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Glycogen storage diseases with liver involvement: a literature review of GSD type 0, IV, VI, IX and XI



Glycogen storage diseases (GSDs) with liver involvement are classified into types 0, I, III, IV, VI, IX and XI, depending on the affected enzyme. Hypoglycemia and hepatomegaly are hallmarks of disease, but muscular and renal tubular involvement, dyslipidemia and osteopenia can develop. Considering the paucity of literature available, herein we provide a narrative review of these latter forms of GSDs.

Main body

Diagnosis is based on clinical manifestations and laboratory test results, but molecular analysis is often necessary to distinguish the various forms, whose presentation can be similar. Compared to GSD type I and III, which are characterized by a more severe impact on metabolic and glycemic homeostasis, GSD type 0, VI, IX and XI are usually known to be responsive to the nutritional treatment for achieving a balanced metabolic homeostasis in the pediatric age. However, some patients can exhibit a more severe phenotype and an important progression of the liver and muscular disease. The effects of dietary adjustments in GSD type IV are encouraging, but data are limited.


Early diagnosis allows a good metabolic control, with improvement of quality of life and prognosis, therefore we underline the importance of building a proper knowledge among physicians about these rare conditions. Regular monitoring is necessary to restrain disease progression and complications.


Glycogen storage diseases (GSDs) are a group of rare inborn disorders of glycogen metabolism [1], a multibranched polysaccharide of glucose that serves as a rapidly consumable form of energy storage in mammalians. Glycogen is composed by chains formed by glucose units linked together linearly by α(1 → 4) glycosidic bonds from one glucose to the next, meanwhile branches are linked to the chains by α(1 → 6) glycosidic bonds [2]. After a meal, plasma glucose levels increase; then glucose is metabolized either to pyruvate or stored as glycogen (Fig. 1). In the first case, under aerobic conditions, pyruvate is either converted into Acetyl coenzyme A which enters the Krebs Cycle or is used to produce fatty acids. By contrast, under anaerobic conditions, lactate is derived from pyruvate as an alternative energy source. Glycogen synthesis and breakdown are regulated by different hormones such as glucagon, adrenaline, cortisol and insulin [1, 2].

Fig. 1
figure 1

Simplified chart of glycogen metabolism in hepatocytes. After a meal, plasma glucose is metabolized either to pyruvate or stored as glycogen. Enzymes involved in GSDs type 0, IV, VI, IX and XI are pointed out. UDP glucose: uridine diphosphate glucose; glucose-1-P: glucose 1-phosphate; glucose-6-P: glucose-6-phosphate

GSDs may show a similar clinical presentation, although they may have a variable expressivity. Their overall incidence is approximately 1:10,000 live births [3] and they are classified, depending on the defective enzyme and the primarily affected tissues [1]. GSDs types 0a (gene GYS2, OMIM # 240600), IV or Andersen disease (GBE1, OMIM # 232500), VI or Hers disease (PYGL, OMIM # 232700), IXa (PHKA2, OMIM # 306000), IXb (PHKB, OMIM # 261750), IXc (PHKG2, OMIM # 613027) and XI or Fanconi-Bickel syndrome (SLC2A2, OMIM # 227810) are included into the group of hepatic GSDs together with types I and III. Differently from the two latter GSDs, the former types have been considered as more benign, however there are growing evidences of a significant clinical variability, with some patients exhibiting a severe phenotype [4]. All GSDs are autosomal recessive except for type IXa, which shows an X-linked inheritance [3]. Hepatic GSDs share some clinical signs, such as fasting hypoglycemia and hepatomegaly [1, 3], albeit GSD type 0 usually shows hypoglycemia without signs of liver involvement [5]. Furthermore, some GSD type IXa may present merely with ketotic hypoglycemia [6]. Patients with GSDs types 0, IV, VI, IX and XI are usually good at birth, with symptoms developing in early infancy or childhood. Except for a few types, the prognosis is good if a strict dietary treatment and surveillance of complications are achieved. Although a clear genotype–phenotype correlation has not been drawn, different mutations may justify the wide spectrum of phenotypes, with different grade of severity [7]. In the recent years, additional knowledge has been gained about the pathophysiology, clinical course and treatment of these conditions and several case series are now available. In the present review we provide an overview about clinical and laboratory characteristics of GSDs types 0, IV, VI, IX and XI, in order to support a punctual diagnosis, which can influence the prognosis and the quality of life of the patients, and to highlight the importance of a regular follow-up of the disease progression leading to the organ damage.


The literature search occurred in November 2021. All potentially relevant articles were selected from three electronic databases: Google Scholar, Medline and PubMed. Search terms such as “glycogen storage disease”, “glycogen storage disease type 0”, “GYS2 defects”, “glycogen storage disease type IV”, “GBE1”, “glycogen storage disease type VI”, “PYGL”, “glycogen storage disease type IX”, “PHKA2”, “PHKB”, “PHKG2”, “glycogen storage disease type XI”, “GLUT2 deficiency”, “Fanconi-Bickel syndrome” were used in various combinations and permutations.



GSD type 0

GSD type 0a is caused by defects of the hepatic isoform of glycogen synthase, encoded by GYS2 (chromosome 12p12.2), which catalyzes the linear addition of glucose residues to the branching structure of glycogen. Mutations of the muscle-specific isoform of glycogen synthase encoded by GYS1 gene originate GSD type 0b. Clinically, it exhibits weakness, exercise intolerance and arrythmias without liver involvement [8].

A focus on GSD subtype 0a is provided in this review and it will be referred to as “GSD type 0”. The onset of symptoms occurs before 3.5 years old on average [9]. Affected toddlers are incapable of synthetizing glycogen and having adequate glycemic response to stress or fasting periods. For this reason, they show fasting ketotic hypoglycemia, that can be either symptomatic or asymptomatic. Symptomatic hypoglycemia is revealed by pallor, sweating, hyporeactivity, lethargic state until generalized seizures [10, 11]. After a meal or an oral glucose tolerance test (OGTT), hyperglycemia and hyperlactatemia are observed [12], whereas hypoglycemia can manifest after three hours from the last feeding [13]. Patients cannot switch to gluconeogenesis rapidly enough to ensure a normal hepatic glucose output. It could be speculated that the post-prandial hyperglycemia typical of GSD type 0 suppresses the glucagon activity and that glucagon to insulin ratio remains too low to stimulate phosphoenolpyruvate carboxykinase, the rate-limiting enzyme for gluconeogenesis [12]. Fasting glucagon stimulus test may not increase glycemia as the expected, confirming the presence of poor glycogen deposits [14], with a response in the fed state not consistent among patients [10]. The presentation with post-prandial hyperglycemia and glycosuria, along with fasting ketonuria, places GSD type 0 in differential diagnosis with early phases of diabetes mellitus and Fanconi-Bickel syndrome [14]. However, ketonuria is not a constant finding and measurement of ketones in blood is preferable [13]. Hepatomegaly is not associated to this disorder [10, 12, 15,16,17], although a mild liver enlargement has been described in some patients [13]. Slightly different phenotypes might be related to different degrees of enzyme residual activity. Growth failure is reported [9, 12]. Furthermore, two patients lacking of post-prandial hyperglycemia/hyperlactatemia were diagnosed with GSD type 0 by targeted NGS [18].

