Progressive Proximal Limb Weakness Research Articles

Spinal muscular atrophy caused by compound heterozygous SMN1 mutations: two cases and literature review.

Spinal muscular atrophy (SMA) is a rare neuromuscular disease, which is characterized by the degeneration of motor neurons, leading to symmetrical muscle weakness and atrophy.Description of two novel SMN1 mutations (patient1: c.683T > A, p.Leu228Ter; patient2: c.347 T > C, p.Ile116 Thr).We reported two patients with SMN1 mutations with the clinical features, and provided a literature review of the previously reported 22 cases.Two SMA patients showed progressive proximal lower limb weakness and milder clinical symptom. In a total of 22 cases, the most commonly observed SMN1 gene alteration was missense mutation (55%), followed by splicing defect (27%), nonsense (9%) and frameshift (9%).We discuss the possible decisive role of these intragenic mutations in the phenotypic results, which enriched the SMN 1 fine mutation database.

An unusual presentation of dermatomyositis: dermatomyositis sine dermatitis presenting with rapidly progressive myositis

Dermatomyositis sine dermatitis (DMSD) is a rare variant of dermatomyositis where progressive muscle weakness presents without the characteristic rash but with muscle histology of dermatomyositis. A 55-year-old woman presented with progressive severe proximal limb, neck, pharyngeal and respiratory muscle weakness, without dermatologic manifestations. Elevated muscle enzymes and myopathic electromyogram pointed towards inflammatory myositis while the muscle biopsy confirmed DMSD. Her condition improved with steroids, intravenous immunoglobulin, methotrexate, and rituximab. This case emphasises the necessity of maintaining a high index of suspicion for dermatomyositis, even when a classic skin rash is absent and the criticality of early aggressive treatment. Anti-NXP-2 antibody positivity could indicate severe disease.

Clinical spectrum, biochemical profile and disease progression of Kennedy disease in an Indian cohort.

Kennedy disease (KD) is a slowly progressive lower motor neuron degenerative disease. The prevalence of KD is unknown in India. To describe the phenotypic and laboratory features of an Indian cohort of KD patients. A retrospective study was done on seven genetically confirmed KD patients based on demographic, clinical and laboratory details. Mean age at onset and presentation was 37 ± 11.9 and 44.6 ± 13.5 years respectively. Progressive asymmetric proximal and distal limb weakness was the commonest symptom (57.1%). All patients had motor symptoms along with non-specific symptoms such as cramps from the onset. Easy fatigability, decremental response along with ptosis were noted in two patients, which was a novel finding. Gynaecomastia and tongue wasting with fasciculations were universal findings. All five patients with nerve conduction studies showed sensorimotor neuropathy. Magnetic resonance imaging muscle done in two patients showed a prominent moth-eaten appearance in the thigh and posterior leg compartment in one patient. The mean cytosine-adenine-guanine repeats were 44 ± 3.7, and there was no association between age of onset or severity with repeat length. Only one patient required an assistive device for ambulation after 15 years of symptom onset. This study showed phenotypic heterogeneity in the Indian cohort. The age of onset was earlier with a slowly progressive indolent course as compared with other ethnic cohorts. This highlights the importance of considering the KD diagnosis in patients with the indolent course and suspected ALS diagnosis even with ptosis and fatigability in an appropriate clinical context.

Atypical Overlapping Features Complicating Diagnoses of Dysferlinopathy and Immune-Mediated Necrotizing Myopathy. (P6-8.006)

