INTRODUCTION — Glycogen is the stored form of glucose and serves as a buffer for glucose needs. It is composed of long polymers of a 1-4 linked glucose, interrupted by a 1-6 linked branch point every 4 to 10 residues. Glycogen is formed in periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1).
There are a number of inborn errors of glycogen metabolism that result from pathogenic variants in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation. Those disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs). They have largely been categorized by number, according to the chronology of recognition of the responsible enzyme defect (table 1). The age of onset varies from in utero to adulthood.
Glycogen is most abundant in liver and muscle, which are most affected by these disorders. The physiologic importance of a given enzyme in liver and muscle determines the clinical manifestations of the disease.
●The main role of glycogen in the liver is to store glucose for release to tissues that are unable to synthesize significant amounts during fasting. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly. (See "Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus".)
●Glycogen is the primary source of energy for high-intensity muscle activity by providing substrates for the generation of adenosine triphosphate (ATP). The major manifestations of disorders of glycogen metabolism affecting muscle are muscle cramps, exercise intolerance and easy fatigability, and progressive weakness.
Glycogen branching enzyme (GBE) deficiency (GSD IV, MIM #232500) is also known as Andersen disease. This topic will review GBE deficiency (GSD IV). An overview of GSD is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
PATHOGENESIS — GBE (amylo [1,4 to 1,6] transglucosidase) catalyzes the attachment of short glucosyl chains to a naked peripheral chain of nascent glycogen (figure 1). Deficiency results in abnormal structure of glycogen (similar to amylopectin), known as polyglucosan, with fewer branch points and longer alpha-1-4-linked glucose polymers.
GENETICS — GBE deficiency is an autosomal-recessive disorder caused by pathogenic variants in the GBE1 gene, located at 3p14. Although the enzyme is broadly expressed, the specific mechanisms that account for the variable clinical presentations are uncertain. However, absent enzyme activity is associated with severe disease, while milder phenotypes have residual enzyme activity . Multiple pathogenic variants of the GBE gene have been associated with the neuromuscular form of the disease [2,3]. Truncating GBE1 pathogenic variants cause a spectrum of disease severity ranging from intrauterine hydrops to fatal perinatal hypotonia and cardiomyopathy, resulting in death during the first months of life .
CLINICAL FEATURES — Affected patients typically present in early infancy with hepatosplenomegaly and failure to thrive. Hypoglycemia has traditionally been viewed as a feature that does not appear until late in the course of the disease, when it is associated with cirrhosis, esophageal varices, and ascites. However, more recent case reports describe fasting intolerance and/or ketosis in patients prior to the onset of irreversible liver disease . Hepatocellular carcinoma may develop in patients with progressive liver disease . The disorder can be rapidly progressive, leading to terminal liver failure without transplantation .
The less common neuromuscular form of GSD IV is clinically and genetically heterogeneous. Four main phenotypic variants have been distinguished based on the age of onset :
●A perinatal form with fetal akinesia deformation sequence (FADS) characterized by multiple congenital contractures, hydrops fetalis, cardiac dysfunction, and perinatal death [4,8-10].
●A congenital form with congenital hypotonia, muscle atrophy, cardiomyopathy, and weakness and a rapidly deteriorating course with death in early infancy [4,11-15]. Severe congenital cases are almost uniformly associated with "null" mutations.
●A late-childhood form with skeletal myopathy or cardiomyopathy [16,17].
●An adult form that can present as an isolated myopathy or cardiomyopathy or as adult polyglucosan body disease (APBD), a multisystem disorder [18,19]. These patients have symptoms and signs of upper and lower motor neuron involvement. In a review of 50 cases of APBD, the typical first manifestation was bladder incontinence, followed by gait disturbance and lower limb paresthesias . Progressive dementia is seen in patients with APBD . Some patients have an atypical form of APBD, with onset in early adulthood, a history of liver involvement in infancy, and a subacute relapsing-remitting course similar to multiple sclerosis .
