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PubMed2003

Phenotype modulators in myophosphorylase deficiency.

Myophosphorylase deficiency is characterized by exercise intolerance, muscle cramps, and recurrent myoglobinuria. Some patients are severely affected, whereas others are minimally affected or asymptomatic. The molecular basis of the disease has been elucidated but does not provide an explanation for the clinical variability. In a large cohort of patients with myophosphorylase deficiency, we tested the hypothesis that polymorphic variants in either myoadenylate deaminase (MADA) or angiotensin-converting enzyme (ACE) could act as modulators of phenotype expression. Forty-seven patients were evaluated. Clinical severity was assessed according to a severity scale of four grades. MADA activity was studied by histochemical and biochemical analysis of muscle, and the Q12X mutation in the adenine monophosphate deaminase 1 gene (AMPD1) and the insertion/deletion polymorphism in the ACE gene were assessed genetically. A complete MADA defect together with the Q12X mutation was detected in one severely affected patient. Eleven patients were heterozygous for the Q12X mutation. There was no association between clinical grading and MADA status. In contrast, we found a highly significant (p < 0.01) association between ACE genotype and clinical severity, with strong correlation between severe phenotype and number of D alleles. We show that ACE insertion/deletion polymorphism may play a significant role as phenotype modulator in McArdle's disease.

AMP Deaminase↗
PubMed2006

McArdle disease: the mutation spectrum of PYGM in a large Italian cohort.

Deficiency of the muscle isozyme of glycogen phosphorylase is causative of McArdle disease or Glycogen storage disease type V (GSD-V), the most common autosomal recessive disorder of glycogen metabolism. The typical clinical presentation is characterized by exercise intolerance with cramps, and recurrent myoglobinuria. To date, 46 mutations in the PYGM gene have been detected in GSD-V patients. We report the mutational spectrum in 68 Italian patients. We identified 30 different mutations in the PYGM gene, including 19 mutations that have not been reported previously. The novel mutations include: eight missense mutations (c.475G>A, p.G159R; c.689C>G, p.P230R; c.1094C>T, p.A365E; c.1151C>A, p.A384D; c.1182C>T, p.R428C; c.1471C>T, p.R491C; c.2444A>C, p.D815A; c.2477G>C, p.W826S), two nonsense mutations (c.1475G>A, p.W492X; c.1627A>T, p.K543X), five splice site mutations (c.855 +1G>C; c.1092 +1G>A; c. 1093-1G>T; c.1239 +1G>A; c.2380 +1G>A), and four deletions (c.715_717delGTC, p.V239del; c.304delA, p.N102DfsX4; c.1970_2177del, p.V657_G726; c.2113_2114delGG, p.G705RfsX16). Whereas we confirmed lack of direct correlation between the clinical phenotype and the genotype, we also found that the so-called 'common mutation' (p.R50X) accounted for about 43% of alleles in our cohort and that no population-related mutations are clearly identified in Italian patients.

Adolescent↗
PubMed2007

A proposed molecular diagnostic flowchart for myophosphorylase deficiency (McArdle disease) in blood samples from Spanish patients.

McArdle disease is a metabolic myopathy due to molecular defects in the myophosphorylase gene (PYGM), usually diagnosed in muscle biopsy. The aims of this study were to characterize genetically a large series of patients and to establish a protocol of molecular diagnosis on blood samples. We studied 55 Spanish unrelated patients with McArdle disease. Screening for the three more frequent mutations in the PYGM gene in the Spanish population (c.148C>T, p.R50X; c.613G>A, p.G205S; and c.2392T>C, p.W798R) were performed with polymerase chain-reaction and restriction fragment length polymorphism (PCR-RFLP) methods. To identify other mutant alleles, the coding region of PYGM gene was sequenced. The p.R50X mutation was observed in 38 patients, the p.G205S substitution in eight, and the p.W798R change in nine. Nine novel mutations, five missense (c.247A>T, p.I83F; c.521G>A, p.G174D; c.1094C>T, p.A365V; c.1468C>T, p.R490W; and c.1730A>G, p.Q577R), one nonsense mutation (c.2352C>A, p.C784X), three frameshift (c.402del, p.N134KfsX161; c.212_218dup, p.Q73HfsX7; c.1470dup, p.R491AfsX7), and nine previously reported mutations were found. In addition, we also updated the molecular data of 95 unrelated patients with McArdle disease studied thus far in our center. Of these patients, 56 were either homozygous or compound heterozygous for the p.R50X, p.G205S, or p.W798R mutation. By including in the molecular diagnosis protocol sequencing of the exons 1, 14, 17 and 18 of the PYGM gene, 16 further patients were characterized, and therefore we were able to detect the molecular defect in 72 out of 95 patients. A proposed molecular diagnosis protocol of the disease based on blood DNA would avoid muscle biopsy in 75.8% [95% confidence interval (95% CI): 62.1%-78.6%] of patients with McArdle disease.