<h3>Objective:</h3> To present overlapping features and atypical characteristics of dysferlinopathy and immune-mediated necrotizing myopathy (IMNM). <h3>Background:</h3> Dysferlinopathy typically presents with early onset progressive muscle weakness that can be proximal or distal. Definitive diagnosis is made with DYSF gene testing. Treatment is supportive. IMNM is an autoimmune inflammatory myopathy that affects older individuals and is often associated with occult malignancy. Aggressive immunotherapy improves outcomes. Muscle biopsy (MBx) reveals inflammatory infiltrates in both conditions. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> <h3>Case 1:</h3> A 35-year-old man presented with subacute progressive limb weakness and elevated creatine phosphokinase (CPK) &gt;8,000 units/L. MBx showed necrotizing myopathy and sarcolemmal C5b-9 staining; dystrophy stains were omitted due to the patient’s age and subacute symptoms. Anti-signal recognition peptide (SRP) and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies and malignancy screen were negative. The patient was initially diagnosed with seronegative IMNM and treated with steroids, methotrexate and IVIG without improvement. He was subsequently diagnosed with dysferlinopathy based on genetic testing showing double heterozygous pathogenic DYSF gene mutations. <h3>Case 2:</h3> An 18-year-old man presented with 3-years of progressive proximal limb weakness associated with Gower’s sign and elevated CPK &gt;10,000 units/L. Broad muscular dystrophy genetic testing was negative. MBx showed necrotizing myopathy and sarcolemmal C5b-9 staining suggestive of IMNM. Anti-SRP and anti-HMGCR antibodies, serum paraneoplastic panel, and malignancy screening with tumor markers, contrasted CT imaging, and scrotal ultrasound were negative. The patient was diagnosed with early-onset seronegative IMNM. CPK improved and symptoms stabilized with prednisone, methotrexate and IVIG therapy. <h3>Conclusions:</h3> Dysferlinopathy and IMNM can have overlapping clinical features and MBx findings. Heightened awareness of atypical features aids in timely diagnosis. Accurate diagnosis of dysferlinopathy based on genetic testing limits further invasive workup and the side effects of ineffective empiric therapy, whereas early diagnosis of IMNM allows for prompt immunotherapy which is shown to improve prognosis. <b>Disclosure:</b> Dr. Stout has nothing to disclose. Dr. Su has nothing to disclose.

The Association of Hepatitis B and Polymyositis: Rare but Real

Aims: Hepatitis B virus infection is a global health concern. Although Hepatitis B virus primarily affects hepatocytes, it sometimes develops disease manifestations outside the liver and can present as full fledged proximal myopathy. &#x0D; Presentation of Case: We report a 68-year-old man presenting with progressive proximal bilateral lower limb weakness for the last 14 days. The weakness was associated with pain and one episode of fever. Examination revealed 3/5 power in the shoulder and hip joint without any sensory deficit. Biochemical investigation showed elevated CPK levels (1102 IU/L) and liver enzymes (AST – 625 IU/L, ALT – 356 IU/L). HBsAg and HBeAg came out to be positive with HBV DNA of 73000 copies/mL. MRI shoulder and hip joints revealed diffuse intramuscular and myofascial edema suggesting inflammatory myositis. Muscle biopsy was suggestive of Necrotizing Autoimmune Myopathy.&#x0D; Discussion: Patient symptoms improved after starting IV Prednisolone and Entecavir therapy suggesting a close association between Hepatitis B infection and myopathy.&#x0D; Conclusion: Although Hepatitis B virus primarily affects hepatocytes, it sometimes develops disease manifestations outside the liver, such as Polymyositis. Therefore, it is imperative to screen for Viral markers in these patients.

Hereditary myopathy with early respiratory failure: case report

BackgroundHereditary myopathy with early respiratory failure (HMERF) is a rare myopathy that affects respiratory muscles in the early course of the disease leading to respiratory insufficiency. It is caused by mutation in titin (TTN) gene.Case reportAt the age of 29, our female patient presented with a slowly progressive proximal lower limb and axial muscle weakness and respiratory issues. Her late mother had similar problems, she died at a young age and was never properly diagnosed. Patient’s creatine kinase level was elevated up to three times above the upper limit of normal. Whole exome sequencing showed a pathogenic variant c.95372G>A in the TTN gene leading to the final diagnosis of HMERF. Cardiac examination was normal. Patient started to use a non-invasive nocturnal ventilation at age of 35.ConclusionsOur case is the first described case of HMERF in Serbian population. Multidisciplinary neurological and pulmonary approach is of great importance in HMERF and similar diseases. This case highlights the importance of considering early neuromuscular respiratory insufficiency as a distinctive syndrome leading to a challenging and broad differential diagnosis.

