A newborn with glycogen storage disease type Ib presenting with hypoglycemia and evidence of mitochondrial dysfunction

Abstract

Glycogen storage disease type Ib (GSDIb) is an inherited disorder of carbohydrate metabolism that commonly presents in infancy. Here, we describe a case of GSDIb who presented on the first day of life with severe hypoglycemia and lactic acidosis, prompting a broad differential diagnosis. Additional testing revealed hyperlipidemia, relatively low ketones, and elevations of TCA-cycle intermediates in urine suggestive of primary or secondary mitochondrial dysfunction. The diagnosis of GSDIb was established by genome sequencing showing homozygous likely pathogenic variants in SLC37A4. This case highlights the importance of including GSDIb in the differential diagnosis of neonatal hypoglycemia and reinforces the underreported metabolic pattern of mitochondrial dysfunction that can be seen in GSDIb.

1. Introduction

Glycogen storage disease type I (GSDI) is an autosomal recessive disorder caused by defects in glucose-6-phosphatase, a multi-protein complex that releases free glucose from glucose-6-phosphate (G6P) in the shared final step of glycogenolysis and gluconeogenesis. This complex is localized to the endoplasmic reticulum (ER) in liver and kidney and includes the glucose-6-phosphatase catalytic enzyme, which is defective in GSDIa due to biallelic variants in G6PC1 (MIM #232200), and the translocase required for ER G6P import, which is defective in GSDIb due to biallelic variants in SLC37A4 (MIM #232220) [1]. Both GSDIa and GSD1b result in hypoglycemia, hepatomegaly, and growth failure that typically present around three to six months of age, accompanied by lactic acidemia, hyperlipidemia, hyperuricemia, and mild elevations of transaminases [2], [3]. GSDIb is additionally characterized by neutropenia and neutrophil dysfunction that predispose to later complications including recurrent infections and inflammatory bowel disease [4].

While GSDI is most often diagnosed during infancy, neonatal presentations have been reported [5], [6], [7] and typically manifest as severe hypoglycemia and metabolic acidosis. However, these features are nonspecific and can arise from a wide range of environmental, endocrine, or metabolic causes. The workup of neonatal hypoglycemia is therefore broad, and careful interpretation of hormonal and biochemical testing can narrow the list and inform further evaluations. First-line biochemical tests including glucose, lactate, ketones, anion gap, plasma acylcarnitines (AC) and urine organic acids (UOA) are used to evaluate for inborn errors of metabolism (IEM) associated with neonatal hypoglycemia, particularly disorders of fatty acid oxidation, gluconeogenesis, ketone body metabolism, and primary mitochondrial disorders. UOA and AC patterns in neonatal GSDI cases have not been reported, but studies of older patients and animal models have demonstrated abnormal elevations of TCA-cycle and fatty acid intermediates suggestive of mitochondrial dysfunction [8], [9], [10], [11], [12]. These studies mainly included patients with GSDIa, and less is known about laboratory evidence of mitochondrial dysfunction in GSDIb.

Here, we describe a neonate with genetically confirmed GSDIb who presented with severe hypoglycemia with lactic acidosis, hyperlipidemia, and relatively low ketones for the degree of hypoglycemia. UOA and AC testing showed elevated urinary TCA-cycle intermediates and very mild long-chain AC deviations that were suggestive of primary or secondary mitochondrial dysfunction. This case highlights the importance of including GSDIb in the differential diagnosis of neonatal hypoglycemia and reinforces the metabolic pattern of mitochondrial dysfunction that can be seen in clinical investigations.

2. Methods

Patient clinical information and laboratory results were extracted from the electronic medical record. Rapid trio genome sequencing was conducted using peripheral blood sample from the patient and buccal samples from the parents. Informed parental consent for research publication was obtained.

3. Case presentation

The patient was born at 37 weeks and 4 days via spontaneous vaginal delivery to a primigravid mother. Pregnancy and delivery were uncomplicated, with no known risk factors for hypoglycemia. Apgar scores were 8 and 9 at one and five minutes, respectively. Family history was unremarkable, and consanguinity was denied. Physical examination was notable only for bilateral supernumerary nipples. No organomegaly was observed.

At approximately two hours of life (HOL), the infant was noted to have hypothermia (temperature 36.1 °C) and severe hypoglycemia (blood glucose <2 mg/dL). The hypothermia resolved with use of a radiant warmer, but hypoglycemia persisted despite administration of glucose gel and enteral feeds. The patient was admitted to the intermediate care nursery (ICN) and started on 10% dextrose (D10) intravenous fluids with electrolytes appropriate for age. His blood glucose stabilized with a glucose infusion rate (GIR) of 1.7–4.1 mg/kg/min and breastfeeding every 3 h. Initial laboratory evaluation at 12 HOL revealed an anion gap metabolic acidosis with elevated lactate (5.68 mmol/L; ref. < 2) and anion gap (21 mmol/L; ref. 5–15), low bicarbonate (13 mmol/L; ref. 22–29), and mild elevation of aspartate aminotransferase (AST; 155 U/L; ref. 47–150). Evaluation for infection was negative, with normal white blood cell count, C-reactive protein, and blood culture. He completed 36 h of antibiotics.

