The multifaceted musculoskeletal hydatid disease.

Musculoskeletal hydatid disease is rare and can be located anywhere but most commonly the bone and muscles of the spine, pelvis, then the lower limbs. Imaging is essential for its diagnosis, performing the pre-therapeutic assessment, guiding possible percutaneous treatments, and providing post-therapeutic follow-up. Musculoskeletal hydatidosis can take several forms that may suggest other infections and tumors or pseudotumors. MRI and CT are superior for its diagnosis but ultrasound and radiography remain the most accessible examinations in developing countries where this parasitosis is endemic. In this review, we provide an overview of this disease and describe its different imaging patterns in soft tissue and bone involvement that should be sought to support the diagnosis.

Caveolinopathy: Clinical, histological, and muscle imaging features and follow-up in a multicenter retrospective cohort.

BACKGROUND AND PURPOSE: CAV3 gene mutations, mostly inherited as an autosomal dominant trait, cause various skeletal muscle diseases. Clinical presentations encompass proximal myopathy, distal myopathy, or isolated persistent high creatine kinase (CK) with a major overlapping phenotype. METHODS: Twenty-three patients with CAV3 symptomatic mutations, from 16 different families, were included in a retrospective cohort. Mean follow-up duration was 24.2 ± 15.0 years. Clinical and functional data were collected during the follow-up. The results of muscle imaging, electroneuromyography, muscle histopathology, immunohistochemistry, and caveolin-3 Western blot analysis were also compiled. RESULTS: Exercise intolerance was the most common phenotype (52%). Eighty percent of patients had calf hypertrophy, and only 65% of patients presented rippling. One patient presented initially with camptocormia. A walking aid was required in only two patients. Electroneuromyography was mostly normal. CK level was elevated in all patients. No patient had cardiac or respiratory impairment. Muscle imaging showed fatty involvement of semimembranosus, semitendinosus, rectus femoris, biceps brachialis, and spinal muscles. Almost all (87%) of the biopsies were abnormal but without any specific pattern. Whereas a quarter of patients had normal caveolin-3 immunohistochemistry results, Western blots disclosed a reduced amount of the protein. We report nine mutations, including four not previously described. No phenotype-genotype correlation was evidenced. CONCLUSIONS: Caveolinopathy has diverse clinical, muscle imaging, and histological presentations but often has limited functional impact. Mild forms of the disease, an atypical phenotype, and normal caveolin-3 immunostaining are pitfalls leading to misdiagnosis.

Infectious sacroiliitis: MRI- and CT-based assessment of disease extent, complications, and anatomic correlation.

OBJECTIVE: To describe the frequency of MR and CT features of infectious sacroiliitis (ISI) and assess its extent and complications MATERIALS AND METHODS: This retrospective study included patients with ISI who were evaluated between 2008 and 2021 in a single center. Two radiologists reviewed MRI and CT images to determine the anatomical distribution (unilateral/bilateral, iliac/sacral bone, proximal/middle/distal), severity (bone marrow edema [BME]/periostitis/erosions), concurrent infection (vertebral/nonvertebral), and complications (abscess/probable adjacent osteomyelitis/cavitation/devitalized areas/sequestrum/pelvic venous thrombosis) of ISI. Interobserver reproducibility was assessed. Correlation analysis evaluated the effect of the causative microorganism on severity. Two human bodies were dissected to outline possible ways that ISI can spread. RESULTS: Forty patients with ISI (40 years ± 22; 26 women) were evaluated. Ten patients had bilateral ISI. Concurrent vertebral infection was associated in 15% of cases. Reproducibility of sacral BME, periostitis, and reactive locoregional abnormalities was perfect (κ = 1). Reproducibility was low for erosion count (κ = 0.52[0.52-0.82]) and periarticular osteopenia (κ = 0.50[0.18-0.82]). Inflammatory changes were BME (42/42 joints), muscle edema (38/42), and severe periostitis along the ilium (33/37). Destructive structural changes occurred with confluent erosions (iliac, 20/48; sacral, 13/48), sequestrum (20/48), and cavitation (12/48). Complications occurred in 75% of cases, including periarticular abscesses (n = 30/47), probable adjacent osteomyelitis (n = 16/37), and pelvic thrombophlebitis (n = 3). Tuberculous ISI (6/40) correlated with sclerosis (rs = 0.45[0.16; 0.67]; p < 10-2) and bone devitalization (rs = 0.38[0.16; 0.67]; p = .02). The anatomical study highlighted the shared venous vascularization of sacroiliac joints, pelvic organs, and mobile spine. CONCLUSION: Complications of ISI are frequent, including abscesses, adjacent osteomyelitis, and periostitis. ISI had bilateral involvement nonrarely and is commonly associated with another spinal infection.

