Transition memories: experiences of trans adult women with hormone therapy and their beliefs on the usage of hormone blockers to suppress puberty.

PURPOSE: In recent years, an increasing number of specialized gender clinics have been prescribing gonadotropin-releasing hormone (GnRH) analogs to adolescents diagnosed with gender dysphoria (GD) to suppress puberty. This paper presents qualitative research on the hormone therapy (HT) experiences of older trans-people and their views on puberty suppression. The main aim of this research was to explore the psychological aspects of hormonal treatments for gender non-conforming adults, including the controversial use of puberty suppression treatments. METHODS: Using a semi-structured interview format, ten adult trans-women were interviewed (mean age: 37.4) to explore their personal histories regarding GD onset and development, their HT experiences, and their views on the use of GnRH analogs to suppress puberty in trans-children and adolescents. RESULTS: the interview transcripts were analyzed using the consensual qualitative research method from which several themes emerged: the onset of GD, childhood experiences, experiences with puberty and HT, views on the puberty suspension procedure, and the effects of this suspension on gender identity and sexuality. CONCLUSIONS: The interviews showed that overall, the participants valued the new treatment protocol due to the opportunity to prevent the severe body dysphoria and social phobia trans-people experience with puberty. It seems that the risk of social isolation and psychological suffering is increased by the general lack of acceptance and stigma toward trans-identities in the Italian society. However, during gender transitions, they highlight the need to focus more on internal and psychological aspects, rather than over-emphasize physical appearance. This study gives a voice to an under-represented group regarding the use of GnRH analogs to suppress puberty in trans-individuals, and collected firsthand insights on this controversial treatment and its recommendations in professional international guidelines.

Association study reveals novel risk loci for sporadic inclusion body myositis.

BACKGROUND AND PURPOSE: The aim was to identify potential genetic risk factors associated with sporadic inclusion body myositis (sIBM). METHODS: An association based case-control approach was utilized on whole exome sequencing data of 30 Finnish sIBM patients and a control cohort (n = 193). A separate Italian cohort of sIBM patients (n = 12) was used for evaluation of the results. RESULTS: Seven single nucleotide polymorphisms were identified in five genes that have a considerably higher observed frequency in Finnish sIBM patients compared to the control population, and the previous association of the genetic human leukocyte antigen region was confirmed. CONCLUSIONS: All seven identified variants could individually or in combination increase the susceptibility for sIBM.

Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.

BACKGROUND: The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. METHODS: We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. RESULTS: A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%). CONCLUSIONS: Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

Depression in multiple sclerosis: effect of brain derived neurotrophic factor Val66Met polymorphism and disease perception.

BACKGROUND AND PURPOSE: Depression is common amongst subjects with multiple sclerosis (MS), and several investigations have explored different determinants of this condition, including physical disability, psychological and psychosocial factors. The brain derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with depression. The aim of this study was to analyze the influence of disease-related factors, BDNF Val66Met polymorphism and perception of disease on the severity of depression in MS. METHOD: In total, 136 MS patients (88 women) were recruited and genotyped for BDNF rs6265 polymorphism at nucleotide 196 (G/A) using 'high resolution melting'. Depressive symptoms were assessed by the Multiple Sclerosis Depression Rating Scale. Perception of health status was assessed using the SF-36 questionnaire. RESULTS: A multivariable linear regression model showed that the best predictors of depression were the SF-36 General health (ß = -0.209; P = 0.013), Mental health (ß = -0.410; P < 0.001) and Social activity (ß = -0.195; P = 0.035) scores; physical disability (assessed by the Extended Disability Status Scale score) was directly correlated to depression severity on univariate analysis, but it was not a relevant predictor of depression on multivariate analysis; other variables directly related to the disease (treatment, annual relapsing rate) and the BDNF Val66Met polymorphism were not significantly associated with depression. CONCLUSION: Perception of the health status is the principal predictor of depressive symptoms in our sample. This result supports the hypothesis that the subjective interpretation of the disease's consequences is one of the main factors in determining depression in MS.

Muscle MRI in female carriers of dystrophinopathy.

