Glycogen Storage Disease, Type Ixd

A number sign (#) is used with this entry because glycogen storage disease IXd (GDS9D), also known as X-linked muscle phosphorylase kinase deficiency, is caused by mutation in the PHKA1 gene (311870), which encodes the alpha subunit of muscle phosphorylase kinase, on chromosome Xq13.

See also hepatic PHK deficiency (GSD9A; 306000).

Description

Glycogen storage disease type IXd is an X-linked recessive, relatively mild metabolic disorder characterized by variable exercise-induced muscle weakness or stiffness. Most patients have adult-onset of symptoms, and some can remain asymptomatic even in late adulthood. The phenotype is usually only apparent with intense exercise (summary by Preisler et al., 2012).

Clinical Features

Abarbanel et al. (1986) reported a 35-year-old man with severe exercise intolerance and muscle cramps. Muscle biopsy showed subsarcolemmal and intermyofibrillar accumulation of glycogen. Muscle phosphorylase kinase activity was 12% of control values.

Clemens et al. (1990) reported 2 unrelated patients with muscle phosphorylase kinase deficiency. Patient 1 was a 58-year-old man who had predominantly distal weakness beginning at age 46 years, but no cramps on exertion. Patient 2 was a 26-year-old man who had had cramps on exertion since age 6, but no muscle weakness. Muscle lactate production during ischemic exercise was impaired only in the first patient. In both patients, serum creatine kinase level was elevated, muscle phosphorylase kinase activity was low, and red cell activity was normal. Liver-specific phosphorylase kinase (300798) activity, measured in patient 1, was also normal. Wehner et al. (1994) provided follow-up on patient 1 reported by Clemens et al. (1990). He had slowly progressive, predominantly distal muscle weakness and atrophy beginning at age 46. He showed symptoms of hypoglycemia upon exertion. At age 64 years, he had weakness of the leg, arm, and abdominal muscles, rapid fatigue on exercise, and requirement for ankle braces. Phosphorylase kinase activity was 0.3% of normal in muscle, but normal in red blood cells and liver. Muscle biopsy showed mild glycogenosis with subsarcolemmal accumulations of glycogen and focal muscle fiber necrosis. The patient's mother, who died at the age of about 26 years, and his daughter, aged 33 at the time of the report, were reportedly asymptomatic. Burwinkel et al. (2003) reported follow-up on patient 2 reported by Clemens et al. (1990). At follow-up, he was a 36-year-old man with exercise-induced cramps, pain, and early fatigue since age 6 years, and occasional pigmenturia after intense exertion. Muscle glycogen concentration was elevated, and subsarcolemmal glycogen accumulation was observed in muscle histology. Total phosphorylase was normal in muscle, and phosphorylase kinase activity was markedly reduced in muscle, but normal in red blood cells.

Wuyts et al. (2005) reported a man with muscle phosphorylase kinase deficiency confirmed by genetic analysis (311870.0004). He first presented at age 43 years with pain and weakness of the quadriceps muscle. Creatine kinase was mildly elevated. Over the subsequent 8 years, he had slowly progressive weakness of the pelvic girdle muscles without pyramidal or cerebellar signs. Muscle biopsy and ultrastructural analysis showed large amounts of subsarcolemmal free glycogen accumulation and a few mitochondrial paracrystalline inclusions. Biochemical analysis showed normal total muscle phosphorylase activity, but absence of phosphorylase kinase activity.

Orngreen et al. (2008) reported a 50-year-old man with muscle phosphorylase kinase deficiency confirmed by genetic analysis (311870.0005). He reported progressive exercise intolerance, muscle stiffness on exercise, and nighttime muscle cramps since childhood. Serum creatine kinase levels were mildly elevated on several occasions, and there was low muscle PHK activity and high muscle glycogen content. During a cycle ergonometry test, the patient showed low-normal maximum oxidative capacity that was higher than that of 12 patients with McArdle disease, or myophosphorylase deficiency (232600). Peak serum lactate of the patient with PHK deficiency was decreased compared to 5 healthy men, but higher than that of the those with McArdle disease, indicating impaired oxidation of carbohydrate in the disease groups. The patient with PHK deficiency showed mild improvement of exercise tolerance with intravenous glucose infusion. There was a normal increase in serum lactate in the forearm ischemic exercise test, suggesting a discrepancy in glycogen breakdown impairment during anaerobic and aerobic exercise in PHK deficiency that may result from different activation pathways for myophosphorylase. Overall, the findings demonstrated that X-linked PHK deficiency is a mild metabolic myopathy characterized by impaired lactate production during moderate-intensity dynamic exercise and mild elevations of plasma creatine kinase and muscle glycogen content. Orngreen et al. (2008) noted that the clinical severity of PHK deficiency resembles another partial glycolytic defect, phosphoglycerate mutase deficiency (261670).

Preisler et al. (2012) reported 2 unrelated adult men with genetically confirmed GSD IXd: a 39-year-old with mild exercise-induced forearm pain and a 69-year-old with persistently increased serum creatine kinase after statin treatment (see 311870.0004), but no other symptoms. Both patients had increased glycogen levels in muscle and PHK activity less than 11% of normal. Both had a normal increase in plasma lactate on anaerobic exercise, but showed an exaggerated 5-fold increase in ammonia levels. An incremental exercise test revealed a blunted lactate response compared to controls; fat and carbohydrate oxidation rates at 70% of peak oxygen consumption were normal. Glucose infusion did not improve work capacity. Preisler et al. (2012) concluded that muscle PHK deficiency may present as an almost asymptomatic condition, despite a mild impairment of muscle glycogenolysis, raised CK levels, and glycogen accumulation in muscle. The relative preservation of glycogenolysis was explained by activation of myophosphorylase (PYGM; 608455) at high exercise intensities.

Molecular Genetics

In patient 1 with phosphorylase kinase deficiency reported by Clemens et al. (1990), Wehner et al. (1994) identified a nonsense mutation in the PHKA1 gene (311870.0001). The findings confirmed that the condition in this patient was a human homolog of the X-linked muscle Phk deficiency of the I-strain mouse (Schneider et al., 1993). In patient 2 of Clemens et al. (1990), Burwinkel et al. (2003) identified a missense mutation in the PHKA1 gene (311870.0003).

Burwinkel et al. (2003) screened 5 other patients with decreased muscle PHK activity for mutations in 6 genes that contribute to muscle PHK, in the muscle isoform of glycogen phosphorylase (PYGM; 608455), and in a muscle-specific regulatory subunit of protein kinase (PRKAG3; 604976). Two patients were heterozygous for single amino acid replacements of unclear significance in the beta subunit of phosphorylase kinase (PHKB; 172490).

Bruno et al. (1998) reported a splice junction mutation in the PHKA1 gene (311870.0002) in a 28-year old Caucasian male with exercise intolerance, myoglobinuria, and muscle phosphorylase kinase deficiency. The patient, reported as patient 1 of Wilkinson et al. (1994), had been diagnosed with PHK deficiency at age 15 years.