Glycogen debrancher deficiency (glycogen storage disease III, Cori disease)

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 mutations 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 healthy individuals and patients with diabetes mellitus".)

●Glycogen serves as 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.

This topic will review glycogen debrancher deficiency (GSD III). An overview of GSD is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)

PATHOGENESIS — Glycogen debrancher deficiency (GSD III, MIM #232400) is also known as Cori disease, Forbes disease, and limit dextrinosis [1].

Glycogenolysis proceeds with stepwise removal of glucose molecules through the action of the enzyme phosphorylase (figure 1). Depolymerization of glycogen by phosphorylase halts when glycogen branches have been reduced to two to four linked glucose molecules (limit dextrins). Glycogen debrancher enzyme has two catalytic activities. One is the cleavage of a dextrin branch from the remaining glycogen molecule (amylo-1,6-glucosidase activity). The other is the transfer of the dextrin to the free end of a dextran polymer (oligo-1,4-1,4-glucanotransferase activity). The transferred dextrin may then be further depolymerized by phosphorylase. The clinical features and enzyme activities in affected patients are quite variable.

GENETICS — GSD III is inherited as an autosomal-recessive trait. It is caused by mutations in the gene that encodes the debrancher enzyme (amyloglucosidase [AGL] gene), which is located at 1p21 [2,3]. Differential ribonucleic acid (RNA) transcription results in the generation of muscle and liver isoforms, with different tissue-specific promoters and an alternative usage of the first exon. At least six transcript isoforms are produced by alternative splicing, with differing tissue distributions [4].

A variety of pathogenic variants are recognized [5]. These allow deoxyribonucleic acid (DNA) diagnosis, particularly in populations with founder mutations. The highest prevalence of GSD III (estimated at 1 in 2500) is in the Canadian Inuit population and is due to a homozygous frameshift deletion, c.4456delT [6]. GSD III in the Faroe Islands is due to the R408X truncating variant [7]. Sephardic Jewish patients in Israel have the 4455delT variant, with a disease frequency of 1 in 5400 [8]. A novel missense pathogenic variant (p.R1147G) leading to isolated glucosidase deficiency, along with nine other AGL pathogenic variants, have been described in 23 patients of Turkish ancestry [9].

Patients with both myopathy and liver involvement have an enzyme defect in both tissues. In those with only liver involvement, enzyme activity is absent in liver and normal in muscle.

CLINICAL FEATURES — Clinical manifestations of the disease are variable and are classified as four types. The majority of patients have both liver and muscle involvement (GSD IIIa). Liver involvement without muscle disease occurs in approximately 15 percent of patients (GSD IIIb). In the rare types IIIc and IIId, activity of amylo-1,6-glucosidase or oligo-1,4-1,4-glucanotransferase is selectively absent. Clinical features depend upon the tissue involved.

GSD III presents during infancy and childhood with hepatomegaly and hypoglycemia due to liver disease. Affected patients also have ketoacidosis, hyperlipidemia, and growth retardation, features that may be indistinguishable from GSD I [10]. However, GSD IIIa can be distinguished from GSD I by hypotonia, weakness, wasting of skeletal muscle, and involvement of the heart. In one series of 21 patients alive at the time of the study and with an average age of nearly 20 years, signs and symptoms of the disease had ameliorated after childhood, but approximately 20 percent had significant complications [11]. Osteopenia and osteoporosis is a common feature and appears related to metabolic control [12].

Hepatomegaly and transaminases typically improve with age and treatment, normalizing after puberty in the majority of cases. Adenomas are occasionally seen [13] and can progress to hepatocellular carcinoma [14]. Rare patients progress to cirrhotic liver disease [15]. The overall rate of severe liver disease in an international cohort of 175 adult and pediatric patients was 11 percent [16]. Persistent hypercholesterolemia was observed in a third of adult and pediatric cases, with hypertriglyceridemia almost universal in children and persistently elevated in 40 percent of adults.

Muscle weakness, which is less prominent in children with GSD IIIa, is the predominant feature in adults. In the latter group, progressive weakness and distal muscle wasting are typical and, in some cases, are associated with peripheral neuropathy [17-21]. Muscle pain with minimal exercise was reported in a third of patients with GSD IIIa and, along with distal myopathy, was associated with the development of cardiomyopathy [16]. Affected females may have polycystic ovaries but remain fertile, and guidelines for management during pregnancies have been proposed [22]. There are also reports of neurocognitive impairment in adults, with limitations in executive functions and social cognition [23].

Overall, 58 percent of the 151 patients with GSD IIIa in an international cohort had cardiac complications, with 15 percent exhibiting cardiomyopathy [16]. Cardiomyopathy with left ventricular hypertrophy is a frequent complication during childhood in patients with GSD IIIa, and it is associated with potential risk of serious arrhythmia and symptomatic heart failure [24]. Cardiomyopathy in conjunction with hepatomegaly and hypoglycemia has been described in adult patients with GSD IIIa [25,26]. A novel homozygous pathogenic variant, R285X, was detected in a 42-year-old Japanese man with hypertrophic cardiomyopathy. This nonsense mutation resulted in truncation of the AGL protein [27].

DIAGNOSIS — Serum creatine kinase concentration is elevated in patients with muscle involvement. Electromyography reveals myopathic changes. Myopathic findings and neuropathy are more likely to be detected by electromyography and nerve conduction studies in older patients, even in those with GSD IIIb [28]. Ischemic forearm muscle testing results in a smaller-than-expected increase in serum lactate concentration. (See "Approach to the metabolic myopathies", section on 'Semi-ischemic exercise test'.)

