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) (table 1).
Glycogen is most abundant in liver and muscle. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly, and the primary features of those defects that affect muscle are muscle cramps, exercise intolerance, easy fatigability, and progressive weakness.
This topic will review phosphoglycerate kinase (PGK) deficiency and phosphoglycerate mutase (PGAM) deficiency (GSD X). An overview of disorders of glycogen metabolism is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
PHOSPHOGLYCERATE KINASE DEFICIENCY — PGK catalyzes the conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate. One molecule of adenosine triphosphate (ATP) is generated in the process. Deficiency of PGK (MIM #311800) results in three different clinical presentations. (See 'Clinical features' below.)
Genetics — PGK1 is a monomeric enzyme encoded by a gene on chromosome Xq13 (PGK1). Thus, inheritance occurs as an X-linked recessive trait [1]. An isoform (PGK2) is expressed in spermatogenic cells. A variety of missense and nonsense variants of PGK1 have been described [2]. No clear genotype-phenotype association has been identified, except that there appears to be clustering of all myopathic variants in the C-terminal domain near the substrate-binding pocket [3]. Another study, however, indicated that the different clinical manifestations associated with PGK1 deficiency chiefly depend upon the distinctive type of perturbations caused by pathogenic variants in the PGK1 gene, highlighting the need for determination of the molecular properties of PGK variants to assist in prognosis and genetic counseling [4].
Clinical features — The age of onset for PGK deficiency is variable. PGK deficiency may present as either isolated or associated involvement of three tissues (erythrocytes, the central nervous system [CNS], and skeletal muscle). The amount of residual enzyme activity appears to modulate the phenotype [5-9]:
●CNS involvement – CNS dysfunction with seizures and intellectual disability that is associated with nonspherocytic hemolytic anemia. The PGK-Barcelona pathogenic variant (a c.140T>A, p.I47N) results in loss of enzyme stability and causes progressive neurologic impairment with associated chronic hemolytic anemia [10]. Patients with hemolytic anemia and CNS involvement usually lack evidence of clinical myopathy [11-14]. However, recurrent myoglobinuria was reported in a 33-year-old man with intellectual disability and reduced PGK1 activity in his muscles and erythrocytes [15]. Also, progressive leukodystrophy was described in a male patient with a history of congenital hemolytic anemia, rhabdomyolysis, and intellectual disability [16].
or
●Erythrocyte involvement – Hereditary nonspherocytic hemolytic anemia without CNS involvement [8]. Heterozygous females may have variable degrees of enzyme activity and may show some signs of hemolytic anemia.
or
●Skeletal muscle involvement – Isolated myopathy with exercise intolerance, myoglobinuria, cramps, and slowly progressive weakness. Patients with myoglobinuria usually do not develop hemolytic anemia [3,17], but concurrent hemolysis and rhabdomyolysis with associated hemoglobinuria and myoglobinuria may occur (PGK-Osaka; p.S62N) [18], and, in two cases, all three clinical features were described (p.A354P and p.I371K) [19,20]. In addition, exertional myoglobinuria and severe parkinsonism, but no hemolytic anemia, was reported in a 25-year-old man with the p.T378P variant [21]. A second, unrelated patient with presumed isolated myopathy and the same PGK1 variant also developed parkinsonism a year later [22]. Parkinsonism was also reported in a 36-year-old female carrier of a PGK1 gene pathogenic variant, suggesting that PGK1 mutations may confer susceptibility to parkinsonism. Her affected son had developed parkinsonism at nine years of age [23]. In a study of three patients with early-onset parkinsonism, 99mTc-TRODAT-1 SPECT, a dopamine transporter-specific tropane derivative, showed severe bilateral reduced putaminal uptake in the absence of structural changes, implicating the glycolytic pathway in nigrostriatal pathology [24]. Only nine cases of isolated myopathy have been reported thus far [3], but patients with PGK deficiency need to be followed for a number of years before concluding that they have only a myopathy [25]. In patients with myopathy, the resting serum creatine kinase (CK) level is usually elevated, although this feature is not uniformly observed. Muscle biopsy may reveal glycogen accumulation.
●Involvement of all three tissues – A novel PGK1 mutation (PKG1 Galveston, c.472 G>C) was reported in a four-year-old boy who presented with all three clinical manifestations [26].
Diagnosis — The diagnosis is made by demonstrating a deficiency of PGK1 enzymatic activity in muscle biopsy tissue and/or erythrocytes or by molecular analysis of the PGK1 gene [27]. There may be a history of known or suspected PGK deficiency in relatives (following an X-linked inheritance pattern). Laboratories that provide this testing are listed separately. (See "Rare RBC enzyme disorders", section on 'Phosphoglycerate kinase (PGK) deficiency'.)
Increased tetraglucoside excretion was documented in the urine of patients with PGK1 deficiency [28]. The authors have proposed measurement of urine tetraglucoside excretion as a screening test for possible glycogenosis.
The myopathic form typically presents in childhood and is difficult to distinguish clinically from glycogen storage disease (GSD) V (muscle phosphorylase deficiency) and GSD VII (muscle phosphofructokinase deficiency) without muscle biopsy and biochemical determinations [29]. (See "Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)" and "Phosphofructokinase deficiency (glycogen storage disease VII, Tarui disease)".)