He was weaned off dextrose-containing fluids by day of life (DOL) 7 and blood glucose remained stable with breastfeeding every 3 h. However, hypoglycemia recurred after a five-hour fasting trial (blood glucose 28 mg/dL). Critical hypoglycemia labs were obtained after five hours of fasting (Table 1) but were not trended throughout the fasting trial. Results showed low insulin (< 0.4 mU/L; ref. 2.6–24.9), elevated lactate (5.4 mmol/L; ref. 0.5–2.2), and normal cortisol (13.2 μg/dL; ref. 2.0–21.0). β-hydroxybutyrate was relatively low for the degree of hypoglycemia (1.0 mmol/L; ref. 0.2–2.8). Plasma carnitine (free and total) and amino acid studies and were essentially normal. Plasma AC was also interpreted as essentially normal, but in hindsight several long-chain species were recognized to be near the upper end of the reference range, particularly C14, C14-OH and C18 (Supplemental Table 1). Qualitative UOA analysis showed large elevations of lactic, fumaric, malic acids, 2-hydroxyglutaric and 2-ketoglutaric acids and more mild elevations of 3-hydroxy-n-butyric and acetoacetic acids as well as several fatty acid species including adipic, 3-hydroxysebacic, octenedioic, and decenedioic acids, which was suggestive of primary or secondary mitochondrial dysfunction (Fig. 1). Uric acid was normal (4.2 mg/dL; ref. 2–7) and triglycerides were elevated (451 mg/dL; ref. < 150). Repeat UOA at age 2 weeks showed persistent lactic aciduria, ketonuria, and elevated TCA cycle metabolites. At the time of repeat UOA, his nutrition regimen consisted of adequate enteral feeds every 2 to 3 h and intravenous dextrose fluids at a GIR of 2.4 mg/kg/min. Given the concern for a potential mitochondrial disorder, the patient was started on coenzyme Q10 supplementation at 30 mg daily (∼10 mg/kg/day), but this was discontinued the following week when molecular genetic testing results were returned.

Table 1.

Patient laboratory results during critical hypoglycemic episode after 5 h of fasting at 7-days-old.

Category	Test	Result	Reference Range
Endocrine Labs	Insulin	<0.4 mU/L	2.6–24.9
	Cortisol	13.2 μg/dL	2.0–21.0
Metabolic Labs	Glucose	28 mg/dL	45–140
	Lactate	5.4 mmol/L	2.8–4.0
	Ammonia	84 umol/L	56–107
	β-hydroxybutyrate	1.0 mmol/L	0.2–2.8
	Triglycerides	451 mg/dL	<150
	Uric Acid	4.2 mg/dL	2.0–7.0

Fig. 1.

Total Ion Chromatogram of UOA analysis from DOL7 during critical hypoglycemia period. IS = Internal Standard (p-chlorobenzoic acid); 1: Lactic; 2: ß-hydroxybutyric; 3: Acetoacetic; 4: Fumaric; 5: Malic; 6: Adipic; 7: 2-hydroxyglutaric; 8: 2-ketoglutaric; 9: Octenedioic; 10: cis-aconitic; 11: Citric; 12: Decenedioic; 13: p-hydoryxphenyllactic; 14: 3-hydroxysebacic acids.

Rapid trio genome sequencing (GS) identified homozygous, biparentally inherited, likely pathogenic variants in SLC37A4 NM_001164277.1:c.1019_1038del p.(Phe340Cysfs*55), consistent with a diagnosis of GSDIb. Mitochondrial genome sequencing was negative.

Following genetic diagnosis, the patient was started on Elecare formula every 2 h. Glucose levels remained stable, and he was discharged from the ICN at 3 weeks of age. Additional evaluations included a baseline abdominal ultrasound that showed increased hepatic fat fraction of 17.3% and no focal liver lesions. Absolute neutrophil count (ANC) on DOL 1 was slightly elevated at 21.61 K/uL (ref 5–21 K/uL) and remained within normal limits during the neonatal period; however, he developed neutropenia at 3.5 months with ANC 0.88 K/uL (ref 1–9 K/uL). At his most recent outpatient evaluation at 4 months of age, he was growing well with stable home blood glucose checks and feeding by mouth every 2 h.