Macroglossia: A potentially severe complication of late-onset Pompe disease.

BACKGROUND: Pompe disease is a rare neuromuscular disorder caused by a deficiency of a lysosomal enzyme, acid α-glucosidase. Macroglossia is a classic clinical sign of several inherited myopathies and has also been reported to occur progressively in late-onset Pompe disease (LOPD). METHODS: We describe patients with LOPD and macroglossia included in the French national Pompe disease registry. Clinical, functional, and radiological data were collected during periodic follow-up and analyzed retrospectively. These cases were compared with 15 previously reported cases. RESULTS: Five patients, three females and two males, aged 71-88 years, were included in this study. All but one of the patients suffered from symptoms related to macroglossia before the diagnosis of Pompe disease. Three had localized tongue atrophy and one had significant localized tongue hypertrophy which led to glossectomy 10 years before diagnosis. Two patients had severe dysphagia, one of whom underwent gastrostomy for enteral nutritional support. One patient experienced the persistence of numerous sleep apneas despite nocturnal bilevel positive airway pressure (BiPAP) ventilation. All our patients had dysarthria, and two required speech therapy. Four patients had a tongue hypersignal on magnetic resonance imaging (MRI) T1 sequences. CONCLUSIONS: Detection of macroglossia should be part of the clinical diagnosis and follow-up of patients with LOPD, with a careful evaluation of its main consequences. Macroglossia can have severe functional impacts on speech, swallowing, and sleep. Whole-body MRI with facial sections may facilitate the early diagnosis of Pompe disease with the "bright tongue sign".

INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.

Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

RASA1 phenotype overlaps with hereditary haemorrhagic telangiectasia: two case reports.

Background We report two cases of RASA1-related capillary malformation-arteriovenous malformation (CM-AVM1) syndrome mimicking hereditary haemorrhagic telangiectasia (HHT).Methods and results A 28-year-old man, previously embolised for cerebral arteriovenous malformations (AVMs), presented with epistaxis and typical nasal telangiectasias of HHT. CT scan revealed a large portocaval shunt. The second patient was a 9-year-old girl presenting with cyanosis and several mucocutaneous telangiectasias, similar to those observed in typical cases of HHT. CT scan revealed a huge and complex pulmonary AVM of the right lower lobe and a hepatic AVM within the left lobe. HHT diagnosis was considered possible according to the Curaçao criteria for the two patients, with at least two criteria for each. Genetic tests did not find any mutation in the three classic genes (Endoglin, Activin receptor-like kinase 1 or Mothers against decapentaplegic homolog 4), but identified in both cases an RASA1 mutation, known to cause CM-AVM1 syndrome.Conclusions Pulmonary AVM and portocaval shunt, usually encountered in HHT, have not yet been described in the CM-AVM1 syndrome. RASA1 screening may be considered in case of HHT suspicion, particularly when mutations are not found in the usually affected genes.

Occurrence of pulmonary embolism related to COVID-19.

