Myositis with prominent B cell aggregates may meet classification criteria for sporadic inclusion body myositis.

The objective of this study was to report the clinical, serological and pathological features of patients with autoimmune myositis other than dermatomyositis, who displayed both muscle weakness on physical examination and prominent B cell aggregates on muscle pathology, defined as ≥ 30 CD20+ cells/aggregate. Specifically, the presence of a brachio-cervical inflammatory myopathies or a sporadic inclusion body myositis (sIBM) phenotype was recorded. Over a three-year period, eight patients were identified from two university neuropathology referral centers. Seven of 8 (88%) patients had an associated connective tissue disease (CTD): rheumatoid arthritis (n=3), systemic sclerosis (n=2), Sjögren's syndrome (n=1) and systemic lupus erythematosus (n=1), while one patient died on initial presentation without a complete serological and cancer investigation. A brachio-cervical phenotype, i.e. neck weakness, proximal weakness more than distal and shoulder abduction weakness greater than hip flexors, was seen in two patients (25%), while one patient had both proximal and diaphragmatic weakness. In contrast, an IBM-like clinical phenotype was seen in the last five patients (63%), who either had finger flexor weakness and/or quadriceps weakness ≤ 4 on the manual muscle testing MRC-5 scale. Although these 5 patients met at least one set of classification criteria for sIBM, an integrated clinico-sero-pathological approach argued against a diagnosis of sIBM. In summary, in a weak patient with myositis plus an associated CTD and lymphoid aggregates at muscle pathology, B cell predominant aggregates may represent a morphological biomarker against a diagnosis of sIBM.

Myositis with prominent B-cell aggregates causing shrinking lung syndrome in systemic lupus erythematosus: a case report.

BACKGROUND: Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus (SLE) characterized by decreased lung volumes and diaphragmatic weakness in a dyspneic patient. Chest wall dysfunction secondary to pleuritis is the most commonly proposed cause. In this case report, we highlight a new potential mechanism of SLS in SLE, namely diaphragmatic weakness associated with myositis with CD20 positive B-cell aggregates. CASE PRESENTATION: A 51-year-old Caucasian woman was diagnosed with SLE and secondary Sjögren's syndrome based on a history of pleuritis, constrictive pericarditis, polyarthritis, photosensitivity, alopecia, oral ulcers, xerophthalmia and xerostomia. Serologies were significant for positive antinuclear antibodies, anti-SSA, lupus anticoagulant and anti-cardiolopin. Blood work revealed a low C3 and C4, lymphopenia and thrombocytopenia. She was treated with with low-dose prednisone and remained in remission with oral hydroxychloroquine. Seven years later, she developed mild proximal muscle weakness and exertional dyspnea. Pulmonary function testing revealed a restrictive pattern with small lung volumes. Pulmonary imaging showed elevation of the right hemidiaphragm without evidence of interstitial lung disease. Diaphragmatic ultrasound was suggestive of profound diaphragmatic weakness and dysfunction. Based on these findings, a diagnosis of SLS was made. Her proximal muscle weakness was investigated, and creatine kinase (CK) levels were normal. Electromyography revealed fibrillation potentials in the biceps, iliopsoas, cervical and thoracic paraspinal muscles, and complex repetitive discharges in cervical paraspinal muscles. Biceps muscle biopsy revealed dense endomysial lymphocytic aggregates rich in CD20 positive B cells, perimysial fragmentation with plasma cell-rich perivascular infiltrates, diffuse sarcolemmal upregulation of class I MHC, perifascicular upregulation of class II MHC, and focal sarcolemmal deposition of C5b-9. Treatment with prednisone 15 mg/day and oral mycophenolate mofetil 2 g/day was initiated. Shortness of breath and proximal muscle weakness improved significantly. CONCLUSION: Diaphragmatic weakness was the inaugural manifestation of myositis in this patient with SLE. The spectrum of myologic manifestations of myositis with prominent CD20 positive B-cell aggregates in SLE now includes normal CK levels and diaphragmatic involvement, in association with SLS.

Canadian Guidelines for Hereditary Transthyretin Amyloidosis Polyneuropathy Management.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.