Adolescent↗
PubMed2003

Two novel mutations in the myophosphorylase gene in a patient with McArdle disease.

We identified two novel mutations in exon 2 of the myophosphorylase gene in a 33-year-old German women with McArdle disease. The patient was compound heterozygous for a novel nonsense mutation at codon 84 changing tyrosine to stop codon (Y84X) and for a novel missense mutation at codon 93 changing arginine to tryptophan (R93W). These mutations are the first to be described in exon 2 and expand the genetic heterogeneity in patients with McArdle disease.

Adult↗
PubMed2003

Two novel mutations in the muscle glycogen phosphorylase gene in McArdle's disease.

We report on a Spanish family with myophosphorylase (EC 2.4.1.1) deficiency (McArdle's disease). The proband and his symptomatic sister were compound heterozygous for two novel mutations: a T-to-G transversion in exon 14 (c1722 T>G) that changes a tyrosine to a stop codon (Y573X), and a G-to-A transition in exon 15 (c1827 G>A) that disrupts the consensus signal at the donor splicing site. These findings further expand knowledge of the genetic bases of muscle glycogen phosphorylase deficiency.

Adult↗
PubMed2007

Double trouble (McArdle's disease and myasthenia gravis): how can exercise help?

We report a 29-year-old patient with McArdle's disease and myasthenia gravis. She had been debilitated with McArdle's disease since childhood (with marked rhabdomyolysis) and was obese. Myasthenia gravis was diagnosed at 24 years of age. After 3 months of aerobic exercise training, her exercise capacity increased significantly and she regained the ability to live independently. We conclude that even patients with profound neuromuscular diseases may benefit from carefully prescribed exercise training.

Adult↗
PubMed2003

Muscle- and fibre type-specific expression of glucose transporter 4, glycogen synthase and glycogen phosphorylase proteins in human skeletal muscle.

The muscle- and fibre type-specific expression of skeletal muscle glucose transporter 4 (GLUT4), glycogen synthase (GS) and glycogen phosphorylase (GP) was investigated in six young male subjects. Single muscle fibres were dissected from vastus lateralis (VL), soleus (SO) and triceps brachii (TB) muscle biopsy samples. On the basis of myosin heavy chain (MHC) expression, fibres were pooled into three groups (MHC I, MHC IIA and MHC IIX) and the GLUT4, GS and GP content of 15-40 pooled fibres determined using SDS-PAGE and immunological detection. In VL, the GLUT4 content in the pooled muscle fibres expressing MHC I was approximately 33% higher ( P<0.05) than in fibres expressing MHC IIA or IIX. There was no difference in GLUT4 content between fibres expressing MHC IIA or IIX, nor were there any differences in GS and GP content between any of the fibre types. In SO, there was no difference in GLUT4, GS and GP between fibres expressing MHC I or IIA. No fibres expressing type IIX were detected. In TB, fibres expressing MHC IIA and IIX had significantly ( P<0.05) more GP (66% and 55 % in MHC IIA and MHCIIX, respectively) than those expressing MHC I, whilst there was no difference in GP between MHC IIA and MHC IIX fibres. The GLUT4 and the GS content was similar in fibres expressing MHC I, IIA and IIX in the TB. Our data directly demonstrate that some proteins, like GLUT4 and GP, are expressed in a fibre type-specific manner in some, but not all, muscles, whilst other proteins, like GS, are not. In human skeletal muscle the GLUT4, GS and GP content thus seems to be related primarily to factors other than the fibre type as defined by the expression of contractile protein. These findings imply that it is not possible to generalize fibre type-dependent protein expression on the basis of biopsies from only one muscle.

Adult↗
PubMed2007

Molecular genetics of McArdle's disease.

This review highlights recent advances in our understanding of McArdle's disease, including the mechanisms involved in the regulation of the clinical phenotype. The latest molecular genetic studies have demonstrated the genetic heterogeneity of the disorder, with more than 65 mutations identified to date. There is not a specific treatment for McArdle's disease, but some nutritional treatments in combination with aerobic conditioning could improve the quality of life in most patients.

