Authors

A.J. van der Kooi, M.D., Ph.D
M. de Visser, M.D., Ph.D.
E.M. Hoogerwaard, M.D., Ph.D.

Clinical features

There is a wide range in age of onset (2-35 year), but in most cases the first symptoms were noticed between the 6th and 18th year of life with a mean age of onset of 11,1 years. Although the time of clinical onset is admittedly an unreliable parameter most studies have found a similar mean age at onset. BMD can also present with delayed walking which is related to an earlier age of onset. Usually patients present with symptoms, including frequent falling, difficulty climbing stairs, waddling gait, poor running, which can be ascribed to weakness of the muscles of the lower extremities. There are exceptional cases in which the dystrophinopathy remains asymptomatic for a long time and causes muscle weakness in the seventh decade. Other reported presenting symptoms are myalgia or cramps, especially in the calf region, toe walking, rhabdomyolysis, exercise or anaesthesia-triggered, life-threatening arrhytmias and cardiac arrest associated with succinylcholine during induction of anaesthesia or malignant hyperthermia.  Some of these features may be the sole manifestation. Muscle weakness and wasting is usually symmetric and starts in the proximal muscles of the lower extremities. The calf muscles remained preserved until late stages of the disease, as did the fore arm muscles, intrinsic muscles of the feet and hands, and the sternocleidomastoids. Facial muscles remain unaffected. There are cases of molecular genetically proven BMD who manifest with so-called quadriceps myopathy, in whom muscle weakness, and especially wasting, is initially restricted to the quadriceps femoris muscles Muscle hypertrophy is often, but not invariably noticed. Muscle hypertrophy may precede muscle weakness. In particular the calf muscles are hypertrophic, but virtually every limb muscle and also the erector trunci muscle can show enlargement. Muscle imaging revealed that there is often replacement of fat within the enlarged muscle (pseudohypertrophy). Achilles tendon contractures are an early sign and considered as a compensatoy mechanism for weakness of the gluteus maximus muscles, as is also the case in DMD.
Pes cavus is found in patients.  Other contractures and scoliosis are usually seen in advanced stages of the disease, especially when the patient has become bedridden. Cardiac involvement is not an exception in BMD as was thought for a long time. As in DMD, it seems more likely that the heart muscle invariably becomes affected. The most frequently observed electrocardiographic abnormalities include a high R-wave and pathological Q-waves. Based on studies in DMD this most likely reflects damage of the posterobasal and inferior wall of the left ventricle and are probably the first signs of left ventricular involvement, ultimately leading to DCM. Marked variability between and within families, as is also the case with skeletal muscle involvement. Cardiomyopathy may be more pronounced than skeletal muscle involvement and even precluding skeletal muscle weakness. Mental retardation in DMD is known to occur in about 30% of the cases. Intellectual impairment (defined as IQ < 75) was found in 25% of patients with BMD. A correlation was found with the loss of an isoform of dystrophin (Dp 140) with predominant expression during foetal brain development, rather than with the duration of the disease as had been previously thought. Behavoural and emotional disturbances in addition to cognitive disturbances have also been described.

Natural course and prognosis
The clinical picture is heterogeneous. Patients can be asymptomatic until their mid sixties, whereas the occasional patient shows rapid progression of muscle weakness comparable to that of DMD.
The age of loss of ambulation ranges from 12 to over 70. Age at death is also highly variable (17-74 years). The same variability holds true with regard to heart involvement. Some patients die due to a fulminating cardiomyopathy whereas their family members may have marked subclinical left ventricle dilatation for decades.

Epidemiology
The prevalence rate of BMD is approximately 2,5/100 000 in all epidemiological studies.
The cumulative birth incidence of BMD is at least 1 in 18 450 male live births.

Differential diagnosis

There are two diseases which may mimic BMD: limb girdle muscular dystrophy  and spinal muscular atrophy, type III. Since about a decade rapid molecular genetic developments have expanded the field of limb girdle muscular dystrophies (LGMD) which is the most important disease BMD has to differentiated from. The clinical picture of BMD and of autosomal recessive LGMD can be almost identical. Even cardiac involvement may occur in LGMD, albeit in only a small proportion of patients. Ancillary studies including estimation of CK, EMG and histological examination of a muscle biopsy specimen are not helpful in distinguishing one disease from the other. Immunohistochemical analysis of the dystrophin-related proteins, the sarcoglycans, and immunobiochemical analysis of calpain-3 and dysferlin, followed by subsequent identification of the disease-causing mutation, is then the appropriate means to properly establish the diagnosis.