Lignes directrices sur la prise en charge de l'amylose héréditaire à transthyrétine, accompagnée de polyneuropathie, au Canada.L'amylose héréditaire à transthyrétine (ATTRh) est une maladie évolutive, causée par des mutations du gène de la transthyrétine (TTR), qui entraînent un dysfonctionnement plurisystémique. L'agrégation, le mauvais repliement et la fibrillisation pathogènes de la TTR aboutissent au dépôt de protéines amyloïdes dans plusieurs organes, et affectent souvent le système nerveux périphérique et le cœur. Les troubles neurologiques fréquents comprennent une polyneuropathie sensorimotrice (PN), une neuropathie autonome, une polyneuropathie des petites fibres et le syndrome du canal carpien. Chez bon nombre de patients, la maladie a connu une évolution importante en raison de la pose tardive du diagnostic, la PN-ATTRh ne faisant pas l'objet d'un diagnostic différentiel. Santé Canada a approuvé, depuis peu, deux nouveaux médicaments modificateurs de la PN-ATTRh et efficaces contre l'affection, soit l'inotersen et le patisiran. La pose précoce du diagnostic revêt une importance cruciale dans l'instauration, en temps opportun, de ces tout nouveaux traitements qui atténuent les troubles, améliorent la qualité de vie et prolongent la survie. Les auteurs, par l'élaboration de la nouvelle ligne directrice, espèrent sensibiliser la communauté médicale à la PN-ATTRh, et améliorer les résultats cliniques qui y sont associés, en formulant des recommandations sur le diagnostic et le traitement de la maladie au Canada ainsi que sur la surveillance de son évolution.

Autoantibody profiles delineate distinct subsets of scleromyositis.

OBJECTIVE: Scleromyositis remains incompletely characterized owing in part to its heterogeneity. The purpose of this study was to explore the role of autoantibody profiles to define subsets of scleromyositis. METHODS: Subjects with scleromyositis from a prospective cohort were divided into three groups based on autoantibody profiles: subjects with SSc-specific autoantibodies (anti-centromere, -topoisomerase 1, -RNA polymerase III, -Th/To, -fibrillarin), subjects with SSc-overlap autoantibodies (anti-PM/Scl, -U1RNP, -Ku) and subjects without SSc-related autoantibodies. Clinical features, laboratory tests and histopathological findings were retrieved and compared between groups. RESULTS: Of 42 scleromyositis subjects (79% female, mean age at diagnosis 55 years, mean disease duration 3.5 years), 8 (19%) subjects had SSc-specific autoantibodies, 14 (33%) SSc-overlap autoantibodies and 20 (48%) had no SSc-related autoantibodies. One-third had no skin involvement, a finding more frequent in the SSc-overlap subjects and those without SSc-related autoantibodies. Proximal and distal weakness was common and head drop/bent spine was found in 50% of the SSc-specific and 35% of the subjects without SSc-related autoantibodies. Of note, the group without SSc-related autoantibodies had the only cases of severe cardiac systolic dysfunction (n = 1) and scleroderma renal crisis (n = 1), as well as three out of the four cancers and three out of the four deaths. CONCLUSION: In this carefully phenotyped series of scleromyositis subjects, absence of SSc-related autoantibodies was common and associated with distinct features and poor prognosis. Future studies are needed to validate these results and possibly identify novel autoantibodies or other biomarkers associated with scleromyositis.

Poor Yield of Routine Transthyretin Screening in Patients with Idiopathic Neuropathy.

BACKGROUND AND OBJECTIVES: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is caused by a mutation in the transthyretin (TTR) gene. Although classically described as rapidly progressive and life-threatening, recent studies on TTR-FAP show significant genetic and phenotypic heterogeneity depending on geographic localization. In light of new therapeutic advances and their implication for patient management, the aim of our study was to determine the prevalence of TTR-FAP within patients with idiopathic neuropathy in a North American population. METHODS: We sequenced the TTR gene in a cohort of patients with idiopathic neuropathy. Genetic screening was performed in 110 patients from two neuromuscular clinics in Montreal, Canada. RESULTS: No variants of unknown significance or pathogenic mutations were detected in the TTR gene. CONCLUSION: Our study confirms that TTR-FAP is a rare entity in our patient population, and that diagnostic yield of screening all patients with idiopathic neuropathy is very low.

Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on the Evaluation and Management of Patients With Cardiac Amyloidosis.

