GSD-1a: Glycogen Storage Diseases type 1a; AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase; ALP: Alkaline Phosphatase; SGA: Small for Gestational Age; NDD: Neurodevelopmental Delay; WHO: World Health Organization; Hb: Hemoglobin; MCV: Mean Corpuscular Volume; FBS: Fasting Blood Sugar; Cr: Creatinine; BUN: Blood Urea Nitrogen; Ca: Calcium; U/A: Urinalysis; U/SG: Urine Specific Gravity; MSUD: Maple Syrup Disease; DHA: Docosahexaenoic Acid; HDL: High-Density Lipoprotein; LDL: Low-Density Lipoprotein; TC: Total Cholesterol; CPK: Creatine Phosphokinase; LDH: Lactate Dehydrogenase; TFT: Thyroid Function Test; TSH: Thyroid Stimulating Hormone; WES: Whole-Exome Sequencing; G6PC: G6Pase-α Catalyst; G6PT: Glucose-6-Phosphate Transporter; G6P: Glucose 6 Phosphate; FSGS: Focal Segmental Glomerulosclerosis; MRI: Magnetic Resonance Imaging; RTA: Renal Tubular Acidosis; ACE: Angiotensin-Converting Enzyme

GSDs are a series of disorders associated with enzyme deficiencies in glycogen anabolic or catabolic processes [1]. The enzyme glucose-6-phosphatase plays a special role in the processes of gluconeogenesis and glycogenolysis. The defect that causes GSD, called GSD type 1, is transmitted in an autosomal recessive manner [2]. GSD-1a is the most common form of GSD type 1, accounting for approximately 80% of these cases. This enzyme is located on the long arm of chromosome 17 and is expressed only in organs such as liver, kidney and intestine [3,4].

The clinical manifestations of these patients include disease onset before age 1 year, hypoglycemia (if fasting is likely), hepatomegaly, developmental delay, psychomotor delay, muscle weakness, diarrhea, osteopenia, delayed onset of puberty, and increased risk of bleeding. Laboratory findings in these patients also included anemia, platelet dysfunction, hyperlactatemia, hyperuricemia, and hyperlipidemia [5]. According to the above findings, the lack of metabolic control in these patients predisposes them to complications. Due to hyperuricemia: It can progress to gout, nephrocalcinosis, and renal dysfunction. Metabolic alterations may cause hepatic adenoma. Due to hypertriglyceridemia: It may predispose to pancreatitis [2,3].

A key point in these patients is the study of enzymatic activity for diagnosis. There is no definitive treatment, but choosing the right treatment improves clinical presentation and reduces complications. Treatments that may be used include nasogastric tube and cornstarch feeding. Consideration of these therapies reduces liver span, prevents hypoglycemia, and improves patient growth status [5]. We will describe the clinical, paraclinical, mutational, and therapeutic findings in a 16-month-old boy diagnosed with GSD-1a.

A 16-month-old boy (currently a 14-year-old boy) presented to our pediatric clinic with developmental delay and kidney and liver problems. He had a history of neonatal jaundice. He also had a history of hospitalization accompanied by fever, liver and kidney complications. Grade 2 fatty liver and elevated liver enzymes (aspartate aminotransferase (AST): 141, alanine aminotransferase (ALT): 139, alkaline phosphatase (ALP): 649) have reported in his liver assessment. In addition, his renal examination reported mild hydronephrosis and grade 3 medullary nephrocalcinosis of the left and right kidneys. The patient was the first child of a family of three children that parents were consanguineous. They had a history of miscarriages and one death. The patient was born term by cesarean section. His birth weight was 2100 g, which was small for his gestational age (SGA). The patient was breastfed and was well tolerated. The patient's weight and height at referral were 7.5 kg and 67.5 cm, respectively, both below 3rd percentile on World Health Organization (WHO) growth chart. The patient had neurodevelopmental delay (NDD) standing with the help of others. The patient's motor development was not appropriate for his age.