Treatment — Enzyme replacement therapy for PGK deficiency is not available. Supportive care (eg, folic acid supplementation), routine monitoring, and the role of splenectomy are discussed separately. (See "Rare RBC enzyme disorders", section on 'General principles of management' and "Rare RBC enzyme disorders", section on 'Phosphoglycerate kinase (PGK) deficiency'.)
Hematopoietic cell transplantation may be an option. Allogeneic bone marrow transplant for PGK deficiency was performed in a three-year-old child with hemolytic anemia and progressive neurologic involvement [30]. The patient continued to experience significant improvement four years posttransplant, with no hemolytic episodes and amelioration of his neurologic symptoms.
PHOSPHOGLYCERATE MUTASE DEFICIENCY — PGAM catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate. Deficiency of the muscle isoform of the enzyme (PGAM2; MIM # 261670) results in muscle disease (glycogen storage disease [GSD] X) that becomes apparent in childhood or adolescence.
Genetics — The muscle form of phosphoglycerate mutase (PGAM-M) maps to chromosome 7p13-p12.3 [31]. The gene for the brain subunit (PGAM-B) maps to chromosome 10q25 [32,33]. Human PGAM is a dimer consisting of different amounts of muscle (MM) isozyme, brain (BB) isozyme, and the intermediate hybrid (MB) isozyme.
Inheritance is autosomal recessive. Various distinct pathogenic variants have been described in studies of African American, African, and White patients with PGAM-M deficiency [34-39]. Symptomatic heterozygotes have been reported [40,41], as has an asymptomatic patient with a partial PGAM deficiency [42] and a late-onset case at the age of 44 years [38].
Clinical features — PGAM deficiency presents primarily with dynamic symptoms, such as exercise intolerance, muscle aches, cramps, and myoglobinuria following intense physical activity [5,43]. Symptoms may begin in childhood or adolescence and mimic the manifestations of GSD V (muscle phosphorylase deficiency, McArdle disease). However, in contrast to patients with McArdle disease, a second-wind phenomenon does not occur, and infusion of lipid and lactate does not improve exercise capacity [44]. Between attacks, serum creatine kinase (CK) levels may be elevated.
Diagnosis — Muscle biopsy shows mild glycogen storage in most cases. Subsarcolemmal tubular aggregates have been detected in type 2 fibers in muscle biopsies from patients with PGAM deficiency [34,42,45]. Albeit nonspecific, this pathologic finding in a patient with exercise-induced cramps and recurrent myoglobinuria is highly suggestive of PGAM deficiency. PGAM-M activity is decreased on enzyme assay, and molecular analysis like targeted exome sequencing may reveal pathogenic variants in the PGAM gene [46].
Treatment — No effective therapy is available for PGAM deficiency. A single patient with PGAM deficiency became asymptomatic on dantrolene treatment and had a forearm ischemic test without exercise-induced contractures. This patient had tubular aggregates and increased Ca2+-adenosine triphosphatase (ATP) and calcium content in muscle tissue [47].
SUMMARY AND RECOMMENDATIONS
●Overview – Inborn errors of glycogen metabolism include the inherited glycogen storage diseases (GSDs) (table 1). The major manifestations of disorders of glycogen metabolism affecting muscle are muscle cramps, exercise intolerance, easy fatigability, and progressive weakness. (See "Other disorders of glycogen metabolism: GLUT2 deficiency and aldolase A deficiency", section on 'Introduction' and "Overview of inherited disorders of glucose and glycogen metabolism".)
●Phosphoglycerate kinase (PGK) deficiency – PGK deficiency can result in one of three distinct presentations or a variable combined presentation: central nervous system (CNS) dysfunction with seizures and intellectual disability that is associated with nonspherocytic hemolytic anemia; hereditary nonspherocytic hemolytic anemia without CNS involvement; isolated myopathy with exercise intolerance, myoglobinuria, cramps, and slowly progressive weakness; or all three findings. The diagnosis is confirmed by demonstrating a deficiency of PGK enzymatic activity in muscle biopsy tissue and/or erythrocytes or molecular analysis of the PGK1 gene. Enzyme replacement therapy for PGK deficiency is not available. Folic acid supplementation for hemolytic anemia is appropriate, along with monitoring for gallstones and for iron overload if frequent transfusions are needed. Hematopoietic cell transplantation may be an option. (See 'Phosphoglycerate kinase deficiency' above and "Rare RBC enzyme disorders", section on 'General principles of management' and "Rare RBC enzyme disorders", section on 'Phosphoglycerate kinase (PGK) deficiency'.)
●Phosphoglycerate mutase (PGAM) deficiency (GSD X) – PGAM deficiency (GSD X) presents primarily with dynamic symptoms, such as exercise intolerance, muscle aches, cramps, and myoglobinuria following intense physical activity. The diagnosis is confirmed by demonstrating a deficiency of PGAM-enzymatic activity in muscle biopsy tissue or molecular analysis of the PGAM2 gene. (See 'Phosphoglycerate mutase deficiency' above.)
9 : Level of residual enzyme activity modulates the phenotype in phosphoglycerate kinase deficiency.
24 : Parkinsonism in PGK1 deficiency implicates the glycolytic pathway in nigrostriatal dysfunction.
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