GSD type IV (Andersen disease)

The branching enzyme deficiency (GBE1 gene, chromosome 3p14) causes the GSD type IV or Andersen disease. The branching enzyme adds a segment of a minimum of six α-1,4 linked glycosyl units into an α-1,6 position; this activity is fundamental for the correct glycogen storage and degradation. Indeed, GBE1 deficiency induces the accumulation of an amylopectin-like molecule called polyglucosan, an insoluble polymer which has fewer branching points and longer outer chains than normal glycogen [19].

GSD type IV includes two hepatic subtypes (the classical progressive and the non-progressive hepatic disease), three neuromuscular subtypes (distinguished in the perinatal, congenital and childhood disease, depending on the age of onset) and a multisystem form (adult polyglucosan body disease). Indeed, the GSD type IV has a very heterogeneous clinical presentation, ranging between myopathy, cardiomyopathy, neuropathy and liver failure variously combined [20, 21]. One of the first reports available in the literature described this condition as “a new cause of floppy infant” [22].

The classical progressive hepatic form is characterized by an initially normal phenotype with rapid deterioration in infancy, when hepatomegaly and failure to thrive appear. Prolonged partial thromboplastin time and prothrombin time progressively develop, along with hypoalbuminemia. Linear glycogen molecules can be metabolized, so this prevents severe hypoglycemia. Nevertheless, it may develop in the final stages of liver failure [23]. The final evolution is toward progressive fibrosis, cirrhosis and its complications, such as portal hypertension, ascites and esophageal varices, with death occurring before the age of five owing to liver failure [24, 25]. Liver transplantation remains the only effective treatment for patients with the progressive hepatic subtype of GSD type IV who develop liver failure. However, some patients treated by liver transplantation displayed over time extrahepatic manifestations, such as cardiomyopathy and myopathy [26,27,28,29].

The non-progressive hepatic disease exhibits different grades of severity, with the milder phenotype showing hepatomegaly and inconstant elevation of transaminases. McConkie-Rosell et al. [30] in 1996 described four patients with hepatomegaly associated to elevated hepatic enzymes at young ages, who showed liver fibrosis without signs of progression toward cirrhosis nor portal hypertension nor liver failure in a follow-up ranging from 2 to 19 years. Conversely, Dhawan et al. [31] described a patient who only showed hepatomegaly until 12 years old, when he rapidly developed cirrhosis with portal hypertension requiring liver transplantation. The severity of the phenotype might depend both on the involvement of different tissue isozymes [1] and the residual activity of branching enzyme [21]. GSD type IV patients exhibit a continuum of different phenotypes, with extremely variable clinical features. Hypoglycemia has traditionally been considered a late manifestation, related to hepatocellular dysfunction; notably, a recent report documented fasting intolerance in patients without any sign of liver involvement [26].

The neuromuscular variants of GSD type IV are very rare; nevertheless, the perinatal variant should be considered one of the differential diagnoses in neonates with severe hypotonia and in pregnancies complicated by polyhydramnios, fetal hydrops, reduced fetal movements, arthrogryposis, hypoplastic lungs of unknown etiology [19,20,21, 32]. The congenital neuromuscular subtype begins in the newborn period with profound hypotonia, respiratory distress, and dilated cardiomyopathy and, as well as the previous one, results in death in the neonatal period. The childhood neuromuscular subtype, which is the rarest one, has most variable course. Its onset ranges from the second life decade with a mild disease course to a more severe, progressive course resulting in death in the third decade [21]. Neurological adult form can present as isolated myopathy or as widespread upper and lower motor neuron lesions (adult polyglucosan body disease), which presents usually after the age of 50 years. Its hallmarks are progressive spastic paraparesis, neurogenic bladder, and axonal neuropathy [29, 33].

GSD type VI (Hers disease)

PYGL gene (chromosome 14q21-q22) mutations are associated to GSD type VI, also known as Hers disease [34]. Affected individuals lack the glycogen phosphorylase activity, which breaks up glycogen into glucose units as a response to hypoglycemia. This is a rate limiting step in glycogen degradation, hence the untreated child shows moderate fasting hypoglycemia with mild ketosis, hyperlipidemia, elevated liver enzymes, abdominal distension, hepatomegaly and growth failure. Pre-albumin is also reduced [34, 35]. Symptoms begin at the pre-school age; hypoglycemia may originate during prolonged fasting, illnesses or stressful conditions, thus a strict surveillance must be realized in these cases [34, 36]. Ketotic hypoglycemia without hepatomegaly has also been recently described in GSD type VI as the only sign of disease [6].

GSD type VI was previously considered as a mild disease. However, recent reports highlighted the possibility of a progression to fibrosis and cirrhosis, and a degeneration to hepatocellular carcinoma, so a rigorous long-term monitoring of hepatic function is needed [4, 37, 38].

GSD type IX

The above mentioned glycogen phosphorylase is functionally activated by the phosphorylase kinase (PhK), a serine/threonine-specific protein kinase. PhK is composed of four different subunits: α, β, γ and δ. Subunits α and β have regulatory functions, the γ-subunit has catalytic function and δ-subunit is a calmodulin protein. The subunits possess tissue-specific isoforms; the liver-specific isoforms of the α-, β- and γ-subunits are encoded by PHKA2, PHKB and PHKG2 respectively, and are causative of GSD IX subtypes IXa, IXb and IXc [39]. However, PHKB is expressed in both liver and muscle. Furthermore, the α- and γ-subunits have a muscle-specific isoform, encoded by PHKA1 and PHKG1 respectively. The α-subunit isoforms are inherited in an X-linked fashion, while the other isoforms have an autosomal recessive inheritance [40]. Furthermore, the subtype IXa is distinguished in types XLG I and XLG II, two clinically similar entities basically differing for the possibility to discover the enzyme deficiency on erythrocytes [41].

GSD type IX represents the most frequent type of glycogen storage disease, with a prevalence of 1:100,000 births [42]. The phenotype is dominated by short stature, a characteristic round face (“doll face”), liver enlargement with elevated transaminases, triglycerides and cholesterol, normal uric acid and lactic acid concentrations. Renal tubulopathy is an inconstant finding [37]. Hypoglycemia is not always pronounced because gluconeogenesis and fatty acid oxidation are intact, and normal blood glucose concentrations are often maintained [43, 44]. When hypoglycemia is present, ketosis is associated in fasting conditions [45]. More recently, isolated ketotic hypoglycemia without hepatomegaly has been related to PhK deficiency, mostly due to PHKA2 mutations [6].

PhK deficiency was generally considered a benign condition, with symptoms of hypoglycemia, hepatomegaly and growth retardation improving after the early introduction of a strict dietary treatment [43]. Nevertheless, recent studies have focused on the existence of complications and different prognosis depending on the causative mutation. For instance, an evolution to liver fibrosis and chronic liver disease associated to PHKA2 mutations has been reported [46, 47]. Furthermore, Burwinkel et al. [47] reported two patients displaying peculiar features such as kidney dysfunction due to renal tubular acidosis and neurological involvement with outcome of delayed cognitive and speech abilities, confirming that the spectrum of the disease is extremely broad.

The phenotype associated to PHKB mutations is similar to what observed in the milder PHKA2 mutations; symptoms related to muscular involvement may be present [48]. PHKG2 associated phenotypes show a more severe presentation [49]. The clinical spectrum includes fasting hypoglycemia, hepatomegaly, elevated transaminases, liver fibrosis, cirrhosis, muscle weakness, hypotonia, motor developmental delay, growth retardation and fatigue [50, 51]. More recently, the presence of variable degree of liver fibrosis and cirrhosis still in early childhood has been reported in the three subtypes [4].

