Colchicine Treatment in Children With Familial Mediterranean Fever: Is it a Risk Factor for Neuromyopathy?

BackgroundWe cared for a 17-year-old adolescent with familial Mediterranean fever under colchicine treatment. Because of the increased creatinine kinase level (3937 U/L) observed in this individual, we planned to assess all pediatric patients with familial Mediterranean fever under colchicine treatment to detect any resultant neuromyopathy.MethodsThe study included 88 children with familial Mediterranean fever who were receiving colchicine. The patient with myopathy was not included in the study. Serum creatinine kinase levels were measured and nerve conduction studies were carried out in all patients.ResultsThe study included 88 patients (47 female, 53.4%) with an average age of 10.1 ± 3.35 years. The average period of colchicine use was 28.25 ± 17.66 months. Side effects of colchicine were detected in 10 patients (11%)—as diarrhea in eight patients, leukopenia in one patient, and hair loss in one patient. Nerve conduction studies determined incidental carpal tunnel syndrome in only one patient.ConclusionsOur study did not suggest an elevated risk of neuromyopathy associated with the use of colchicine for familial Mediterranean fever.     

A role of peripheral myelin protein 2 in lipid homeostasis of myelinating schwann cells

Peripheral myelin protein 2 (Pmp2, P2 or Fabp8), a member of the fatty acid binding protein family, was originally described together with myelin basic protein (Mbp or P1) and myelin protein zero (Mpz or P0) as one of the most abundant myelin proteins in the peripheral nervous system (PNS). Although Pmp2 is predominantly expressed in myelinated Schwann cells, its role in glia is currently unknown. To study its function in PNS biology, we have generated a complete Pmp2 knockout mouse (Pmp2^‐/‐). Comprehensive characterization of Pmp2^‐/‐ mice revealed a temporary reduction in their motor nerve conduction velocity (MNCV). While this change was not accompanied by any defects in general myelin structure, we detected transitory alterations in the myelin lipid profile of Pmp2^‐/‐ mice. It was previously proposed that Pmp2 and Mbp have comparable functions in the PNS suggesting that the presence of Mbp can partially mask the Pmp2^‐/‐ phenotype. Indeed, we found that Mbp lacking Shi^‐/‐ mice, similar to Pmp2^‐/‐ animals, have preserved myelin structure and reduced MNCV, but this phenotype was not aggravated in Pmp2^‐/‐/Shi^‐/‐ mutants indicating that Pmp2 and Mbp do not substitute each other's functions in the PNS. These data, together with our observation that Pmp2 binds and transports fatty acids to membranes, uncover a role for Pmp2 in lipid homeostasis of myelinating Schwann cells. GLIA 2014;62:1502–1512     

Disruption of actin‐binding domain‐containing Dystonin protein causes dystonia musculorum in mice

The Dystonin gene (Dst) is responsible for dystonia musculorum (dt), an inherited mouse model of hereditary neuropathy accompanied by progressive motor symptoms such as dystonia and cerebellar ataxia. Dst‐a isoforms, which contain actin‐binding domains, are predominantly expressed in the nervous system. Although sensory neuron degeneration in the peripheral nervous system during the early postnatal stage is a well‐recognised phenotype in dt, the histological characteristics and neuronal circuits in the central nervous system responsible for motor symptoms remain unclear. To analyse the causative neuronal networks and roles of Dst isoforms, we generated novel multipurpose Dst gene trap mice, in which actin‐binding domain‐containing isoforms are disrupted. Homozygous mice showed typical dt phenotypes with sensory degeneration and progressive motor symptoms. The gene trap allele (Dst^Gt) encodes a mutant Dystonin‐LacZ fusion protein, which is detectable by X‐gal (5‐bromo‐4‐chloro‐3‐indolyl‐β‐D‐galactoside) staining. We observed wide expression of the actin‐binding domain‐containing Dystonin isoforms in the central nervous system (CNS) and peripheral nervous system. This raised the possibility that not only secondary neuronal defects in the CNS subsequent to peripheral sensory degeneration but also cell‐autonomous defects in the CNS contribute to the motor symptoms. Expression analysis of immediate early genes revealed decreased neuronal activity in the cerebellar‐thalamo‐striatal pathway in the homozygous brain, implying the involvement of this pathway in the dt phenotype. These novel Dst^Gt mice showed that a loss‐of‐function mutation in the actin‐binding domain‐containing Dystonin isoforms led to typical dt phenotypes. Furthermore, this novel multipurpose Dst^Gt allele offers a unique tool for analysing the causative neuronal networks involved in the dt phenotype.     

