| Editorial introductions, |
Charcot–Marie–Tooth disease and related disorders: an evolving landscape Purpose of review Charcot–Marie–Tooth (CMT) disease and related disorders are the commonest group of inherited neuromuscular diseases and represent a heterogeneous group of disorders. This review will cover recent advances in genetic diagnosis and the evolving genetic and phenotype landscape of this disease group. We will review recent evidence of the increasingly recognized phenotypic overlap with other neurodegenerative conditions including hereditary spastic paraplegia, hereditary ataxias and mitochondrial diseases and highlight the importance of deep phenotyping to inform genetic diagnosis and prognosis. Recent findings Through whole exome sequencing and multicentre collaboration new genes are being identified as causal for CMT expanding the genetic heterogeneity of this condition. In addition, an increasing number of variants have been identified in genes known to cause complex inherited diseases in which the peripheral neuropathy is part of the disorder and may be the presenting feature. The recent discovery of a repeat expansion in the RFC1 gene in cerebellar ataxia, neuropathy, vestibular areflexia syndrome highlights the prevalence of late-onset recessive conditions which have historically been considered to cause early-onset disease. Summary CMT is an evolving field with considerable phenotypic and genetic heterogeneity and deep phenotyping remains a cornerstone in contemporary CMT diagnostics. |
Autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy Purpose of review Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous disorder that includes diverse clinical presentations and immunopathological mechanisms. Antibodies targeting proteins of the node of Ranvier are present in a subset of CIDP patients. These autoantibodies are pathogenic and associate with specific clinical phenotypes and therapeutic peculiarities. This review summarizes the novel insights that the discovery of novel autoantibodies has brought to the understanding of CIDP. Recent findings Several reports have confirmed the association of the antineurofascin 155 (NF155) antibodies with tremor, ataxia and poor response to IVIG, and with novel pathological features in CIDP patients. The association of nephrotic syndrome with anticontactin 1 (CNTN1) and antinodal neurofascin antibodies has also been described. Also, complement-fixing IgG3 antibodies targeting paranodal proteins have been associated with acute-onset CIDP. Importantly, detection of these autoantibodies has helped selecting CIDP patients for rituximab treatment. Finally, anti-CNTN1 and anti-NF155 antibodies have proven to be the first pathogenic autoantibodies described in CIDP. Summary The discovery of autoantibodies against nodal and paranodal proteins has proven useful in clinical practice, has uncovered novel pathophysiological mechanisms, clinical phenotypes, therapeutic response and prognosis within the CIDP disease spectrum and has boosted the search for other clinically relevant autoantibodies. |
Neuropathies and paraproteins Purpose of review There is an increasingly recognized association between haematological and neurological disease. This is especially true in the peripheral nervous system in which, to an extent, proof of a link is easier to achieve. The most sensitive low level paraprotein detection methods should always be employed in which a paraprotein is suspected. Peripheral nerves can be damaged not only by the immunological targeting of the myelin by the paraprotein, but by deposition (light chain amyloid and cryoglobulins) or direct infiltration (neurolymphomatosis). This has resulted in other defined paraprotein-related disease pathogeneses. Recent findings Our opportunities for treating these patients are greater not only through better recognition of disease but also treatments introduced from haematological research. Beyond rituximab, combination therapies, proteasome inhibition and novel biological treatments are being described in haematological practice with early efficacy in neurology. Important developments here should be exploited in neurology to improve outcomes. Summary This review of the current literature focuses not only on the long-term outcome studies in anti-myelin-associated glycoprotein neuropathy, but developments in the diagnosis and treatment of monoclonal gammopathy of undetermined significance and Waldenström's Macroglobulinaemia. |
The challenges of diabetic polyneuropathy: a brief update Purpose of review The current review addresses one of the most common neurological disorders, diabetic polyneuropathy (DPN). DPN is debilitating, irreversible and dwarfs the prevalence of most other chronic disorders of the nervous system. Its complications include foot ulceration, amputation, falling and intractable neuropathic pain. Moreover, tight control of hyperglycemia reduces the incidence of DPN in type 1 diabetes mellitus but its role in type 2 diabetes mellitus is less clear. Recent findings New therapeutic options to reverse the development of DPN or its associated pain have been proposed but none have significantly changed the clinical approach. The cause of DPN remains controversial traditionally focused on the impact of metabolic abnormalities, polyol flux, microvascular changes, mitochondria, oxidative stress, lipid biology and others. In particular, there has been less attention toward how this chronic disorder alters peripheral neurobiology. It is now clear that in chronic models of diabetes mellitus there exists a unique form of neurodegeneration with a range of protein, mRNA and microRNA alterations to consider. How to reconcile these molecular and structural alterations with metabolic mechanisms is a challenge. In sensory neurons alone, a primary target of DPN, both central perikaryal cytoplasmic and nuclear changes and altered distal sensory axon terminal plasticity may be involved. Summary In this review, the current therapeutic status of DPN is described with greater emphasis on some new but selected thoughts on its neurobiology. New mechanistic understanding will be essential to developing precision therapeutics for DPN. |