Late-onset Pompe disease - literature review and summary of current knowledge

Introduction: Pompe disease is a glycogen storage disorder caused by the deficient activity of the lysosomal enzyme acid α-glucosidase (GAA). Mutations in the GAA gene lead to the accumulation of glycogen in different organs. In a late-onset form (late-onset Pompe disease), the disease is characterized by slow, progressive proximal limb and respiratory muscle weakness. The diagnosis is based on a low level of GAA either in the muscle biopsy or in the leucocytes. LOPD is treated with enzyme replacement therapy (ERT). Purpose: Summary of currently knowladge about Late-onset Pompe disease - characteristic, diagnosis and treatment. Methods: A review of literature available in the PubMed database and Google Scholar. by searching for keywords: Pompe disease, Late-onset Pompe disease, LOPD, alglucosidase- α. Results: The diagnosis of late-onset Pompe disease can often be difficult. It is a very rare disease and the clinical presentation is similar to other neuromuscular disorders, such as Duchenne and Backer muscular dystrophies, glycogenosis or autoimmune or mitochondrial myopathies and others. Despite available specific enzyme replacement therapy LOPD is progressive. Patients require support from a multidisciplinary team of specialists, including care from neurologists, pulmonologists or physiotherapists. Conclusion: Although rare, Pompe disease should be considered in patients with proximal paresis and respiratory failure. More research into LOPD can help increasing precocity of diagnosis and treat it more effectively.

Clinical manifestations and acid alpha-glucosidase mutation characterisation of a cohort of patients with late-onset Pompe disease in eastern China.

BackgroundPompe disease is a rare, progressive, and life-threatening autosomal recessive disorder. In its late-onset form, the disease is primarily characterised by mild progressive proximal limb and respiratory muscle weakness. Mutations in the acid alpha-glucosidase (GAA) gene cause lysosomal enzyme GAA to be significantly reduced or missing altogether, for which supplementation can be given through enzyme replacement therapy.MethodsFourteen patients diagnosed with late-onset Pompe disease (LOPD) in the First Affiliated Hospital of Nanjing Medical University from 2017 to 2021 were enrolled. GAA activity was measured based on enzymatic activity in dried blood spots, and next-generation sequencing was used to detect mutations in the GAA gene. The impacts of novel missense variants were determined by five different prediction algorithms. The structural figures of novel variants and their wide types were processed with PyMOL.ResultsThe study included 14 patients with LOPD (male-to-female ratio, 1:1) from eastern China. The median age at symptom onset and diagnosis was 15.0 years (7–36 years) and 21.5 years (8–47 years), respectively. The median diagnostic delay from onset was 3.0 years (0–22 years). Proximal muscle weakness was the first prominent symptom in 8 patients, while the other 6 patients experienced respiratory failure, chest congestion and asthma, and scoliosis. The most frequent mutation of the GAA gene was c.2238G>C (p.W746C), which was observed at an allele frequency of 14.3% (4/28) and in 28.6% of patients (4/14). Four novel variants potentially related to the pathogenicity of LOPD were found: c.1299G>C (p.Q433H), c.1409A>G (p.N470S), c.2242delG (p.E748Rfs*16), and c.2832delA (p.E945Sfs*78).ConclusionsThe c.2238G>C (p.W746C) mutation was the most common mutation in 14 patients with LOPD from eastern China. This study has identified four novel variants in patients with LOPD. Predicting the pathogenicity of these novel variants may increase the understanding of the genetic mutation spectrum in LOPD. Our findings may also improve recognition of the characteristics of Chinese patients with LOPD.

Recent Progress in Oculopharyngeal Muscular Dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset intractable myopathy, characterized by slowly progressive ptosis, dysphagia, and proximal limb weakness. It is caused by the abnormal expansion of the alanine-encoding (GCN)n trinucleotide repeat in the exon 1 of the polyadenosine (poly[A]) binding protein nuclear 1 gene (11–18 repeats in OPMD instead of the normal 10 repeats). As the disease progresses, the patients gradually develop a feeling of suffocation, regurgitation of food, and aspiration pneumonia, although the initial symptoms and the progression patterns vary among the patients. Autologous myoblast transplantation may provide therapeutic benefits by reducing swallowing problems in these patients. Therefore, it is important to assemble information on such patients for the introduction of effective treatments in nonendemic areas. Herein, we present a concise review of recent progress in clinical and pathological studies of OPMD and introduce an idea for setting up a nation-wide OPMD disease registry in Japan. Since it is important to understand patients’ unmet medical needs, realize therapeutically targetable symptoms, and identify indices of therapeutic efficacy, our attempt to establish a unique patient registry of OPMD will be a helpful tool to address these urgent issues.

