Submission Details

GYS2, glycogen storage disorder due to hepatic glycogen synthase deficiency (MONDO:0009414), autosomal recessive

GYS2 was first described as a glycogen storage disorder (GSD)-causing gene in 1998 (Orho et al. 1998, PMID: 9691087). The specific disease entity, glycogen storage disorder 0 (also referred to as glycogen storage disorder due to hepatic glycogen synthase deficiency) (MONDO:0009414, OMIM:240600), is one of at least 15 different glycogen storage disorders which affect the body and its ability to correctly use or store glycogen. Some of the most common patient phenotypes are: Hypoglycemia after fasting, ketones in blood and/or urine, ketonuria, enlargement of the liver, short stature, low glycogen synthase activity in liver biopsies and the use of cornstarch supplements to prevent hypoglycemia.

Twenty-five variants: (15 Missense, 1 Synonymous variant associated with exon skipping and premature termination, 1 In-Frame Deletion, 3 Frameshift, 3 Nonsense and 2 Canonical Splice Site) that have been reported in 20 probands in 10 publications (PMIDs: 32779500, 33489759, 32395408, 30968641, 29167993, 26937415, 9691087, 37574425, 33473338, 20051115) are included in this curation.

Many of the probands were diagnosed during childhood after experiencing hypoglycemia and fasting symptoms. However, their symptoms were largely able to be controlled through dietary changes or ingesting dosages of cornstarch. Siblings of the probands were also found to be affected to varying degrees of severity.

Below are two unique case studies that deviate from the profile of a typical GYS2 proband:

Holsten et al. 2018 (PMID: 29167993) included “4-year-old Turkish boy”, a Turkish male proband who had the c.1015G>C (p.Ala339Pro) variant. He was initially referred for evaluation due to mild hypoglycemia and ketonuria after overnight fasting. Clinical evaluation did not show an enlarged liver but revealed an unusual broad-based posture. A fasting study was performed but did not show any further hormonal or biochemical abnormalities. Glucagon was not able to normalize hypoglycemia. However, recurrent postprandial hyperglycemia and lactic acidemia indicated that there was a defect in glycogen synthesis. Both parents of the proband were found to be heterozygous and asymptomatic. Genetic analysis found that allelity was evidenced through two polymorphisms (c.941+64A>G and c.942-83T>G), which were then detected on the non-affected allele of the parents, but not in the sequence of the patient. Orally administered cornstarch was able to successfully treat the patient. At 4.5 years of age, the proband developed a malignant brain tumor, which was classified as a group 3 medulloblastoma. The proband’s gait abnormality deteriorated into frank ataxia and he experienced a sudden loss of consciousness episode. Following this, a cranial MRI showed a posterior fossa tumor. Radio-chemotherapy according to the HIT-2000 protocol was provided, however, the patient relapsed and developed spinal metastases 2 years later. 27 months after initial diagnosis, “4-year-old Turkish boy” died from the tumor disease. Grünert et al. 2021 had a proband called “32‐year‐old GSD 0”. “32‐year‐old GSD 0” had two variants - c.1015G>C (p.Ala339Pro) and c.1472T>G (p.Met491Arg). She was originally diagnosed with GSD 0 at the age of 4 years and a clinical description of her until 8 years old had been published previously (PMID:8831078). She developed normally until the age of 3.5 years when she was noted to be drowsy in the mornings and occasionally vomited. Laboratory testing revealed hypoglycemia with marked ketonuria. Liver biopsy performed at 4 years yielded a reduced glycogen content of 0.9 g/100 g (normal 2.4‐6.4 g/100 g) and a very low glycogen synthase activity. A high protein diet with frequent daytime meals, a late dinner, and two doses of 30 g of uncooked cornstarch during the night were recommended. On this regimen, the patient showed normal growth and development, her BMI at the age of 5 years was normal with 16.1 kg/m2. Further hypoglycemias only occurred during physical activity, such as swimming or other sports, and regular blood glucose monitoring was abandoned. Mutation analysis in GYS2 was performed and yielded compound heterozygosity for the two novel variants, c.1015G > C (p.A339P) and c.1472T>G (p.M491R). From the teenage years until the age of 27 the patient was not regularly followed and did not take cornstarch supplements. At the age of 27, she presented to the metabolic center of her region while planning her first pregnancy. At age of 28, she gave birth to a healthy girl (birth weight 3610 g, 73th centile, 39 + 1 weeks of gestation), and 1.5 years later a healthy boy was born (4195 g, 94th centile, 39 + 1 weeks of gestation, large for gestational age). The first pregnancy was complicated by severe nausea and vomiting, and the patient was admitted to the hospital twice for glucose infusions due to recurrent hypoglycemia. During the second pregnancy the patient suffered from dizziness, but was otherwise well. Both pregnancies and deliveries were managed without major complications, and both children show normal growth and development so far. The patient first presented at a metabolic clinic at the age of 31 years. At that time, she did not follow a specific diet, and blood glucose levels were not regularly monitored. A three‐day dietary protocol revealed a slightly hypocaloric diet (1700 kCal/d, normal for age 2200 kCal/d) with a protein intake of only 0.9 g/kg/d accounting for 17% of the daily energy intake. The patient reported to feel unwell during both hypoglycemic and hyperglycemic episodes. Muscle pain and muscle weakness were not reported, but she complained about fatigue. Blood glucose monitoring for 2 days revealed no relevant hypoglycemias (<3.9 mmol/L). Laboratory testing yielded normal transaminase and creatine kinase activities. Abdominal ultrasound was also normal. At 35 weeks gestation, the patient complained about progressive pruritus. Labor was induced at 37 weeks gestation. During delivery, the patient received a high glucose infusion with 10 g glucose/h, under which blood glucose levels remained stable within the normal range. She delivered a healthy girl by vacuum extraction due to fetal bradycardia. The child required non‐invasive mechanical ventilation for 6 days due to respiratory distress. No laboratory signs of infection were observed. Glucose infusion was necessary until day 5 due to low blood glucose concentrations. Echocardiography of the neonate on day 2 showed a persistent arterial duct that was no longer detectable on day 7. The myocardium was slightly thickened which was considered to be due to diabetic fetopathy. Ultrasound of the brain was normal. Maternal blood glucose concentrations postpartum were more stable than during the last trimester, and no hypoglycemias or severe hyperglycemias occurred during early lactation. One dose of Glycosade (60 g) together with protein powder was sufficient to maintain normal glucose levels overnight. The child was mainly breastfed with supplementation of formula milk. Overall, the mechanism of pathogenicity appears to be loss of function as shown in the probands.