Toxic neuropathies: Chemotherapy Induced Peripheral Neurotoxicity Purpose of review Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and distressing side-effect of many chemotherapy regimens. Currently, aside from symptomatic treatments for neuropathic pain, there are no treatments to prevent CIPN or treat established CIPN. We discuss recent articles addressing clinimetric issues and treatment of CIPN. Recent findings There are important clinimetric issues that need to be addressed so that robust clinical trials in CIPN can be performed. There are new compounds in early development that may treat CIPN, but larger studies are needed. Summary A multidisciplinary, international approach is needed to unravel CIPN; the Toxic Neuropathy Consortium (TNC) of the Peripheral Nerve Society may be the home for such efforts. |
Update on classification, epidemiology, clinical phenotype and imaging of the nonsystemic vasculitic neuropathies Purpose of review Single-organ vasculitis of the peripheral nervous system (PNS) is often designated nonsystemic vasculitic neuropathy (NSVN). Several variants or subtypes have been distinguished, including migratory sensory neuropathy, postsurgical inflammatory neuropathy, diabetic radiculoplexus neuropathies, skin-nerve vasculitides, and, arguably, neuralgic amyotrophy. NSVN often presents as nondiabetic lumbosacral radiculoplexus neuropathy (LRPN). This review updates classification, clinical features, epidemiology, and imaging of these disorders. Recent findings A recent study showed the annual incidence of LRPN in Olmstead County, Minnesota to be 4.16/100 000:2.79/100 000 diabetic and 1.27/100 000 nondiabetic. This study was the first to determine the incidence or prevalence of any vasculitic neuropathy. In NSVN, ultrasonography shows multifocal enlargement of proximal and distal nerves. In neuralgic amyotrophy, MRI and ultrasound reveal multifocal enlargements and focal constrictions in nerves derived from the brachial plexus. Histopathology of these chronic lesions shows inflammation and rare vasculitis. Diffusion tensor imaging of tibial nerves in NSVN revealed decreased fractional anisotropy in one study. Summary Single-organ PNS vasculitides are the most common inflammatory neuropathies. Neuralgic amyotrophy might result from PNS vasculitis, but further study is necessary. The usefulness of focal nerve enlargements or constrictions in understanding pathological mechanisms, directing biopsies, and monitoring disease activity in NSVN should be further investigated. |
The congenital myasthenic syndromes: expanding genetic and phenotypic spectrums and refining treatment strategies Purpose of review Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins whose function is essential for the integrity of neuromuscular transmission. This review updates the reader on the expanding phenotypic spectrum and suggested improved treatment strategies. Recent findings As next-generation sequencing is taken into the clinic, its use is both continuing to unearth new causative genes in which mutations underlie CMS and also broadening the phenotypic spectrum for known CMS genes. The number of genes in which mutations may cause neuromuscular transmission defects has now passed 30. The defective transmission may be part of an overall more complex phenotype in which there may be muscle, central nervous system or other involvement. Notably, mutations in series of genes encoding proteins located in the presynatic motor bouton have been identified. Rare cases of mutations in basal laminar proteins of the synaptic cleft are coming to light and additional mutations/phenotypic features have been located in some of the larger neuromuscular junction proteins such as AGRN and MUSK, where previously mutation screening by sanger sequencing was time consuming and costly. Finally, there are more reports of the beneficial effects of treatment with β2-adrenergic receptor agonists in patients, and the study of their action in disease models. Summary Recent studies of the CMS illustrate the increasing complexity of the genetics and pathophysiological mechanisms involved. With therapy tailored for the underlying disease mechanism treatment, although incomplete, is usually life-transforming. However, treatment for newly identified conditions in which myasthenia is only one component within complex multisystem disorder will prove challenging. |
Classification of idiopathic inflammatory myopathies: pathology perspectives Purpose of review Idiopathic inflammatory myopathies (IIM) are rare diseases with heterogenous clinicopathological features. In recent years, new classification systems considering various combinations of clinical, serological, and pathological information have been proposed. This review summarizes recent clinicoseropathological development in major subgroups of IIM. Recent findings Considering clinicoseropathological features, IIM are suggestively classified into four major subgroups: dermatomyositis, immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASS), and inclusion body myositis (IBM). Many historically diagnosed polymyositis have been mainly reclassified as IBM, IMNM, and ASS. Different types of myositis-specific antibodies (MSA) suggest distinct clinicopathological subsets of IIM. Excluding IBM, at least one-third of the IIMs have no known associated MSA. Summary MSA are crucial for IIM classification but can be negative. Thus, IIM should be universally classified using stepwise or integrated information on clinical, serological, and pathological findings. |
Advances in primary mitochondrial myopathies Purpose of review Although mitochondrial diseases impose a significant functional limitation in the lives of patients, treatment of these conditions has been limited to dietary supplements, exercise, and physical therapy. In the past few years, however, translational medicine has identified potential therapies for these patients. Recent findings For patients with primary mitochondrial myopathies, preliminary phase I and II multicenter clinical trials of elamipretide indicate safety and suggest improvement in 6-min walk test (6MWT) performance and fatigue scales. In addition, for thymidine kinase 2-deficient (TK2d) myopathy, compassionate-use oral administration of pyrimidine deoxynucleosides have shown preliminary evidence of safety and efficacy in survival of early onset patients and motor functions relative to historical TK2d controls. Summary The prospects of effective therapies that improve the quality of life for patients with mitochondrial myopathy underscore the necessity for definitive diagnoses natural history studies for better understanding of the diseases. |
Πέμπτη 29 Αυγούστου 2019
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