BACKGROUND AND PURPOSE: Duchenne muscular dystrophy carriers represent a rare condition that needs to be recognized because of the possible implications for prenatal diagnosis. Muscle biopsy is currently the diagnostic instrument of choice in sporadic patients. We wanted to verify whether muscle magnetic resonance imaging (MRI) could identify a pattern of involvement suggestive of this condition and whether it was similar to that reported in Duchenne and Becker muscular dystrophy. METHODS: Evaluation of pelvic and lower limb MRI scans of 12 dystrophinopathy carriers was performed. RESULTS: We found a frequent involvement of the quadratus femoris, gluteus maximus and medius, biceps femoris long head, adductor magnus, vasti and paraspinal muscles, whilst the popliteus, iliopsoas, recti abdominis, sartorius, and gracilis were relatively spared. Asymmetry was a major feature on MRI; it could be detected significantly more often than with sole clinical examination and even in patients without weakness. CONCLUSIONS: The pattern we describe here is similar to that reported in Duchenne and Becker muscular dystrophy, although asymmetry represents a major distinctive feature. Muscle MRI was more sensitive than clinical examination for detecting single muscle involvement and asymmetry. Further studies are needed to verify the consistency of this pattern in larger cohorts and to assess whether muscle MRI can improve diagnostic accuracy in carriers with normal dystrophin staining on muscle biopsy.

Upper body involvement in GNE myopathy assessed by muscle imaging.

Upper body muscle involvement has never been systematically investigated in GNE myopathy (GNEM). Aims of our study were to explore upper body involvement in GNEM patients by means of muscle MRI, to compare the degree of pathology with that of lower body and to validate the MRI pattern of the lower limbs in novel patients. MRI scans of 9 GNEM patients were retrospectively evaluated. T1-weighted and short-tau inversion recovery images were scored. As a result, serratus anterior was involved in all patients, followed by subscapularis and trapezius muscles. The majority of scans consistently showed hypotrophy of pectoralis minor. Conversely, cranial muscles including the tongue were always spared while pectoralis major and latissimus dorsi were relatively spared. We confirmed the known pattern of involvement in the pelvic girdle and limbs, that were more significantly affected than the upper girdle in all disease stages. Paraspinal muscles were also frequently affected displaying both a cranio-caudal and latero-medial gradient of severity along the body axis. Upper girdle MRI highlights a selective muscle involvement in GNEM, offering an added value in patients' diagnostic workup and deep stratification.

Risk of multiple sclerosis relapses when switching from fingolimod to cell-depleting agents: the role of washout duration.

BACKGROUND: Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1-2 months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if initiated before lymphocyte recovery has occurred. OBJECTIVE: To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent in relation to washout duration using data from the Italian MS Register. METHODS: The risk of relapses was assessed in relation to different washout durations (< 6, 6-11, 12-17 and > / = 18 weeks) in patients starting alemtuzumab, rituximab, ocrelizumab or cladribine following FTY discontinuation. RESULTS: We included 329 patients in the analysis (226F, 103 M; mean age 41 ± 10 years). During the cell-depleting treatment, the incidence rate ratio for a relapse was significantly greater in patients with a washout period of 12-17 and > / = 18 weeks compared to the reference period (< 6 weeks). The risk of a relapse was significantly influenced by the occurrence of relapses during FTY treatment and by washout length, with hazard ratios markedly increasing with the washout duration. CONCLUSION: The risk of relapses increases with the washout duration when switching from FTY to lymphocyte-depleting agents.

Hereditary inclusion-body myopathy with sparing of the quadriceps: the many tiles of an incomplete puzzle.

The hereditary inclusion-body myopathies encompass several syndromes with autosomal recessive or dominant inheritance. Despite a different clinical presentation they all have a progressive course leading to severe disability and share similar pathologic findings at the muscle biopsy. Quadriceps-sparing autosomal recessive hereditary inclusion-body myopathy (h-IBM) is the commonest form and is tied to mutations of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been clarified how mutations of the GNE gene impair muscle homeostasis. Although several lines of evidence argue in favor of an abnormal sialylation of muscle glycoproteins playing a key role in h-IBM pathogenesis, others studies have demonstrated new functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h-IBM and the main clues available to date concerning the possible pathogenic mechanisms of this disorder. Understanding the molecular mechanism underlying h-IBM pathology is a fundamental requisite to plan a future attempt to therapy.