Central Core Disease - A Disease That Is Easily Misdiagnosed as Duchenne Muscular Dystrophy

As a kind of congenital myopathy (CM), central core disease (CCD) is mainly characterized by low muscle tension, slow progressive or static proximal limb weakness. CM can be characterized by no symptoms to be unable to walk independently in the clinic, pathological changes can be manifested as only significant type 1 muscle fiber dominant type to typical central axial space structure, and there are also many genetic ways. Duchenne muscular dystrophy (DMD) is a common congenital myopathy, which is mainly manifested in the typical pathological changes of early progressive myasthenia and muscular dystrophy. Both CCD and DMD show similar clinical symptoms and their serum creatine kinase can be increased, which is often difficult to distinguish them through clinical characterization and laboratory examination. In this study, we report the clinical and genetic characteristics of two patients with progressive muscle weakness with elevated creatine kinase. They are the product of a first-cousin marriage and seek medical treatment due to asymptotic walking difficulties, muscle atrophy, joint contracture, scoliosis, and elevated creatine kinase levels. It was previously suspected as Duchenne muscular dystrophy. After that, the patient's DNA was sequenced by whole-exome sequencing (WES), and all coding regions were investigated. It was found that a new heterozygous missense mutation c.5092g > A in the RYR1 gene. Similar mutations have not been reported in the literature before. Bioinformatics software predicts that they have the possibility of pathogenesis, which is highly correlated with CCD. The purpose of this case is to report a new heterozygous mutation of the RYR1 gene, summarize the similarities and differences of clinical manifestations, genetic characteristics, and pathological changes of CCD and DMD, and provide a new idea for its differential diagnosis.

F42. EMG findings in patients with limb-girdle muscular dystrophy due to heterozygous CAPN3 mutations

Introduction Limb-girdle muscular dystrophy type 2A (LGMD2A) is the most common autosomal recessive (AR) LGMD subtype worldwide. The disease is caused by homozygous pathogenic mutations in the calpain 3 gene (CAPN3). Although strict AR inheritance is assumed for CAPN3-related myopathies, recent reports described symptomatic patients carrying a single CAPN3 mutation. The LGMDs share common clinical and laboratory findings such as weakness and atrophy of proximal muscles, often affecting lower extremities first; elevated creatine kinase (CK) levels; and dystrophic findings on muscle biopsy. Some clinical and imaging findings help to differentiate LGMD2A, such as asymmetric weakness and atrophy and early scapular winging. On muscle MRI, calpain deficiency characteristically reveals preferential involvement of posterior thigh muscles and the adductor magnus muscle with relative sparing of the anterior thigh muscles. There are few reports on EMG findings in patients with single CAPN3 mutations. Methods Two unrelated patients with LGMD and harboring single CAPN3 mutations were identified. They underwent detailed neurological evaluation, muscle biopsy, muscle MRI and electroneuromyography (ENMG). Results Patient one: man, 28 years old, born from nonconsanguineous parents, presenting progressive calves atrophy since 24 years old. Genetic analysis showed the variant c.258dupT;p. (Leu87Serfs*4) at CAPN3 in heterozygosity. ENMG showed myopathic motor unit action potential (MUAP) on left gastrocnemius and pectoralis major, and on right biceps brachii, without fibs or positive sharp waves. Right gastrocnemius muscle biopsy showed moderate myopathic changes. Patient two: woman, 77 years old, born from nonconsanguineous parents, presenting progressive proximal lower limb weakness in the last 2 years. Genetic analysis revealed the heterozygous frameshift variant c.550delA; p. (Thr184Argfs*36) in the CAPN3 gene. ENMG showed moderate diffuse myopathy, with preferential involvement of posterior tigh muscles and gastrocnemius with fibs and positive sharp waves. MRI showed severe atrophy of posterior tight muscles. Right quadriceps femoris biopsy revealed minimal myopathic changes. Conclusion The typical clinical, imaging and electrophysiological findings from LGMD2A can be found in patients presenting heterozygous pathogenic mutations in CAPN3 gene, indicating that a dominantly inherited form of calpainopathy exists, but with a milder fenotype. EMG reveals a predominantly posterior leg pattern of involvement.

P.292 - Novel homozygous recessive MYH2 variant associated with an autosomal dominant clinical pathological phenotype

Mutations in MYH2 cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with congenital joint contractures that resolve with age, external opthalmoplegia, and later onset progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and intranuclear and cytoplasmic inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, a distinct phenotype occurs in patient's with recessive MYH2 mutations. These patients also have severe opthalmoplegia but instead have a more mild and diffuse pattern of weakness that is early in onset and largely non-progressive. Muscle biopsy reveals small or absent type 2a fibers with no vacuole or inclusion pathology. We identified a patient with childhood onset opthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient's disease course and histopathology is consistent with patients carrying dominant MYH2 mutations, whole exome sequencing revealed a novel c.737 G > A p.(Arg246Thr) homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies.