This gene-disease relationship is also supported by multiple forms of experimental evidence such as Expression A (Quantity: 1), Protein Interaction (Quantity: 1), Biochemical Function B (Quantity: 1), Biochemical Function A (Quantity: 1) and Non-Human Model: Mouse (Quantity: 1) (PMIDs: 23715323, 35690592, 1731614, and 20178984. First, GTEx data showed high levels of expression of GYS2 in the liver, which is consistent with the liver-related features of GSD0 (PMID:23715323). Next, Marr et al. 2022 documented the protein interaction between GYG1 and GYS2, showing that the interaction between GYS2 and GYG1 via the C-terminus is necessary in order for GYS2-mediated glycogen synthesis to occur (Figure 2). Westphal et al. 1992 (PMID: 1731614) describes how the glycogen synthase activity in the human liver was able to be recapitulated in the mouse liver. Additionally, western blotting with antibodies evaluating the liver glycogen synthase isoform showed that the protein is essentially absent in the liver of LGSKO mice and that there was a decrease in glycogen synthase activity. The results of which were consistent in both the GYS1 and GYS2 transcripts. This is significant because GYS1 and GYS2 are both genes that are involved in glycogen storage disease 0. The gene-disease relationship between GYS1 and GSD0 has been designated as "definitive" by the General IEM GCEP (Irimia et al. 2010, PMID: 20178984). Lastly, the Irimia et al. 2010 paper includes a mouse model where it was shown that both the probands and models experienced hypoglycemia when they were in a fasted state which shows their inability to process glucose (PMID: 20178984).

In conclusion, GYS2 is definitively associated with glycogen storage disorder 0 (also referred to as glycogen storage disorder due to hepatic glycogen synthase deficiency). This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time.

This classification was approved by the General IEM GCEP on March 22nd, 2024 (SOP Version 10).