Mesoangioblasts of inclusion-body myositis: a twofold tool to study pathogenic mechanisms and enhance defective muscle regeneration.

Mesoangioblasts are a class of adult stem cells of mesoderm origin, potentially useful for the treatment of primitive myopathies of different etiology. Extensive in vitro and in vivo studies in animal models of muscular dystrophy have demonstrated the ability of mesoangioblast to repair skeletal muscle when injected intra-arterially. In a previous work we demonstrated that mesoangioblasts obtained from diagnostic muscle biopsies of IBM patients display a defective differentiation down skeletal muscle and this block can be corrected in vitro by transient MyoD transfection. We are currently investigating different pathways involved in mesoangioblasts skeletal muscle differentiation and exploring alternative stimulatory approaches not requiring extensive cell manipulation. This will allow to obtain safe, easy and efficient molecular or pharmacological modulation of pro-myogenic pathways in IBM mesoangioblasts. It is of crucial importance to identify factors (ie. cytokines, growth factors) produced by muscle or inflammatory cells and released in the surrounding milieu that are able to regulate the differentiation ability of IBM mesoangioblasts. To promote myogenic differentiation of endogenous mesoangioblasts in IBM muscle, the modulation of such target molecules selectively dysregulated would be a more handy approach to enhance muscle regeneration compared to transplantation techniques. Studies on the biological characteristics of IBM mesoangioblasts with their aberrant differentiation behavior, the signaling pathways possibly involved in their differentiation block and the possible strategies to overcome it in vivo, might provide new insights to better understand the etiopathogenesis of this crippling disorder and to identify molecular targets susceptible of therapeutic modulation.

A pilot study of lncRNAs expression profile in serum of progressive multiple sclerosis patients.

OBJECTIVE: Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease that affect both white and gray matter. The relapsing and the eventually progressive course of MS is heterogeneous; thus, a confident long-term prediction of individual prognosis is not possible yet. Recent studies have demonstrated the role of long non-coding RNA (lncRNAs) as potential biomarkers that could provide information to predict disease activity and progression. PATIENTS AND METHODS: By qRT-PCR, we analysed the lncRNAs expression in the serum of 16 secondary progressive MS (SP-MS), 12 primary progressive (PP-MS) patients and 8 healthy controls. RESULTS: We found that TUG1 was upregulated in SP-MS, while the comparison of PP-MS vs. controls showed a downregulation of non-protein coding RNA 188 (LRRC75A-AS1) and a significant upregulation of two lncRNAs: long intergenic non-protein coding RNA 293 (LINC00293) and RP11-29G8.3. Moreover, we performed an in-silico analysis using DIANA-LncBase v2 and HMDD v3.0 software, in order to predict the possible interaction of these four lncRNAs with miRNAs. We identified 21 miRNAs prediction targets possibly involved in MS. CONCLUSIONS: Our data indicate a regulatory function of these lncRNAs in autoimmune and inflammatory processes related to MS suggesting their potential role in progressive MS pathogenesis.

Prevalence and clinical impact of VIral Respiratory tract infections in patients hospitalized for Community-Acquired Pneumonia: the VIRCAP study.

Prevalence and clinical impact of viral respiratory tract infections (VRTIs) on community-acquired pneumonia (CAP) has not been well defined so far. The aims of this study were to investigate the prevalence and the clinical impact of VRTIs in patients with CAP. Prospective study involving adult patients consecutively admitted at medical wards for CAP and tested for VRTIs by real-time PCR on pharyngeal swab. Patients' features were evaluated with regard to the presence of VRTI and aetiology of CAP. Clinical failure was a composite endpoint defined by worsening of signs and symptoms requiring escalation of antibiotic treatment or ICU admission or death within 30 days. 91 patients were enrolled, mean age 65.7 ± 10.6 years, 50.5% female. 62 patients (68.2%) had no viral co-infection while in 29 patients (31.8%) a VRTI was detected; influenza virus was the most frequently identified (41.9%). The two groups were similar in terms of baseline features. In presence of a VRTI, pneumonia severity index (PSI) was more frequently higher than 91 and patients had received less frequently pre-admission antibiotic therapy (adjusted OR 2.689, 95% CI 1.017-7.111, p = 0.046; adjusted OR 0.143, 95% CI 0.030-0.670, p = 0.014). Clinical failure and antibiotic therapy duration were similar with regards to the presence of VRTI and the aetiology of CAP. VRTIs can be detected in almost a third of adults with CAP; influenza virus is the most relevant one. VRTI was associated with higher PSI at admission, but it does not affect patients' outcome.