Abdominal examination showed a normal liver. Laboratory test of his first visit included; hemoglobin (Hb): 11 mg/dl, mean corpuscular volume (MCV): 74 fL, fasting blood sugar (FBS): 47mg/dl, AST: 202 U/L, ALT: 186 U/L, ALP: 588 U/L, Creatinine (Cr): 0.5 mg/dl, Blood urea nitrogen (BUN): 21 mg/dl, Calcium (Ca): 12 mg/dl, Phosphorus: 5.5 mg/dl, Ferritin: 136 micg/L, Na:138 mEq/L, K:4.7 mEq/L , Urine specific gravity (U/SG):1010, Urinalysis (U/A): normal. Based on evidence, hepatic and renal complications, metabolic disturbances were suspected, and urinary organic acid testing was considered for him. Maple syrup disease (MSUD) was suspected based on elevated urinary lactic acid level (121mg/dl). Depending on the intended diagnosis, thiamine (B1) 100 mg twice daily, biotin 5 mg twice daily, L-carnitine syrup 500 mg 2 cc twice daily, vitamin E 100 mg daily, coenzyme Q10 30 mg daily started. A 2-week follow-up was also recommended. At the next visit; lactate level decreased by 48mg/dl, FBS: 152 mg/dl, AST: 126 U/L, ALT: 151 U/L. Dietary advice was sought depending on the decrease in lactate levels. Docosahexaenoic acid (DHA) drop 40 mg 0.5 cc twice daily was recommended in addition to the patient's previous treatment regimen, and lactate levels were rechecked after 2 weeks.

In his next evaluation; lipid profiles were normal included, high-density lipoprotein (HDL): 30 mg/dl, low-density lipoprotein (LDL): 49 mg/dl and total cholesterol (TC): 111 mg/dl, increased transaminases (AST: 141 mg/dl and ALT:151 mg/dl), Cr: 0.5 mg/dl, Lactate: 77 mg/dl, creatine phosphokinase (CPK): 172 mcg/L, lactate dehydrogenase (LDH): 577 U/L, Aldolase: 18.3 U/dL, Na:136 mEq/L, K:4.1 mEq/L, U/SG:1014 . To investigate abnormal liver function, patient was evaluated for secondary causes such as hypothyroidism. Thyroid function test (TFT, thyroid stimulating hormone (TSH): 2 m IU/L, Free T4: 1.13 micg/dl) was normal with no pathological findings. According to abnormal liver enzymes test, no pathological findings such as itching, jaundice, also no complications like ascites and splenomegaly was observed. As a next step, we requested Whole-Exome Sequencing (WES) test for the patient. The patient's DNA analysis by WES method revealed mutation of c.G193C (P.A65P), which is associated with deficiency of the glucose 6-phosphatase enzyme. The reported mutation followed an autosomal recessive course of inheritance with a homozygous variant located in exon 1 of chromosome 17. Once the diagnosis of GSD was confirmed, frequent meals and complex carbohydrates were recommended instead of simple carbohydrate and low-fat meals. B-complex and vitamin E, DHA, and L-carnitine were also considered as nutritional supplements for the patient. Regular physical activity is recommended. His LFT has improved. The spleen and liver are of normal size on examination and ultrasound. Also, his growth condition is desirable.

We visited patients at an age older than the onset of clinical symptoms that had not been previously assessed or diagnosed. Mitochondrial diseases were initially addressed due to developmental delay, high lactate level and lack of hypoglycemia. The continuation of the investigation was interesting in that, due to the lack of justification in the patient's presentation, genetic testing was performed, and a diagnosis of GSD 1 was made.

GSD-1a, also known as von Gierke disease, is a metabolic disorder caused by mutations in the glucose-6-phosphatase enzyme. This enzyme is based on a complex of four proteins consisting of a glucose transporter, G6Pase-α catalyst (G6PC), an inorganic phosphate transporter, and a glucose-6-phosphate transporter (G6PT), was first identified by Arion et al. [6]. The G6PC subunit of the enzyme glucose 6-phosphatase, encoded by the G6PC gene, is impaired in GSD-1a and inherited in an autosomal recessive manner. The gene is located on the long arm (17q21) of chromosome 17, spans 12.6 kilobases and contains 5 exons [7].

Von Gierke disease was first described by Gerty and Carl Cori (1952), who observed clinical evidence supporting glucose-6-phosphatase deficiency in 5 patients [8]. The G6PC portion of the glucose 6-phosphatase complex is expressed in intestinal mucosa, liver, and kidney. This enzyme plays a vital role in regulating blood sugar, and its dysfunction resulted in GSD-1a disorder causing problems with both gluconeogenesis and glycogenolysis[9].

Patients with GSD-1a often present in the form of growth retardation, hepatomegaly, severe fasting hypoglycemia, developmental delay, and failure to thrive in the first few months of life. Other common symptoms encompassed drowsiness, irritability, seizures, muscle weakness, and sweating associated with hypoglycemia in patients. Elevated triglycerides, lactate, uric acid, and platelet dysfunction (represented by nosebleeds and bruising), regardless of hypoglycemia, were common findings in their laboratory studies [10,11]. In these patients, glucose 6 phosphate (G6P) is shifted into the glycolytic pathway, pentose phosphate is synthesized instead of glucose, subsequently triglyceride, fatty acid, and uric acid production is increased [12,13]. On clinical examination, short stature, normal spleen size, hepatomegaly due to excess accumulation of glycogen that did not progress to cirrhosis, hypotrophic muscle changes, central obesity, and a doll-like appearance are observed. Appropriate metabolic control has been suggested to improve growth conditions and reduce liver size.

