Mobility shift of beta-dystroglycan as a marker of GMPPB gene-related muscular dystrophy.

BACKGROUND: Defects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (GMPPB), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes. METHODS: We describe clinical, genetic and biochemical findings of 21 patients with GMPPB-associated dystroglycanopathy. RESULTS: We report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (ß-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormal N-linked glycosylation of ß-DG. CONCLUSIONS: Our data demonstrate that a change in ß-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in GMPPB.

Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure.

OBJECTIVE: Titin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement. METHODS: We studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology. RESULTS: We identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450. CONCLUSIONS: Mutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely to be globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.

Role of MRI in the diagnosis and management of patients with clinical scaphoid fracture.

PURPOSE: The American College of Radiologists (ACR) recognises the value of magnetic resonance imaging (MRI) as the investigation of choice in patients with a clinically suspected scaphoid fracture but normal plain radiographs. The Royal College of Radiologists (RCR) in the UK produces no similar guidelines, as evidenced by the inconsistent management of such cases in hospitals around the UK. In discussion with our musculoskeletal radiologists, we implemented new guidelines to standardise management of our patients and now report our findings. METHODS: A consecutive series of 137 patients referred to the orthopaedic department with clinically suspected scaphoid fracture but normal series of plain radiographs were prospectively followed up over a two-year period. We implemented the use of early MRI for these patients and determined its incidence of detected scaphoid injury in addition to other occult injuries. We then prospectively examined results of these findings on patient management. RESULTS: Thirty-seven (27%) MRI examinations were normal with no evidence of a bony or soft-tissue injury. Soft-tissue injury was diagnosed in 59 patients (43.4%). Of those, 46 were triangular fibrocartilage complex (TFCC) tears (33.8%) and 18 were intercarpal ligament injuries (13.2 %). Bone marrow oedema with no distinct fracture was discovered in 55 cases (40.4%). In 17 (12.5%) cases, this involved only the scaphoid. In the remainder, it also involved the other carpal bones or distal radius. Fracture(s) were diagnosed on 30 examinations (22.0%). CONCLUSIONS: MRI should be regarded as the gold standard investigation for patients in whom a scaphoid fracture is suspected clinically. It allows the diagnosis of occult bony and soft-tissue injuries that can present clinically as a scaphoid fracture; it also helps exclude patients with no fracture. We believe that there is a need to implement national guidelines for managing occult scaphoid fractures.

Hemophilic arthropathy: a review of imaging and staging.

Hemophilic arthropathy (HA) contributes the greatest morbidity and cost in the hemophilic population. Imaging plays a crucial role in accurately monitoring the disease process in all phases and evaluating treatment. It has been shown that prophylactic factor VIII replacement therapy, if given early in life, can prevent or delay the progression of HA and reduce the frequency of hemarthroses. This review evaluates the role of the different imaging modalities used in the staging of HA. It is noteworthy that a new refined consensus magnetic resonance imaging scale for assessment of HA has recently been published which together with introduction of semiquantitative scoring systems in ultrasound will help to provide a more tailored approach to the management of HA in the future.

Muscle MRI findings in limb girdle muscular dystrophy type 2L.

Limb girdle muscular dystrophy type 2L (LGMD2L) is an adult-onset slowly progressive muscular dystrophy associated with recessive mutations in the ANO5 gene. We analysed the muscle MRI pattern in a cohort of 25 LGMD2L patients in order to understand the extent and progression of muscle pathology in LGM2L and assess if muscle MRI might help in the diagnostic work-up of these patients. Our results showed a homogeneous pattern of muscle pathology on muscle MRI, with a predominant involvement of the posterior compartment muscles in both the thighs and calves. The muscles of the anterior compartments in the leg together with the sartorius and gracilis muscles were best preserved, which partially overlaps with patterns observed for other recessive LGMDs. Muscle MRI therefore does not appear to be as useful in the diagnostic work up of LGMD2L as for other neuromuscular diseases, such as Bethlem myopathy or myofibrillar myopathy.