Clinical Guidance

No strong genotype-phenotype correlations that can explain the clinical and biochemical features or the response to treatment have been identified for GSD I . G6PC1. Two case reports suggested that individuals with GSD Ia who are homozygous for the pathogenic splicing variant may be at increased risk of developing hepatocellular carcinoma (HCC) . However, it should be noted that this pathogenic variant is the most common cause of GSD Ia in individuals of Japanese descent. Of 19 Japanese adults who were homozygous for c.648GT, three had HCC, one had cholangiocellular carcinoma, and seven had hepatic adenoma . A study of 40 individuals who were homozygous for this pathogenic variant found that c.648GT is associated with a milder phenotype with respect to hypoglycemia .

Source: GeneReviews — "Glycogen Storage Disease Type I"

Diagnostic Criteria

The two major subtypes of glycogen storage disease type I (GSD I) are:

• GSD type Ia, caused by the deficiency of glucose-6-phosphatase (G6Pase) catalytic activity; and

• GSD type Ib, caused by a defect in glucose-6-phosphate exchanger SLC37A4 (transporter).

The lack of either G6Pase catalytic activity or glucose-6-phosphate exchanger SLC37A4 (transporter) activity in the liver leads to inadequate conversion of glucose-6-phosphate into glucose through normal glycogenolysis and gluconeogenesis pathways, resulting in severe hypoglycemia and many other signs and symptoms typical of the GSD I disorders. Guidelines for diagnosis and management have been published by the American College of Medical Genetics and Genomics (full text).

Suggestive Findings

GSD I should be suspected in individuals with the f...

Source: GeneReviews — "Glycogen Storage Disease Type I"

Differential Diagnosis

Disorders that can present clinically like glycogen storage disease type I (GSD I) include those summarized in . Table 2. Disorders in the Differential Diagnosis of Glycogen Storage Disease Type I

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type I (GSD I), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3. Recommended Evaluations at Initial Diagnosis in Individuals with Glycogen Storage Disease Type I

Clinical Guidance

Avoid sucrose, galactose, fructose, high-fructose corn syrup, honey, maple syrup, molasses, agave nectar, and sorbitol. Due to potential negative effects of sex hormones (containing estrogen) on hepatic adenomas, combined oral contraception (including high-dose estrogen) should be avoided in women with GSD I, especially those with adenomas . Progestin-only contraceptives may be considered; however, given the potential risk to develop low BMD and osteoporosis, follow-up assessment for bone disease is recommended. Metformin and lactate-containing infusions such as Ringers lactate should be avoided. Amoxicillin/clavulanic acid has been associated with an increased risk of diarrhea in individuals with GSD I (common); there is also a risk for idiopathic liver failure due to clavulanic acid (rare). Glucagon should not be used to treat hypoglycemia because it is ineffective and may increase the risk of lactic acidosis.

Source: GeneReviews — "Glycogen Storage Disease Type I"

Therapies Under Investigation

Current dietary treatment prevents hypoglycemia and greatly improves the life expectancy of individuals with GSD I. However, long-term complications – including progressive kidney failure and development of hepatic adenomas that progress to hepatocellular carcinoma – still occur. The development of new therapies for GSD I has recently evolved into new concepts involving the following:

Source: GeneReviews — "Glycogen Storage Disease Type I"

Surveillance Guidelines

Follow GSD I guidelines published by a group of experts in the field . Perform home blood glucose monitoring using a glucometer or continuous glucose monitoring (CGM) when available. CGM is a reliable noninvasive tool that assesses glucose trends in real time with good concordance with finger-stick glucose values. The benefits of CGM include improved self-monitoring and management of blood sugars while assessing the effect of treatment regimens on glucose levels in the outpatient setting rather than the hospital, which does not reflect or capture situations that the individual is likely to encounter. Under supervision of a metabolic dietitian, individuals are able to adjust dietary and cornstarch regimens, empowering them to take control of their own management. CGM allows 24-hour glucose monitoring for hypoglycemia and hyperglycemia (due to overtreatment) in those who may be asymptomatic – information that may be missed if monitoring is done by glucose finger stick. The data generated by CGM are useful for comparing trends and adjusting cornstarch doses and dietary plans as indicated without need for hospitalization .

Table 4.

Recommended Surveillance for Individuals with Glycogen Storage Disease Type I

System/Concern | Evaluation | Frequency

Liver disease

| Serum AST, ALT, albumin, bilirubin, PT/INR, aPTT to monitor for liver damage | Every 6-12 mos

Liver ultrasound to assess for adenomas | Every 12-24 mos until age 16 yrs

Source: GeneReviews — "Glycogen Storage Disease Type I"