Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency?

OBJECTIVE: It is unclear to what extent muscle phosphorylase b kinase (PHK) deficiency is associated with exercise-related symptoms and impaired muscle metabolism, because 1) only four patients have been characterized at the molecular level, 2) reported symptoms have been nonspecific, and 3) lactate responses to ischemic handgrip exercise have been normal. METHODS: We studied a 50-year-old man with X-linked PHK deficiency using ischemic forearm and cycle ergometry exercise tests to define the derangement of muscle metabolism. We compared our findings with those in patients with McArdle disease and in healthy subjects. RESULTS: Sequencing of PHKA1 showed a novel pathogenic mutation (c.831G>A) in exon 7. There was a normal increase of plasma lactate during forearm ischemic exercise, but lactate did not change during dynamic, submaximal exercise in contrast to the fourfold increase in healthy subjects. Constant workload elicited a second wind in all patients with McArdle disease, but not in the patient with PHK deficiency. IV glucose administration appeared to improve exercise tolerance in the patient with PHK deficiency, but not to the same extent as in the patients with McArdle disease. Lipolysis was higher in the patient with PHK deficiency than in controls. CONCLUSION: These findings demonstrate that X-linked PHK deficiency causes a mild metabolic myopathy with blunted muscle glycogen breakdown and impaired lactate production during dynamic exercise, which impairs oxidative capacity only marginally. The different response of lactate to submaximal and maximal exercise is likely related to differential activation mechanisms for myophosphorylase.

Identification of Alu-mediated, large deletion-spanning introns 19-26 in PHKA2 in a patient with X-linked liver glycogenosis (hepatic phosphorylase kinase deficiency).

X-linked liver glycogenosis (XLG) is one of the most common glycogen storage diseases. We present the first case of a large PHKA2 gene deletion from intron 19 to intron 26 in an XLG patient. An aberrant cDNA with skipping of exons 20-26 was detected. Alu element-mediated unequal homologous recombination between an Alu-Jo in intron 19 and another Alu-Sg in intron 26 appears to be responsible for this deletion.

Glycogen storage diseases in animals and their potential value as models of human disease.

Glycogen storage diseases (GSD) are inborn errors of glycogen metabolism. Of the eight human GSD types in which the enzymatic deficiency has been identified, spontaneous animal counterparts have been reported for GSD I (glucose-6-phosphatase deficiency) in the mouse, for GSD II (acid alpha-glucosidase deficiency) in the dog, in cattle and in the quail, for GSD III (debrancher enzyme deficiency) in the dog and for GSD VIII (phosphorylase kinase deficiency) in the rat and the mouse. Experimentally induced GSD-like conditions have been described in the rat (Acarbose-induced GSD II-like conditions, iodoacetate-induced symptoms of myophosphorylase (GSD V) and myophosphofructokinase (GSD VII) deficiency) and the chicken (ochratoxin A-induced symptoms of cyclic AMP-dependent protein kinase deficiency). Enzymatic defects that are typical of the human GSD types have not been clearly identified in the induced animal conditions. The homology of animal and human GSD types is discussed. It is concluded that clinical, pathogenic and therapeutic studies of GSD may benefit from the use of animal models. For genetic studies of human GSD these models may prove to be of limited value, as the picture of several human GSD types is already obscured by genetic heterogeneity.