Effects of Home Mechanical Ventilation on Left Ventricular Function in Sarcoglycanopathies (Limb Girdle Muscular Dystrophies).

Cardiac and respiratory function may be impaired in sarcoglycanopathies, a subgroup of muscular dystrophies due to sarcoglycan proteins (α, ß, γ, and δ) genes mutations. Management of patients with restrictive respiratory failure mainly relies on home mechanical ventilation (HMV). Little is known about the cardiac effects of prolonged mechanical ventilation in patients with muscular dystrophy and restrictive respiratory insufficiency. We aimed to assess the effects of HMV on cardiac function in sarcoglycanopathies. We retrospectively included 10 genetically proven patients with sarcoglycanopathy followed at the HMV unit of the Raymond Poincare University Hospital (4 patients with α-sarcoglycanopathy and 6 patients with γ-sarcoglycanopathy). We collected cardiorespiratory clinical baseline data and left ventricular ejection fraction (LVEF) at baseline before initiation of HMV and at the end of follow-up. At baseline, median age was 30.5 years (27 to 39) and median pulmonary vital capacity was 27% of the predicted value (21 to 36). Forty percent of the patients had documented sleep apnea. Cardiomyopathy, defined as LVEF <50%, was found in 3 patients with γ-sarcoglycanopathy. After a median follow-up of 3 years (1.0 to 4.5), there was a significant increase in LVEF after initiation of HMV, that is, 62% (48 to 65) versus 53% (45.5 to 56.5) (p = 0.0039). In conclusion, HMV in sarcoglycanopathies is not harmful and may protect left ventricular function by its thoracic physiological effects.

Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse.

Muscular dystrophy is characterized by progressive skeletal muscle weakness and dystrophic muscle exhibits degeneration and regeneration of muscle cells, inflammation and fibrosis. Skeletal muscle fibrosis is an excessive deposition of components of the extracellular matrix including an accumulation of Collagen VI. We hypothesized that a reduction of Collagen VI in a muscular dystrophy model that presents with fibrosis would result in reduced muscle pathology and improved muscle function. To test this hypothesis, we crossed γ-sarcoglycan-null mice, a model of limb-girdle muscular dystrophy type 2C, with a Col6a2-deficient mouse model. We found that the resulting γ-sarcoglycan-null/Col6a2Δex5 mice indeed exhibit reduced muscle pathology compared with γ-sarcoglycan-null mice. Specifically, fewer muscle fibers are degenerating, fiber size varies less, Evans blue dye uptake is reduced and serum creatine kinase levels are lower. Surprisingly, in spite of this reduction in muscle pathology, muscle function is not significantly improved. In fact, grip strength and maximum isometric tetanic force are even lower in γ-sarcoglycan-null/Col6a2Δex5 mice than in γ-sarcoglycan-null mice. In conclusion, our results reveal that Collagen VI-mediated fibrosis contributes to skeletal muscle pathology in γ-sarcoglycan-null mice. Importantly, however, our data also demonstrate that a reduction in skeletal muscle pathology does not necessarily lead to an improvement of skeletal muscle function, and this should be considered in future translational studies.

Alpha-sarcoglycanopathy presenting as exercise intolerance and rhabdomyolysis in two adults.

Two patients with exercise-induced myalgias and rhabdomyolysis with myoglobinuria were evaluated with muscle biopsy and comprehensive myopathy next generation sequencing (NGS) gene panels. Genetic analysis revealed homozygosity for two known pathogenic SGCA mutations (R284C in Patient 1 and V247M in Patient 2). Muscle biopsy showed minimal changes with normal immunohistochemistry for α-sarcoglycan. Western blotting showed 27% and 35% of normal α-sarcoglycan immunoreactivity when compared to age matched controls, confirming the diagnosis of α-sarcoglycanopathy in both patients. The sarcoglycan genes should be added to the differential diagnosis for cases that present with rhabdomyolysis, exercise intolerance, and hyperCKemia, even in the absence of muscle weakness or normal α-sarcoglycan immunohistochemistry. Work-up of patients with these types of non-specific presentation may be best facilitated through the use of non-specific NGS myopathy panels.

Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E.

OBJECTIVE: To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease. METHODS: All LGMD2E patients followed in participating centers were included. A specific clinical protocol was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed. RESULTS: Thirty-two patients were included (16 male, 16 female; age 7-67 years; 15 severe, 12 mild, and 5 unknown). Neurologic examination showed proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). Seventeen different mutations were identified, and 3 were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation. CONCLUSIONS: This study expands the spectrum of phenotype in ß-sarcoglycanopathy and provides strong evidence that severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan protein expression.

Sarcoid polyneuropathy masquerading as chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Sarcoid polyneuropathy is a rare and clinically heterogeneous disorder that may be the initial presentation of sarcoidosis. METHODS: We report the clinical, electrophysiological, and pathological findings of a patient who carried a diagnosis of sensory-predominant chronic inflammatory demyelinating polyneuropathy (CIDP) for over a decade but was ultimately found to have sarcoid polyneuropathy. RESULTS: A 36-year-old man presented with a several-week history of gait difficulty and muscle cramps. He had a diagnosis of CIDP but had not received lasting benefit from steroid-sparing immunosuppressive drugs. Electrodiagnostic studies were consistent with a chronic demyelinating polyradiculoneuropathy with conduction blocks. After he developed systemic symptoms, tissue biopsies revealed granulomatous disease. Symptoms improved with steroid therapy. CONCLUSIONS: Sarcoid polyneuropathy presents a diagnostic challenge, but, in patients with atypical neuropathy, characteristic systemic symptoms, or a poor response to standard treatment, nerve and muscle biopsies can help diagnose this treatable disorder.

Sarcolemmal alpha and gamma sarcoglycan protein deficiencies in Turkish siblings with a novel missense mutation in the alpha sarcoglycan gene.

BACKGROUND: The sarcoglycan alpha gene, also known as the adhalin gene, is located on chromosome 17q21; mutations in this gene are associated with limb-girdle muscular dystrophy type 2D. We describe two Turkish siblings with findings consistent with limb-girdle muscular dystrophy type 2D. The evaluation excluded a dystrophinopathy, which is the most common form of muscular dystrophy. PATIENTS: Both siblings had very high levels of creatinine phosphokinase and negative molecular tests for deletions and duplications of the dystrophin gene. The older boy presented at 8 years of age with an inability to climb steps and an abnormal gait. His younger brother was 5 years old and had similar symptoms. The muscle biopsy evaluation was performed only in the older brother. RESULTS: The muscle biopsy showed dystrophic features as well as a deficiency in the expression of two different glycoproteins: the alpha sarcoglycan and the gamma sarcoglycan. Sarcolemmal expressions of dystrophin and other sarcoglycans (beta and delta) were diffusely present. DNA analysis demonstrated the presence of previously unknown homozygous mutations [c.226 C > T (p.L76 F)] in exon 3 in the sarcoglycan alpha genes of both siblings. Similar heterozygous point mutations at the same locus were found in both parents, but the genes of beta, delta, and gamma sarcoglycan were normal in the remaining family members. CONCLUSIONS: We describe two siblings with limb-girdle muscular dystrophy type 2D with a novel missense mutation. These patients illustrate that the differential diagnosis of muscular dystrophies is impossible with clinical findings alone. Therefore, a muscle biopsy and DNA analysis remain essential methods for diagnosis of muscle diseases.