Recent reports have suggested an increased risk of pulmonary embolism (PE) related to COVID-19. The aim of this cohort study is to compare the incidence of PE during a 3-year period and to assess the characteristics of PE in COVID-19. We studied consecutive patients presenting with PE (January 2017-April 2020). Clinical presentation, computed tomography (CT) and biological markers were systematically assessed. We recorded the global number of hospitalizations during the COVID-19 pandemic and during the same period in 2018-2019. We included 347 patients: 326 without COVID-19 and 21 with COVID-19. Patients with COVID-19 experienced more likely dyspnea (p=0.04), had lower arterial oxygen saturation (p<0.001), higher C-reactive protein and white blood cell (WBC) count (p<0.0001 and p=0.001, respectively), and a significantly higher in-hospital mortality (14% versus 3.4%, p=0.04). Among COVID-19 patients, diagnosis of PE was performed at admission in 38% (n=8). COVID-19 patients with diagnosis of PE during hospitalization (n=13) had significantly more dyspnea (p=0.04), lower arterial oxygen saturation (p=0.01), less proximal PE (p=0.02), and higher heart rate (p=0.009), CT severity score (p=0.001), C-reactive protein (p=0.006) and WBC count (p=0.04). During the COVID-19 outbreak, a 97.4% increase of PE incidence was observed as compared to 2017-2019 and the proportion of hospitalizations related to PE was 3.7% versus 1.3% in 2018-2019 (p<0.0001). In conclusion, the COVID-19 pandemic leads to a dramatic increased incidence of PE. Physicians should be aware that PE may be diagnosed at admission, but also after several days of hospitalization, with a different clinical, CT and biological features of thrombotic disease.

Ruptured Intercostal Artery Aneurysm with Radiculomedullary Branch Downstream Treated with Endovascular Stenting.

Intercostal artery aneurysms are extremely rare, and could be associated with aortic coarctation, systemic diseases like neurofibromatosis, or more rarely Marfan syndrome. They could be life-threatening when ruptured, leading to hemothorax or mediastinal hematoma. Endovascular management before or after rupture of intercostal aneurysms, should be considered. Radiculomedullary branch, especially Adamkiewicz one, emanating from intercostal artery needs special focus during endovascular management, to avoid spinal cord ischemia. We present herein the first case of a ruptured intercostal artery aneurysm with a downstream Adamkiewicz artery in a suspected Marfan patient. Aneurysmal exclusion using stent graft was the unique therapeutic option.

Predictive factors for positive disco-vertebral biopsy culture in pyogenic vertebral osteomyelitis, and impact of fluoroscopic versus scanographic guidance.

BACKGROUND: The aims of this study were to identify the predictive factors for microbiological diagnosis through disco-vertebral biopsy (DVB) in patients with pyogenic vertebral osteomyelitis (PVO) and negative blood cultures, and compare the performance of DVB under fluoroscopic versus scanographic guidance. METHODS: We performed a cohort study comparing positive and negative DVB among patients with PVO. All cases of PVO undergoing a DVB for microbiological diagnosis in our center were retrospectively reviewed. Infections due to Mycobacterium tuberculosis, infections on foreign device, and non-septic diseases were excluded. Anamnestic, clinical, biological, microbiological, as well as radiological data were collected from medical charts thanks to a standardized data set. RESULTS: A total of 111 patients were screened; 88 patients were included. Microbiological cultures were positive in 53/88 (60.2%) patients. A thickening of the paravertebral tissue ≥10 mm on magnetic resonance imaging (MRI) in axial MR scans was a predictive factor of DVB microbiological positivity (52.4% vs. 13.3%; p = 0.006; OR = 5.4). Overall, 51 DVB were performed under fluoroscopic guidance and 37 under scanographic guidance. Considering lumbar DVB, 25/36 (69.4%) of cases yielded positive results under fluoroscopic guidance versus 5/15 (33.3%) under scanographic guidance (p = 0.02; OR = 4.4). No adverse event linked to DVB was notified. CONCLUSION: Every patient with PVO and negative blood cultures should undergo a DVB. A thickening of the paravertebral tissue ≥10 mm on MRI is associated with a higher rate of positive DVB culture. A lumbar DVB under fluoroscopic guidance is more sensitive than under scanographic guidance to identify the micro-organism involved.

Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy.

BACKGROUND AND OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the PABPN1 gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data. METHODS: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data. RESULTS: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the adductor magnus and the soleus were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, adductor magnus and soleus can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.

Whole-Body Muscle Magnetic Resonance Imaging in Glycogen-Storage Disease Type III.