Fatty acid oxidation defects presenting as primary myopathy and prominent dropped head syndrome

Fatty acid oxidation disorders presenting as primary myopathy is relatively rare and also diagnostically challenging. Its association with “dropped head syndrome” is reported till date in single cases of carnitine deficiency and multiple acyl CoA dehydrogenase deficiency (MADD).We studied nineteen cases of primary progressive myopathy confirmed to have fatty acid oxidation defects by Tandem Mass Spectrometry. The detailed clinical, muscle histopathology, tandem mass spectrometry and muscle magnetic resonance imaging (MRI) findings are presented here. The fatty acid oxidation defects identified were sub-grouped into: medium chain acyl CoA dehydrogenase deficiency (MCAD) = 4; very long chain acyl CoA dehydrogenase deficiency (VLCAD) = 7; MADD = 6; carnitine uptake defect and short chain acyl CoA dehydrogenase (SCAD) deficiency = 1 each. The age at onset for MCAD, VLCAD and MADD ranged from 11.5 to 15, 8 to 17 and 10 to 38 years respectively. The patients with carnitine uptake defect and SCAD had onset at 29 and 15 years of age. The dominant symptoms were exertion induced myalgia and progressive proximal limb weakness in all. 12/19 (63.2%) had classical dropped head syndrome. Ptosis and bulbar weakness were present in a few cases. This study emphasizes that fatty acid oxidation disorders presenting as primary myopathy are probably under diagnosed and should be entertained in the differential diagnosis of acute or chronic limb girdle syndromes. Hitherto, unreported we describe “dropped head syndrome” as a prominent phenomenon in MCAD and VLCAD. The presence of ptosis and bulbar weakness in fatty acid oxidation defects expands the clinical spectrum.

Subacute myopathy as the initial presentation of anca positive vasculitis associated with crohn’s disease

Objectives Myopathy as the presenting symptom from an ANCA positive vasculitis is uncommon. Vasculitis secondary to Crohn’s disease is an equally uncommon phenomenon. We report the first case of Crohn’s associated ANCA positive vasculitis causing a subacute proximal myopathy as the initial clinical manifestation. We also highlight the clinical improvement following institution of rituximab as rescue therapy. Case A 27 years old female with recently diagnosed active Crohn’s disease presented with a 9 months history of progressive proximal upper and lower limb weakness. She had been treated with a course of steroids 6 months prior. She denied any constitutional symptoms. Examination revealed proximal muscle wasting and weakness in both upper and lower limbs. Positive investigations included a positive ANCA with high PR3 titre and a muscle biopsy demonstrating probable vasculitis. She was diagnosed with myopathy secondary to Crohn’s associated ANCA-positive vasculitis. She was treated with adalumimab and then infliximab which was upgraded to rituximab as rescue therapy when there was no response. The rituximab led to significant improvement to her weakness clinically. Conclusions Vasculitis should be considered as a differential diagnosis for subacute myopathy in patients with an inflammatory or autoimmune phenotype. Muscle biopsy and ANCA immunofluorescence and titres are useful investigations. Whilst there is a lack of established evidence about the ideal agent for treating Crohn’s associated vasculitis, case reports suggest using TNF-alpha inhibitors or rituximab.

Correlation between PABPN1 genotype and disease severity in oculopharyngeal muscular dystrophy.

Objective:Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant adult-onset disease characterized by progressive ptosis, dysphagia, and proximal limb weakness. The genetic cause is an expanded (GCN)n mutation in the PABPN1 gene encoding for the polyadenylate-binding protein nuclear 1. We hypothesized a potential correlation between the size of the (GCN)n expansion and the severity of the phenotype. To do this, we characterized the distribution of the genotypes as well as their correlation with age at diagnosis and phenotypical features in a large cohort of heterozygous and homozygous patients with OPMD in France with a confirmed molecular diagnosis of PABPN1.Methods:We explored 354 unrelated index cases recruited between 1999 and 2014 in several neuromuscular centers in France.Results:This cohort allowed us to characterize the frequency of mutated alleles in the French population and to demonstrate a statistical correlation between the size of the expansion and the mean age at diagnosis. We also confirmed that homozygous patients present with a more severe disease.Conclusions:It has been difficult to establish phenotype–genotype correlations because of the rare nature of this disease. Our work demonstrates that patients with OPMD with longer PABPN1 expansion are on average diagnosed at an earlier age than patients with a shorter expansion, confirming that polyalanine expansion size plays a role in OPMD, with an effect on disease severity and progression.