GSD type XI (Fanconi–Bickel syndrome)

GSD type XI is caused by defective glucose and galactose transporter GLUT2 (SLC2A2 gene, chromosome 3q26.1–26.3), expressed in hepatocytes, pancreatic β-cells, enterocytes and renal tubular cells [52]. This condition causes impaired influx and efflux of glucose from the aforementioned cell types, and it may have a role in insulin secretion [53]. This is a severe disease with a peculiar clinical presentation. Both transport and metabolism of glucose and galactose are defective, with subsequent increased hepatorenal glycogen storage leading to hepatomegaly. At early stages, a slight elevation of transaminases is recorded.

Neonatal screening may show hypergalactosemia but cataract is not present in this condition [54]. Impaired renal glucose reabsorption, as well as the accumulation of glucose in the liver, which reduces glycogen breakdown, causes fasting ketotic hypoglycemia. Conversely, in the fed state hyperglycemia is observed. This may be due to the impairment of glucose transportation from the enterocytes and decreased glucose uptake by the liver, consequent to impaired insulin secretion [53]. Signs and symptoms usually begin between 3 and 10 months of life with poor feeding, failure to thrive and laboratory findings as glycosuria [54]. The proximal renal tubular dysfunction implicates glycosuria, proteinuria, phosphaturia, aminoaciduria and bicarbonate wasting, resulting in a metabolic hyperchloremic acidosis with normal anion gap [52]. Hypercalciuria is a constant finding. In older children, pubertal delay and hypophosphatemic rickets are described [55, 56]. Tendency to hyponatremia and hypokalemia is frequent owing to renal losses. Polyuria may be present as a consequence of high osmotic load. Patients may exhibit chronic diarrhea secondary to intestinal malabsorption. Hyperlipidemia is recorded, leading to moon-shaped face and fat deposition on shoulders and abdomen, which are typical features [1, 54]. Notably, a GLUT2 deleted mouse model exhibited an increased expression of ChREBP (Carbohydrate Response Element Binding Protein) which in turn activates the lipogenic target genes transcription [57]. Patients with Fanconi-Bickel syndrome manifest a dysregulation of glucose homeostasis, with presentation of fasting hypoglycemia, post-prandial hyperglycemia, glucose intolerance, transient neonatal diabetes, gestational diabetes and frank diabetes mellitus. Impaired glucose control along with low birth weight suggest that GLUT2 might have a role in insulin physiology from fetal to adult age [53]. A few cases of patients with a similar phenotype but without any mutation of SLC2A2 were reported, suggesting other genes involved in the pathogenesis of this condition, remaining unknown so far [58]. Remarkably, the mutations p.R63W and LRG_483t1:c.427-1G > A in the HNF4α gene cause hyperinsulinemic hypoglycemia associated to hepatomegaly and renal Fanconi syndrome. These HNF4α mutations might decrease the SLC2A2 expression in both liver and kidney, resulting in nonfunctional GLUT2 and are responsive to therapy with diazoxide [59, 60].

Focus on the main GSDs clinical features

Glucose homeostasis

Fasting ketotic hypoglycemia is a hallmark of hepatic GSDs [26, 61]. Patients with GSD type 0 and XI show also a typical post-prandial hyperglycemia [12, 16, 53]. In GSD type IV, hypoglycemia can appear late in the clinical course, but it can be also found in patients without signs of liver disease [26]. Ketotic hypoglycemia without hepatomegaly has also been recently described in GSD type VI and IX [6]. Futhermore, isolated ketonemia with normoglycemia has been described in patients with GSD types VI and IX [62]. GSD type XI exhibits a wide range of alterations in glucose homeostasis, including fasting hypoglycemia, hyperglycemia in the fed state, glucose intolerance up to diabetes mellitus in rare cases [53].

Lipid homeostasis

Elevated triglyceridemia and cholesterolemia are common findings in GSDs with liver involvement. In these conditions, the dysregulation of glucose metabolism leads to fasting intolerance, enhancing secondary lipolysis and increased mitochondrial fatty acid oxidation [1]. In GDS type XI, the administration of statins may be required [63]. In the other forms, the dyslipidemia is generally moderate and an appropriate nutritional therapy is effective to reduce plasma lipid values [64].

Liver involvement

As previously mentioned, the distinctive element of the glycogen synthase deficiency is the absence of hepatomegaly, since hepatic glycogen storage is impaired [9, 12], although enlarged liver has been reported in some cases of GSD type 0 [13, 16]. By contrast, hepatomegaly is the hallmark of the GSD type IV, VI, IX and XI with various degrees of severity, which may show an improvement after puberty in treated GSD type IX patients [64, 65]. However, a progression of the liver disease may occur despite a reduction of the liver size [44].

In GSD type IV the accumulation of abnormal glycogen, less soluble than normal glycogen, causes a foreign body reaction with consequent osmotic swelling and cell death [50], leading to interstitial fibrosis evolving toward cirrhosis [24]. Liver fibrosis is outlined also in individuals with GSD types VI [38, 66] and IX [4, 51]. Particularly, in GSD type IX fibrosis has been recently reported to range between 33 and 95% depending on the subtype still in early infancy [4].

Furthermore, cirrhosis has recently been depicted in GSD type VI [38]. Among the GSD IX subtypes, the progression to liver cirrhosis had initially been described only in patients affected by PHKG2 mutations [49]. Nevertheless, Tsilianidis et al. [43] described precocious liver cirrhosis in two patients with PHKA2 mutations. More recently, early appearance of liver cirrhosis in a 2 years old child with homozygous mutations in PHKB has been reported [40].

Tumor degeneration is described in GSD type IV, VI and IX. Hepatocellular adenoma and carcinoma have been described in GSD type IV [67]. GSD type VI can be rarely complicated by focal nodular hyperplasia [68] and one case of hepatocellular carcinoma has been reported to date [69]. With regards to GSD type IX, hepatocellular adenomas have been reported in IXa and IXb subtypes [4, 44]. Furthermore, the development of hepatocellular carcinoma associated to GSD type IXc has recently been described [70]. In GSD type XI, liver histology shows marked accumulation of glycogen in hepatocytes along with steatosis. The degeneration to hepatic adenomas or carcinomas is rare [54]. The first case of hepatocellular carcinoma in a young boy affected by Fanconi-Bickel syndrome was described in 2017 by Pogoriler and colleagues [71].

Renal involvement

Renal involvement is not described in GSDs types 0 and VI to date.

Conversely, individuals affected by PHKA2 and PHKG2 mutations can display renal tubular acidosis and tubulopathy with secondary development of rickets in a patient with GSD type IXc. The establishment of an adequate nutritional therapy improves tubular acidosis [37].

In addition, renal involvement represents a hallmark of GSD type XI, in which the renal epithelial cells are damaged by the accumulation of glycogen and monosaccharides; this alteration leads to proximal tubular dysfunction, documented by glycosuria and aminoaciduria. Although this condition is related to a severe phenotype, rare cases of patients with mild renal dysfunction have been described [8].

Growth impairment and bone metabolism

Normal length and weight at birth are usually observed, suggesting that the metabolic disorders do not interfere with fetal growth [11, 19, 72], except for newborns with GSD type XI, which are typically low birth weight [53].