INTRODUCTION: The main objective of this study was to describe muscle involvement on whole-body magnetic resonance imaging scans in adults at different stages of glycogen-storage disease type III (GSDIII). METHODS: Fifteen patients, 16-59 years of age, were examined on a 3-T system. The examinations consisted of coronal and axial T1-weighted images or fat images with a Dixon technique, and were scored for 47 muscles using Mercuri's classification. Muscle changes consisted of internal bright signals of fatty replacement. RESULTS: Distribution across muscles showed predominant signal alteration in the lower limbs and postural muscles. This finding is consistent with the overall clinical presentation of GSDIII and the results of heatmap scores. Review of the MRI scans provided new information regarding recurrent muscle changes, particularly in the soleus, gastrocnemius medial head, and thoracic extensor muscles. DISCUSSION: Whole-body muscle imaging provides clinically relevant information regarding muscle involvement in GSDIII. A severity score may contribute to improved patient management. Muscle Nerve, 2019.

WES homozygosity mapping in a recessive form of Charcot-Marie-Tooth neuropathy reveals intronic GDAP1 variant leading to a premature stop codon.

Charcot-Marie-Tooth disease (CMT) refers to a group of clinically and genetically heterogeneous inherited neuropathies. Ganglioside-induced differentiation-associated protein 1 GDAP1-related CMT has been reported in an autosomal dominant or recessive form in patients presenting either axonal or demyelinating neuropathy. We report two Sri Lankan sisters born to consanguineous parents and presenting with a severe axonal sensorimotor neuropathy. The early onset of the disease, the distal and proximal weakness and atrophy leading to major disability, along with areflexia, and, most notably, vocal cord and diaphragm paralysis were highly evocative of a GDAP1-related CMT. However, sequencing of the coding regions of the gene was normal. Whole-exome sequencing (WES) was performed and revealed that the largest region of homozygosity was around GDAP1 with several variants, mostly in non-coding regions. In view of the high clinical suspicion of GDAP1 gene involvement, we examined the variants in this gene and this, along with functional studies, allowed us to identify an alternative splicing site revealing a cryptic in-frame stop codon in intron 4 responsible for a severe loss of wild-type GDAP1. This work is the first to describe a deleterious mutation in GDAP1 gene outside of coding sequences or intronic junctions and emphasizes the importance of interpreting molecular analysis, and in particular WES results, in light of the clinical and electrophysiological phenotype.

Recessive MYPN mutations cause cap myopathy with occasional nemaline rods.

Congenital myopathies are phenotypically and genetically heterogeneous. We describe homozygous truncating mutations in MYPN in 2 unrelated families with a slowly progressive congenital cap myopathy. MYPN encodes the Z-line protein myopalladin implicated in sarcomere integrity. Functional experiments demonstrate that the mutations lead to mRNA defects and to a strong reduction in full-length protein expression. Myopalladin signals accumulate in the caps together with alpha-actinin. Dominant MYPN mutations were previously reported in cardiomyopathies. Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance. Ann Neurol 2017;81:467-473.

MRI in sarcoglycanopathies: a large international cohort study.

OBJECTIVES: To characterise the pattern and spectrum of involvement on muscle MRI in a large cohort of patients with sarcoglycanopathies, which are limb-girdle muscular dystrophies (LGMD2C-2F) caused by mutations in one of the four genes coding for muscle sarcoglycans. METHODS: Lower limb MRI scans of patients with LGMD2C-2F, ranging from severe childhood variants to milder adult-onset forms, were collected in 17 neuromuscular referral centres in Europe and USA. Muscle involvement was evaluated semiquantitatively on T1-weighted images according to a visual score, and the global pattern was assessed as well. RESULTS: Scans from 69 patients were examined (38 LGMD2D, 18 LGMD2C, 12 LGMD2E and 1 LGMD2F). A common pattern of involvement was found in all the analysed scans irrespective of the mutated gene. The most and earliest affected muscles were the thigh adductors, glutei and posterior thigh groups, while lower leg muscles were relatively spared even in advanced disease. A proximodistal gradient of involvement of vasti muscles was a consistent finding in these patients, including the most severe ones. CONCLUSIONS: Muscle involvement on MRI is consistent in patients with LGMD2C-F and can be helpful in distinguishing sarcoglycanopathies from other LGMDs or dystrophinopathies, which represent the most common differential diagnoses. Our data provide evidence about selective susceptibility or resistance to degeneration of specific muscles when one of the sarcoglycans is deficient, as well as preliminary information about progressive involvement of the different muscles over time.