500. Gene Therapy Rescues Disease Phenotype in the Oculopharyngeal Muscular Dystrophy Mouse Model

Among triplet expansion diseases, oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. OPMD is caused by a short trinucleotide repeat expansion in the polyadenylate-binding protein nuclear 1 (PABPN1) gene that results in an N-terminal expanded polyalanine tract. PABPN1 controls several biological processes such as the length of mRNA poly(A) tails, the mRNA export from the nucleus and the alternative poly(A) site usage. OPMD is characterized by nuclear aggregates of expanded PABPN1, fibrosis and muscle atrophy. Here we demonstrate that treating mice affected by OPMD over 4 months with an AAV gene therapy strategy based on DNA-directed RNA interference to silence the endogenous expPABPN1, combined with the re-expression of a healthy sequence-optimized human PABPN1 gene, significantly reduced the amount of nuclear aggregates in affected muscles, decreased the intramuscular fibrosis and reverted the muscle strength to the level of healthy wild-type muscles. Furthermore, although muscle atrophy was not reverted, the expression of a healthy PABPN1 markedly increased the cross sectional area of muscle fibres. These results obtained in a relevant mammalian animal model of OPMD pave the way for the clinical application of a gene therapy approach as a treatment for OPMD patients.

ID 230 – Adult onset acid maltase deficiency – EMG aids diagnosis in Intensive Care Unit

A 25 year old man was admitted to Intensive Care Unit with the clinical problems of worsening shortness of breath and a history of progressive proximal limb weakness and bilateral ptosis. He was found to have marked type II respiratory failure and significant proximal weakness both the upper and lower limbs and also marked extra-ocular muscle weakness. Arterial Blood Gas Analysis was consistent with type II respiratory failure. Muscle enzymes – CK levels were elevated -1174 U. Acetyl Choline Receptor antibodies – Negative. Neurophysiological Studies – Normal nerve conduction studies; EMG evaluation demonstrated marked myopathic abnormalities in proximal and distal muscles in lower as well as upper limbs. Some muscles showed frequent pseudo-myotonic discharges. The clinical presentation of progressive muscle weakness and Type II respiratory failure along with EMG features raised the possibility of adult onset Acid Maltase deficiency. Muscle biopsy demonstrated accumulation of glycogen within membrane bound vacuoles consistent with adult onset Acid Maltase Deficiency (Pompe’s disease of adult onset). Awareness of clinical and neurophysiological features of Acid Maltase Deficiency aid the diagnosis of this disorder, particularly in the context of evaluation of respiratory failure cases in an Intensive Care Unit.

Proximal Limb Weakness in a Patient with Celiac Disease: Copper Deficiency, Gluten Sensitivity, or Both as the Underlying Cause?

Celiac disease has been associated with several neurologic disorders which may result from micronutrient deficiencies, coexisting autoimmune conditions, or gluten sensitivity. Copper deficiency can produce multiple neurologic manifestations. Myeloneuropathy is the most common neurologic syndrome and it is often irreversible, despite copper replacement. We report the case of a 55-year-old man who presented with progressive proximal limb weakness and weight loss in the setting of untreated celiac disease without gastrointestinal symptoms. He had anemia, neutropenia, and severe hypocupremia. The pattern of weakness raised the suspicion that there was an underlying myopathy, although this was not confirmed by electrodiagnostic studies. Weakness and hematologic abnormalities resolved completely within 1 month of total parenteral nutrition with copper supplementation and a gluten-free diet. Myopathy can rarely occur in patients with celiac disease, but the mechanism is unclear. Pure proximal limb weakness has not been previously reported in copper deficiency. We propose that this may represent a novel manifestation of hypocupremia and recommend considering copper deficiency and gluten sensitivity in patients presenting with proximal limb weakness.

A de novo mutation of the MYH7 gene in a large Chinese family with autosomal dominant myopathy.

