Case report Unusual presentation of phosphoglycerate mutase deficiency due to two different mutations in PGAM-M gene Paola Tonin a, * , Claudio Bruno c , Denise Cassandrini c , Chiara Savio a , Eleonora Tavazzi b , Giuliano Tomelleri a , Giovanni Piccolo b a Department of Neurological Sciences and Vision, Section of Neurology, University of Verona, Italy b IRCCS Fondazione C. Mondino, Pavia, Italy c Muscular and Neurodegenerative Disease Unit, Giannina Gaslini Institute, Genova, Italy article info Article history: Received 9 April 2009 Received in revised form 28 July 2009 Accepted 10 August 2009 Keywords: Phosphoglycerate mutase Glycogenosis abstract Phosphoglycerate mutase (PGAM) deficiency causes a rare metabolic myopathy characterized by exer- cise-related myalgia and myoglobinuria. This disorder was described in 13 patients and five different mutations in the PGAM-M gene were identified. We report on a new patient with an unusual clinical presentation. As a youth, he participated in different sports without complaining of muscular symptoms, but at 44 years of age, after a brief, intense effort, he experienced lightheadedness without fainting. Serum CK was elevated and the ischemic exercise test showed a pathological lactate response. Muscle biopsy showed only mild abnormalities, but biochemical study revealed a defect of PGAM and genetic analysis showed two different mutations in the PGAM-M gene. Our case expands the clinical spectrum of PGAM deficiency and suggests that the frequency of this met- abolic myopathy may be underestimated. Ó 2009 Elsevier B.V. All rights reserved. 1. Introduction Deficiency of muscle phosphoglycerate mutase (PGAM), an enzyme of terminal glycolysis, causes a rare autosomal recessive metabolic myopathy (glycogenosis type X) characterized by exer- cise-induced cramps and myoglobinuria [1]. Mature human skele- tal muscle contains a muscle specific subunit (PGAM-M), but also a brain specific subunit (PGAM-B) that accounts for the residual activity (usually less than 7%) observed in PGAM-deficient patients. The PGAM-M gene has been assigned to chromosome 7 [2] and, so far, five different mutations have been reported [3,4] the most common being a nonsense mutation at codon 78 (W78X). Here, we report a new patient with an unusual presentation and two different mutations in the PGAM-M gene. 2. Case report A 44-year-old man experienced blurred vision, tinnitus, feeling of chest oppression and palpitations during a brief, strenuous effort. The following day serum CK was 3200 IU/L (normal range 24–195). During the next six months, CK levels ranged from 492 to 1038 IU/L, which brought the patient to our attention. He was born to non-consanguineous parents and there was no family history of neuromuscular diseases. His medical history was unre- markable except for bilateral neurosensory hearing loss; he denied neuromuscular symptoms and reported that in his youth he had participated in football, volleyball and judo without problems. Neurological examination was normal, but the patient developed cramps in the sternocleidomastoid and quadriceps muscles after repeated voluntary contractions. Forearm ischemic exercise test, performed according to DiMauro [5], showed a blunted rise of venous lactate (1-fold) with 6-fold increase of ammonia levels. The patient did not experience muscle cramps during the test. EMG showed polyphasic motor unit potentials in proximal and distal muscles of all the four limbs. Biopsy of quadriceps muscle showed scattered atrophic and hypertrophic fibers and no evidence of glycogen or lipid storage. By histochemistry, phosphorylase and phosphofructokinase stain- ing were normal. Biochemical analysis showed a severe defect of PGAM with 3% residual activity; myophosphorylase and other enzymes of termi- nal glycolysis were normal (Table 1). Sequence analysis of the PGAM-M gene revealed a heterozygous G > A mutation at nucleotide 29 (c.G29A), leading to the replace- ment of arginine with glutamine at position 10 (p.R10Q) and a sin- 0960-8966/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2009.08.007 * Corresponding author. Address: Department of Neurological Sciences and Vision, Section of Clinical Neurology, University of Verona, P.le L.A. Scuro 10, 37134 Verona, Italy. Tel.: +39 045 8074285; fax: +39 045 8027492. E-mail address: paola.tonin@azosp.vr.it (P. Tonin). Neuromuscular Disorders 19 (2009) 776–778 Contents lists available at ScienceDirect Neuromuscular Disorders journal homepage: www.elsevier.com/locate/nmd