Patients diagnosed with GSD type 0 may show either normal or poor growth with a delayed bone age in early childhood [15, 17]. A catch-up growth has been described after the introduction of adequate dietary therapy, comprising uncooked cornstarch [9]. Osteopenia is a possible complication [5].

Growth impairment is not a hallmark of GDS type IV and it may be present or not, depending on the causing mutation and the clinical subtype [24].

In contrast, short stature is a common feature in GSD types VI and IX, with a variability in the degree of improvement of parameters in treated patients reaching the adult age [36]. Most individuals affected by PhK deficiency achieve standard adult stature parameters, but they show a peculiar growth pattern, with an initial growth retardation in the first 2–3 years of age, followed by a gradual normalization of the linear growth [65]. Abnormal bone mineralization with and without osteopenia has been reported in GSDs types VI and IX [37, 73]. Dietary deficiencies and chronic ketosis are speculated to be contributory factors [37]. Rickets has been reported in a case of GSD type IXc, due to renal tubulopathy with an inappropriate parathyroid response [37].

Severe growth impairment is described in Fanconi-Bickel syndrome. Patients affected by proximal renal tubular dysfunction of variable genetic causes show growth retardation ascribed to renal losses but the short stature observed in Fanconi-Bickel syndrome is more pronounced, suggesting other mechanisms not clearly understood [74]. Newborns are generally low birth weight, likely effect of the insulin deregulation starting in utero [53]. Furthermore, dwarfism is a striking feature in adult patients [1], with scarce response to nutritional therapy. Remarkably, Pennisi and colleagues [63] reported a substantial improvement of height and weight by the administration of nocturnal enteral nutrition from the age of 1 year, in five patients. The nocturnal enteral feeding provided an appropriate glucose rate intake for age (8–9 mg/kg/min in infants, 5–7 mg/kg/min in children and 2–4 mg/kg/min in adolescents); diet granted 55–60% of caloric intake as carbohydrates, 30% as lipids, and 10% as proteins. Four patients were supplemented with uncooked cornstarch in the enteral nutrition. All patients showed a catch-up growth from 3rd percentile or below to 10th/50th percentiles for height and weight at last follow up (age range 15–24 years). Notably, untreated patients reached an adult height ranging from 131.5 to 153 cm [75].

Among all GSDs, bone is mostly affected in GSD type XI, where hypophosphatemic rickets, frequent fractures and bone deformities are described as a result of the renal tubular dysfunction [76]. Limbs deformities and lumbar hyperlordosis may appear in patients with delayed diagnosis, as observed in developing countries [74].

Muscular and cardiac involvement

Skeletal muscle and myocardial involvement is not observed in GSD type 0a [9].

Heart failure after orthotropic liver transplantation has been described in patients with the progressive liver form of GSD type IV with no previous history of cardiac involvement [27, 28]. This could be due to a progression of disease, despite liver transplantation. Indeed, in patients dead after liver transplantation, amylopectin deposits have been observed in different organs and tissues (myocardial fibers, skeletal muscle fibers, central and peripheral nervous system cells, macrophages) at autopsy [77]. A good clinical response to liver transplantation may be explained by a mechanism of microchimerism, through which the donor cells transfer the deficient enzyme to the host cells, thus reducing amylopectin deposits [78].

Mild to severe myopathy and dilated cardiomyopathy are also described in the neuromuscular forms of GSD type IV [24, 79]. Remarkably, cardiomyopathy has been reported as the sole presenting symptom of branching enzyme deficiency in one case [21].

Muscular cramps or fatigue after physical exercise have been recorded in a minority of reports of GSD type VI, usually related to undertreatment and protein deficiency [36]. Muscle weakness may or may not be observed in PhK deficiency with any genotype [48, 49].

In a recent case series, asymptomatic left ventricular and septal hypertrophy was reported in a patient with GSD type VI, and interventricular septal hypertrophy was found in a patient with GSD type IXb. The authors recommended echocardiogram every 1–2 years for patients with GSD type VI and IX after 5 years of age [44]. A systematic review of the literature did not reveal other individuals with GSD type VI or IX and cardiac problems [3]. Muscular involvement can be seen in the context of dyselectrolytemia in GSD type XI [52], revealed by exercise intolerance and rhabdomyolysis [33].

Psychomotor development and nervous system

Developmental delay has been described in 22% of children with GSD type 0 [5], whereas undiagnosed GSD type 0 was associated to a higher incidence of neurodevelopmental impairment caused by severe recurrent hypoglycemia. In these patients, hypoglycemia is often non symptomatic, as the loss of neuroglycopenic signs in recurrent hypoglycemia is notable [14]. The phenomenon, noted as hypoglycemia-associated autonomic failure, is due to a defective glucose counter-regulation with an attenuated sympathoadrenal and neural response leading to reduced neurogenic and cerebral symptoms [80]. Seizures are uncommon [5].

Mild developmental delay was also reported in GSD types VI, IX and XI [36, 76]. With regards to GSD type IX, a recently published literature review with data analysis of 174 patients outlined that a mild developmental delay was present in type IXc, with a frequency two times higher than other subtypes [4].

With respect to the motor impairment, GSD type IV, VI, IX and XI deserve to be mentioned.

In the progressive hepatic GSD type IV the muscle tone is often normal at the time of diagnosis, but progression to generalized hypotonia may develop within the two years of life [20]. GSD type IV shows a complex involvement of neuromuscular system. The perinatal and congenital neuromuscular subtypes show severe congenital hypotonia and respiratory distress, which impose the differential diagnosis with spinal muscular atrophy and the inherited storage disorders with neuromuscular involvement (eg Pompe disease, Zellweger disease) [19, 20]. Patients affected by the childhood neuromuscular subtype show skeletal myopathy and hypotonia and may experience motor developmental delay with possible death in early adulthood [24]. Furthermore, progressive spastic paraparesis, neurogenic bladder, and axonal neuropathy have been described in the adult polyglucosan body disease [33]. This is a rare condition due to the accumulation of polyglucosan bodies into the neuronal axons and processes of astrocytes and oligodendrocytes. This process leads to a sensorimotor neuropathy, with involvement of both upper and lower motor neuron and onset around the fifth decade. The clinical presentation is very variable, characterized by symptoms of neurogenic bladder, legs weakness, gait disturbances, spasticity, cognitive dementia with different grades of severity. Among the neurologic signs, spasticity, reduced ankle reflexes, extensor plantar response and sensory deficits of lower extremities are seen [81].

Mild hypotonia was reported in a few GSD type VI patients [36].

Hypotonia and motor delay can be rarely associated to PHKB and PHKG2 mutations [48, 51]. With regards to PHKA2 mutations, Lau et al. [82] and colleagues described a young patient exhibiting an impairment of gross motor ability in the context of a borderline developmental delay. Hypotonia and motor impairment were also recorded in GSD type XI [1, 3].

A summary of the main clinical features of the GSDs is provided in Table 1.