Complications such as hepatic, renal (including nephropathy and focal segmental glomerulosclerosis (FSGS)), and osteoporosis have been reported in these patients during adulthood. Appropriate metabolic control has been reported to reduce these complications [10,11]. Liver adenoma is a common liver finding during puberty, most of which are benign. Of those, only 5-10% were at risk of malignancy [14]. Impairment of the gluconeogenic process disrupts the NADH/NAD+ and ATP/ADP balance in the Krebs cycle, leading to a shift in signaling pathways towards the production of lactate and pyruvate, which may play a role in the tumorigenic process [12,13]. In these patients, the efficacy of adequate metabolic regulation to prevent progression of liver adenoma to malignancy has been reported [14].

Ultrasound or magnetic resonance imaging (MRI) is recommended for liver adenomas. Resection should be regarded by the size of more than 5 cm owing to the risk of malignancy. Renal complications may be associated with hyperfiltration (as microalbuminuria or progressing to overt proteinuria) or hypofiltration (as FSGS or interstitial fibrosis). It may also be associated with proximal and distal tubular dysfunction that correlates with renal tubular acidosis (RTA) type 2 and hypercalciuria, respectively [15]. Another complication in these patients is kidney stones, which are a result of hypocitricuria and do not correlate with adequate metabolic control, so citrate supplements are effective. Appropriate metabolic control and angiotensin-converting enzyme (ACE) inhibitors can help reduce the progression of renal complications regardless of kidney stones. Another complication is anemia in patients with hepatic adenoma, which is associated with hepcidin secretion, which is proportional to the size of the adenoma. Therefore, removal of hepatic adenoma can resolve anemia in these patients [16]. In general, findings such as nephromegaly with hypoglycemia, hepatomegaly without splenomegaly, lactic acidosis with elevated uric acid levels, and elevated triglyceride levels are indicative of GSD-1[17]. AST and ALT levels are also usually slightly elevated (approximately 100 U/L)[18].

The goals of treatment for these patients are to achieve target levels, provide adequate metabolic control, and prevent hypoglycemia. Diet plays a special role in creating this cornstarch-based balance. It is associated with a reasonable prognosis. This regimen can be taken by gastric tube or uncooked, depending on the patient's age and family preference. The use of the cornstarch diet can be used in children under 2 years of age and even at the age of 6 months, but it should be noted that intolerance limits its use due to immaturity of intestinal and pancreatic amylases. In older children, it can be tolerated and used about 5 times a day. Of note, the cornstarch dose should be adjusted based on lactate and glucose levels (measured both at home and in the clinic), lower than 2.2 mmol/L and higher than 75 mg/dL, respectively. Slow-release formulations have been suggested to maintain their metabolic profile for approximately 7-10 hours [19]. Fructose, galactose and sucrose consumption should be minimized to prevent uncontrolled metabolic profile and hepatomegaly. The diets provided to these patients do not meet all their needs, so multivitamin supplements can help offset the dietary restrictions of these patients. Vitamin D and calcium supplements can help slow the progression of osteoporosis in these patients.

In addition to diet and supplements that meet daily needs, the incidence of drug-induced complications in these patients should be reduced. Use of ACE inhibitors to reduce protein excretion and intraglomerular pressure, fish oil or fibrates may reduce triglyceride levels and subsequent pancreatitis, and allopurinol may help hyperuric acid disorders [20]. In addition to the above points, there are some issues to be aware of in these patients. 1) Due to the high risk of bleeding and lactic acidosis, it is necessary to perform surgery with more tenacity. 2) Conditions intolerable to oral intake, such as infections, require hospitalization of the patient and administration of intravenous glucose as needed. 3) Liver transplantation can be considered in patients with liver cancer and non-surgical adenoma[21].

Because of growth and developmental delay, also complications, a GSD-1a diagnosis should be considered in unexplained hypoglycemia and/or hepatomegaly. We presented a GSD-1a case with a known c.G193C (P.A65P) mutation. Uncooked cornstarch and minimal consumption of simple carbohydrates can help improve the patient's condition and delay the onset of complications.

Hereby, we sincerely thank all the collaborators who helped us advancing this project.

The authors declare that there is no conflict of interest regarding the publication of this article.

A written informed consent to publish/present this case was obtained from the patient’s parents.

Ethical approval is not mandatory at our institution to publish an anonymous case report.

None.