Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz-Jampel syndrome

Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive condition defined by the association of myotonia with chondrodysplasia. SJS results from mutations in the HSPG2 gene, which encodes perlecan, a major component of basement membranes. Only eight HSPG2 mutations have been reported in six SJS families. Here, we describe the molecular findings in 23 families (35 patients) with SJS, being one-third of the SJS cases reported in the medical literature. We identified 22 new HSPG2 mutations and unreported polymorphisms. Mutations included nine deletion or insertion (41%), six splice site (27%), five missense (23%), and two nonsense mutations (9%). All but four mutations were private, and we found no evidence for a founder effect. Analyses of HSPG2 messenger RNA (mRNA) and perlecan immunostaining on patients' cells revealed a hypomorphic effect of the studied mutations. They also demonstrated distinct consequences of truncating and missense mutations on perlecan expression as truncating mutations resulted in instability of HSPG2 mRNA through nonsense mRNA-mediated decay, whereas missense mutations involving cysteine residues led to intracellular retention of perlecan, probably due to quality control pathways. Our analyses strengthen the idea that SJS results from hypomorphic mutations of the HSPG2 gene. They also propose tools for its molecular diagnosis and provide new clues for the understanding of its pathophysiology.     

Cardiac and pulmonary investigations in Bethlem myopathy

BACKGROUND: Bethlem myopathy is considered a relatively mild neuromuscular disorder without significant cardiac and respiratory involvement. OBJECTIVE: To investigate cardiac and respiratory involvement in Bethlem myopathy. DESIGN: Cross-sectional study. SETTING: University hospitals. Patients Fifty patients with Bethlem myopathy from 26 families. INTERVENTIONS: Cardiac examinations, including electrocardiography and echocardiography (n = 37) and pulmonary investigations (n = 43). Holter monitoring was performed in 16 patients. MAIN OUTCOME MEASURES: Cardiac and respiratory abnormalities. RESULTS: Several cardiac abnormalities were found that were considered unrelated to the muscular disorder. Seven (16%) of 43 patients had a forced vital capacity less than 70% of the predicted value. One of 2 patients with a forced vital capacity less than 50% was also receiving respiratory support. All patients with compromised respiratory function were still ambulatory, and we found no significant correlation between the severity of arm weakness and the severity of respiratory muscle involvement. CONCLUSIONS: There is no evidence of cardiac involvement in Bethlem myopathy. Respiratory failure is part of the clinical spectrum and can occur in ambulatory patients.     

Muscular mitochondrial function in amyotrophic lateral sclerosis is progressively altered as the disease develops: a temporal study in man

We performed repeated analysis of mitochondrial respiratory function in skeletal muscle (SM) of patients with early-stage sporadic amyotrophic lateral sclerosis (SALS) to determine whether mitochondrial function was altered as the disease advanced. SM biopsies were obtained from 7 patients with newly diagnosed SALS, the same 7 patients 3 months later, and 7 sedentary controls. Muscle fibers were permeabilized with saponin, then skinned and placed in an oxygraphic chamber to measure basal and maximal adenosine diphosphate (ADP)-stimulated respiration rates and to assess mitochondrial regulation by ADP. We found that the maximal oxidative phosphorylation capacity of muscular mitochondria significantly increased, and muscular mitochondrial respiratory complex IV activity significantly decreased as the disease advanced. This temporal study demonstrates for the first time that mitochondrial function in SM in human SALS is progressively altered as the disease develops.     

CAPN3 mutations in patients with idiopathic eosinophilic myositis

OBJECTIVE: Eosinophilic myositis (EM) constitutes a rare pathological entity characterized by eosinophilic infiltration of skeletal muscles, usually associated with parasite infections, systemic disorders, or the intake of drugs or L-tryptophan. The exclusion of such causes defines the spectrum of idiopathic EM. Based on a protein analysis performed in one affected patient, we identified the gene encoding calpain-3, CAPN3, as a candidate for a subset of idiopathic EM. METHODS: We screened CAPN3 for mutations using DHPLC and direct sequencing in six unrelated patients, recruited for EM diagnosed after histological examination of muscle biopsy samples, without any identified causative factor. RESULTS: We identified CAPN3 mutations in the six unrelated patients originally diagnosed with idiopathic EM. INTERPRETATION: Mutations in CAPN3 can cause EM. Thus, a subset of idiopathic EM is genetically determined, with an autosomal recessive mode of inheritance. Patients presented with a triad that appears to be indicative of CAPN3 mutations: (1) EM in the first decade, (2) elevated serum creatine phosphokinase levels (isolated or with little corresponding weakness), and (3) inconstant peripheral hypereosinophilia. However, that EM represents a distinct phenotype associated to CAPN3 mutations or, rather, an early histopathological picture of LGMD2A must be further evaluated. Our findings should be of interest toward further investigating the role of calpain-3 in skeletal muscle. Furthermore, patients with idiopathic EM should undergo calpain-3 protein analysis and be considered for subsequent molecular analysis of the CAPN3 gene.     

