in mice to target a G6PC-p.R83C variant that is prevalent in humans. The study showed that treated mice had increased G6Pase activity to >3% and tolerated longer periods of fasting, which may lead to the development of genetic therapy for GSD Ia.[20]

Surgical Care and Consultations

Surgical care

Partial liver resection or liver transplantation may be required in patients with hepatic adenomas. Whether transplantation prevents further complications remains unclear, although a study by Matern et al demonstrated the correction of metabolic abnormalities after transplantation.[21]

Patients whose kidney function deteriorates may also require kidney transplant.

Consultations

Owing to the progressive kidney dysfunction, referral to a nephrologist may be appropriate.

Consultation with a hepatologist may be necessary for management of liver dysfunction.

Diet

Prevention of hypoglycemia in affected infants can be challenging. Nasogastric drip-feeding has allowed continuous feeding during the night. Uncooked cornstarch is another commonly used dietary intervention. Lactose- and fructose-restricted diets may also help in limiting pathways that lead to lactic acid production.[9]

Early diet therapy may help prevent hepatic disease and developmental delay.