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.


CONCLUSIONS
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.
Ørngreen
M C
MC
Neuromuscular Research Unit 7611, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. rh10679@rh.dk
Schelhaas
H J
HJ
Jeppesen
T D
TD
Akman
H O
HO
Wevers
R A
RA
Andersen
S T
ST
ter Laak
H J
HJ
van Diggelen
O P
OP
DiMauro
S
S
Vissing
J
J
D041321:Chromosomes, Human, X; D005080:Exercise Test; D006003:Glycogen / Q000378:metabolism; D006012:Glycogen Storage Disease Type V / Q000235:genetics / Q000378:metabolism; D006015:Glycogen Storage Disease Type VIII / Q000235:genetics* / Q000378:metabolism; D050261:Glycogenolysis / Q000235:genetics*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology; D018384:Oxidative Stress / Q000235:genetics; D010764:Phosphorylase Kinase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005082:Physical Exertion / Q000502:physiology; D017354:Point Mutation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism
D021122:Protein Subunits; D019344:Lactic Acid; D006003:Glycogen; D010764:Phosphorylase Kinase