Glycogen Phosphorylase, Muscle Form↗
PubMed2005

Glycogen metabolism in rat ependymal primary cultures: regulation by serotonin.

Ependymal primary cultures are a model for studying ependymal energy metabolism. Intracellular glycogen is built up in the cultures dependent on culture age and the presence of glucose and glutamate. This energy store is mobilized upon glucose withdrawal, stimulation with isoproterenol, forskolin or serotonin and after uncoupling of oxidative phosphorylation from ATP production. Serotonin regulates ependymal glycogen metabolism predominantly via 5-HT receptor (5-HTR) 7, which elicits an increase in the level of ependymal cyclic AMP. Although the most abundant mRNAs for serotonin receptors are those of 5-HTR 2B and 5-HTR 3A, ependymal cells in primary culture do not respond to serotonin with an increase in their concentration of cytosolic calcium ions. The mRNAs of 5-HTRs 1A, 6, 1B, 5B, 7, 1/2C and 5A are also detectable in order of decreasing abundance. The mRNAs for 5-HTRs 1D, 1F, 3B and 4 are absent from the cultured cells. The ability of serotonin to mobilize ependymal glycogen depends on the culture age and the time allowed for glycogen buildup. During glycogen buildup time, glutamate is consumed by the cells. An increased ability of 5-HT to mobilize ependymal glycogen stores is noticed after the depletion of glutamate from the glycogen buildup medium. In ependymal primary cultures, cilia are colocalized with glycogen phosphorylase isozyme BB, while the MM isoform is not expressed. It is known from the literature that an increase in the concentration of cytosolic cAMP in ependymal cells leads to a decrease in ciliary beat frequency. Therefore, the present data point towards a function for ependymal glycogen other than supplying energy for the movement of cilia.

Animals↗
PubMed2005

Variable presentation of the clinical phenotype of McArdle's disease in a kindred harbouring a novel compound genotype in the muscle glycogen phosphorylase gene.

We report a Spanish family with muscle glycogen phosphorylase (PYGM) deficiency (McArdle's disease) harbouring a novel compound genotype (A659D/L586P). Four individuals who had the same genotype for PYGM, showed a wide variability in the presentation of the clinical phenotype, including one patient with a restrictive respiratory pattern, which is unusual in McArdle's disease. Moreover, these patients were studied for the insertion/deletion (I/D) trait in the angiotensin converting enzyme (ACE) which has been suggested to be a strong modulator of severity in McArdle's disease. Our results indicate no association of the I/D ACE trait in this family, suggesting that other factors would be more relevant in determining the severity of the clinical presentation.

Aged↗
PubMed2006

Muscle pain in myophosphorylase deficiency (McArdle's disease): the role of gender, genotype, and pain-related coping.

Pain characteristics were examined in 24 patients with myophosphorylase deficiency (McArdle's disease). Pain parameters were related to mutation analyses as well as psychosocial data using a pain questionnaire including an assessment of psychosocial distress and coping measures (Beck Depression Inventory BDI; Kiel Pain Inventory KPI, Multidimensional Fatique Inventory MFI). Twenty-three patients complained of pain, which was intermittent and exercise-induced in 15 patients. Eight patients complained of permanent pain, which was superimposed by exercise-induced pain in 7 patients. Patients reported 3-7 different pain characters and various localisations. Patients with permanent pain were significantly more frequently female, experienced higher impact on general activities and sleep as well as higher scores on the MFI. Furthermore, these patients revealed higher scores regarding several psychosocial risk factors including avoidance behavior whereas patients with intermittent pain predominantly showed endurance coping. There was no correlation between age or disease duration, pain intensity as well as mutation type and development of permanent or intermittent pain. In addition, severity of the clinical phenotype did not correlate with ACE polymorphism. Although McArdle's disease is a muscle glycogenosis with marked biochemical homogeneity, the clinical presentation can be quite heterogeneous. A substantial number of patients revealed permanent pain as a major clinical symptom. As permanent pain is not related to age or disease duration, it might be a clinically important subgroup of McArdle's disease. Gender-related genetic factors as well as maladaptive pain-related coping may contribute to the development of such a chronic pain symptom.

Adaptation, Psychological↗
PubMed2005

A novel mutation in the PYGM gene in a family with pseudo-dominant transmission of McArdle disease.