Muscular MRI-based algorithm to differentiate inherited myopathies presenting with spinal rigidity.

OBJECTIVES: Inherited myopathies are major causes of muscle atrophy and are often characterized by rigid spine syndrome, a clinical feature designating patients with early spinal contractures. We aim to present a decision algorithm based on muscular whole body magnetic resonance imaging (mWB-MRI) as a unique tool to orientate the diagnosis of each inherited myopathy long before the genetically confirmed diagnosis. METHODS: This multicentre retrospective study enrolled 79 patients from referral centres in France, Brazil and Chile. The patients underwent 1.5-T or 3-T mWB-MRI. The protocol comprised STIR and T1 sequences in axial and coronal planes, from head to toe. All images were analyzed manually by multiple raters. Fatty muscle replacement was evaluated on mWB-MRI using both the Mercuri scale and statistical comparison based on the percentage of affected muscle. RESULTS: Between February 2005 and December 2015, 76 patients with genetically confirmed inherited myopathy were included. They were affected by Pompe disease or harbored mutations in RYR1, Collagen VI, LMNA, SEPN1, LAMA2 and MYH7 genes. Each myopathy had a specific pattern of affected muscles recognizable on mWB-MRI. This allowed us to create a novel decision algorithm for patients with rigid spine syndrome by segregating these signs. This algorithm was validated by five external evaluators on a cohort of seven patients with a diagnostic accuracy of 94.3% compared with the genetic diagnosis. CONCLUSION: We provide a novel decision algorithm based on muscle fat replacement graded on mWB-MRI that allows diagnosis and differentiation of inherited myopathies presenting with spinal rigidity. KEY POINTS: • Inherited myopathies are rare, diagnosis is challenging and genetic tests require specialized centres and often take years. • Inherited myopathies are often characterized by spinal rigidity. • Whole body magnetic resonance imaging is a unique tool to orientate the diagnosis of each inherited myopathy presenting with spinal rigidity. • Each inherited myopathy in this study has a specific pattern of affected muscles that orientate diagnosis. • A novel MRI-based algorithm, usable by every radiologist, can help the early diagnosis of these myopathies.

Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues.

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.

Hyperckemia and myalgia are common presentations of anoctamin-5-related myopathy in French patients.

INTRODUCTION: Patients with anoctamin-5 (ANO5) mutations may present not only with limb-girdle muscular dystrophy type 2L or adult-onset Miyoshi-type myopathy but also with asymptomatic hyperCKemia, exercise intolerance, or rhabdomyolysis. MATERIALS AND METHODS: Data from 38 patients in France with ANO5 mutations with and without muscle weakness on first examination were compared. RESULTS: Twenty patients presented without muscle weakness. Median age at symptom onset or discovery of hyperCKemia was 23 years. Creatine kinase levels ranged from 200 to 40,000 U/L. Electromyography showed a myopathic pattern in 5 patients, and muscle imaging showed involvement of posterior calf muscles in 10 patients. Mild cardiac involvement was observed in 2 patients. Sixteen patients remain free of weakness after a median follow-up period of 5 years. DISCUSSION: Asymptomatic, sometimes mild hyperCKemia or exercise intolerance is a presentation of ANO5-related myopathy and may remain isolated or precede muscle weakness by many years. Muscle Nerve 56: 1096-1100, 2017.

Prospective exploratory muscle biopsy, imaging, and functional assessment in patients with late-onset Pompe disease treated with alglucosidase alfa: The EMBASSY Study.