T-bet, pSTAT1 and pSTAT3 expression in peripheral blood mononuclear cells during pregnancy correlates with post-partum activation of multiple sclerosis.

In pregnant women affected by multiple sclerosis (MS) we observed increased percentages of CD4(+)CD25(+)Foxp3(+) T regulatory cells at the 1st and the 2nd trimester of gestation that was associated with a decreased T-bet expression in CD4(+) T cells. In women showing clinical relapse and/or new lesions at MRI after delivery we found, a higher expression of T-bet, pSTAT1 and pSTAT3 in CD4(+), CD8(+) T cells and CD14(+) cells, associated with an increase of IFNgamma and IL17 production by PBMC at the 3rd trimester of gestation and after delivery. Our data suggest that the expansion of circulating CD4(+)CD25(+)Foxp3(+) regulatory T cells and the lower expression of T-bet in CD4(+) T cells may account for the decreased MS activity during pregnancy. The expression of T-bet, pSTAT1 and pSTAT3 in peripheral blood CD4(+) and CD8(+) T cells and monocytes could be useful to identify MS patients who will develop a relapse after delivery.

The predictive value of CSF multiple assay in multiple sclerosis: A single center experience.

BACKGROUND: Multiple sclerosis (MS) is a chronic, immune-mediated, inflammatory, neurodegenerative disorder. Many studies are investigating the potential role of body fluid biomarkers as prognostic factors for early identification of patients presenting with clinical isolated syndrome (CIS) at high risk for conversion to MS or to recognize RRMS patients at high risk for progression. OBJECTIVES: To evaluate the correlation between levels of BAFF, chitinase 3-like 1 (CHI3L1), sCD163, Osteopontin (OPN), both on serum and cerebral spinal fluid (CSF), and the disease activity and progression. We also want to explore a possible relationship between serological and CSF biomarker's levels. PATIENTS AND METHODS: We enrolled 82 patients between June 2014 and June 2016. Seventy-one received a diagnosis of demyelinating disease of CNS (46 RRMS and 25 CIS), while 11 were affected by other neurological diseases. All patients underwent a neural axis MRI, lumbar puncture and blood samples. Levels of BAFF, CHI3L1, sCD163, OPN on serum and CSF were analyzed by Luminex xMAP system, with a kit 11-plex ad hoc. RESULTS: The CSF CHI3L1, sCD163 and OPN levels were significantly higher in MS patients than in controls. We did not find significant differences in serum CHI3L1, sCD163 and OPN levels, nor CSF or serum BAFF levels between patient and control groups. We found significantly higher CSF level of sCD163 and CHI3L1 in all patients' subgroups compared with controls, while OPN was higher in CIS and RR subgroups. We did not find significant differences for serum and CSF levels of all the markers between patients with or without clinical or radiological disease activity. CSF sCD163 and CHI3L1 levels was significant higher in CIS patients who converted to MS (p < 0.05). Using ROC curve analysis, CSF sCD163 resulted the best predictive factor. CSF CHI3L1 and OPN levels resulted useful independent predictors too. Combined ROCs of those three analytes demonstrated a better predictive value, with sCD163 and CHI3L1 resulting as the best combination. CONCLUSIONS: CSF sCD163 CHI3L1 and OPN levels were higher in MS patients whereas serum CHI3L1, sCD163 and OPN levels did not show differences compared with controls. This finding confirms the high CSF specificity with regards to the analysis of processes, inflammatory and non-inflammatory, that occur within the CNS.

ANCA-related vasculitic neuropathy mimicking motor neuron disease.