Laing distal myopathy (LDM) is an autosomal dominant myopathy that is caused by mutations in the slow/beta cardiac myosin heavy-chain (MYH7) gene. It has been recently reported that LDM presents with a wide range of clinical manifestations. We herein report a large Chinese family with autosomal dominant myopathy. The affected individuals in the family presented with foot drop in early childhood, along with progressive distal and proximal limb weakness. Their characteristic symptoms include scapular winging and scoliosis in the early disease phase and impairment of ambulation in the advanced phase. Although limb-girdle muscle dystrophy (LGMD) was suspected initially, a definite diagnosis could not be reached. As such, we performed linkage analysis and detected four linkage regions, namely 1q23.2-24.1, 14q11.2-12, 15q26.2-26.3 and 17q24.3. Through subsequent whole exome sequencing, we found a de novo p.K1617del causative mutation in the MYH7 gene and diagnosed the disease as LDM. This is the first LDM case in China. Our patients have severe clinical manifestations that mimic LGMD in comparison with the patients with the same mutation reported elsewhere.

Treatment for inclusion body myositis.

Inclusion body myositis (IBM) is a late-onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness. Treatment options have attempted to target inflammatory and atrophic features of this condition (for example with immunosuppressive and immunomodulating drugs, anabolic steroids, and antioxidant treatments), although as yet there is no known effective treatment for reversing or minimising the progression of inclusion body myositis. In this review we have considered the benefits, adverse effects, and costs of treatment in targeting cardinal effects of the condition, namely muscle atrophy, weakness, and functional impairment. To assess the effects of treatment for IBM. On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Additionally in November 2014 we searched clinical trials registries for ongoing or completed but unpublished trials. We considered randomised or quasi-randomised trials, including cross-over trials, of treatment for IBM in adults compared to placebo or any other treatment for inclusion in the review. We specifically excluded people with familial IBM and hereditary inclusion body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials. We did not include studies of exercise therapy or dysphagia management, which are topics of other Cochrane systematic reviews. We used standard Cochrane methodological procedures. The review included 10 trials (249 participants) using different treatment regimens. Seven of the 10 trials assessed single agents, and 3 assessed combined agents. Many of the studies did not present adequate data for the reporting of the primary outcome of the review, which was the percentage change in muscle strength score at six months. Pooled data from two trials of interferon beta-1a (n = 58) identified no important difference in normalised manual muscle strength sum scores from baseline to six months (mean difference (MD) -0.06, 95% CI -0.15 to 0.03) between IFN beta-1a and placebo (moderate-quality evidence). A single trial of methotrexate (MTX) (n = 44) provided moderate-quality evidence that MTX did not arrest or slow disease progression, based on reported percentage change in manual muscle strength sum scores at 12 months. None of the fully published trials were adequately powered to detect a treatment effect. We assessed six of the nine fully published trials as providing very low-quality evidence in relation to the primary outcome measure. Three trials (n = 78) compared intravenous immunoglobulin (combined in one trial with prednisone) to a placebo, but we were unable to perform meta-analysis because of variations in study analysis and presentation of trial data, with no access to the primary data for re-analysis. Other comparisons were also reported in single trials. An open trial of anti-T lymphocyte immunoglobulin (ATG) combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy, based on percentage change in quantitative muscle strength sum scores at 12 months (MD 12.50%, 95% CI 2.43 to 22.57). Data from trials of oxandrolone versus placebo, azathioprine (AZA) combined with MTX versus MTX, and arimoclomol versus placebo did not allow us to report either normalised or percentage change in muscle strength sum scores. A complete analysis of the effects of arimoclomol is pending data publication. Studies of simvastatin and bimagrumab (BYM338) are ongoing. All analysed trials reported adverse events. Only 1 of the 10 trials interpreted these for statistical significance. None of the trials included prespecified criteria for significant adverse events. Trials of interferon beta-1a and MTX provided moderate-quality evidence of having no effect on the progression of IBM. Overall trial design limitations including risk of bias, low numbers of participants, and short duration make it difficult to say whether or not any of the drug treatments included in this review were effective. An open trial of ATG combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy based on the percentage change data given. We were unable to draw conclusions from trials of IVIg, oxandrolone, and AZA plus MTX versus MTX. We need more randomised controlled trials that are larger, of longer duration, and that use fully validated, standardised, and responsive outcome measures.