GBE activity ranges from 8 to 25 percent, depending upon the specific genetic defect [18,23,24]. Neuropathologic examination reveals accumulation of polyglucosan bodies (PBs) in the cortex (processes of neurons) and white matter (astrocytes and microglial cells) of the whole brain . PBs also accumulate in the peripheral nervous system .
Most patients are of Ashkenazi Jewish heritage, but non-Jewish patients have been reported as well [18,23]. Thirty percent of cases were apparent symptomatic heterozygotes . However, these patients were subsequently found to also have a deep intronic pathogenic variant that leads to abnormal RNA splicing .
DIAGNOSIS — Liver biopsy shows excessive glycogen accumulation with a characteristic staining pattern. In addition to the normal-appearing glycogen arranged in alpha and beta particles, fibrillar aggregations of glycogen are detected by electron microscopy. Fibrosis and cirrhosis are invariably present in the classic form of the disease. The diagnosis is confirmed by absent branching enzyme activity in skin fibroblasts, muscle, or liver and/or mutation analysis of the entire coding region of the GBE gene (GBE1), gene panel testing, or whole-exome sequencing . In genetically confirmed cases, prenatal diagnosis can be performed accurately in subsequent pregnancies by analysis of DNA from chorionic villi or cultured amniocytes . Polyglucosan bodies (PBs) have also been detected in placenta at 25 and 35 weeks of gestation in two genetically confirmed cases, raising the possibility of prenatal diagnosis by histologic evaluation of placental biopsies .
In patients with neuromuscular disease, the serum creatine kinase level is usually elevated. Elevated chitotriosidase, a marker of activated macrophages that is also increased in various lysosomal storage disorders, has been observed in several patients . Muscle biopsy reveals the storage of periodic acid-Schiff (PAS) stain-positive material that resists digestion with diastase. The glycogen particles appear abnormal by electron microscopy, but they are often associated with normal beta particles. PBs are also observed in genetically distinct disorders, in particular deficiencies of the muscle isoform of glycogen synthase (GYS1), the autoglycosylating protein glycogenin-1 (GYG1) that serves as the building block for glycogen synthesis, and the ubiquitin ligase RBCK1. The progressive neurologic disorder, Lafora disease, also accumulates PBs .
TREATMENT — No specific treatment is available. However, dietary management is potentially useful in patients with GBE deficiency. A high-protein, low-carbohydrate diet with frequent feeding designed to reduce polyglucosan body (PB) accumulation and ketosis is reported to improve liver function and growth in a subset of patients . Liver transplantation has been performed with evidence of reduction in glycogen storage in both heart and skeletal muscle in some patients [32,33] but extrahepatic disease progression reported in other cases . In an in vitro study, polyglucosan neurotoxicity caused by GBE deficiency was reversed with rapamycin, indicating potential therapeutic value of glycogen synthase inhibition for treating GSDs .
●Glycogen branching enzyme (GBE) deficiency (glycogen storage disease [GSD] IV, Andersen disease, MIM #232500) is an autosomal-recessive disorder caused by pathogenic variants in the GBE1 gene. It results in abnormal structure of glycogen. (See 'Pathogenesis' above and 'Genetics' above.)
●Affected patients typically present in early infancy with hepatosplenomegaly and failure to thrive. Hypoglycemia occurs late in the disease, when it is associated with cirrhosis, esophageal varices, and ascites, but fasting intolerance and/or ketosis may also occur earlier in the disease process. GBE is rapidly progressive, leading to terminal liver failure without transplantation. (See 'Clinical features' above.)
●A less common neuromuscular form of GBE deficiency is clinically heterogeneous, with four main phenotypic variants, distinguished by age of onset (perinatal, congenital, late childhood, and adult). (See 'Clinical features' above.)
●The diagnosis is confirmed by absent or reduced branching enzyme activity in skin fibroblasts, muscle, or liver and/or mutation analysis of the entire coding region of the GBE1 gene, gene panel, or whole-exome sequencing testing. DNA testing is commercially available. (See 'Diagnosis' above.)
●No specific treatment is available, although intervention may benefit a subset of patients. Liver transplantation has been performed with evidence of reduction in glycogen storage in heart and skeletal muscle. (See 'Treatment' above.)