Table 1 Main clinical features of GSDs 0, IV, VI, IX and XI


A careful clinical history and examination together with laboratory findings may suggest the diagnosis. An OGTT can be realized when GSD types 0, VI and IX are suspected; in all forms elevated lactate will be recorded at 120 min. Patients with GSD type 0 will show hyperglycemia within the first two hours, then hypoglycemia might be observed at a prolonged OGTT, likely due to hyperglycemia-induced hyperinsulinemia [12]. In the past, enzymatic activity in peripheral blood cells and cultured skin fibroblasts was performed. The reduced activity of branching enzyme in leucocytes, erythrocytes and fibroblasts confirmed the diagnosis of GSD type IV, however normal activity in leukocytes could not exclude the neuromuscular forms [24]. In GSD type VI a reduced phosphorylase activity could be detected in erythrocytes and leukocytes [35]. The deficiency of phosphorylase kinase activity could be outlined in leucocytes, erythrocytes and fibroblasts, except for the forms associated to certain missense mutations of PHKA2 and PHKB [41, 47]. In the case of normal enzymatic activity in peripheral blood cells, a liver biopsy for enzymatic assay in hepatocytes was assessed [47]. More recently, molecular analysis became the method of choice to confirm the diagnosis for each GSD type. However, these forms may have similar clinical and biochemical presentation. Thus, performing single gene analysis would result time consuming and expensive. In the last decade, next generation sequencing technology (as gene panel or clinical exome) found a wide application for the diagnosis of inborn errors of metabolism for the genetic heterogeneity of these conditions, allowing to carry out large molecular characterization of patients within an useful timeframe and at a reasonable cost [18]. However, with these techniques non-coding and structural variants cannot be captured, the gene coverage may be variable, deletions/duplications can be missed, and the identification of variants of uncertain significance poses a diagnostic challenge [83, 84]. In these cases, histology and enzyme testing on a liver biopsy specimen may be required to confirm the diagnosis [37].

Treatment and follow-up

A strict dietary regimen high in proteins and low in simple carbohydrates, which includes frequent intake of complex carbohydrates such as maltodextrin and uncooked cornstarch, is fundamental to prevent hypoglycemia in ketotic GSDs [6]. Indeed, a metabolic imbalance results in overnight hypoglycemia and ketosis, that are associated to short stature, osteopenia, and neurologic complications [43]. GSDs types 0, VI and particularly type IX would benefit from a strict glycemia monitoring. A minority of patients with mutations of PHKA2 and PHKG2 associated to a severe phenotype often require overnight feeding to maintain euglycemia [85]. Since gluconeogenesis is preserved, protein supplementation provides gluconeogenic precursors that can be used for repletion of Krebs cycle intermediates and endogenous glucose production in GSD types 0, IV, VI and IX. By improving glucose homeostasis, hepatic glycogen accumulation and secondary complications might be restrained. Diet should be high in protein and provide 2–3 g of protein/kg or ~ 20–25% of total calories [26, 37, 61]. High protein intake is especially needed in GSD type VI to improve muscle function [44]. Carbohydrates should provide ~ 45–50% of total calories, with complex carbohydrates and protein in every meal. The dosage of raw cornstarch 1 g/kg at bedtime allows to maintain normoglycemia for 4–8 h in infants and children [37]. In 2015 Ross and co-workers [85] described the efficacy of an extended-release cornstarch (Glycosade) in GSD types 0, III, VI and IX to achieve a longer time of euglycemia during the night, with stable values of other markers of metabolic control and hepatic function. In the United States, the extended-release cornstarch preparation has been approved for nocturnal use in GSD patients above 5 years of age. However, the administration of Glycosade in patient between 2 and 5 years of age resulted safe and effective as well [86]. Adverse effects such as abdominal distension, diarrhea and flatulence have been reported, but to date they were not recorded in patients with GSD types 0, VI and IX [61].

Patients with GSD type 0 are treated with frequent feeds of hyperglucidic diet plus cornstarch and protein supplementation. Patients with GSD type IV are managed with hyperglucidic diet plus cornstarch, nocturnal enteral feeding, protein enrichment with the aim to limit the accumulation of glycogen, to prevent catabolism and to improve growth and fasting tolerance. The more severe forms are treated with liver transplantation [26]. For GSD type XI, Pennisi and co-workers [63] proposed the nocturnal enteral nutrition in younger children and in patients with a severe growth delay in order to prevent fasting hypoglycemia. Frequent, small meals, restricted in glucose and galactose, and raw cornstarch administration at night are used to prevent metabolic acidosis, which may occur at times of surgery or other stresses. Hypercholesterolemia may require a medical treatment with statins after five years of age; bicarbonate supplementation may be required to balance the urinary bicarbonate loss [63].

According to the available data, universally accepted guidelines for the management of these types of GSDs have not been defined. Nevertheless, an appropriate follow-up should be provided, in order to establish a good metabolic control and monitor the possible complications. Medical and nutritional evaluations and blood assessment, including complete liver and renal function, lipid profile, calcium-phosphate metabolism, serum electrolytes, blood gas analysis and urinalysis, should be fulfilled every 6 months on average; a higher frequency is recommended in younger patients and in those who have not achieved a metabolic balance. A continuous glucose monitoring may be helpful to survey the glycemic fluctuations, especially in younger patients. Alpha-fetoprotein levels along with abdomen ultrasound can be used to screen for hepatocellular carcinoma, even though there are no validated surveillance protocols to date [37]. Liver fibroscan might be an useful and non-invasive tool for the monitoring of the progression of fibrosis/cirrhosis in GSD type IV, VI and IX [64, 87].

GSD type IV patients require a complete cardiac function evaluation, including electrocardiogram and echocardiography. For patients with GSD types VI and IX after 5 years of age a cardiac evaluation is recommended every 1–2 years [44].

Regarding the bone metabolism, a careful assessment of calcium and vitamin D intake and monitoring of 25-OH vitamin D level is recommended. Calcium, phosphate and vitamin D supplementations, along with annual DXA scan evaluation, are required to prevent osteopenia and fractures, particularly in GSD type XI, along with a surveillance of renal function [61]. Skeletal X-Rays are required in GSD type XI to evaluate rickets evolution [55, 56]. Recommendations for vitamin and mineral supplementation are based on individual patient’s diet and nutrient needs.


GSDs type 0, IV, VI, IX and XI with liver involvement may have a similar clinical presentation. However, these diseases exhibit a phenotypic continuum, and even in the mildest forms, regular monitoring and dietary adjustments are necessary to restrain disease progression and complications. Some cases may exhibit a clinical burden with severe organ complications. Building a proper knowledge among physicians about these rare conditions is crucial to improve prognosis and quality of life of patients, especially those affected by the most severe forms. Further studies are needed to outline the genotype–phenotype correlation and define personalized therapies and management.

Availability of data and materials

Not applicable.



Carbohydrate-response element-binding protein


Glycogen branching enzyme


Glucose transporter 2


Glycogen storage disease


Glycogen synthase


Hepatocyte nuclear factor 4α


Glycogen phosphorylase


Oral glucose tolerance test


Phosphorylase kinase


Solute carrier family member 2


  1. Ozen H. Glycogen storage diseases: new perspectives. World J Gastroenterol. 2007;13:2541–53.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS. Glycogen and its metabolism: some new developments and old themes. Biochem J. 2012;441:763–87.

    CAS  Article  PubMed  Google Scholar 

  3. Beyzaei Z, Geramizadeh B, Karimzadeh S. Diagnosis of hepatic glycogen storage disease patients with overlapping clinical symptoms by massively parallel sequencing: a systematic review of literature. Orphanet J Rare Dis. 2020;15:286.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fernandes SA, Cooper GE, Gibson RA, Kishnani PS. Benign or not benign? deep phenotyping of liver glycogen storage disease IX. Mol Genet Metab. 2020;131:299–305.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Weinstein DA, Correia CE, Saunders AC, Wolfsdorf JI. Hepatic glycogen synthase deficiency: an infrequently recognized cause of ketotic hypoglycemia. Mol Genet Metab. 2006;87:284–8.

