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 phosphorylase b kinase (PBK) deficiency (MIM #306000), which is usually an X-linked disorder. There is confusion over the GSD classification of PBK deficiency as both numbers VIII and IX have been assigned. An overview of GSD is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
PHOSPHORYLASE B KINASE — PBK is required for the activation of phosphorylase by converting the less enzymatically active phosphorylase b to the more active phosphorylase with a resulting increase in glycogenolysis. PBK also catalyzes the conversion of glycogen synthase from a more to a less active form. Because of these reciprocal changes, glycogen degradation is active when glycogen synthesis is inactive and vice versa.
The enzyme is composed of four separate subunits (alpha, beta, gamma, delta), each encoded by a distinct gene [1,2]. The holoenzyme is made up of four copies of each isoform for a final complex of 16 subunits.
GENETICS — PBK (or PHK) deficiency is genetically heterogeneous, with both autosomal recessive and X-linked forms. This has led to inconsistent classification schemes. The disease has been subclassified depending on the subunit involved. Defects in the alpha subunit account for 75 percent of cases.
PBK deficiency has considerable locus and allelic heterogeneity. The majority of cases are the X-linked liver-specific disease, caused by a variety of mutations in the phosphorylase kinase regulatory subunit alpha 2 (PHKA2) locus at Xp22 and resulting in a defective alpha or L (liver isoform) subunit. A common cause of hepatic PBK deficiency in Dutch patients is a missense variant in the PHKA2 gene that results in a leucine rather than a proline at amino acid 1205 (p.Pro1205Leu) [3].
The mutation type in patients with disease isolated to the liver appears to correlate with clinical severity. Red blood cell enzyme activity is preserved with hypomorphic variants and lost with more severe loss-of-function variants [4]. Rarely, female carriers of the X-linked form manifest clinical features.
Mutations in the beta subunit of the phosphorylase b kinase gene (PHKB) located at 16q12 have been described in patients with combined liver and muscle deficiency (glycogen storage disease [GSD] IXb) [5,6]. Autosomal liver disease is caused by pathogenic variants in the catalytic gamma subunit encoded by the PHKG2 gene at 16p12 (GSDIXc) [7,8]. These patients risk a more severe fibrotic liver disease and hepatocellular carcinoma [9], in addition to symptoms of hypoglycemia. Muscle-specific disease (GSDIXd) is caused by pathogenic variants in the muscle-specific alpha(M) subunit (PHKA1) located at Xq13 [6,10,11]. At least six patients have been described, generally with modest elevation of blood creatine phosphokinase (CPK) and variable degrees of exercise intolerance. One patient had cognitive impairment but no evidence of myopathy, and it was suggested that there is a central nervous system function for this subunit, which is known to be expressed in the brain [12].
No pathogenic variants in the genes encoding the muscle-specific gamma (PHKG1) and delta (PHKD; also called calmodulin 1 [CALM1]) PBK subunits have been described in myopathic patients with PBK deficiency. CALM1 pathogenic variants have been reported in individuals experiencing catecholaminergic polymorphic ventricular tachycardia (CPVT), sudden death, and long QT syndrome [13-15].
CLINICAL FEATURES — Most cases of PBK (or PHK) deficiency are mild. They typically present in early childhood with growth retardation and hepatomegaly, sometimes with hypoglycemia or rarely hypotonia and developmental delay [16]. Unlike some other glycogen storage diseases (GSDs) affecting the liver, the response to glucagon is normal.
In a longitudinal study of 41 patients with PBK deficiency, the following features were described [17]:
●Hepatomegaly – 92 percent
●Growth retardation – 68 percent
●Delayed motor development – 52 percent
●Hypercholesterolemia – 76 percent
●Hypertriglyceridemia – 70 percent
●Elevated glutamate pyruvate transaminase – 56 percent
●Fasting hyperketosis – 44 percent
The course generally is benign. Symptoms resolve over time so that most adults are asymptomatic. The initial growth retardation is typically followed by a spurt of growth that results in a final height that is normal [18].
Other presentations of PBK deficiency include the following:
●Myopathy, which presents primarily with exercise intolerance, cramps, myalgias, weakness in exercising muscles, and, in rare cases, hypotonia in young children. Intense exercise-induced myoglobinuria has been reported in less than 50 percent of cases, usually in children or adolescents [19]. In older individuals, progressive distal weakness is more prominent than proximal weakness [11,20-23]. This myopathic form has autosomal or X-linked inheritance (see 'Genetics' above). Approximately 20 patients with pathogenic variants in the X-linked PHKA1 gene for the alpha subunit of PBK have been reported thus far, and all presented with myopathic symptoms. However, a 17-year-old patient with a PHKA1 gene variant not previously reported presented with cognitive impairment ("borderline" intellectual disability) but no signs of overt myopathy [12].
