Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases

Since Waller and Cajal in the nineteenth and early twentieth centuries, laboratory traumatic peripheral nerve injury studies have provided great insight into cellular and molecular mechanisms governing axon degeneration and the responses of Schwann cells, the major glial cell type of peripheral nerves. It is now evident that pathways underlying injury-induced axon degeneration and the Schwann cell injury-specific state, the repair Schwann cell, are relevant to many inherited and acquired disorders of peripheral nerves. This review provides a timely update on the molecular understanding of axon degeneration and formation of the repair Schwann cell. We discuss how nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile alpha TIR motif containing protein 1 (SARM1) are required for axon survival and degeneration, respectively, how transcription factor c-JUN is essential for the Schwann cell response to nerve injury and what each tells us about disease mechanisms and potential therapies. Human genetic association with NMNAT2 and SARM1 strongly suggests aberrant activation of programmed axon death in polyneuropathies and motor neuron disorders, respectively, and animal studies suggest wider involvement including in chemotherapy-induced and diabetic neuropathies. In repair Schwann cells, cJUN is aberrantly expressed in a wide variety of human acquired and inherited neuropathies. Animal models suggest it limits axon loss in both genetic and traumatic neuropathies, whereas in contrast, Schwann cell secreted Neuregulin-1 type 1 drives onion bulb pathology in CMT1A. Finally, we discuss opportunities for drug-based and gene therapies to prevent axon loss or manipulate the repair Schwann cell state to treat acquired and inherited neuropathies and neuronopathies.

Atypical presentation of Charcot-Marie-Tooth disease type 1C with a new mutation: a case report

Background Charcot-Marie-Tooth 1C (CMT1C) is a rare form of dominantly inherited CMT1 neuropathy caused by a mutated gene encoding lipopolysaccharide-induced tumour necrosis alpha factor (LITAF). Case presentation We report a 56-year-old patient with an atypical clinical phenotype of CMT1C, which started as progressive weakness of a single upper limb resembling acquired inflammatory neuropathy. Nerve conduction studies (NCS) and temporarily limited and partial effects of immunotherapy supported the diagnosis of inflammatory neuropathy. Significant progression of polyneuropathy, despite intensive long-lasting immunotherapy, together with repeatedly negative auxiliary investigations (CSF, MRI and antibodies) and genetic testing results finally led to the diagnosis of CMT1C neuropathy. Conclusions CMT1C should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy.

Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing a wide range of therapeutics, leading to an exciting era of finding treatments for this, until now, incurable group of diseases. Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing while several have also reached clinical trial stage. Some of the treatment approaches are disease-specific targeted to the unique disease mechanism of each CMT form, while other therapeutics target common pathways shared by several or all CMT types. As promising treatments reach the stage of clinical translation, optimal outcome measures, novel biomarkers and appropriate trial designs are crucial in order to facilitate successful testing and validation of novel treatments for CMT patients.

The expanding genetic landscape of hereditary motor neuropathies

Hereditary motor neuropathies are clinically and genetically diverse disorders characterized by length-dependent axonal degeneration of lower motor neurons. Although currently as many as 26 causal genes are known, there is considerable missing heritability compared to other inherited neuropathies such as Charcot-Marie-Tooth disease. Intriguingly, this genetic landscape spans a discrete number of key biological processes within the peripheral nerve. Also, in terms of underlying pathophysiology, hereditary motor neuropathies show striking overlap with several other neuromuscular and neurological disorders. In this review, we provide a current overview of the genetic spectrum of hereditary motor neuropathies highlighting recent reports of novel genes and mutations or recent discoveries in the underlying disease mechanisms. In addition, we link hereditary motor neuropathies with various related disorders by addressing the main affected pathways of disease divided into five major processes: axonal transport, tRNA aminoacylation, RNA metabolism and DNA integrity, ion channels and transporters and endoplasmic reticulum.

Molecular Diagnosis of Hereditary Neuropathies by Whole Exome Sequencing and Expanding the Phenotype Spectrum

Background: Inherited peripheral neuropathies (IPNs) are a group of neuropathies affecting peripheral motor and sensory neurons. Charcot-Marie-Tooth (CMT) disease is the most common disease in this group. With recent advances in next-generation sequencing (NGS) technologies, more than 100 genes have been implicated for different types of CMT and other clinically and genetically inherited neuropathies. There are also a number of genes where neuropathy is a major feature of the disease such as spinocerebellar ataxia (SCA) and hereditary spastic paraplegia (HSP). We aimed to determine the genetic causes underlying IPNs in Iranian families. Methods: We performed whole exome sequencing (WES) for 58 PMP22 deletion-/duplication-negative unrelated Iranian patients with a spectrum of phenotypes and with a preliminary diagnosis of hereditary neuropathies. Results: Twenty-seven (46.6%) of the cases were genetically diagnosed with pathogenic or likely pathogenic variants. In this study, we identified genetically strong variants within genes not previously linked to any established disease phenotype in five (8.6%) patients. Conclusion: Our results highlight the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs. Moreover, functional analysis is required for novel and uncertain variants.

Polyneuropathy in Young Siberian Huskies Caused by Degenerative and Inflammatory Diseases

Polyneuropathy is defined as the simultaneous dysfunction of several peripheral nerves. In dogs, a number of breeds are predisposed to a variety of immune-mediated and/or degenerative inherited forms of polyneuropathy, with laryngeal paralysis and/or megaesophagus as important clinical features of many of these conditions. This case series describes degenerative and inflammatory polyneuropathies in 7 young Siberian huskies that were categorized based on clinicopathological characteristics as follows: (1) slowly progressive laryngeal paralysis and megaesophagus caused by primary axonal degeneration with large fiber loss (n = 2); (2) slowly progressive polyneuropathy without megaesophagus or laryngeal paralysis caused by primary axonal degeneration with large fiber loss (n = 2); (3) acute inflammatory demyelinating neuropathy causing sensory, motor and autonomic nerve deficits (n = 2); and (4) ganglioradiculitis (sensory neuronopathy; n = 1). Based on the predominantly young age at onset, slow progression, relatedness of affected dogs, and clinical and pathological similarities with inherited neuropathies reported in other dog breeds, a hereditary basis for the degenerative polyneuropathies in Siberian huskies is suspected. However, 5 different mutations in 3 genes known to cause polyneuropathy in other dog breeds ( NDRG1, ARHGEF10, or RAB3GAP1) were not detected in the affected Siberian huskies suggesting that more genetic variants remain to be identified. This study highlights the varied underlying lesions of polyneuropathies in young Siberian huskies.