    CAS  Article  PubMed  Google Scholar 

  6. Brown LM, Corrado MM, van der Ende RM, Derks TG, Chen MA, Siegel S, et al. Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children. J Inherit Metab Dis. 2015;38:489–93.

    CAS  Article  PubMed  Google Scholar 

  7. Grünert SC, Schwab KO, Pohl M, Sass JO, Santer R. Fanconi-Bickel syndrome: GLUT2 mutations associated with a mild phenotype. Mol Genet Metab. 2012;105:433–7.

    CAS  Article  PubMed  Google Scholar 

  8. Cameron JM, Levandovskiy V, MacKay N, Utgikar R, Ackerley C, Chiasson D, et al. Identification of a novel mutation in GYS1 (muscle-specific glycogen synthase) resulting in sudden cardiac death, that is diagnosable from skin fibroblasts. Mol Genet Metab. 2009;98:378–82.

    CAS  Article  PubMed  Google Scholar 

  9. Arko JJ, Debeljak M, Tansek MZ, Battelino T, Groselj U. A patient with glycogen storage disease type 0 and a novel sequence variant in GYS2: a case report and literature review. J Int Med Res. 2020;48:300060520936857.

    Article  PubMed  Google Scholar 

  10. Spiegel R, Mahamid J, Orho-Melander M, Miron D, Horovitz Y. The variable clinical phenotype of liver glycogen synthase deficiency. J Pediatr Endocrinol Metab. 2007;20:1339–42.

    CAS  Article  PubMed  Google Scholar 

  11. Soggia AP, Correa-Giannella ML, Fortes MA, Luna AM, Pereira MA. A novel mutation in the glycogen synthase 2 gene in a child with glycogen storage disease type 0. BMC Med Genet. 2010;11:3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Orho M, Bosshard NU, Buist NR, Gitzelmann R, Aynsley-Green A, Blümel P, et al. Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0. J Clin Invest. 1998;102:507–15.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Kamenets EA, Gusarova EA, Milovanova NV, Itkis YS, Strokova TV, Melikyan MA, et al. Hepatic glycogen synthase (GYS2) deficiency: seven novel patients and seven novel variants. JIMD Rep. 2020;53:39–44.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bachrach BE, Weinstein DA, Orho-Melander M, Burgess A, Wolfsdorf JI. Glycogen synthase deficiency (glycogen storage disease type 0) presenting with hyperglycemia and glucosuria: report of three new mutations. J Pediatr. 2002;140:781–3.

    CAS  Article  PubMed  Google Scholar 

  15. Gitzelmann R, Spycher MA, Feil G, Müller J, Seilnacht B, Stahl M, et al. Liver glycogen synthase deficiency: a rarely diagnosed entity. Eur J Pediatr. 1996;155:561–7.

    CAS  Article  PubMed  Google Scholar 

  16. Matei L, Teodorescu MI, Kozma A, Iordan Dumitru AD, Stoicescu SM, Carniciu S. Persistent asymptomatic severe hypoglycaemia due to type 0a Glycogenosis—general and oro-dental aspects. Acta Endocrinol (Buchar). 2019;15:526–30.

    CAS  Article  Google Scholar 

  17. Kasapkara ÇS, Aycan Z, Açoğlu E, Senel S, Oguz MM, Ceylaner S. The variable clinical phenotype of three patients with hepatic glycogen synthase deficiency. J Pediatr Endocrinol Metab. 2017;30:459–62.

    CAS  Article  PubMed  Google Scholar 

  18. Ponzi E, Maiorana A, Lepri FR, Mucciolo M, Semeraro M, Taurisano R, et al. Persistent hypoglycemia in children: targeted gene panel improves the diagnosis of hypoglycemia due to inborn errors of metabolism. J Pediatr. 2018;202:272-78.e4.

    Article  PubMed  Google Scholar 

  19. Sandhu T, Polan M, Yu Z, Lu R, Makkar A. Case of neonatal fatality from neuromuscular variant of glycogen storage disease type IV. JIMD Rep. 2019;45:51–5.

    Article  PubMed  Google Scholar 

  20. Magoulas PL, El-Hattab AW. Glycogen Storage Disease Type IV. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2013 [updated 2019]. P. 1993–2022

  21. Szymańska E, Szymańska S, Truszkowska G, Ciara E, Pronicki M, Shin YS. Variable clinical presentation of glycogen storage disease type IV: from severe hepatosplenomegaly to cardiac insufficiency. Some discrepancies in genetic and biochemical abnormalities. Arch Med Sci. 2018;14:237–47.

    CAS  Article  PubMed  Google Scholar 

  22. Zellweger H, Mueller S, Ionasescu V, Schochet SS, McCormick WF. Glycogenosis. IV. A new cause of infantile hypotonia. J Pediatr. 1972;80:842–4.

    CAS  Article  PubMed  Google Scholar 

  23. Greene HL, Ghishan FK, Brown B, McClenathan DT, Freese D. Hypoglycemia in type IV glycogenosis: hepatic improvement in two patients with nutritional management. J Pediatr. 1988;112:55–8.

    CAS  Article  PubMed  Google Scholar 

  24. Moses SW, Parvari R. The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies. Curr Mol Med. 2002;2:177–88.

    CAS  Article  PubMed  Google Scholar 

  25. Sreekantam S, Rizvi H, Brown R, Santra S, Raiman J, Vijay S, et al. An uncommon cause of early infantile liver disease and raised chitotriosidase. JIMD Rep. 2020;54:22–4.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Derks TGJ, Peeks F, de Boer F, Fokkert-Wilts M, van der Doef HPJ, van den Heuvel MC, et al. The potential of dietary treatment in patients with glycogen storage disease type IV. J Inherit Metab Dis. 2021;44:693–704.

    CAS  Article  PubMed  Google Scholar 

  27. Sokal EM, Van Hoof F, Alberti D, de Ville de Goyet J, de Barsy T, Otte JB. Progressive cardiac failure following orthotopic liver transplantation for type IV glycogenosis. Eur J Pediatr. 1992;151:200–3.

    CAS  Article  PubMed  Google Scholar 

  28. Rosenthal P, Podesta L, Grier R, Said JW, Sher L, Cocjin J, et al. Failure of liver transplantation to diminish cardiac deposits of amylopectin and leukocyte inclusions in type IV glycogen storage disease. Liver Transplant Surg. 1995;1:373–6.

    CAS  Article  Google Scholar 

  29. Liu M, Sun LY. Liver transplantation for glycogen storage disease type IV. Front Pediatr. 2021;9: 633822.

    Article  PubMed  PubMed Central  Google Scholar 

  30. McConkie-Rosell A, Wilson C, Piccoli DA, Boyle J, DeClue T, Kishnani P, et al. Clinical and laboratory findings in four patients with the non-progressive hepatic form of type IV glycogen storage disease. J Inherit Metab Dis. 1996;19(1):51–8.

    CAS  Article  PubMed  Google Scholar 

  31. Dhawan A, Tan KC, Portmann B, Mowat AP. Glycogenosis type IV: liver transplant at 12 years. Arch Dis Child. 1994;71:450–1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Lamperti C, Salani S, Lucchiari S, Bordoni A, Ripolone M, Fagiolari G, et al. Neuropathological study of skeletal muscle, heart, liver, and brain in a neonatal form of glycogen storage disease type IV associated with a new mutation in GBE1 gene. J Inherit Metab Dis. 2009;32(Suppl 1):S161–8.

