Are we prepared for clinical trials in Charcot-Marie-Tooth disease?

There has been considerable progress in developing treatments for Charcot-Marie-Tooth disease with a number of therapies either completing or nearing clinical trials. In the case of CMT1A, the commonest subtype of CMT, there have been more than five randomised, double blind placebo-controlled trials. Although these trials were negative for the primary outcome measure, considerable lessons have been learnt leading to the collection of large prospective natural history data sets with which to inform future trial design as well as the development of new and sensitive outcome measures. In this review we summarise the difficulties of conducting clinical trials in a slowly progressive disease such as CMT1A and the requirement for sensitive, reproducible and clinically relevant outcome measures. We summarise the current array of CMT specific outcome measures subdivided into clinical outcome measures, functional outcome measures, patient reported outcome measures, biomarkers of disease burden and treatment specific biomarkers of target engagement. Although there is now an array of CMT specific outcome measures, which collectively incorporate clinically relevant, sensitive and reproducible outputs, a single outcome measure incorporating all three qualities remains elusive

Next-generation sequencing in Charcot-Marie-Tooth disease: opportunities and challenges

Charcot-Marie-Tooth disease and the related disorders hereditary motor neuropathy and hereditary sensory neuropathy, collectively termed CMT, are the commonest group of inherited neuromuscular diseases, and they exhibit wide phenotypic and genetic heterogeneity. CMT is usually characterized by distal muscle atrophy, often with foot deformity, weakness and sensory loss. In the past decade, next-generation sequencing (NGS) technologies have revolutionized genomic medicine and, as these technologies are being applied to clinical practice, they are changing our diagnostic approach to CMT. In this Review, we discuss the application of NGS technologies, including disease-specific gene panels, whole-exome sequencing, whole-genome sequencing (WGS), mitochondrial sequencing and high-throughput transcriptome sequencing, to the diagnosis of CMT. We discuss the growing challenge of variant interpretation and consider how the clinical phenotype can be combined with genetic, bioinformatic and functional evidence to assess the pathogenicity of genetic variants in patients with CMT. WGS has several advantages over the other techniques that we discuss, which include unparalleled coverage of coding, non-coding and intergenic areas of both nuclear and mitochondrial genomes, the ability to identify structural variants and the opportunity to perform genome-wide dense homozygosity mapping. We propose an algorithm for incorporating WGS into the CMT diagnostic pathway

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

Axonal transport and neurological disease

Axonal transport is the process whereby motor proteins actively navigate microtubules to deliver diverse cargoes, such as organelles, from one end of the axon to the other, and is widely regarded as essential for nerve development, function and survival. Mutations in genes encoding key components of the transport machinery, including motor proteins, motor adaptors and microtubules, have been discovered to cause neurological disease. Moreover, disruptions in axonal cargo trafficking have been extensively reported across a wide range of nervous system disorders. However, whether these impairments have a major causative role in, are contributing to or are simply a consequence of neuronal degeneration remains unclear. Therefore, the fundamental relevance of defective trafficking along axons to nerve dysfunction and pathology is often debated. In this article, we review the latest evidence emerging from human and in vivo studies on whether perturbations in axonal transport are indeed integral to the pathogenesis of neurological disease

TDP43 pathology in the brain, spinal cord, and dorsal root ganglia of a patient with FOSMN

OBJECTIVE: To describe the histopathologic features of a case of facial-onset sensory and motor neuronopathy (FOSMN). METHODS: We describe a postmortem examination performed on a 54-year-old man with FOSMN associated with personality change. RESULTS: Postmortem examination revealed TAR DNA-binding protein (TDP) 43 proteinopathy with widespread distribution. TDP43 pathology was seen in the neurons and glial cells and was most pronounced in the subthalamic nucleus followed by the spinal cord, including dorsal root ganglia, brainstem, and other deep cerebral nuclei. In the medial temporal lobe, neocortex and subcortical hemispheric white matter TDP43 pathologic inclusions were very rare. In contrast to TDP43 pathologies associated with typical amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD)–TDP, in this case, there were more frequent TDP43-positive oligodendroglial, coiled body–like cytoplasmic inclusions than neuronal inclusions. Neuronal cytoplasmic TDP43 inclusions with globular and skein-like morphology were seen in both anterior horn cells and dorsal root ganglia. No β-amyloid, α-synuclein, or significant hyperphosphorylated tau pathology was seen. CONCLUSION: This case provides further evidence that FOSMN is a neurodegenerative disease characterized by TDP43 pathology. Despite minimal cortical TDP43 pathology, the clinical features of the behavioral variant of FTD in this patient suggest that FOSMN may fall within or overlap with the FTD-ALS spectrum

A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder

Mutations in the kinesin family member 1A (KIF1A) gene have been associated with a wide range of phenotypes including recessive mutations causing hereditary sensory neuropathy and hereditary spastic paraplegia and de novo dominant mutations causing a more complex neurological disorder affecting both the central and peripheral nervous system. We identified by exome sequencing a de novo dominant missense variant, (c.38G>A, p.R13H), within an ATP binding site of the kinesin motor domain in a patient manifesting a complex phenotype characterized by autism spectrum disorder (ASD), spastic paraplegia and axonal neuropathy. The presence of ASD distinguishes this case from previously reported patients with de novo dominant mutations in KIF1A

Clinical Presentation, Diagnosis and Treatment of TTR Amyloidosis

Systemic amyloidosis can be hereditary or acquired with autosomal dominant mutations in the transthyretin gene (TTR) being the most common cause of hereditary amyloidosis. ATTRm amyloidosis is a multi-system disorder with cardiovascular, peripheral and autonomic nerve involvement that can be difficult to diagnose due to phenotypic heterogeneity. This review will focus on the neuropathic manifestations of ATTRm, the genotype-phenotype variability, the diagnostic approach and the recent therapeutic advances in this disabling condition