Primary beta-sarcoglycanopathy manifesting as recurrent exercise-induced myoglobinuria R. Cagliani a , G.P. Comi a, * , L. Tancredi a , M. Sironi b , F. Fortunato a , R. Giorda b , A. Bardoni b , M. Moggio a , A. Prelle a , N. Bresolin a,b , G. Scarlato a a Centro Dino Ferrari, Istituto di Clinica Neurologica, Universita Á degli Studi di Milano, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy b IRCCS E. Medea, Associazione La Nostra Famiglia, Bosisio Parini (LC), Italy Received 17 July 2000; accepted 4 October 2000 Abstract We report an unusual presentation of a primary b-sarcoglycanopathy (LGMD type 2E). A 12- year-old boy came to our attention after six episodes of exercise-induced myoglobinuria. Electromyogram showed mild myopathic features of the proximal lower limb muscles. Electrocardiogram was normal. Neurological examination revealed normal muscle strength and reduced deep tendon re¯exes. A muscle biopsy showed rare regenerating ®bers; the immunohistochemistry was normal for dystrophin, while all the sarcoglycans were diffusely decreased. Western blot analysis showed a relevant decrease of all sarcoglycan proteins and a mild dystrophin reduction. b-Sarcoglycan gene analysis demonstrated a compound heterozygous status for these mutations: a novel A±T base pair substitution at nucleotide 85 in exon 2, changing the codon Arg to a stop codon; a C±T base pair substitution at nucleotide 272 in exon 3 changing a Arg to a Cys residue. We consider that exercise-induced myoglobinuria may be the presenting sign of primary b-sarcoglycanopathy. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Myoglobinuria; Primary b-sarcoglycanopathy; Limb girdle muscular dystrophies-2E 1. Introduction Limb girdle muscular dystrophies (LGMD) are a geneti- cally heterogeneous group of disorders, characterised clini- cally by predominant proximal muscle weakness of variable severity, elevated CK levels and dystrophic changes on muscle biopsy. Based on pattern of inheritance, LGMDs are divided in autosomal dominant (LGMD1, A±E) and autosomal recessive forms (LGMD2, A±I) [1,2]. Within the autosomal recessive forms, the LGMD2 C±F are caused by primary mutations in four genes encoding the compo- nents of the dystrophin associated sarcoglycan (SG) complex, namely g-SG (LGMD 2C), a-SG (LGMD 2D), b-SG (LGMD 2E) and d-SG (LGMD 2F) [3±7]. Among the sarcoglycanopathies, clinical variability of age at onset, degree and evolution of muscle weakness, and evidence of heart involvement have been observed with two main phenotypes: a Duchenne-like presentation, also referred to as Severe Childhood Autosomal Recessive Muscular Dystrophy, and a later-onset Becker-like presen- tation, with limb-girdle progressive muscle hypotrophy and weakness and calves pseudohypertrophy. A mutation in any of the sarcoglycan genes may lead to a secondary de®ciency of the other SG proteins, presumably due to destabilization of the SG complex. Loss-of-function mutations of SG genes account for severe phenotypes; meanwhile missense mutations have a wider range of clinical presentations, some of them resulting in very severe forms and others in milder clinical involve- ment [8,9]. Although the entire spectrum of possible corre- lations has yet to be de®ned for each SG gene and protein, it is assumed that even amino acid substitutions may result in changes in secondary structure of SG proteins, leading to impaired interactions within the SG complex and severe biochemical and clinical phenotype. Atypical presentations of primary sarcoglycanopathy, including pseudometabolic forms, were also observed [10,11]. Here, we describe the clinical features and the immunohistochemical, biochemical and genetic characteri- sation of a patient affected with primary LGMD type 2E, presenting with recurrent episodes of exercise induced myoglobinuria. Neuromuscular Disorders 11 (2001) 389±394 0960-8966/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S0960-8966(00)00207-8 www.elsevier.com/locate/nmd * Corresponding author. Tel.: 139-02-5503-3817; fax: 139-02-5519- 0392. E-mail address: gpcomi@mailserver.unimi.it (G.P. Comi).