Several conditions have been reported to mimic motor neuron disease (MND) and misdiagnosis remains a common clinical problem. Peripheral neuropathy is a classic feature of many vasculitic syndromes and in some patients it may be the only manifestation of vasculitis. We report a case of ANCA-related vasculitic neuropathy where the clinical presentation was suggestive of MND. A 42-year-old woman was admitted to our centre to confirm a diagnosis of MND made elsewhere. Clinical examination revealed postural tremor at the right hand, mild tongue atrophy with diffuse fasciculations and brisk tendon reflexes without other muscular weakness or atrophies. Electromyography demonstrated denervation in tongue and in the first dorsal interosseous of right hand ; motor evoked potentials disclosed normal central motor conduction time. Laboratory studies revealed only a mild increase of p-ANCA. A muscle biopsy showed a small inflammatory infiltrate around a vessel. The patient started high dosage of oral steroids. After one year of follow-up the patient suspended oral steroids, postural tremor of the right hand disappeared and tongue fasciculations were reduced. Vasculitis may mimic a MND, particularly in the absence of sensory involvement. Caution should be exercised in the clinical diagnosis of MND. Muscle biopsy is indicated in patient with atypical MND especially in those with an exclusive involvement of lower motor neuron.

Focal muscle vibration, an effective rehabilitative approach in severe gait impairment due to multiple sclerosis.

Gait impairment is one of the most frequent and life-altering consequences of Multiple sclerosis (MS), frequently associated with lower limb spasticity. Focal muscle vibration (fMV) is a technique that applies a vibratory stimulus to a specific muscle or its tendon, reducing spasticity. The aim of our study is to evaluate the efficacy of fMV in ameliorating gait impairment in MS patients with severe lower limb spasticity, measured by Gait Analysis (GA) and objective and patient-oriented scales scores. Fourteen patients affected by Secondary Progressive MS (SPMS) with a lower limb spasticity with a low or no response to antispastic drugs, received repetitive fMV (r-fMV) over the quadriceps and the lumbar paraspinal muscles. The effect of r-fMV on gait was measured by a GA evaluation and objective and patient-oriented scales scores, performed before r-fMV (T0), and 1week (T1) and 1month (T2) after the last session of r-fMV. After the r-fMV the most of spatio-temporal parameters calculated by GA were improved. Moreover, clinical evaluation related results showed an improvement of SM patients' quality of life. In conclusion, r-fMV improves gait function in MS patients affected by severe spasticity of lower limb, non-responsive to common oral antispastic drugs.

Reliability of the Hammersmith functional motor scale for spinal muscular atrophy in a multicentric study.

The aim of this study was to validate the Hammersmith functional motor scale for children with spinal muscular atrophy in a large cohort of 90 non-ambulant children with spinal muscular atrophy type 2 or 3. All had a baseline assessment (T0) and were reassessed either at 3 months (T1) (n = 66) or at 6 months (T2) (n = 24). Inter-observer reliability, tested on 13 children among 3 examiners, was > 95%. Of the 66 children examined after 3 months 4 had adverse effects in between assessments and were excluded from the analysis. Forty-two (68%) of the remaining 62 reassessed had no variation in scores between T0 and T1 and 13 (21%) were within +/- 1 point. 9 (37.5%) of the 24 children reassessed after 6 months had no variation in scores between T0 and T2 and another 9 (37.5%) had variations within +/- 1 point. Our study confirms previous observations of the reliability of the scale and helps to establish a baseline for assessing changes of functional ability over 3 and 6 month intervals. This information can be valuable in view of therapeutic trials.

Effect of preexposure on methylphenidate-induced taste avoidance and related BDNF/TrkB activity in the insular cortex of the rat.

RATIONALE: Exogenous brain-derived neurotrophic factor (BDNF) in the insular cortex (IC) is known to influence conditioned taste avoidance (CTA) learning, but little is known of its endogenous role in the phenomenon. Preexposure to many abusable compounds attenuates their ability to induce CTA, thus providing a possible platform from which to further elucidate the endogenous role of IC BDNF in CTA. OBJECTIVES: The role of IC BDNF in CTA learning was examined by assessing the effect of preexposure to methylphenidate (MPH) on MPH-induced CTA, followed by expression between preexposure groups of BDNF in the IC, central nucleus of the amygdala (CeA), and the nucleus accumbens (NAc). METHODS: Following preexposure to MPH (18 mg/kg), CTAs induced by MPH (0, 10, 18, and 32 mg/kg) were assessed in adult male Sprague-Dawley rats (n = 64). In separate groups (n = 31), differences in BDNF and tropomyosin-related kinase receptor-B (TrkB) were assessed using Western blots following similar preexposure and conditioning procedures. RESULTS: Preexposure to MPH significantly blunted MPH-CTA compared to preexposure to vehicle. Unexpectedly, there were no significant effects of MPH on BDNF activity following CTA, but animals preexposed to MPH exhibited decreased activity in the CeA and enhanced activity in the IC and NAc. CONCLUSIONS: Preexposure to MPH attenuates its aversive effects on subsequent presentations, and BDNF's impact on CTA learning may be dependent upon its temporal relation to other CTA-related intracellular cascades.

