The clinical spectrum of sarcoglycanopathies

Patients and methods.

From the cohort of more than 4,000 neuromuscular patients examined in our center and diagnosed by clinical examination and muscle biopsy, we selected 204 muscular dystrophy patients in whom a dystrophinopathy was excluded by dystrophin immunohistochemistry and Western blot analysis. Twenty-one primary sarcoglycanopathy patients were identified first by screening their muscle biopsies by α-sarcoglycan immunohistochemistry or quantitative immunoblot (running all patient samples in few blots and comparing the bands with those of controls) and then by molecular analysis.4 The clinical progression of the disease was monitored by a grading system already validated for mild dystrophinopathy patients,5 consisting of five graded functional tests, such as walking ability for 10 meters, arising from the floor (Gowers’ sign), rising from a chair, and climbing a standardized four-step stair. The following end points were used in defining our clinical severity score (CSS): grade 1, patient showed Gowers’ sign (i.e., unilateral or bilateral hand support on the floor or on the thighs when rising); grade 2, patient was unable to stand up from the floor; grade 3, patient was wheelchair-bound. Patients were then divided into the following disease courses: rapidly progressive course (patients advanced one or more CSS grade every 5 years or less) or slowly progressive course (patients advanced one or more CSS grades in more than 5 years or became wheelchair-bound after 25 years of age).

Results.

The 21 patients with primary sarcoglycanopathy included 11 patients with mutations in the α-sarcoglycan gene, 5 in the β-sarcoglycan, and 5 in the γ-sarcoglycan (table 1). These patients were from 18 Italian families; three pairs of affected siblings were included. Two of these adult-sibling pairs with α-sarcoglycan gene mutations showed a heterogeneous clinical phenotype with a definite discrepancy in their functional test performance. Two distinct clinical courses were present in α-sarcoglycanopathy patients (table 2, figure): four (36%) had a rapidly progressive course and seven (64%) had a slowly progressive course. Five patients were unable to rise from the floor before age 15 years, and three after age 40 years (figure 1). A 36-year-old man (Patient 11) was virtually asymptomatic and was diagnosed on a family screening; he had only elevated creatine kinase (CK) and scoliosis.

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Figure. Clinical course in patients with α-, β-, γ-sarcoglycanopathies. The principal clinical end points of the disease are plotted against the age at which they are reached (clinical severity score [CSS] grade 1 = presence of Gowers’ sign; CSS grade 2 = inability to stand up from the floor; CSS grade 3 = inability to walk). Each line represents one patient. α, β, γ = sarcoglycan gene mutations.

The percentage of residual α-sarcoglycan protein on Western blot analysis correlated significantly with the age at which the patients first demonstrated Gowers’ sign (r = 0.90; p < 0.0005) and with the age at which patients were unable to stand up from the floor (r = 0.97; p < 0.00005). The clinical course in β-sarcoglycanopathy patients was rapidly progressive and more homogeneous than for α-sarcoglycanopathy patients: 4 of 5 patients (80%) had a rapidly progressive course (see figure 1); four patients were unable to rise from the floor at a mean age of 10 years, and three became wheelchair-bound at a mean age of 14.3 years (see table 2). Of five patients with γ-sarcoglycanopathy, three (60%) had a rapidly progressive course. The mean age at which patients were unable to rise from the floor was 12.2 years, and the mean age at which patients became wheelchair-bound was 17.5 years. Although the course of these patients was severe and rapidly progressive, it appeared milder than in β-sarcoglycanopathy. No involvement of facial or ocular muscles was observed.

Discussion.

Sarcoglycan-deficient patients have been identified in other European countries and in Japan, the United States, and North Africa2,3,6-9; a clinical spectrum is emerging.7-9 The common features of our patient series are autosomal recessive inheritance; preferential and early involvement of lower girdle muscles; subsequent involvement of shoulder girdle muscles, with scapular winging and difficulty in raising arms; distal muscles less affected (typically); and no involvement of facial or ocular muscles. Early onset dystrophy or late-onset LGMD should alert the clinician and induce appropriate studies of protein and DNA levels to diagnose a sarcoglycanopathy. In the Erb scapulohumeral type of muscular dystrophy, there is a preferential involvement of shoulder girdle; this phenotype has been associated with calpain-3 mutations.10 A striking difference between sarcoglycanopathies and dystrophinopathies is the absence of mental retardation and overt cardiac involvement. Previous clinical observations in a series of α-sarcoglycanopathy patients reported also calf hypertrophy as a distinguishable feature,7 which was not always present in our patients. The severe clinical phenotype is characterized by marked quadriceps involvement, early involvement of scapular fixator muscles, and evolution to respiratory insufficiency; this phenotype is associated with no residual α-sarcoglycan protein. We observed a group of late-onset α-sarcoglycan patients who had slowly progressive pelvic muscle weakness and did not lose ambulatory ability. Variable levels of residual α-sarcoglycan protein explain the milder clinical course. Subclinical patients with minimal muscle involvement are also found and may be revealed only by increased CK level. β-Sarcoglycan gene mutations are usually associated with a severe phenotype: patients become wheelchair-bound before 18 years of age. In the first child we identified as having β-sarcoglycan mutation, CK was grossly elevated and Gowers’ sign was present at age 3 years.8 Her clinical course has been followed up only to age 6 years. In the northern Indiana Amish population with the same β-sarcoglycan gene mutation,5 the clinical phenotype was homogeneous: the mean age at onset was 7.6 years, and loss of ambulation occurred at 25 years; macroglossia and calf pseudohypertrophy was observed by Fardeau and Jackson (personal communication).

The clinical course of γ-sarcoglycanopathy in our series is intermediate between Duchenne muscular dystrophy and Becker muscular dystrophy and is severe. Patients had lower girdle muscle weakness and early atrophy. These patients had onset of weakness in childhood and became wheelchair-bound before age 25 years. Kyphoscoliosis and respiratory insufficiency were prominent features in the wheelchair-bound patients. A marked intrafamilial variability was observed in SCARMD patients described by Ben Hamida,2 suggesting that epigenetic factors have a role in the clinical phenotype. Moreover, mild and severe muscular dystrophy were observed in patients with the same γ-sarcoglycan mutation.9

In this study, sarcoglycanopathy was diagnosed in 10% of proximal muscular dystrophy patients; 52% had a rapidly progressive course and 48% a slowly progressive course. Clinical progression is highly variable, even in the same family. The childhood variety represents one end of the spectrum, whereas some of our patients had a relatively late onset and benign course.