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A multidisciplinary study was conducted in order to assess dystrophin expression in a large series of mild X-linked muscular dystrophy patients, with well-defined clinical phenotype. Patients (104) were divided in 4 clinical groups, according to clinical severity: asymptomatic (sub-clinical), benign, moderate and severe, Cardiopathy was also assessed, and dilated cardiomyopathy was found in 47% of sub-clinical and benign cases. Myoglobinuria, cramps and myalgia were also associated with a sub-clinical or benign clinical status. Dystrophin immunohistochemical pattern of labelling and dystrophin amount decreased gradually across clinical groups. Our study showed a significative correlation between: (1) dystrophin amount and immunohistochemical score (p < 0.05); (2) dystrophin amount and clinical score (p < 0.05). Therefore, the combined use of these different techniques for prognosis of mild X-linked muscular dystrophy patients is useful. Our study assesses the prevalence of the various disease courses in a large cohort of mild X-linked muscular dystrophy patients. From our series, up to 30% of patients may be either asymptomatic or have sub-clinical changes.

Mutations in the sarcoglycan genes cause autosomal-recessive muscular dystrophies. Because sarcoglycan genes and their protein products are highly expressed both in skeletal and cardiac muscle, patients with these mutations might be expected to be at risk to develop dilated cardiomyopathy. We therefore studied 13 patients with alpha-, beta-, gamma-sarcoglycan gene mutations by thorough cardiological assessment. Electrocardiographic or echocardiographic abnormalities were observed in about 30% of cases showing a severe course of muscular dystrophy. No correlation was found between the presence of cardiac abnormalities and the type of mutation or sarcoglycan gene involved. The cardiac involvement was never severe, but it may be detected in early stages of the muscle disease. The absence of overt cardiac dysfunction may be due to lower sarcoglycan protein expression in cardiac than skeletal muscle or to less sarcolemmal instability at the myocardial level, possibly related to the different distribution of forces generated by contraction of the myocardium with respect to proximal limb-girdle muscles.

Background Several cases of Becker's muscular dystrophy (BMD) have been reported, which showed mild or subclinical skeletal muscle involvement with an overt dilated cardiomyopathy. Here, for the first time, a group of 28 patients with BMD who had a subclinical or benign myopathy have been studied through a thorough cardiological assessment. Methods and Results Each patient underwent ECG and echocardiographic examinations. Molecular analyses of the dystrophin gene and protein were performed. An unexpectedly high incidence of myocardial involvement was observed among patients affected with subclinical (72%) or benign (60%) BMD. The cardiac involvement appears to develop early from the right ventricle. Both the increase in left ventricular end-diastolic volume and the reduction in the ejection fraction appeared to be age related. Severe left ventricular dilation with reduced ejection fraction, which could be complicated by life-threatening arrhythmias, may occur. Contrary to previous reports, which indicated the involvement of 5′-end mutations in cardiomyopathies as a result of dystrophin gene alterations, this study shows that despite the apparent concentration of deletions in two regions (5′-end and exons 47 through 49), no general conclusions can be drawn regarding the involvement of specific gene mutations in the development of cardiomyopathy. Conclusions Cardiomyopathy is the main clinical feature and complication in patients affected by subclinical or mild BMD. The cardiac manifestation is characterized by early right ventricular involvement and is later associated with left ventricular impairment. In mild BMD, myocardial damage may develop because the patients, who are unaware of a possible cardiac involvement, are still able to perform strenuous muscle exercise and, through pressure or volume overload, may induce mechanical stress, which is harmful for dystrophin-deficient myocardial cells.

One hundred twenty five patients from 105 families were considered, showing in-frame intragenic deletion or duplication of the dystrophin gene and/or abnormal dystrophin on muscle biopsy. According to clinical status of patients, the affection was classified as subclinical, benign, moderate or severe. Significant decrease of dystrophin abundance was observed with increasing clinical severity (p < 0.05). Detailed clinical data were available in 68 patients in whom a long-term follow-up (6-39 years) was obtained. Functional performance at different ages and disease endpoints were recorded in order to analyze the rate of disease progression. We identified three different disease courses: stable, slow and rapid progression. We observed a significantly lower level of dystrophin and immunohistochemical score (p < 0.05 vs. the other courses) in patients with rapid course. Deletion or duplication in the 5' end of the gene was associated with poor prognosis. Prognosis was substantially better, showing a stable course, in patients with large deletions or duplications in the proximal rod region. These subjects often suffered from a cramps/myalgia syndrome or experienced rhabdomyolisis. Cardiac involvement was detected in 65% of cases. A significant increase of right ventricular volume was seen in all clinical groups (p < 0.05). A left ventricular dilation was observed in 25% and a decreased ejection fraction in 29% of our patients. The reduction of ejection fraction and the increase of left ventricular volume were age-related. Since sudden death may occur as a consequence of cardiomyopathy, severe left ventricular dysfunction in dystrophinopathic patients is another important adverse prognostic factor, although not always directly correlated with skeletal muscle impairment.

A group of 204 muscular dystrophy patients were screened for immunohistochemical and biochemical alpha-sarcoglycan defect and their DNA was analyzed for pathogenetic mutation in the four sarcoglycan genes. We identified 21 patients with alpha-, beta-, or gamma-sarcoglycan gene mutations. Patients with alpha-sarcoglycan gene mutations were clinically heterogeneous and showed either a rapid progressive or a late-onset slow course. In the slowly evolving group, a residual alpha-sarcoglycan protein was present, and its level correlated with a milder disease course and significant later inability to stand up from the floor (p < 0.00005). Most patients with beta- and gamma-sarcoglycan gene mutations presented a severe clinical course. There is a considerably different pattern of muscle involvement and disease course in these disorders, compared with dystrophinopathies.

BACKGROUND: The autosomal recessive limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous muscle diseases characterised by progressive proximal limb muscle weakness. Six different loci have been mapped and pathogenetic mutations in the genes encoding the sarcoglycan complex components (alpha-, beta-, gamma-, and delta-sarcoglycan) have been documented. LGMD patients affected with primary "sarcoglycanopathies" are classified as LGMD2D, 2E, 2C, and 2F, respectively. METHODS: A geographical area in north east Italy (2,319,147 inhabitants) was selected for a genetic epidemiological study on primary sarcoglycanopathies. Within the period 1982 to 1996, all patients living in this region and diagnosed with muscular dystrophy were seen at our centre. Immunohistochemical and immunoblot screening for alpha-sarcoglycan protein deficiency was performed on all muscle biopsies from patients with a progressive muscular dystrophy of unknown aetiology and normal dystrophin. Sarcoglycan mutation analyses were conducted on all patient muscle biopsies shown to have complete or partial absence of alpha-sarcoglycan immunostaining or a decreased quantity of alpha-sarcoglycan protein on immunoblotting. RESULTS: Two hundred and four patient muscle biopsies were screened for alpha-sarcoglycan protein deficiency and 18 biopsies showed a deficiency. Pathogenetic mutations involving one gene for sarcoglycan complex components were identified in 13 patients: alpha-sarcoglycan in seven, beta-sarcoglycan in two, gamma-sarcoglycan in four, and none in the delta-sarcoglycan gene. The overall prevalence of primary sarcoglycanopathies, as of 31 December 1996, was estimated to be 5.6 x 10(-6) inhabitants. CONCLUSION: The prevalence rate estimated in this study is the first to be obtained after biochemical and molecular genetic screening for sarcoglycan defects.