●Fatal infantile cardiomyopathy was described in patients reported to have infantile-onset PBK deficiency [24,25], a puzzling finding given that there is no cardiac isoform of PBK. However, it has since been determined that the "pseudo PHK deficiency" in these patients is secondary to de novo heterozygous activating pathogenic variants in the gamma-2 subunit of adenosine monophosphate (AMP) activated protein kinase (PRKAG2) gene, the product of which is abundantly expressed in the heart [26,27]. Adults with unclassified muscle glycogenosis and cardiac involvement with conduction abnormalities may harbor similar point mutations [28,29]. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'PRKAG2 and LAMP2 genes'.)
●The liver and muscle disease subtype is characterized by liver enlargement and nonprogressive muscle disease in childhood [22].
●Clinical severity varies widely in patients with mutations in the gamma subunit of PBK gene (PHKG2) [30]. Some patients may develop cirrhosis [31].
●Fetal onset has been described in a premature female newborn with history of diminished fetal movements, hypotonia at birth, absent spontaneous movements, increased flexor tone in the extremities, lack of psychomotor development, and death at two months due to central apnea [32]. No hypoglycemic episodes were documented, and myocardial function was normal. While muscle biopsy and enzymatic studies were consistent with PBK deficiency, molecular confirmation of the diagnosis is missing in this case.
DIAGNOSIS — To avoid tissue biopsies, deoxyribonucleic acid (DNA) testing can be performed first [33]. If necessary, the diagnosis can be confirmed by reduced or absent PBK (or PHK) activity in the affected tissue, either liver or muscle. Patients with muscle involvement typically have elevated serum creatine kinase activity. If the liver is affected, biopsy reveals excessive glycogen accumulation. The rosettes have a less compact appearance than in other liver glycogenoses. Hepatic fibrosis may be seen.
Molecular testing
●Use of next-generation sequencing panels is recommended because multiple genes are involved.
●Limitations of molecular testing should be recognized, and the diagnosis pursued by other methods if there is a strong clinical suspicion and molecular testing is negative.
●PBK (or PHK) enzyme activity can be normal or elevated in blood cells, including erythrocytes, in affected persons. Liver or muscle biopsy may be necessary for confirmation of the diagnosis if variants of unknown significance are identified by genetic testing [34].
Forearm ischemic exercise test — In affected individuals, the forearm ischemic exercise test (FIET) reveals a normal or only partially impaired rise of venous lactate levels. This finding is probably related to activation of residual PBK by calcium or cyclic adenosine monophosphate (cAMP) dependent protein kinase or the direct activation of PBK by exercise-increased inosine monophosphate or inorganic phosphorous metabolites. In an adult patient with X-linked PBK deficiency, there was a normal lactate response during FIET. However, during 60 percent of maximal exercise, there was no increase in blood lactate compared with a fourfold increase in healthy controls [35]. The different response of lactate to submaximal aerobic and maximal anaerobic exercise suggests differential activation mechanisms for PBK under these circumstances.
Muscle biopsy — The muscle biopsy is usually normal or reveals subsarcolemmal accumulation of glycogen, primarily in type 2B fibers. The glycogen particles appear free and structurally normal by electron microscopy. Quantitation of muscle glycogen reveals either normal or slightly increased amounts. Immunohistochemical study of frozen muscle sections for phosphorylase is normal, and biochemical determination of PBK activity in muscle reveals either total absence or markedly decreased activity [1]. However, the myopathic presentation is relatively mild, which has raised the question of whether this is a true disease or just a metabolic variant [19,36].
TREATMENT — There is no specific therapy for this disorder. Carbohydrate-rich feedings should be provided in patients with hypoglycemia, and increased protein intake (to 2 to 3 g/kg/day) is recommended by some experts [37-39]. Nighttime cornstarch can be used as a slowly absorbed form of glucose. Patients should be monitored for progressive liver disease, particularly in the autosomal form.
SUMMARY
●Phosphorylase b kinase (PBK) converts phosphorylase b (less active) to phosphorylase a (more active) with a resulting increase in glycogenolysis. PBK also catalyzes the conversion of glycogen synthase from a more to a less active form. (See 'Phosphorylase b kinase' above.)
●PBK deficiency is genetically heterogeneous, with both autosomal recessive and X-linked forms. (See 'Genetics' above.)
●Many cases of PBK deficiency are mild, but more severe disease can be seen. They typically present in early childhood with growth retardation and hepatomegaly, sometimes with hypoglycemia or inappropriate ketosis. The response to glucagon is normal. Symptoms generally resolve over time so that most adults are asymptomatic. (See 'Clinical features' above.)
●The diagnosis is made by genetic testing or by reduced or absent PBK activity in the affected tissue, either liver or muscle, if molecular testing is negative. (See 'Diagnosis' above.)
●There is no specific therapy for PBK deficiency. Carbohydrate-rich feedings and increased dietary protein should be provided in patients with hypoglycemia and/or ketosis. Patients should be monitored for progressive liver disease. (See 'Treatment' above.)
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