Neurofilament light mutation causes hereditary motor and sensory neuropathy with pyramidal signs

To identify novel mutations causing hereditary motor and sensory neuropathy (HMSN) with pyramidal signs, a variant of Charcot‐Marie‐Tooth disease (CMT), we screened 28 CMT and related genes in four members of an affected Japanese family. Clinical features included weakness of distal lower limb muscles, foot deformity, and mild sensory loss, then late onset of progressive spasticity. Electrophysiological studies revealed widespread neuropathy. Electron microscopic analysis showed abnormal mitochondria and mitochondrial accumulation in the neurons and Schwann cells. Brain magnetic resonance imaging (MRI) revealed an abnormally thin corpus callosum. In all four, microarrays detected a novel heterozygous missense mutation c.1166A>G (p.Y389C) in the gene encoding the light‐chain neurofilament protein (NEFL), indicating that NEFL mutations can result in a HMSN with pyramidal signs phenotype.     

Association of antibodies to ganglioside complexes and conduction blocks in axonal Guillain‐Barré syndrome presenting as acute motor conduction block neuropathy

A close relationship between acute motor conduction block neuropathy and antibodies against the complex of GM1 and GalNAc‐GD1a has been reported. This study investigates the hypothesis that conduction block at the early phase of axonal Guillain‐Barré syndrome (GBS) is also associated with such ganglioside complexes. Sera were obtained from seven French patients with initial evidence of isolated conduction blocks that resolved or progressed to acute motor axonal neuropathy. Serum IgG to asialo‐GM1 and gangliosides of LM1, GM1, GM1b, GD1a, GalNAc‐GD1a, GD1b, GT1a, GT1b, and GQ1b as well as their complexes were measured. Five of seven patients progressed within the first month of disease to AMAN. One patient had IgG antibodies against the complex of asialo‐GM1 and each of the other ganglioside antigens. Another patient carried IgG antibodies against GM1 complex with GM1b, GD1a, and GT1a as well as asialo‐GM1 complex with GD1a and GT1a. None had IgG antibodies against GM1/GalNAc‐GD1a complex. Six patients had IgG against single antigens GM1, GD1a, GalNAc‐GD1a, GD1b, and asialo‐GM1. In three patients, a reduced reaction against GM1/GalNAc‐GD1a complex was observed. The presence of conduction block in axonal GBS is not always associated with anti‐GM1/GalNAc‐GD1a complex antibodies.     

Characterization of the mitofusin 2 R94W mutation in a knock‐in mouse model

Charcot‐Marie‐Tooth disease (CMT) comprises a group of heterogeneous peripheral axonopathies affecting 1 in 2,500 individuals. As mutations in several genes cause axonal degeneration in CMT type 2, mutations in mitofusin 2 (MFN2) account for approximately 90% of the most severe cases, making it the most common cause of inherited peripheral axonal degeneration. MFN2 is an integral mitochondrial outer membrane protein that plays a major role in mitochondrial fusion and motility; yet the mechanism by which dominant mutations in this protein lead to neurodegeneration is still not fully understood. Furthermore, future pre‐clinical drug trials will be in need of validated rodent models. We have generated a Mfn2 knock‐in mouse model expressing Mfn2^R94W, which was originally identified in CMT patients. We have performed behavioral, morphological, and biochemical studies to investigate the consequences of this mutation. Homozygous inheritance leads to premature death at P1, as well as mitochondrial dysfunction, including increased mitochondrial fragmentation in mouse embryonic fibroblasts and decreased ATP levels in newborn brains. Mfn2^R94W heterozygous mice show histopathology and age‐dependent open‐field test abnormalities, which support a mild peripheral neuropathy. Although behavior does not mimic the severity of the human disease phenotype, this mouse can provide useful tissues for studying molecular pathways associated with MFN2 point mutations.     

Multifocal motor neuropathy with high titers of anti‐MAG antibodies

Multifocal motor neuropathy (MMN) and anti‐myelin‐associated glycoprotein (anti‐MAG)‐associated neuropathy are clinically and electrophysiologically distinct entities. We describe a patient with characteristic features of both neuropathies, raising the possibility of an overlap syndrome. A 49‐year‐old patient reported a history of slowly progressive predominantly distal tetraparesis, with mild sensory deficits. Nerve conduction studies demonstrated persistent motor conduction blocks outside compression sites, typical of MMN. Laboratory findings revealed persistently high titers of anti‐MAG immunoglobulin Mλ (IgMλ) paraprotein in the context of a monoclonal gammapathy of unknown significance. Skin biopsy of distal lower limb revealed IgM positive terminal nerve perineurium deposits. This case suggests that the distinction between subtypes of chronic inflammatory neuropathies may not be as clear as initially thought, and that the pattern of pathogenicity of anti‐MAG antibodies may vary.     

Painful neuropathies: the emerging role of sodium channelopathies

Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage‐gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where Na_V1.7, Na_V1.8, and Na_V1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain‐of‐function SCN9A mutations. Recent studies have expanded this spectrum with gain‐of‐function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch‐clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell‐type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length‐dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain‐of‐function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.