MON-205 - Severe Hypoglycemia Mimicking Hyperinsulinism in Glycogen Storage Disease Type IV

Background:
Glycogen storage disease type IV (GSD IV) is caused by deficiency of the glycogen-branching enzyme encoded by GBE1, resulting in accumulation of abnormal glycogen in the liver, muscle and other tissues. Hypoglycemia is not a typical presenting feature unless advanced liver failure is present. However, we encountered a patient with severe hypoglycemia and biochemical findings suggestive of hyperinsulinism, posing a diagnostic challenge.

Objective:
To characterize the initial clinical presentation of patients with GSD IV at our clinical center

Methods:
We detail the case of an unusual presentation of a patient with GSD IV and performed a retrospective chart review of all patients diagnosed with GSD IV at our institution between 2010 and 2025.

Results:
Ten patients with GSD IV were identified (7 males, 3 females, age range from 1 month to 29 years). Four patients had no documentation of initial presentation. Two patients presented with congenital hypotonia and respiratory failure at birth. One patient presented with elevated liver enzymes and hepatomegaly at 3 months old. One patient presented with jaundice and abdominal distention at 1 year old. One patient presented with motor and developmental delays at 1 year old.

One patient presented with emesis and profound hypoglycemia (nadir serum glucose 27 mg/dL) at 1 month old. A critical sample obtained at a serum glucose of 52 mg/dL demonstrated suppressed β-hydroxybutyrate (0.19 mmol/L) with inadequately suppressed insulin (2.9 mU/L) and C-peptide (0.94 ng/mL). However, this sample was drawn 4 minutes after glucagon administration and was therefore non-interpretable. A second critical sample obtained at a point-of-care glucose of 52 mg/dL showed similar biochemical findings (β-hydroxybutyrate 0.14 mmol/L, insulin 4.1 mU/L, C-peptide 1.28 ng/mL), though confirmatory serum glucose was not obtained. During a diagnostic fast, hypoglycemia (serum glucose 42 mg/dL) developed in 4 hours with suppressed β-hydroxybutyrate (0.18 mmol/L), insulin levels ( < 1mU/L) and detectable C-peptide (0.58 ng/mL), but without a glycemic response to glucagon. Uric acid and triglycerides were not elevated. In the context of elevated transaminases and lactate, and small-volume ascites on abdominal ultrasound, rapid whole-genome sequencing identified biallelic pathogenic variants in GBE1, confirming GSD IV.

Conclusions:
GSD IV exhibits marked phenotypic heterogeneity. Although hypoglycemia is not classically associated with GSD IV, it may represent an early and prominent feature and can present with biochemical findings mimicking hyperinsulinism. Increased awareness of this atypical presentation among pediatric endocrinologists may facilitate earlier diagnosis and timely genetic evaluation.

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