A novel sequence of the PHKG2 mutation associated with the first case of glycogen storage diseases type IXc in Syria: a case report and review of literature

Abstract

Background

Glycogen storage diseases are a group of inherited metabolic disorders that affect the body’s ability to break down and/or store glycogen. Type IX glycogen storage disease is an inherited disorder caused by a deficiency of phosphorylase kinase, which leads to various symptoms. We report the first reported case in Syria of glycogen storage disease type IXc caused by a novel phosphorylase B kinase catalytic subunit gamma 2 gene mutation, emphasizing the importance of early diagnosis and genetic counseling.

Case presentation

A 6-month-old Syrian male infant of Arab ethnicity presented with developmental delay, hepatomegaly, and hypoglycemia. Genetic testing identified a previously unreported phosphorylase B kinase catalytic subunit gamma 2 variant (c.801G > A p.( =)), classified as a variant of uncertain significance. Liver biopsy and clinical features were consistent with glycogen storage disease type IXc.

Discussion

This report expands the current understanding of phosphorylase B kinase catalytic subunit gamma 2-related glycogen storage disease type IXc by documenting a novel synonymous mutation with potential clinical significance. It underscores the critical role of early genetic testing in consanguineous populations, not only for accurate diagnosis but also for guiding family counseling and long-term management.

Conclusion

The identification of this novel mutation contributes to expanding the known phosphorylase B kinase catalytic subunit gamma 2 mutation spectrum and stresses the need for genetic counseling in similar populations.

Background

Glycogen storage disease type IX (GSD IX) is a heterogeneous group of metabolic disorders resulting from phosphorylase kinase (PHK) deficiency, an enzyme essential for glycogenolysis. GSD IX is classified into subtypes on the basis of the affected gene subunit: PHKA1, PHKA2, PHKB, PHKG1, and PHKG2. Among these, GSD IXc is caused by mutations in the phosphorylase B kinase catalytic subunit gamma 2 (PHKG2) gene, leading primarily to hepatic manifestations such as hepatomegaly, fasting hypoglycemia, growth retardation, and elevated transaminases. Compared with other subtypes, GSD IXc may show more severe hepatic outcomes, including fibrosis and rarely cirrhosis.

We report the first confirmed case of GSD IXc in Syria, caused by a novel PHKG2 variant, and highlight the relevance of genetic screening in populations with high consanguinity. This case contributes to the growing understanding of PHKG2-related phenotypes and expands the mutational spectrum of GSD IXc.

Type IX GSD is an inherited disorder caused by a deficiency of phosphorylase kinase (PHK). This enzyme is composed of four subunits. The gene that codes for this enzyme is located on the short arm of chromosome 16 (16p11.2) and includes **PHKA1** and **PHKA2**, which encode the PHK α subunit; the **PHKB** gene, which encodes the β subunit; the **PHKG1** and **PHKG2** genes, which encode the γ subunit; and the **CALM1**, **CALM2**, and **CALM3** genes, which encode the δ subunit. GSD IXc is caused by a mutation in the PHKG2 gene [1]. Patients usually present with short stature, hyperlipidemia, hepatomegaly, hypotonia, and hypoglycemia. These findings are more severe in patients with GSD type IXc than in those with IXa [2]. Some patients develop cirrhosis, fibrosis, and hepatocellular carcinoma (HCC), while others may improve with age [3]. On ultrasonography, signs of chronic liver disease can be observed, such as splenomegaly, fibrosis, cirrhosis, liver adenoma (rarely), and portal hypertension [4, 5].

We present a case of a 6-month-old Syrian male infant with hepatomegaly and failure to thrive. This is the first reported case of glycogen storage disease type IXc (GSD IXc) in Syria.

The aim of this study is to report the first case of glycogen storage disease type IXc (GSD IXc) in Syria, caused by a novel mutation in the PHKG2 gene, and to highlight the importance of early diagnosis and genetic counseling for families affected by this disorder. By documenting this rare case, we also aim to raise awareness about GSDs in Syria, where consanguineous marriages are prevalent, and provide valuable genetic information for future diagnostic and therapeutic management.

Case presentation

A 6-month-old Syrian male infant was referred to the pediatric inherited metabolic disease clinic due to hepatomegaly. He was the first child of a consanguineous family, with parents who were third-degree relatives, originating from Daraa, Syria. The patient exhibited developmental delays, failure to thrive, and recurrent episodes of unexplained vomiting and hypoglycemia. Hepatomegaly was initially detected incidentally by a local pediatrician, with abdominal ultrasonography revealing a liver span of 18 cm. At 18 months, the child’s growth parameters included a height of 80 cm, weight of 11.5 kg, and head circumference of 47 cm (corresponding to the 50th percentile for height, 75th percentile for weight, and 25th percentile for head circumference, based on World Health Organization (WHO) growth standards). Laboratory investigations, including fasting and blood tests (Table 1), indicated significant metabolic abnormalities.