BACKGROUND: Late-onset Pompe disease is characterized by progressive skeletal myopathy followed by respiratory muscle weakness, typically leading to loss of ambulation and respiratory failure. In this population, enzyme replacement therapy (ERT) with alglucosidase alfa has been shown to stabilize respiratory function and improve mobility and muscle strength. Muscle pathology and glycogen clearance from skeletal muscle in treatment-naïve adults after ERT have not been extensively examined. METHODS: This exploratory, open-label, multicenter study evaluated glycogen clearance in muscle tissue samples collected pre- and post- alglucosidase alfa treatment in treatment-naïve adults with late-onset Pompe disease. The primary endpoint was the quantitative reduction in percent tissue area occupied by glycogen in muscle biopsies from baseline to 6months. Secondary endpoints included qualitative histologic assessment of tissue glycogen distribution, secondary pathology changes, assessment of magnetic resonance images (MRIs) for intact muscle and fatty replacement, and functional assessments. RESULTS: Sixteen patients completed the study. After 6months of ERT, the percent tissue area occupied by glycogen in quadriceps and deltoid muscles decreased in 10 and 8 patients, respectively. No changes were detected on MRI from baseline to 6months. A majority of patients showed improvements on functional assessments after 6months of treatment. All treatment-related adverse events were mild or moderate. CONCLUSIONS: This exploratory study provides novel insights into the histopathologic effects of ERT in late-onset Pompe disease patients. Ultrastructural examination of muscle biopsies demonstrated reduced lysosomal glycogen after ERT. Findings are consistent with stabilization of disease by ERT in treatment-naïve patients with late-onset Pompe disease.

Pre-surgical CT-assessment of neurogenic myositis ossificans of the hip and risk factors of recurrence: a series of 101 consecutive patients.

BACKGROUND: Neurogenic Myositis Ossificans (NMO) is a rare disabling pathology characterized by peri-articular heterotopic ossifications following severe peripheral or central nervous system injuries. It results in ankylosis and vessels or nerves compressions. Our study aimed to describe the pre-operative findings of patients with NMO of the hip using biphasic computerized tomography (CT). METHODS: Between 2006 and 2012, we retrospectively analyzed 101 consecutive patients with hip NMO. We analyzed all CTs and surgical reports following a standardized grid depicting the osteoma and its relations with joint capsule, vessels and nerves and bone mineralization. We studied surgical complications and recurrence during follow-up. Chi2-test and Fischer's test were performed to compare qualitative values with respectively normal and non-normal distribution. Quantitative values were analyzed with a one factor analysis of variance (ANOVA) test. Agreement between pre-surgical CT and surgical observations was evaluated with Cohen's kappa test. RESULTS: Correlation between pre-operative CT and surgical findings was excellent regarding relationships with vessels (0,82) and was good concerning relationships with sciatic nerves (0.62) and with joint capsule (0.68). Close contact or disruption of joint capsule (p = 0.005), joint space narrowing (p = 0.007) and bone demineralization (p < 0.001) were correlated with NMO recurrence. CONCLUSIONS: Biphasic enhanced-CT allows pre-operative assessment of NMO with good correlation to surgical observations and helps prevent surgical complications.

Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss.

We report on an autosomal-recessive variant of Ehlers-Danlos syndrome (EDS) characterized by severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment, and normal pyridinoline excretion in urine. Clinically, the disorder shares many features with the kyphoscoliotic type of EDS (EDS VIA) and Ullrich congenital muscular dystrophy. Linkage analysis in a large Tyrolean kindred identified a homozygous frameshift mutation in FKBP14 in two affected individuals. Based on the cardinal clinical characteristics of the disorder, four additional individuals originating from different European countries were identified who carried either homozygous or compound heterozygous mutations in FKBP14. FKBP14 belongs to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases). ER-resident FKBPs have been suggested to act as folding catalysts by accelerating cis-trans isomerization of peptidyl-prolyl bonds and to act occasionally also as chaperones. We demonstrate that FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. Furthermore, indirect immunofluorescence of FKBP14-deficient fibroblasts indicated an altered assembly of the extracellular matrix in vitro. These findings suggest that a disturbance of protein folding in the ER affecting one or more components of the extracellular matrix might cause the generalized connective tissue involvement in this disorder. FKBP14 mutation analysis should be considered in all individuals with apparent kyphoscoliotic type of EDS and normal urinary pyridinoline excretion, in particular in conjunction with sensorineural hearing impairment.