Cardiac amyloidosis is an under-recognized and potentially fatal cause of heart failure and other cardiovascular manifestations. It is caused by deposition of misfolded precursor proteins as fibrillary amyloid deposits in cardiac tissues. The two primary subtypes of systemic amyloidosis causing cardiac involvement are immunoglobulin light chain (AL), a plasma cell dyscrasia, and transthyretin (ATTR), itself subdivided into a hereditary subtype caused by a gene mutation of the ATTR protein, and an age-related wild type, which occurs in the absence of a gene mutation. Clinical recognition requires a high index of suspicion, inclusive of the extracardiac manifestations of both subtypes. Diagnostic workup includes screening for serum and/or urine monoclonal protein suggestive of immunoglobulin light chains, along with serum cardiac biomarker measurement and performance of cardiac imaging for findings consistent with amyloid infiltration. Modern cardiac imaging techniques, including the use of nuclear scintigraphy with bone-seeking radiotracer to noninvasively diagnose ATTR cardiac amyloidosis, have reduced reliance on the gold standard endomyocardial biopsy. Disease-modifying therapeutic approaches have evolved significantly, particularly for ATTR, and pharmacologic therapies that slow or halt disease progression are becoming available. This Canadian Cardiovascular Society/Canadian Heart Failure Society joint position statement provides evidence-based recommendations that support the early recognition and optimal diagnostic approach and management strategies for patients with cardiac amyloidosis. This includes recommendations for the symptomatic management of heart failure and other cardiovascular complications such as arrhythmia, risk stratification, follow-up surveillance, use of ATTR disease-modifying therapies, and optimal clinical care settings for patients with this complex multisystem disease.

A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade.

Mutations in FIG4, coding for a phosphoinositol(3,5) bisphosphate 5' phosphatase and involved in vesicular trafficking and fusion, have been shown causing a recessive form of Charcot-Marie-Tooth (CMT). We have identified a novel intronic mutation in the FIG4 in a wheel-chair bound patient presenting with a severe form of CMT4J and provide a longitudinal study. Investigations indicated a demyelinating sensorimotor polyneuropathy with diffuse active denervation and severe axonal loss. Genetic testing revealed that the patient is heterozygous for 2 FIG4 mutations, p.I41T and a T > G transversion at IVS17-10, the latter predicted to cause a splicing defect. FIG4 was severely diminished in patient's fibroblasts indicating loss-of-function. Consistent with FIG4's function in phosphoinositol homeostasis and vesicular trafficking, fibroblasts contained multiple large vacuoles and vesicular organelles were abnormally dispersed. FIG4 deficiency has implications for turnover of membrane proteins. The transient receptor cation channel, TRPV4, accumulated at the plasma membrane of patient's fibroblasts due to slow turnover. Knocking down Fig4 in murine cultured motor neurons resulted in vacuolation and cell death. Inhibiting TRPV4 activity significantly preserved viability, although not correcting vesicular trafficking. In conclusion, we demonstrate a new FIG4 intronic mutation and, importantly, a functional interaction between FIG4 and TRPV4.

An unusual cause of Achilles tendon xanthoma.

Tendinous xanthomas are often thought to be pathognomonic for familial hypercholesterolemia. In this report, we present the case of a young man with a normal lipid profile and Achilles tendon xanthoma. Biochemical and genetic studies confirmed the diagnosis of cerebrotendinous xanthomatosis in this patient. Cerebrotendinous xanthomatosis is a rare autosomal recessive disease associated with xanthoma in tendons and the brain as well as progressive neurologic deficits. Unfortunately, this rare form of reversible dementia is thought to be underdiagnosed. Early diagnosis and treatment of this disease with chenodeoxycholic acid is essential and has been shown to greatly improve the patient's symptoms and prognosis.

Diabetic cervical radiculoplexus neuropathy: a distinct syndrome expanding the spectrum of diabetic radiculoplexus neuropathies.