Table 1.

Fasting and blood test results (14-hour fasting)

Test	Result	Normal range
Fasting glucose	54 mg/dL	70–100 mg/dL
Uric acid	6.3 mg/dL	3.5–7.2 mg/dL
Total proteins	6.1 g/dL	6.0–8.3 g/dL
Cholesterol	58 mg/dL	125–200 mg/dL
Triglycerides (TG)	168 mg/dL	> 150 mg/dL
Glutamate pyruvate transaminase (GPT) alanine aminotransferase (ALT)	315 U/L	7–56 U/L
Glutamate oxaloacetate transaminase (GOT) aspartate aminotransferase (AST)	398 U/L	10–40 U/L
Lactate	10 mg/dL	4.5–19.8 mg/dL
Bicarbonate (HCO3)	15 mEq/L	22–28 mEq/L
Creatine kinase (CK)	48 U/L	22–198 U/L
Prothrombin time (PT)	13 seconds	11–13.5 seconds
Activated partial thromboplastin time (aPTT)	33 seconds	25–35 seconds

A liver biopsy demonstrated abnormalities in the hepatic lobular architecture and fine fibrosis within the portal areas. However, images of the liver biopsy were not available for publication at the time of manuscript submission. The fasting glucose levels and histopathological findings were consistent with a glycogen storage disease, potentially type III, VI, or IX.

Subsequently, the patient’s family had a female sibling who exhibited mild hepatomegaly and fasting hypoglycemia at 5 months of age. Genetic testing in the sibling revealed the same PHKG2 variant (c.801G > A p.( =)), confirming autosomal recessive inheritance, raising suspicion of a similar condition. Genetic testing (CentoXome^® Solo) identified a novel variant in the PHKG2 gene: c.801G > A p.( =). According to CENTOGENE and the American College of Medical Genetics and Genomics (ACMG) guidelines, this was classified as a variant of uncertain significance (class 3). This variant has not been previously reported in genetic databases.

The findings were consistent with glycogen storage disease type IXc. Further genetic testing in the parents and siblings was recommended to confirm inheritance patterns.

Therapeutically, cornstarch was initiated, with two nighttime doses administered every 6 hours to maintain fasting blood glucose levels above 70 mg/dL and prevent hypoglycemia. This intervention proved effective in stabilizing glucose levels and mitigating symptoms. A chronological summary of the patient’s clinical course is presented in Table 2.

Table 2.

Timeline of case presentation

Time point	Clinical event
Birth	Normal delivery
6 months	Hepatomegaly detected, referred for evaluation
6–18 months	Symptoms persisted, lab abnormalities, liver biopsy
18 months	Genetic testing reveals novel PHKG2 mutation
After diagnosis	Cornstarch therapy initiated, clinical improvement noted
T + 1 month	Biochemical and growth improvement after starting cornstarch
T + 2 months	Genetic confirmation of similar variant in younger sibling (5 months)

T = time of initiation of cornstarch therapy. After starting cornstarch therapy, the patient demonstrated improvement in fasting glucose levels, normalization of transaminases, and catch-up growth in weight and height.

Discussion

GSD IXc is caused by a PHKG2 gene mutation, which is rare in the population (estimated prevalence: 2/277,190) [1]. We present this rare case, which is considered the first confirmed case of GSD IXc reported in Syria. Parental consanguinity is high in Syria (30–40%) [6], and the prevalence of hereditary metabolic diseases has remained unknown and underestimated owing to the lack of enzymatic and genetic studies in our country. Consanguinity is a deeply rooted tradition in Syria, especially in some regions, such as the Daraa countryside, where the family originated, and in underdeveloped areas.

The PHKG2 gene mutation has wide clinical manifestations [7]. Hepatomegaly and growth retardation are the most common symptoms [7]. Compared with their peers, some patients develop splenomegaly, a delay in growth and motor development, ascites, and failure to thrive. Fatigue is also common [7]. Jaundice, a doll-like face, a protuberant abdomen, and mild hepatic dysfunction are common in patients with GSDs [8]. Neuromuscular symptoms can also be observed, especially hypoglycemic seizures, generalized muscular hypotonia, and weakness [4, 9].

