Both Sodium Taurocholate Cotransporting Polypeptide Deficiency (NTCPD) and Glycogen Storage Disease Type VI (GSD-VI) are autosomal recessive (AR) genetic disorders that affect liver metabolism in newborns. NTCPD is primarily caused by mutations in the Solute Carrier Family 10 Member 1 (SLC10A1) gene, resulting in decreased bile acid transport function, while GSD-VI is caused by mutations in the phosphorylase glycogen liver (PYGL) gene, leading to a deficiency of liver glycogen phosphorylase. Both diseases are rare, and there have been no previous reports of their coexistence in a single patient. This case report details the rare occurrence of NTCP and GSD-VI in a 2-year-11-month-old female child. The patient presented with mild jaundice, hepatomegaly, and growth retardation. After 1 year and 6 months of treatment and follow-up, the patient's liver function and growth showed significant improvement. This case highlights the importance of comprehensive genetic analysis in diagnosing complex metabolic disorders.

Glycogen storage disease type IX (GSD IX) arises from hepatic phosphorylase b kinase (PhK) deficiency attributable to pathogenic variants in the PHKA2, PHKB, and PHKG2 genes. This multicenter retrospective study evaluated clinical and biochemical data from 52 patients diagnosed across three European countries, with a median follow-up of 9.3 years (range: 1-49). In the cohort, 86.5% were classified as GSD IXa, whereas GSD IXb and IXc accounted for 7.7% and 3.8%, respectively; one diagnosis was based solely on enzymatic testing. Null variants in PHKA2 consistently resulted in severe PhK deficiency, whereas missense variants and in-frame deletions were associated with variable enzymatic impairment (8/19 tested cases). The median age at symptom onset was 1.6 years, and the mean age at diagnosis was 2.0 years. Predominant manifestations included hepatomegaly (82%), elevated aminotransferases (81%), hypertriglyceridemia (71%), hypercholesterolemia (67%), hypoglycemia (46%), hyperlactatemia (38%), and short stature (30%). Aberrant apolipoprotein C-III glycosylation was detected in 80% of analyzed samples. Nutritional intervention was associated with improved growth (height SD score - 0.8 ± 1.3 vs -0.2 ± 1.65; p = 0.031) and fewer documented fasting hypoglycemia episodes (20/44 vs 9/44; p = 0.012), although hepatomegaly frequently persisted. Liver biopsies showed steatosis, fibrosis, and/or chronic hepatitis in 52% of examined cases. A single hepatic adenoma was identified in a 14-year-old male. Overall, the clinical course of GSD IX was favorable, with hepatomegaly, elevated liver enzymes, and dyslipidemia as the most prevalent features. Severe hypoglycemic episodes were uncommon, and no clear genotype-phenotype correlation emerged.

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. 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. 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. 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.