Diabetic lumbosacral radiculoplexus neuropathy is a subacute painful, asymmetrical lower limb neuropathy due to ischaemic injury and microvasculitis. The occurrence of a cervical diabetic radiculoplexus neuropathy has been postulated. Our objective was to characterize the clinical features and pathological alterations of diabetic cervical radiculoplexus neuropathy, to see if they are similar to diabetic lumbosacral radiculoplexus neuropathy and due to ischaemic injury and microvasculitis. We identified patients with diabetic cervical radiculoplexus neuropathy by review of the Mayo Clinic database from 1996 to 2008. We systematically reviewed the clinical features, laboratory studies, neurophysiological findings, neuroimaging and pathological features and compared the findings with a previously published diabetic lumbosacral radiculoplexus neuropathy cohort. Eighty-five patients (56 males, 67 with Type 2 diabetes mellitus) were identified. The median age was 62 years (range 32-83). The main presenting symptom was pain (53/85). At evaluation, weakness was the most common symptom (84/85), followed by pain (69/85) and numbness (56/85). Neuropathic deficits were moderate (median motor neuropathy impairment score 10.0 points) and improved at follow-up. Upper, middle and lower brachial plexus segments were involved equally and pan-plexopathy was not unusual (25/85). Over half of patients (44/85) had at least one additional body region affected (30 contralateral cervical, 20 lumbosacral and 16 thoracic) as is found in diabetic lumbosacral radiculoplexus neuropathy. Recurrent disease occurred in 18/85. Neurophysiology showed axonal neuropathy (80/80) with paraspinal denervation (21/65), and abnormal autonomic (23/24) and sensory testing (10/13). Cerebrospinal fluid protein was elevated (median 70 mg/dl). Magnetic resonance imaging showed brachial plexus abnormality in all (38/38). Nerve biopsies (11 upper and 11 lower limbs) showed ischaemic injury (axonal degeneration, multifocal fibre loss 15/22, focal perineurial thickening 16/22, injury neuroma 5/22) and increased inflammation (epineural perivascular inflammation 22/22, haemosiderin deposition 6/22, vessel wall inflammation 14/22 and microvasculitis 5/22). We therefore conclude that (i) diabetic cervical radiculoplexus neuropathy is a predominantly monophasic, upper limb diabetic neuropathy with pain followed by weakness and involves motor, sensory and autonomic fibres; (ii) the neuropathy begins focally and often evolves into a multifocal or bilateral condition; (iii) the pathology of diabetic cervical radiculoplexus neuropathy demonstrates ischaemic injury often from microvasculitis; and (iv) diabetic cervical radiculoplexus neuropathy shares many of the clinical and pathological features of diabetic lumbosacral radiculoplexus neuropathy, providing evidence that these conditions are best categorized together within the spectrum of diabetic radiculoplexus neuropathies.

Mitochondrial myopathy due to novel missense mutation in the cytochrome c oxidase 1 gene.

We report a novel heteroplasmic mutation p.Y440C in the mitochondrial DNA-encoded subunit I of the cytochrome c oxidase (COX) gene in a patient with late onset progressive painless weakness. Her muscle biopsy showed scattered COX-negative fibers and several small collections of inflammatory cells. The mutation was detected in the patient's muscle but not in her blood. The low mutant load in muscle could explain the patient's late onset of the myopathy and milder phenotype when compared to the previously published cases with MTCO1 mutations.

Polymerase gamma 1 mutations: clinical correlations.

BACKGROUND: Mitochondrial disorders result from primary defects in the mitochondrial DNA (mtDNA) or from defects in nuclear genes which cause disease by affecting the mtDNA. POLG1 is a nuclear gene which encodes for the catalytic subunit of the mtDNA polymerase gamma, essential for mtDNA replication. Less than a decade ago, POLG1 mutations were discovered in patients with progressive external ophthalmoplegia. Since then, it has emerged that POLG1 mutations can result in a spectrum of clinical manifestations, resulting in autosomal recessive or dominant mitochondrial diseases. REVIEW SUMMARY: Here we summarize the common clinical phenotypes associated with POLG1 mutations. Alpers syndrome, progressive external ophthalmoplegia with or without limb myopathy, ataxia-neuropathy syndrome, and epilepsy are frequent clinical manifestations of the POLG1-related disease. Childhood progressive encephalopathy, Parkinsonism, stroke-like events, and isolated exercise intolerance can occur in association with POLG1 mutations. Muscle biopsy can show signs of mitochondrial dysfunction by histologic and biochemical studies or it can be unrevealing. mtDNA analysis of affected tissues can reveal depletion, multiple deletions or point mutations, but it can be occasionally noninformative by routine analysis. CONCLUSIONS: : POLG1 mutations result in extremely heterogenous phenotypes which often have overlapping clinical findings, making it difficult to categorize patients into syndromes. The lack of signs of mitochondrial dysfunction in the muscle biopsy does not exclude a POLG1-related disease. Analysis of mtDNA of clinically affected tissues is often informative, but not always. Molecular analysis of POLG1 is essential when POLG1-related disease is suspected. Sodium valproate should be avoided because of the risk of liver failure.