Laboratory tests are unhelpful because the changes are nonspecific and overlap with other hepatic and muscle types [9]. Tests reveal fasting hypoglycemia, hepatic enzyme elevation, high serum transaminase levels, ketosis, cholestasis, increased plasma cholesterol, triglycerides, and total lipids, as indicated by pathological glucagon tolerance tests [1, 5, 8, 10]. Normal uric acid levels, creatine phosphokinase (CPK), and a slight increase in plasma aminotransferases usually distinguish type IXc from GSD type III [4, 11]. Lactic acidosis is less common in patients with type IX than in those with type I GSD [4, 11].

Ultrasonography revealed an increase in liver size, periportal and parenchymal echogenicity, cholestasis, and altered flow in hepatic vessels [4, 9]. The architecture of liver lobes often remains normal, as fibrosis and cirrhosis are less likely to occur in these patients than in those with GSD III. Endoscopic ultrasound may reveal esophageal varices [1]. Erythrocyte and leukocyte tests can be helpful for detecting PHKG2 activity, but some patients may be normal [8, 12].

Liver biopsy guided us to GSD IXc because glycogen particle accumulation, glycogenosis, peripheral cell organelle changes, decreased activity of the PHK enzyme, a lack of hepatic activated phosphorylase, and fibrosis were detected [5]. Muscle biopsy revealed a high amount of ß-glycogen particles and decreased activity of phosphorylase kinase [8].

GSD IXc is known for its genetic complexity, with mutations occurring in specific candidate genes. To accurately diagnose this condition, high-throughput gene sequencing, which involves the analysis of many candidate genes, is the preferred diagnostic method. This advanced method helps doctors identify the exact genes causing GSD IXc with high precision. Liver enzyme activity was checked, in addition to genetic analysis [1]. Enzymatic studies are unavailable in Syria, very expensive, and not easy to perform. Whole-exome sequencing (WES) was performed and revealed the variant c.801G > A p.( =) in the PHKG2 gene. This new sequence is classified as a variant of uncertain significance. In precision medicine, it is important to understand how a genetic change affects a patient’s health. The mutation corresponds to our conditions; therefore, it is compatible with GSD IXc.

Most studies have shown that uncooked cornstarch and low-fat and high-protein diets are the most helpful treatments for patients with GSD IXc [10].

Our patient showed normal growth and no fasting hypoglycemia under cornstarch treatment or dietary management, which included avoiding sugar and lipid-rich foods and favoring protein intake. The same procedure was used for his sister. The family could benefit from perinatal genetic diagnosis to avoid giving birth to another child with the same disease, as the risk of affected offspring is 25% for autosomal recessive diseases. The patient showed improvement in development, symptoms, and growth.

Compared with previously reported PHKG2 mutations in literature, the c.801G > A p.( =) variant reported in our case is novel and has not been described in existing genomic databases or publications. Although this is a synonymous variant, its classification as a variant of uncertain significance (VUS) raises questions about potential regulatory effects on gene expression, splicing, or mRNA stability. This highlights the importance of functional studies and genotype–phenotype correlation to clarify its clinical relevance. Furthermore, the early clinical presentation and positive response to dietary therapy in our case suggest that even variants traditionally considered “silent” may have pathological consequences, warranting further investigation.

Conclusion

This case report presents the first documented instance of glycogen storage disease type IXc (GSD IXc) in Syria caused by a novel PHKG2 gene variant. The identification of the c.801G > A p.( =) variant adds to the mutational spectrum of GSD IXc and underscores the importance of considering synonymous variants in genetic diagnoses. In populations with high rates of consanguinity, such as Syria, early genetic testing and counseling are crucial for diagnosis and prevention. This report not only contributes new genetic data to existing literature but also emphasizes the need for further functional studies to explore the pathogenicity of novel variants classified as uncertain.

Abbreviations

GSDs

Glycogen storage diseases

GSD IXc

Glycogen storage disease type IXc

PHKG2

Phosphorylase B kinase catalytic subunit gamma 2

Author contributions

All the named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this article and have approved this version for publication. Shady Daher, Shaza Shahoud, and Seba Harh reviewed literature, collected relevant clinical information, wrote the initial draft of the manuscript and revised it, and edited the grammar and spelling. Dr. Diana Alasmar provided medical management and therapeutic decisions, supervised the scientific and academic aspects of the manuscript, and critically revised it. All the authors read and approved the final manuscript.

Funding

This research was funded by Damascus University_Funder no. 501100020595.

Data availability

The datasets used in this case report are available from the corresponding author upon request.

Declarations

Ethics approval and consent to participate

We have clarified the ethical considerations. Ethical approval was not required for this case report as it does not involve any experimental procedures or interventions on human subjects outside of standard medical care. This determination was waived by the Ethics Committee of Damascus University Faculty of Medicine. Written informed consent for participation in this case report was obtained from the patient’s legal guardian.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that there are no competing interests.