Inherited Neuropathies

Fridman, Vera; Reilly, Mary M.

doi:10.1055/s-0035-1558981

Cited by 36 publications

(31 citation statements)

References 93 publications

(166 reference statements)

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“…Proteins which are involved in sensory neurodegeneration affect distinct molecular pathways: sphingolipid-metabolism, membrane-shaping of organelles, regulation of ion channels, endoplasmic reticulum turnover and axonal trafficking[1, 4–8]. However, the molecular mechanisms underlying sensory neurodegeneration are still incompletely understood and disease-causing mutations remain to be identified in a substantial number of patients.…”

Section: Introductionmentioning

confidence: 99%

Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception

et al. 2016

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Pain is necessary to alert us to actual or potential tissue damage. Specialized nerve cells in the body periphery, so called nociceptors, are fundamental to mediate pain perception and humans without pain perception are at permanent risk for injuries, burns and mutilations. Pain insensitivity can be caused by sensory neurodegeneration which is a hallmark of hereditary sensory and autonomic neuropathies (HSANs). Although mutations in several genes were previously associated with sensory neurodegeneration, the etiology of many cases remains unknown. Using next generation sequencing in patients with congenital loss of pain perception, we here identify bi-allelic mutations in the FLVCR1 (Feline Leukemia Virus subgroup C Receptor 1) gene, which encodes a broadly expressed heme exporter. Different FLVCR1 isoforms control the size of the cytosolic heme pool required to sustain metabolic activity of different cell types. Mutations in FLVCR1 have previously been linked to vision impairment and posterior column ataxia in humans, but not to HSAN. Using fibroblasts and lymphoblastoid cell lines from patients with sensory neurodegeneration, we here show that the FLVCR1-mutations reduce heme export activity, enhance oxidative stress and increase sensitivity to programmed cell death. Our data link heme metabolism to sensory neuron maintenance and suggest that intracellular heme overload causes early-onset degeneration of pain-sensing neurons in humans.

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Section: Introductionmentioning

confidence: 99%

Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception

et al. 2016

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“…Based on nerve conduction velocities, the disease can be divided into demyelinating CMT disease (CMT1), axonal CMT disease (CMT2) and intermediate CMT disease [2]. There is wide clinical heterogeneity among patients [3]. In general, patients with CMT disease experience slowly progressive weakness and wasting in the distal muscles, orthopedic abnormalities and sensory losses of temperature, touch and pain [1].…”

Section: Introductionmentioning

confidence: 99%

Psychoacoustics and neurophysiological auditory processing in patients with Charcot‐Marie‐Tooth disease types 1A and 2A

Choi

Seol

Seok

et al. 2020

Euro J of Neurology

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Background and purpose Hidden hearing loss has been reported in patients with Charcot‐Marie‐Tooth (CMT) disease; however, the auditory‐processing deficits have not been widely explored. We investigated the psychoacoustic and neurophysiological aspects of auditory processing in patients with CMT disease type 1A (CMT1A) and type 2A (CMT2A). Methods A total of 43 patients with CMT1A and 15 patients with CMT2A were prospectively enrolled. All patients with CMT disease had normal sound‐detection ability by using pure‐tone audiometry. Spectral‐ripple discrimination, temporal modulation detection and auditory frequency‐following response were compared between CMT1A, CMT2A and control groups. Results Although all participants had normal audiograms, patients with CMT disease had difficulty understanding speech in noise. The psychoacoustic auditory processing was somewhat different depending on the underlying pathophysiology of CMT disease. Patients with CMT1A had degraded auditory temporal and spectral processing. Patients with CMT2A had no reduced spectral resolution, but they showed further reduced temporal resolution than the patients with CMT1A. The amplitudes of the frequency‐following response were reduced in patients with CMT1A and CMT2A, but the neural timing remained relatively intact. Conclusions When we first assessed the neural representation to speech at the brainstem level, the grand average brainstem responses were reduced in both patients with CMT1A and CMT2A compared with healthy controls. As the psychoacoustic aspects of auditory dysfunctions in CMT1A and CMT2A were somewhat different, it is necessary to consider future auditory rehabilitation methods based on their pathophysiology.

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“…Therefore, the concept of intermediate CMT with mMNCVs of 25 to 45 m/s appeared in the 1970s and has recently become more popular due to the importance of direct genetic diagnosis [5] .…”

Section: Introductionmentioning

confidence: 99%

Intermediate Charcot-Marie-Tooth disease

Liu

Zhang

2014

Neurosci. Bull.

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Charcot-Marie-Tooth (CMT) disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria: very slow motor nerve conduction velocity (MNCV) (<15 m/s), slow MNCV (15-25 m/s), intermediate MNCV (25-45 m/s), and normal MNCV (>45 m/s). Based on the inheritance pattern, intermediate CMT can be divided into dominant (DI-CMT) and recessive types (RI-CMT). GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identifi cation of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.

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Inherited Neuropathies

Cited by 36 publications

References 93 publications

Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception

Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception

Psychoacoustics and neurophysiological auditory processing in patients with Charcot‐Marie‐Tooth disease types 1A and 2A

Intermediate Charcot-Marie-Tooth disease

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