4. Discussion

We describe a rare case of neonatal-onset GSDIb presenting with severe hypoglycemia and metabolic acidosis. Additional biochemical testing revealed nonspecific evidence of mitochondrial dysfunction by UOA and AC analysis. While the differential diagnosis for neonatal hypoglycemia is broad, normal levels of insulin, cortisol, and β-hydroxybutyrate argued against common endocrine causes including hyperinsulinism, cortisol deficiency, and hypopituitarism. Additionally, the nondiagnostic plasma AC reduced the likelihood of a primary fatty acid oxidation disorder, such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Elevations of TCA-cycle metabolites in urine, particularly fumarate and malate, suggested primary or secondary mitochondrial dysfunction but did not point to a specific diagnosis. In addition, although plasma AC results were initially interpreted as essentially normal, closer examination revealed mild elevations of several long-chain species that could also be suggestive of mitochondrial impairment [13]. Prior to genetic confirmation, these findings increased concern for a mitochondrial disorder to the extent that a trial of coenzyme Q10 supplementation was recommended. Ultimately, genome sequencing confirmed the diagnosis of GSDIb. Although hypertriglyceridemia was present and supportive of GSDIb, uric acid levels were normal, likely a consequence of the patient's young age. Similarly, absolute neutrophil count was normal during the neonatal period and neutropenia was not noted until 3.5 months of life.

The association between GSDs and mitochondrial dysfunction is well documented [14], including in types II, III, and V. GSDIa has been associated with abnormal mitochondrial structure and function in cell culture and mouse model studies [12], and elevated intermediates of TCA-cycle (e.g., lactate, fumarate, malate) and fatty acid oxidation (adipate, suberate, and others) in human patients [9], [10]. Patients with GSDIa have also demonstrated age-dependent elevations in short- and long-chain ACs, including C14 and C16 in pediatric patients and C16 and C18 in adults [9], [10], consistent with another study highlighting C16, C14OH, total carnitine and acetylcarnitine as strong diagnostic predictors for GSDIa [11]. In contrast, limited studies in GSDIb have suggested that the metabolic perturbations may be milder in this subtype: a group of seven GSDIb patients exhibited a narrower pattern of abnormalities showing only increased urinary lactate, suberate, and 3-methylglutarate as well as elevated short-chain ACs (C0 and C4) [9]. One additional case report described a patient with GSDIb with elevated urinary excretion of 3-methylglutaconic and 3-methylglutaric acids [8], also suggestive of mitochondrial dysfunction [15].

The patient described here presented in the neonatal period with severe hypoglycemia along with elevated TCA-cycle metabolites (e.g., fumaric, malic, 2-ketoglutaric acids), fatty acid oxidation byproducts (e.g., adipic, octenedioic, and decenedioic acids), and mild elevations of several long-chain species (particularly C14, C14-OH and C18) in a pattern suggestive of mitochondrial dysfunction and consistent with previously reported GSDIa patients [9], [10]. This case reinforces that GSDIb can also present with evidence of secondary mitochondrial dysfunction detectable by UOA even in neonates. Because urine organic acid testing is less likely to be included when a GSD is suspected, such abnormalities may be underrecognized in clinical practice. This case highlights the importance of including GSDIb on the differential diagnosis in neonates with severe hypoglycemia and evidence of mitochondrial dysfunction such as elevated TCA-cycle metabolites. Although the mechanism linking GSDIb to these findings remains unclear, several pathways may contribute to mitochondrial dysfunction in this disorder. In mice studies, G6PT deficiency led to impaired hepatic autophagy through downregulation of sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) signaling pathways, which are critical for cellular energy homeostasis and mitochondrial quality control [16]. Additionally, G6PT-deficient neutrophils in mouse models exhibited endoplasmic reticulum stress and activation of the intrinsic mitochondrial apoptotic pathway [17]. Metabolic profiling studies in GSDIb fibroblasts have demonstrated reduced antioxidant defense of the cysteine and glutathione systems and dysfunctional energy production affecting glycolysis and TCA cycle intermediates, suggesting impaired mitochondrial metabolism [18]. These cellular stress responses and metabolic perturbations may collectively contribute to the secondary mitochondrial dysfunction observed in some GSDIb patients. Recognizing this potential feature may improve diagnostic evaluation and inform future research on disease variability and pathophysiology within GSDI.

CRediT authorship contribution statement

Meredith Fuchs: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Laura Keehan: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Tyler Ky: Writing – review & editing. Gregory M. Enns: Writing – review & editing. Tina M. Cowan: Writing – review & editing, Data curation.

Declaration of competing interest

The authors have no conflicts of interest to report.

Appendix A. Supplementary data

Supplementary material

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.