    Article  PubMed  Google Scholar 

  33. Tarnopolsky MA. Myopathies related to glycogen metabolism disorders. Neurotherapeutics. 2018;15:915–27.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Labrador E, Weinstein DA. Glycogen Storage Disease Type VI. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 2009 [updated 2019]. P 1993–2022

  35. Burwinkel B, Bakker HD, Herschkovitz E, Moses SW, Shin YS, Kilimann MW. Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. Am J Hum Genet. 1998;62:785–91.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Grünert SC, Hannibal L, Spiekerkoetter U. the phenotypic and genetic spectrum of glycogen storage disease type VI. Genes (Basel). 2021;12:1205.

    CAS  Article  Google Scholar 

  37. Kishnani PS, Goldstein J, Austin SL, Arn P, Bachrach B, Bali DS, et al. ACMG Work group on diagnosis and management of glycogen storage diseases type VI and IX. Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019;21:772–89.

    Article  PubMed  Google Scholar 

  38. Lu SQ, Feng JY, Liu J, Xie XB, Lu Y, Abuduxikuer K. Glycogen storage disease type VI can progress to cirrhosis: ten Chinese patients with GSD VI and a literature review. J Pediatr Endocrinol Metab. 2020;33:1321–33.

    Article  PubMed  Google Scholar 

  39. Burda P, Hochuli M. Hepatic glycogen storage disorders: what have we learned in recent years? Curr Opin Clin Nutr Metab Care. 2015;18:415–21.

    CAS  Article  PubMed  Google Scholar 

  40. Beyzaei Z, Ezgu F, Geramizadeh B, Alborzi A, Shojazadeh A. Novel mutations in the PHKB gene in an iranian girl with severe liver involvement and glycogen storage disease type IX: a case report and review of literature. BMC Pediatr. 2021;21:175.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Hendrickx J, Coucke P, Hors-Cayla MC, Smit GP, Shin YS, Deutsch J, et al. Localization of a new type of X-linked liver glycogenosis to the chromosomal region Xp22 containing the liver alpha-subunit of phosphorylase kinase (PHKA2). Genomics. 1994;21:620–5.

    CAS  Article  PubMed  Google Scholar 

  42. Fu J, Wang T, Xiao X. A novel PHKA2 mutation in a Chinese child with glycogen storage disease type IXa: a case report and literature review. BMC Med Genet. 2019;20:56.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Tsilianidis LA, Fiske LM, Siegel S, Lumpkin C, Hoyt K, Wasserstein M, et al. Aggressive therapy improves cirrhosis in glycogen storage disease type IX. Mol Genet Metab. 2013;109:179–82.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Roscher A, Patel J, Hewson S, Nagy L, Feigenbaum A, Kronick J, et al. The natural history of glycogen storage disease types VI and IX: long-term outcome from the largest metabolic center in Canada. Mol Genet Metab. 2014;113:171–6.

    CAS  Article  PubMed  Google Scholar 

  45. Johnson AO, Goldstein JL, Bali D. Glycogen storage disease type IX: novel PHKA2 missense mutation and cirrhosis. J Pediatr Gastroenterol Nutr. 2012;55:90–2.

    Article  PubMed  Google Scholar 

  46. Rodríguez-Jiménez C, Santos-Simarro F, Campos-Barros Á, Camarena C, Lledín D, Vallespín E, et al. A new variant in PHKA2 is associated with glycogen storage disease type IXa. Mol Genet Metab Rep. 2017;10:52–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Burwinkel B, Amat L, Gray RG, Matsuo N, Muroya K, Narisawa K, et al. Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene. Hum Genet. 1998;102:423–9.

    CAS  Article  PubMed  Google Scholar 

  48. Burwinkel B, Maichele AJ, Aagenaes O, Bakker HD, Lerner A, Shin YS, et al. Autosomal glycogenosis of liver and muscle due to phosphorylase kinase deficiency is caused by mutations in the phosphorylase kinase beta subunit (PHKB). Hum Mol Genet. 1997;6:1109–15.

    CAS  Article  PubMed  Google Scholar 

  49. Burwinkel B, Rootwelt T, Kvittingen EA, Chakraborty PK, Kilimann MW. Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene. Pediatr Res. 2003;54:834–9.

    CAS  Article  PubMed  Google Scholar 

  50. Chen MA, Weinstein DA. Glycogen storage diseases: diagnosis, treatment and outcome. Transl Sci Rare Dis. 2016;1:45–72.

    Article  Google Scholar 

  51. Waheed N, Saeed A, Ijaz S, Fayyaz Z, Anjum MN, Zahoor Y, et al. Variability of clinical and biochemical phenotype in liver phosphorylase kinase deficiency with variants in the phosphorylase kinase (PHKG2) gene. J Pediatr Endocrinol Metab. 2020;33:1117–23.

    CAS  Article  PubMed  Google Scholar 

  52. Al-Haggar M. Fanconi–Bickel syndrome as an example of marked allelic heterogeneity. World J Nephrol. 2012;1:63–8.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Sharari S, Abou-Alloul M, Hussain K, Ahmad KF. Fanconi–Bickel syndrome: a review of the mechanisms that lead to dysglycaemia. Int J Mol Sci. 2020;21:6286.

    CAS  Article  PubMed Central  Google Scholar 

  54. Mohandas Nair K, Sakamoto O, Jagadeesh S, Nampoothiri S. Fanconi–Bickel syndrome. Indian J Pediatr. 2012;79:112–4.

    CAS  Article  PubMed  Google Scholar 

  55. Afroze B, Chen M. Fanconi–Bickel syndrome: two pakistani patients presenting with hypophosphatemic rickets. J Pediatr Genet. 2016;5:161–6.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Sahin F, Sipahi T, Doğan H, Oksal A, Ertan U. Special feature: pathological case of the month. Glycogen storage disease with renal tubular dysfunction (type XI, Fanconi-Bickel syndrome). Arch Pediatr Adolesc Med. 2000;154:1165–6.

    CAS  Article  PubMed  Google Scholar 

  57. Seyer P, Vallois D, Poitry-Yamate C, Schütz F, Metref S, Tarussio D, et al. Hepatic glucose sensing is required to preserve β cell glucose competence. J Clin Invest. 2013;123:1662–76.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Ozer EA, Aksu N, Uclar E, Erdogan H, Bakiler AR, Tsuda M, et al. No mutation in the SLC2A2 ( GLUT2) gene in a Turkish infant with Fanconi–Bickel syndrome. Pediatr Nephrol. 2003;18:397–8.

    Article  PubMed  Google Scholar 

  59. Stanescu DE, Hughes N, Kaplan B, Stanley CA, De León DD. Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab. 2012;97:E2026–30.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Stanik J, Skopkova M, Brennerova K, Danis D, Rosolankova M, Salingova A, et al. Congenital hyperinsulinism and glycogenosis-like phenotype due to a novel HNF4A mutation. Diabetes Res Clin Pract. 2017;126:144–50.

    CAS  Article  PubMed  Google Scholar 

  61. Ross KM, Ferrecchia IA, Dahlberg KR, Dambska M, Ryan PT, Weinstein DA. Dietary management of the glycogen storage diseases: evolution of treatment and ongoing controversies. Adv Nutr. 2020;11:439–46.