A Caucasian family appeared to transmit McArdle disease in an autosomal dominant manner and was examined for mutations in the myophosphorylase gene. The asymptomatic father was heterozygous for the R49X mutation in exon 1. The symptomatic mother was a compound heterozygote for R49X and a novel 2 bp deletion in exon 1 causing a frameshift at codon 25 (T25fs). Each of three children manifested symptoms of McArdle disease and was either a compound heterozygote for these two mutations or homozygous for R49X.

Adult↗
PubMed2001

Mitochondrial DNA point mutation in the COI gene in a patient with McArdle's disease.

We studied a 57-year-old female patient with clinical and biochemical evidences of McArdle's disease. Her muscle biopsy also revealed signs of mitochondrial proliferation, scattered RRF, and a deficit in complex I of the respiratory chain. Molecular genetic analysis showed that the patient was heterozygous for the most common mutation at codon 49 in the myophosphorylase gene. Mitochondrial DNA analysis of muscle tissue revealed an additional G-to-A transition at nucleotide position 7444 in the cytochrome c oxidase subunit I (COI) gene.

Codon↗
PubMed2002

A new stop codon mutation (Y52X) in the myophosphorylase gene in a Greek patient with McArdle's disease.

We identified a novel stop codon mutation in the myophosphorylase gene in a Greek patient with typical symptoms of McArdle's disease. This is the first genetic study of myophosphorylase deficiency in a Greek family, showing that the proband was a compound heterozygous for the common "caucasian" mutation (R49X) and a new nonsense mutation (Y52X), both within exon 1. The new point mutation, a C-to-G transversion at codon 52, converts an encoded tyrosine to a stop codon. Our study confirms that the R49X is also present in the Greek population. The Y52X may represent a private mutation or a common mutation among Greeks. Our data further expand the already remarkable genetic heterogeneity of McArdle's disease. The prevalence of the Y52X mutation in Greek patients with McArdle's disease remains to be determined.

Adult↗
PubMed2002

Two new mutations in the myophosphorylase gene in Italian patients with McArdle's disease.

We report two new mutations in the myophosphorylase gene (PYGM) in two unrelated Italian patients with myophosphorylase deficiency (McArdle's disease). In one, we identified a missense C-to-T mutation at codon 269 in exon 7, changing CGA (arginine) to TGA (stop codon) (R269X). The second patient carried a G-to-C mutation, changing GCT (alanine) to CCT (proline) at codon 686 (A686P) in exon 17. Both were compound heterozygous, with the common mutation at codon 49 (R49X) on the other allele. Our data further expand the genetic heterogeneity in patients with McArdle's disease, suggesting that the possibility of novel mutations has to be taken into account when performing genetic analysis in distinct ethnic groups.

Codon, Nonsense↗
PubMed2002

Molecular genetic study of myophosphorylase deficiency (McArdle's disease) in two Yemenite-Jewish families.

Using direct sequencing and restriction fragment length polymorphism analysis, we identified two novel mutations in two unrelated Yemenite-Jewish families with typical symptoms of McArdle's disease. In one family, both father and daughter were affected, an example of pseudo-dominant transmission. The daughter was a compound heterozygote for a new nonsense mutation (R207X) and a new missense mutation (R602Q) while her father was homozygous for the R207X mutation. The mother carried only the R602Q mutation and was an asymptomatic heterozygote. In the second family, the only affected member was homozygous for the R207X mutation. This first molecular genetic study of McArdle's disease in Yemenite-Jewish patients expands the already remarkable genetic heterogeneity of McArdle's disease and suggests the existence of ethnic or private mutations within this group.

Adult↗
PubMed2002

A direct StyI polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) test for the myophosphorylase mutation in cattle.

Myophosphorylase deficiency in cattle is a muscle disease induced by a C-->T point mutation in codon 489 of the myophosphorylase gene, which until now has only been diagnosed in the Charolais breed. The disease seems to be inherited in an autosomal monogenic recessive manner. A calf of double muscled phenotype was suspected of suffering from myophosphorylase deficiency based on typical symptoms, i.e. brown-coloured, transparent urine, occurring after exercise; exercise intolerance; symptoms of pain; and an elevated level of plasma creatine kinase. The presence of the previously described mutation was excluded using a newly developed, improved polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) procedure to identify easily heterozygous carriers and homozygous affected animals.

Animals↗