Bone marrow oedema of the knee

Magnetic resonance (MR) imaging is a frequently performed investigation for disease of the knee. Bone marrow oedema (BME) is a common MR finding with a number of causes including trauma, tumour, infection, inflammatory arthropathies and BME syndromes. This article illustrates the range of MR appearances of BME around the knee and describes secondary signs that allow the reader to determine the cause of disease and to distinguish BME from normal marrow signal changes.     

Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity

Nogo, a protein inhibiting axonal regeneration, exhibits a characteristic isoform-specific pattern of expression in skeletal muscle of transgenic mice and patients with amyotrophic lateral sclerosis. Here, the increased levels of Nogo-A or Nogo-B in muscle biopsies of 15 amyotrophic lateral sclerosis patients significantly correlated with the severity of clinical disability and with the degree of muscle fiber atrophy. Nogo-A immunoreactivity was observed selectively in atrophic slow-twitch type I fibers. These results suggest that Nogo expression in muscle is a marker of amyotrophic lateral sclerosis severity.     

Imaging the post-operative meniscus

Considerable developments have occurred in meniscal surgery, and consequently in the imaging of post-operative menisci, over the last 15 years. A drive to preserve meniscal physiologic function for as long as possible, in order to delay osteoarthrosis, has resulted in limited partial meniscectomies, meniscal repairs and meniscal transplants. Each of these techniques affects the imaging appearance of the meniscus, reducing the accuracy of conventional MRI in predicting recurrent tears. The specificity of conventional MRI can be improved by employing at least two T2-weighted sequences, but this still leaves a shortfall in sensitivity. In an attempt to increase the diagnostic accuracy of cross-sectional imaging, MR arthrography (MRA) and CT arthrography (CTA), have been applied to the post-operative meniscus. Sensitivities and specificities for these two techniques approach 90% in predicting recurrent meniscal tears. In the setting of clinical symptoms and gross meniscal deficiency, meniscal allografts are being transplanted with increasing frequency. In these transplants meniscal degeneration, fragmentation and separation are common findings, but the role of imaging in the management of these patients has not yet been well defined. This review explores the imaging techniques available for the evaluation of the post-operative meniscus, their strengths and weaknesses, and the reasons that they may find a place in a rational strategy for imaging of the symptomatic post-operative knee.     

Metastases in the sphenoidal sinus in a patient with papillary thyroid cancer

Tumours that produce metastases in the paranasal sinuses or sphenoidal sinus are rare; the carcinomas of kidney and lung being, the most frequent with this type of metastasis. Distant metastases from differentiated thyroid carcinoma are rare and, moreover, when they metastasize, they do so into lung and bone. We report a patient who had a papillary thyroid carcinoma with metastases into the sphenoidal sinus.     

Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion

neurogenetics - Giant axonal neuropathy (GAN) is an autosomal recessive disease caused by mutations in the GAN gene encoding gigaxonin. Patients develop a progressive sensorimotor neuropathy...     

Subcutaneous thigh fat necrosis as a result of tourniquet control during total knee arthroplasty

The use of a pneumatic tourniquet in total knee arthroplasty has been linked to complications caused by local tissue hypoxia. Fat necrosis is a rare condition that presents as an ill-defined subcutaneous lesion. The clinical features resemble that of a lipoma but histological appearance is characteristic. Ultrasound imaging is helpful in establishing the diagnosis both by sonographic appearance as well as in directing a biopsy if necessary. We present a case of encapsulated fat necrosis caused by the use of a pneumatic tourniquet during total knee arthroplasty.