Myopathy and phosphorylase kinase deficiency caused by a mutation in the PHKA1 gene
ABSTRACT Phosphorylase kinase (PhK) deficiency is the underlying cause of variable clinical symptoms depending on the tissues involved. Until today, only a few cases of myopathy associated with muscle PhK deficiency caused by a mutation in the gene encoding the alpha subunit of phosphorylase kinase (PHKA1) have been reported. We describe a male patient with myopathy and absent muscle PhK activity caused by a frameshift mutation in the gene encoding the alpha subunit of PhK on chromosome Xq12-q13. (C) 2005 Wiley-Liss, Inc.
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- "Defects in PHKA1 result in X-linked deficiency of phosphorylase kinase in muscle . Symptoms include exercise intolerance, cramps, myalgia, weakness and myoglobulinuria, but just four mutations have been reported to date    . The b-subunit, a 125-kDa polypeptide that shows significant identity with the a-subunit, also performs a regulatory role within the phosphorylase kinase complex and is also controlled through phosphorylation by PKA . "
ABSTRACT: Glycogen storage disease type IX (GSD type IX) results from a deficiency of hepatic phosphorylase kinase activity. The phosphorylase kinase holoenzyme is made up of four copies of each of four subunits (alpha, beta, gamma and delta). The liver isoforms of the alpha-, beta- and gamma-subunits are encoded by PHKA2, PHKB and PHKG2, respectively. Mutation within these genes has been shown to result in GSD type IX. The diagnosis of GSD type IX is complicated by the spectrum of clinical symptoms, variation in tissue specificity and severity, and its inheritance, either X-linked or autosomal recessive. We investigated 15 patients from 12 families with suspected GSD type IX. Accurate diagnosis had been hampered by enzymology not being diagnostic in five cases. Clinical symptoms included combinations of hypoglycaemia, hepatosplenomegaly, short stature, hepatopathy, weakness, fatigue and motor delay. Biochemical findings included elevated lactate, urate and lipids. We characterised causative mutations in the PHKA2 gene in ten patients from eight families, in PHKG2 in two unrelated patients and in the PHKB gene in three patients from two families. Seven novel mutations were identified in PHKA2 (p.I337X, p.P498L, p.P869R, p.Y116_T120dup, p.R1070del, p.R916W and p.M113I), two in PHKG2 (p.L144P and p.H48QfsX5) and two in PHKB (p.Y419X and c.2336+965A>C). There was a severe phenotype in patients with PHKG2 mutations, a mild phenotype with patients PHKB mutations and a broad spectrum associated with PHKA2 mutations. Molecular analysis allows accurate diagnosis where enzymology is uninformative and identifies the pattern of inheritance permitting counselling and family studies.Molecular Genetics and Metabolism 09/2007; 92(1-2):88-99. DOI:10.1016/j.ymgme.2007.06.007 · 2.83 Impact Factor
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ABSTRACT: The nutritional management of glycogen storage disease has often been called “the intensive regimen”. The intensive regimen may not be without consequence. This thesis aims to characterise the intensive regimen and implement changes. Chapter 1 discusses concepts of glucose homeostasis in humans and introduces the glycogen storage diseases as a group of disorders. The metabolic physiology of those glycogen storage disorders associated with hypoglycaemia are reviewed and traditional methods used to ameliorate these metabolic disturbances are discussed. Methods used in the study include cornstarch loads, breath enrichment of 13CO2, hydrogen breath tests and dietary assessment as well as participant characteristics are discussed in chapter 2. Chapter 3 examines nutritional management as a cross-sectional dietary survey of children and adults with GSD, comparing the patient group to expert-panel recommendations as well as age and sex matched controls. Chapter 4 looks at the short-term effect a new carbohydrate therapy has on biochemical indices of metabolic control focusing on glucose, lactate and insulin profiles. These studies are double-blind cross-over studies, comparing the novel starch to uncooked cornstarch. Similarly Chapter 5 studies further short-term metabolic effects of the novel starch compared to cornstarch by examining hydrogen breath test data and enrichment of 13C02 in breath in an attempt to gauge the mechanism of action of the novel carbohydrate therapy. Chapter 6 examines the implementation of the new dietary starch into subjects' long-term dietary regimen in the form of a randomised cross-over trial. The primary endpoints are quantity of treatment starch use but safety, efficacy and patient acceptance of therapy are also considered. Chapter 7 brings together these various studies drawing conclusions and suggestions for further study. This chapter highlights the difficulties in performing investigations in rare disorders, when subjects are vulnerable to metabolic decompensation and recommends further study in healthy volunteers.
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ABSTRACT: 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. 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. 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. 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.Neurology 05/2008; 70(20):1876-82. DOI:10.1212/01.wnl.0000289190.66955.67 · 8.30 Impact Factor