Patients with liver disease have elevated serum transaminase levels. In contrast to GSD I, consistent hypertriglyceridemia, lactic acidosis, and hyperuricemia are not present in GSD III.

DNA testing of the AGL gene is commercially available. The diagnosis can be confirmed by measuring reduced or absent debrancher enzyme activity in liver, muscle, or fibroblasts [29]. Liver histology reveals glycogen storage. Fibrosis may be prominent, although fat infiltration usually is not seen. Muscle histology is characterized by free glycogen accumulation. The glycogen particles are periodic acid-Schiff (PAS) stain positive, digestible by diastase, and appear as normal particles by electron microscopy.

TREATMENT — There is no specific therapy for GSD III. Symptomatic treatment includes avoidance of hypoglycemia. This tends to be less severe than in GSD I, so treatment is less demanding. Frequent feeding of uncooked cornstarch (approximately 0.5 to 1 g/kg/dose, four to five times a day) and continuous feeding of formula at night are used to maintain glucose levels [29]. Because GSD III patients have intact gluconeogenesis, a high-protein diet (3 g/kg/day) is useful [30]. Unlike GSD I, avoiding fructose and galactose in the diet is not necessary. A high-protein diet (30 percent of total energy) and avoidance of overtreatment with cornstarch can reverse and may prevent GSD type IIIa-related cardiomyopathy [31]. A high-fat diet may also improve cardiomyopathy, as was seen in two siblings seven and five years of age affected with GSD IIIa 12 months after starting a high-fat (60 percent), high-protein (25 percent), and low-carbohydrate (15 percent) diet [32].

In a pilot study, the use of physically modified cornstarch (waxy maize heat-modified 20 [WMHM20]), a form of starch containing higher amounts of branched polymers, provided better short-term metabolic control and longer duration of euglycemia than uncooked cornstarch in patients with GSD Ia, Ib, and III [33,34]. Modified cornstarch also appears effective in young children [35].

A high-protein diet appears successful in reversing heart failure in some patients [31,36], and a high-fat diet improves cardiomyopathy [32,37]. As an example, a 34-year-old patient with GSD IIIa with associated hypertrophic cardiomyopathy was treated with a modified Atkins ketogenic diet (high fat, high protein with 20 grams carbohydrate per day, fat:protein, 1 to 2:1). Ejection fraction increased from 30 to 45 percent, liver enzymes were reduced, and creatine kinase plasma level decreased from 568 to 327 units/L after 12 months of treatment. In addition, physical activity increased and health-related quality of life improved over time [37]. A high-fat diet may be beneficial in children and adults with GSD IIIa and associated cardiomyopathy; however, careful long-term monitoring for potential complications is necessary to detect early growth delay, liver inflammation, and development of hepatocellular carcinoma [38].

Excellent graft and patient survival has been shown in a small number of patients with GSD III who underwent living donor or deceased donor liver transplantation [39,40].

In a small series, liver transplantation improved metabolic control but did not improve muscle disease [40,41]. Liver transplantation is an option in patients with severe liver dysfunction, hepatic cirrhosis, and/or hepatocellular carcinoma [29]. However, it may worsen myopathy and cardiomyopathy.

Recombinant human acid alpha-glucosidase (rhGAA, alglucosidase alfa), the enzyme defective in Pompe disease, significantly reduced glycogen levels in muscle cells from two patients with GSD IIIa in vitro, indicating that rhGAA is a potential novel therapy for GSD III. In vivo studies are needed to confirm clinical efficacy [42]. In another in vitro study, rapamycin inhibited glycogen accumulation in muscle cells from a patient with GSD IIIa [43]. In vivo studies in dogs with GSD IIIa showed that rapamycin reduced muscle glycogen content, suggesting that this is another potential therapy for GSD IIIa. (See "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)", section on 'Treatment'.)

SUMMARY

●Pathogenesis and genetics – Glycogen debrancher enzyme plays an important role in glycogenolysis (figure 1). Glycogen debrancher deficiency (glycogen storage disease [GSD] III, Cori disease, Forbes disease, limit dextrinosis) is inherited as an autosomal-recessive trait. It is caused by mutations in the gene that encodes the debrancher enzyme (amyloglucosidase [AGL] gene). (See 'Pathogenesis' above and 'Genetics' above.)

●Clinical features – The clinical manifestations vary depending upon the involved tissues (muscle and/or liver) and enzyme activities. In infants and children, GSD III presents with hepatomegaly and hypoglycemia due to liver disease. Additional features may include growth failure, hypotonia, weakness, wasting of skeletal muscle, involvement of the heart, ketoacidosis, osteoporosis, and hyperlipidemia. Muscle weakness is the prominent feature in adults. (See 'Clinical features' above.)

●Diagnosis – Laboratory studies that support the diagnosis of GSD III in patients with muscle involvement include elevated serum creatine kinase concentration in patients, myopathic changes on electromyography, and a smaller-than-expected increase in serum lactate concentration during ischemic forearm muscle testing. Laboratory studies that support the diagnosis in patients with liver involvement include elevated serum transaminase levels. DNA testing is commercially available. The diagnosis can be confirmed by measuring reduced or absent debrancher enzyme activity in liver, muscle, or fibroblasts. (See 'Diagnosis' above.)

●Treatment – There is no specific therapy for GSD III. Symptomatic treatment includes avoidance of hypoglycemia (eg, frequent feeding of uncooked cornstarch, continuous formula feeding of infant overnight). A high-protein diet may be helpful, and a high-fat diet may be appropriate for those with cardiomyopathy. (See 'Treatment' above.)