    Article  PubMed  Google Scholar 

  62. Hoogeveen IJ, van der Ende RM, van Spronsen FJ, de Boer F, Heiner-Fokkema MR, Derks TG. Normoglycemic ketonemia as biochemical presentation in ketotic glycogen storage disease. JIMD Rep. 2016;28:41–7.

    Article  PubMed  Google Scholar 

  63. Pennisi A, Maranda B, Benoist JF, Baudouin V, Rigal O, Pichard S, et al. Nocturnal enteral nutrition is therapeutic for growth failure in Fanconi–Bickel syndrome. J Inherit Metab Dis. 2020;43:540–8.

    CAS  Article  PubMed  Google Scholar 

  64. Szymańska E, Lipiński P, Rokicki D, Książyk J, Tylki-Szymańska A. Over 20-year follow-up of patients with hepatic glycogen storage diseases: single-center experience. Diagnostics (Basel). 2020;10:297.

    Article  Google Scholar 

  65. Willems PJ, Gerver WJ, Berger R, Fernandes J. The natural history of liver glycogenosis due to phosphorylase kinase deficiency: a longitudinal study of 41 patients. Eur J Pediatr. 1990;149:268–71.

    CAS  Article  PubMed  Google Scholar 

  66. Zhan Q, Lv Z, Tang Q, Huang L, Chen X, Yang M, et al. Glycogen storage disease type VI with a novel PYGL mutation: two case reports and literature review. Medicine (Baltimore). 2021;100: e25520.

    Article  Google Scholar 

  67. de Moor RA, Schweizer JJ, van Hoek B, Wasser M, Vink R, Maaswinkel-Mooy PD. Hepatocellular carcinoma in glycogen storage disease type IV. Arch Dis Child. 2000;82:479–80.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Ogawa A, Ogawa E, Yamamoto S, Fukuda T, Sugie H, Kohno Y. Case of glycogen storage disease type VI (phosphorylase deficiency) complicated by focal nodular hyperplasia. Pediatr Int. 2010;52:e150–3.

    Article  PubMed  Google Scholar 

  69. Manzia TM, Angelico R, Toti L, Cillis A, Ciano P, Orlando G, et al. Glycogen storage disease type Ia and VI associated with hepatocellular carcinoma: two case reports. Transplant Proc. 2011;43:1181–3.

    CAS  Article  PubMed  Google Scholar 

  70. Kim TH, Kim KY, Kim MJ, Seong MW, Park SS, Moon JS, et al. Molecular diagnosis of glycogen storage disease type IX using a glycogen storage disease gene panel. Eur J Med Genet. 2020;63: 103921.

    Article  PubMed  Google Scholar 

  71. Pogoriler J, O’Neill AF, Voss SD, Shamberger RC, Perez-Atayde AR. Hepatocellular carcinoma in Fanconi–Bickel syndrome. Pediatr Dev Pathol. 2018;21:84–90.

    Article  PubMed  Google Scholar 

  72. Schippers HM, Smit GP, Rake JP, Visser G. Characteristic growth pattern in male X-linked phosphorylase-b kinase deficiency (GSD IX). J Inherit Metab Dis. 2003;26:43–7.

    CAS  Article  PubMed  Google Scholar 

  73. Beauchamp NJ, Dalton A, Ramaswami U, Niinikoski H, Mention K, Kenny P, et al. Glycogen storage disease type IX: high variability in clinical phenotype. Mol Genet Metab. 2007;92:88–99.

    CAS  Article  PubMed  Google Scholar 

  74. Haffner D, Weinfurth A, Manz F, Schmidt H, Bremer HJ, Mehls O, et al. Long-term outcome of paediatric patients with hereditary tubular disorders. Nephron. 1999;83:250–60.

    CAS  Article  PubMed  Google Scholar 

  75. Santer R, Schneppenheim R, Suter D, Schaub J, Steinmann B. Fanconi-Bickel syndrome–the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature. Eur J Pediatr. 1998;157:783–97.

    CAS  Article  PubMed  Google Scholar 

  76. Dayal D, Dekate P, Sharda S, Das A, Attri S. An Indian girl with Fanconi–Bickel syndrome without SLC2A2 gene mutation. J Pediatr Genet. 2013;2:109–12.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Willot S, Marchand V, Rasquin A, Alvarez F, Martin SR. Systemic progression of type IV glycogen storage disease after liver transplantation. J Pediatr Gastroenterol Nutr. 2010;51:661–4.

    Article  PubMed  Google Scholar 

  78. Starzl TE, Demetris AJ, Trucco M, Ricordi C, Ildstad S, Terasaki PI, et al. Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher’s disease. N Engl J Med. 1993;328:745–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. Reusche E, Aksu F, Goebel HH, Shin YS, Yokota T, Reichmann H. A mild juvenile variant of type IV glycogenosis. Brain Dev. 1992;14:36–43.

    CAS  Article  PubMed  Google Scholar 

  80. Christesen HT, Brusgaard K, Hussain K. Recurrent spontaneous hypoglycaemia causes loss of neurogenic and neuroglycopaenic signs in infants with congenital hyperinsulinism. Clin Endocrinol (Oxf). 2012;76:548–54.

    CAS  Article  Google Scholar 

  81. Hellmann MA, Kakhlon O, Landau EH, Sadeh M, Giladi N, Schlesinger I, et al. Frequent misdiagnosis of adult polyglucosan body disease. J Neurol. 2015;262:2346–51.

    Article  PubMed  Google Scholar 

  82. Lau CK, Hui J, Fong FN, To KF, Fok TF, Tang NL, et al. Novel mutations in PHKA2 gene in glycogen storage disease type IX patients from Hong Kong. China Mol Genet Metab. 2011;102:222–5.

    CAS  Article  PubMed  Google Scholar 

  83. Woerner AC, Gallagher RC, Vockley J, Adhikari AN. The use of whole genome and exome sequencing for newborn screening: challenges and opportunities for population health. Front Pediatr. 2021;9: 663752.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Horton RH, Lucassen AM. Recent developments in genetic/genomic medicine. Clin Sci (Lond). 2019;133:697–708.

    Article  Google Scholar 

  85. Ross KM, Brown LM, Corrado MM, Chengsupanimit T, Curry LM, Ferrecchia IA, et al. Safety and efficacy of chronic extended release cornstarch therapy for glycogen storage disease type I. JIMD Rep. 2016;26:85–90.

    Article  PubMed  Google Scholar 

  86. Hijazi G, Pai N, Nagy LL, Herd S, Dickson J, Ram M, et al. Use of waxy maize heat modified starch in the treatment of children between 2 and 5 years with glycogen storage disease type I: a retrospective study. Mol Genet Metab Rep. 2019;21: 100536.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Boursier J, Hagström H, Ekstedt M, Moreau C, Bonacci M, Cure S, et al. Non-invasive tests accurately stratify patients with NAFLD based on their risk of liver-related events. J Hepatol. 2022;76:1013–20.

    CAS  Article  PubMed  Google Scholar 

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M.M. concepted the study and wrote the original draft of the article; M.M., F.T., C.D., A.M. reviewed and edited the manuscript; A.M. supervised the study. All authors read and approved the final manuscript.

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Massese, M., Tagliaferri, F., Dionisi-Vici, C. et al. Glycogen storage diseases with liver involvement: a literature review of GSD type 0, IV, VI, IX and XI. Orphanet J Rare Dis 17, 241 (2022).

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  • GSDs
  • Glycogen storage diseases
  • Hypoglycemia