Ancillary investigations
Serum creatine kinase (CK) activity is almost invariably elevated. Short-duration, low-amplitude motor unit action potential (MUAPs) are consistent with a myopathy. However, in BMD, it is not unusual to find high frequency discharges, positive sharp waves or fibrillations  (Bradley et al. 1978; Kuhn et al. 1979; Sunohara et al. 1990) or long-duration polyphasic MUAPs (Uncini et al. 1990). These findings were found to correlate with the appearance of regenerating muscle fibres. These apparently ‘neurogenic’ findings may give rise to confusion with autosomal recessive proximal spinal muscular atrophy (Kugelberg-Welander disease), clinically resembling BMD.
There is a wide range of histological changes, mostly compatible with a muscular dystrophy. Although the histological picture resembles that encountered in DMD, there are clear differences. Hyaline fibres and necrosis are observed in BMD, but not as prominent as in DMD (Bradley et al. 1978). Like in EMG studies so-called neurogenic changes such as small angular muscle fibres, clumped pycnotic nuclei (Bradley et al. 1978; Goebel et al. 1979; ten Houten and de Visser 1984; Kaido et al. 1991; Kuhn et al. 1979; McDonald et al. 1991; Ohkoshi et al. 1995; Sunohara et al. 1990) and even type grouping (Kaido et al. 1990), may cause diagnostic difficulties. These changes should probably be considered either as a result of fiber splitting or as regenerating fibres.
Younger patients tend to show more active muscle fibre necrosis and regeneration than do older patients who are found to have more chronic myopathic changes such as moth-eaten fibers, fiber splitting, hypertrophic fibres and  marked endomysial fibrosis (Bradley et al. 1978; ten Houten and de Visser 1984; Kaido et al. 1991; Ringel et al.1977). Unusual histological findings include rimmed vacuoles, and small foci of inflammatory cells (Bradley et al. 1978; McDonald et al. 1991; de Visser et al. 1990

Genetics

Dystrophin gene deletions account for approximately 65% of Becker patients. Deletions are clustered in two ‘hot spots’, one proximal in the 5’ end (exons 2-20) and one more distal 3’, comprising exons 45-53. BMD is mostly associated with rearrangements (deletions, point mutations, and rarely duplications) in which the translational reading frame is maintained. However, rarely out-of-frame deletions were reported in BMD patients. The reading frame rule holds in about 92% of the cases. Dystrophin, the large protein product of the gene that is localised in the surface membrane, was found to be reduced in quantity or with a different molecular weight in muscle of patients with BMD on immunoblots.
Immunocytochemical staining shows a patchy and discontinuous, and usually faint appearance in the surface membrane. However, the interpretation of immunohistochemical staining in some BMD patients can be cumbersome since dystrophin deficient fibres may be ‘false-negative’ due to necrosis or regeneration. In those cases, Western blot analysis is far more superior. In case of point mutations, dystrophin analysis may not be conclusive. 

Therapy
Therapeutic interventions are supportive and aimed at optimisation of mobility and prevention of cardiac failure. It is recommended to refer the patients to rehabilitation medicine as soon as muscle weakness gives rise to walking difficulties. Physical therapy may prevent contractures that develop in particular when the patient becomes wheelchairbound.
Unlike DMD, there have not been studies on prednisone treatment in BMD. There is, however, one case-report by Higuchi et al. (1993) who describe a favourable response to prednisone as regards myalgia.
Since it is convincingly demonstrated that cardiomyopathy is part of dystrophinopathies, regular follow-up of the cardiologial function is recommended, including electrocardiography and echocardiography. Cardiac complications can occur at any stage of the disease and may develop rapidly. There have as yet not been randomised clinical trials for DCM in dystrophinopathies. Supportive measures, vasodilator therapy and angiotensin converting enzyme inhibitors are propagated for asymptomatic DCM from whatever cause, and are therefore also recommended in DMD and BMD patients with this complication. Diuretics have been recommended as adjunctive therapy for DCM in cases with congestive heart failure.
If there is progression despite medical treatment and terminal heart failure is due, the patient should be referred for assessment for heart transplantation.
Rhabdomyolysis is a rare but potentially fatal complication of anaesthesia in dystrophinopathy. In order to prevent such a catastrophe succinyl choline which seems to trigger this event should be avoided during general anaesthesia.
In many countries there are active patient support organisations. These offer the patients information about their disease and, even more important, help them cope through informal get-togethers with other patients.

Links

NMDC Washington
Leiden Muscular Dystrophy pages
VSN

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