Primary adhalinopathy (a-sarcoglycanopathy) : Clinical, pathologic, and genetic correlation in 20 patients with autosomal recessive muscular dystrophy B. Eymard, MD; N.B. Romero, MD; F. Leturcq, PhD; F. Piccolo, PhD; A. Carrib, MS; M. Jeanpierre, MD; H. Collin, MS; N. Deburgrave, MS; K. Azibi, MD; M. Chaouch, MD; L. Merlini, MD; C. Thbmar-Noel, MD; I. Penisson, MD; M. Mayer, MD; 0. Tanguy, MD; K.P. Campbell, PhD; J.C. Kaplan, MD; F.M.S. Tome, MD; and M. Fardeau, MD Article abstract-Primary adhalin (or a-sarcoglycan) deficiency due to a defect of the adhalin gene 1ocaIized on chromo- some 17q21 causes an autosomal recessive myopathy. We evaluated 20 patients from 15 families (12 from Europe and three from North Africa) with a primary adhalin deficiency with two objectives: characterization of the clinical phenotype and analysis of the correlation with the level of adhalin expression and the type of gene mutation. Age at onset and seventy of the myopathy were heterogeneous: six patients were wheel-chair bound before 15 years of age, whereas five other patients had mild disease with preserved ambulation in adulthood. The clinical pattern was similar in all the patients with symmetric characteristic involvement of trunk and limb muscles, calf hypertrophy, and absence of cardiac dysfunction. Immunofluorescence and immunoblot studies of muscle biopsy specimens showed a large variation in the expression of adhalin. The degree of adhalin deficiency was fairly correlated with the clinical severity. There were 15 different mutations (10 missense, five null). Double null mutations (three patients) were associated with severe myopathy, but in the other cases (null/missense and double missense) there was a large variation in the severity of the disease. NEUROLOGY 1997;48:1227-1234 Alterations in the components of the sarcoglycan complex cause different types of muscular dystro- phies. The sarcoglycans form a subcomplex in the dystrophin-glycoprotein-complex, linking the subsar- colemmal cytoskeletal proteins to the extracellular matrix. This subcomplex is composed of four trans- membrane glycoproteins, one of 50, one of 43, and two of 35 kDa, named a- (or adhalin), p-, y-, and &sarc~glycans,~-~ respectively. In 1992, Matsumura et aL5 reported adhalin deficiency in muscle biopsy specimens from Algerian and Lebanese patients pre- senting with a severe childhood autosomal recessive muscular dystrophy (SCARMD). The clinical pheno- type of this disease was close to Duchenne (DMD) and Becker (BMD) muscular dystrophies as reported by Ben Hamida et al.‘j in 1983. Age at onset was between 3 and 15 years, and the patients presented with proximal weakness most often associated with hypertrophy of calves. The levels of serum creatine kinase were usually very high. Presence of dystro- phin in the muscle biopsy specimens7 led to a search for a deficiency in one of the dystrophin-associated glycoproteins (DAG)/dystrophin-associated proteins (DAP) and to the discovery of adhalin defi~iency.~ Sev- eral authors have subsequently reported adhalin defi- ciency in European,s-loBrazilian,llJ2 and pa- tients with SCARMD or milder muscular dystrophies. Genetic studies indicated a heterogeneity of adha- lin deficiencies. Ben Othmane et a1.16 mapped the defective gene, responsible for the form of SCARMD prevalent in North Africa, to chromosome 13q12 and this was confirmed by Azibi et al.17 Passos-Bueno et al.ll reported exclusion of this locus by linkage anal- ysis in three Brazilian families and Romero et al.9 reported similar results in one French family, all affected by adhalin deficiency. Roberds et a1.18 subse- quently mapped the adhalin gene to chromosome 17q12-q21.33 and Roberds et al.19 identified the first missense mutations in a previously reported French family.g Different groups subsequently reported other cases of “primary” adhalin~pathy.~~J~~~~~~ Sec- ondary adhalin deficiencies are due to mutations af- fecting p-, y-, or 6-sarcoglycan genes, which are local- ized to chromosomes 4q12,22,23 13q12,24 or 5q33.3.4 From INSERM U 153 (Drs. Eymard, Romero, Themar-Noel, Tome, and Fardeau, and H. Collin), Institut de Myologie, HBpital de la Salpetnere, Paris; NSERM U 129 & HBpital Cochin (Drs. Leturcq, Piccolo, Jeanpierre, and Kaplan, hnd A. Carrie and N. Deburgrave), Paris; HBpital Bologhine (Dr. Azibi), Alger; HBpital Ben-Aknoun (Dr. Chaouch), Alger; Instituto Ortopedico Rizzoli (Dr. Merlini), Bologna; CHU (Dr. Penisson), Angers; HBpital Saint Vincent de Paul (Dr. Mayer), Paris; CHU (Dr. Tanguy), Clermont-Ferrand; and the Howard Hughes Medical Institute and Department of Physiology and Biophsics (Dr. Campbell), University of Iowa College of Medicine, Iowa City, IA. Supported by the Association Franeaise contre les Myopathies (AFM). K.P. Campbell is an Investigator of the Howard Hughes Institute. Received September 6, 1996. Accepted in final form December 2, 1996. Address correspondence and reprint requests to Professor Michel Fardeau, INSERM U. 153, Institut de Myologie, HBpital de la Salpetriere, 47, boulevard de I’Hijpital, FR-75651 Pans Cedex 13, France. Copyright 0 1997 by the American Academy of Neurology 1227