Difference in expression of phosphorylated tau epitopes between sporadic inclusion-body myositis and hereditary inclusion-body myopathies.

Sporadic inclusion-body myositis (s-IBM) and the hereditary inclusion-body myopathies (h-IBMs) are severe and progressive muscle diseases, characterized pathologically by vacuolated muscle fibers containing paired-helical filaments (PHFs). An interesting feature of the s- and h-IBM muscle phenotype is its striking similarity to Alzheimer-disease (AD) brain. We immunostained muscle biopsies of 9 s-IBM patients, 9 autosomal-recessive h-IBM patients, 1 autosomal-dominant h-IBM patients, and 18 normal and disease-controls with several antibodies known to react with the hyperphosphorylated tau of AD-PHFs. Those included SMI-31, SMI-310, PHF-1, and AT8. In both s- and h-IBM, virtually all vacuolated muscle fibers had strongly immunoreactive inclusions with SMI-31, and by immuno-electronmicroscopy SMI-31 was exclusively localized to PHFs. Approximately 40 to 50% of both s- and h-IBM vacuolated muscle fibers were also immunoreactive with AT8 antibody. To the contrary, in h-IBM, there was no immunoreactivity with SMI-310 and PHF-1 antibodies, whereas in s-IBM the vacuolated muscle fibers had strong immunoreactivity with those two antibodies. By immunoelectronmicorscopy, SMI-310 and PHF-1 also were localized to PHFs. Within s-IBM muscle fibers, the structures immunoreactive with SMI-310 were congophilic, whereas h-IBM muscle fibers did not have congophilia. Our studies: (a) demonstrate a distinct difference between s-IBM and the h-IBMs in regard to expression of immunoreactive phosphorylated tau and congophilia; (b) demonstrate a new "diagnostic duo" combination of SMI-31 and SMI-310 antibodies for identifying and distinguishing s-IBM and the h-IBMs; and (c) provide another close similarity of pathologic phenotypes between s-IBM muscle and AD brain, suggesting that similar cellular pathogenic mechanisms may be active in both diseases.

Premature termination mutations in exon 3 of the SMN1 gene are associated with exon skipping and a relatively mild SMA phenotype.

Autosomal recessive spinal muscular atrophy (SMA) is a common motor neuron disease caused by absence or mutation in the survival motor neuron (SMN1) gene. SNM1 and a nearly identical copy, SMN2, encode identical proteins, but SMN2 only produces a little full length protein due to alternative splicing. The level of functional SMN protein and the number of SMN2 genes correlate with the clinical phenotype ranging from severe to very mild. Here, we report on premature termination mutations in SMN1 exon 3 (425del5 and W102X) which induce skipping of the mutated exon. The novel nonsense mutation W102X was detected in two patients with a relatively mild phenotype who had only two copies of the SMN2 gene, a number that has previously been found associated with the severe form of SMA. We show that the shortened transcripts are translated into predicted in frame protein isoforms. Aminoglycoside treatment suppressed the nonsense mutation in cultured cells and abolished exon skipping. Fibroblasts from both patients show a high number of nuclear structures containing SMN protein (gems). These findings suggest that the protein isoform lacking the exon 3 encoded region contributes to the formation of the nuclear protein complex which may account for the milder clinical phenotype.

Cardiomyopathy may be the only clinical manifestation in female carriers of Duchenne muscular dystrophy.

Cardiomyopathy was reported in a few Duchenne muscular dystrophy (DMD) carriers with clinical evidence of myopathy. We report two carriers with dilated cardiomyopathy, increased serum CK, and no symptoms of muscle weakness. In heart biopsies of both patients, dystrophin-the protein product of DMD locus--was absent in many fibers. Dilated cardiomyopathy may be the only manifestation of dystrophin gene mutation in carriers.