Glycogen storage disease type IX (GSD IX) is a group of inherited metabolic disorders caused by phosphorylase kinase deficiency affecting the liver or muscle. Despite being relatively common among GSDs, GSD IX remains underexplored. A systematic review of GSD IX was conducted per PRISMA guidelines using SCOPUS and PubMed, registered with PROSPERO. Inclusion focused on human clinical studies published up to 31 December 2024. A total of 400 patients with GSD IX were analyzed: 274 IXa (mean age at diagnosis 5.1 years), 72 IXc (mean age at diagnosis 4.9 years), 39 IXb (mean age at diagnosis 4.2 years), and 15 IXd (mean age at diagnosis 44.9 years). Hepatomegaly was commonly reported in types IXa, IXb, and especially IXc (91.7%), but was rare in IXd. Elevated transaminases were frequently observed in types IXa, IXb, and particularly IXc, while uncommon in IXd. Fasting hypoglycemia was occasionally observed in types IXa and IXb, more frequently in IXc (52.7%), and was not reported in IXd. Growth delay or short stature was observed in a substantial proportion of patients with types IXa (43.8%), IXb, and IXc, but was rare in IXd. Muscle involvement was prominent in IXd, with all patients showing elevated CPK (mean 1011 U/L). Neurological involvement was infrequently reported in types IXa and IXc. This systematic review includes the most extensive clinical case history of GSD IX described in the literature. The clinical spectrum of GSD IX varies widely among subtypes, with IXc being the most aggressive. While liver forms are generally present in early childhood, muscle-type IXd shows delayed onset and milder symptoms, often leading to diagnostic delays. For diagnosis, it is essential not to underestimate key clinical features such as hepatic involvement and hypoglycemia in a child under 5 years of age. Other manifestations, including the as-yet unexplored systemic involvement of bone and kidney, remain insufficiently understood and require further investigation. Next-generation sequencing has improved diagnostic precision over traditional biopsy. Dietary management, including uncooked cornstarch, Glycosade®, and high-protein intake, remains the cornerstone of treatment. However, there is a paucity of well-designed, evidence-based studies to determine the most effective therapeutic approach. Despite its historically perceived benign course, the broad phenotypic variability of GSD IX, including progressive liver involvement and potential neurological complications, highlights its substantial clinical relevance and underscores the need for accurate diagnostic classification and long-term multidisciplinary follow-up. Glycogen storage diseases (GSDs) are inherited inborn errors of carbohydrate metabolism that result in abnormal glycogen storage. The onset can range from neonatal life to adulthood, and clinical manifestations result either from a failure to convert glycogen into energy or the toxic accumulation of glycogen.  Glycogen is a branched polymer comprised of glucose monomers (see Image. Glycogen, Free Glucose Release, and Glycogen Storage Diseases, Figure 1). After a meal, the plasma glucose level rises, stimulating the storage of the excess in cytoplasmic glycogen. The liver contains the highest percentage of glycogen by weight (about 10%), whereas muscles can store about 2% by weight. Nevertheless, since the total muscle mass is greater than the liver mass, the total mass of glycogen in muscles is about twice that of the liver. When needed, the glycogen polymer can be broken down into glucose monomers and utilized for energy production. Defects in the enzymes and transporters for these processes cause GSDs. An increasing number of GSDs are being identified, but most are very rare. These subtypes are classified numerically in the order of recognition and identification of the enzyme defect causing the disorder. Classification of Glycogen Storage Disorder GSDs that primarily affect the liver include the following: Glycogen synthase-2 deficiency (GSD type 0a). Glucose-6-phosphatase deficiency (GSD type Ia). Glucose-6-phosphate transporter deficiency (GSD type Ib) . Glycogen debrancher deficiency (GSD type III) . Glycogen branching enzyme deficiency (GSD type IV) . Liver phosphorylase deficiency (GSD type VI) . Phosphorylase kinase deficiency (GSD type IXa). GLUT2 deficiency or Fanconi-Bickel disease. GSDs that primarily affect the skeletal muscles include the following: Muscle phosphorylase deficiency (GSD type V). Phosphofructokinase deficiency (GSD type VII). Phosphoglycerate mutase deficiency (GSD type X). Lactate dehydrogenase A deficiency (GSD type XI) . Aldolase A deficiency (GSD type XII); β-enolase deficiency (GSD type XIII). Phosphoglucomutase-1 deficiency (GSD type XIV). GSDs that affect both skeletal and cardiac muscles include the following: Lysosomal acid maltase deficiency (GSD type IIa). Lysosome-associated membrane protein 2 deficiency (GSD type IIb). Glycogenin-1 deficiency (GSD type XV). Muscle glycogen synthase deficiency (GSD type 0b).

Whether cardiac impairment can be fully discarded in McArdle disease-the paradigm of "exercise intolerance," caused by inherited deficiency of the skeletal muscle-specific glycogen phosphorylase isoform ("myophosphorylase")-remains to be determined. Eight patients with McArdle disease and seven age/sex-matched controls performed a 15-min moderate, constant-load cycle-ergometer exercise bout followed by a maximal ramp test. Electrocardiographic and two-dimensional transthoracic (for cardiac dimension's assessment) and speckle tracking (for left ventricular global longitudinal strain (GLS) assessments) echocardiographic evaluations were performed at baseline. Electrocardiographic and GLS assessments were also performed during constant-load exercise and immediately upon maximal exertion. Four human heart biopsies were obtained in individuals without McArdle disease, and in-depth histological/molecular analyses were performed in McArdle and wild-type mouse hearts. Exercise intolerance was confirmed in patients ("second wind" during constant-load exercise, -55% peak power output vs controls). As opposed to controls, patients showed a decrease in GLS during constant-load exercise, especially upon second wind occurrence, but with no other between-group difference in cardiac structure/function. Human cardiac biopsies showed that all three glycogen phosphorylase-myophosphorylase, but also liver and especially brain-isoforms are expressed in the normal adult heart, thereby theoretically compensating for eventual myophosphorylase deficiency. No overall histological (including glycogen depots), cytoskeleton, metabolic, or mitochondrial (morphology/network/distribution) differences were found between McArdle and wild-type mouse hearts, except for lower levels of pyruvate kinase M2 and translocase of outer-membrane 20-kDa subunit in the former. This study provides preliminary evidence that cardiac structure and function seem to be preserved in patients with McArdle disease. However, the role for an impaired cardiac contractility associated with the second wind phenomenon should be further explored.