Charcot-Marie-Tooth neuropathy type 4D (CMT4D) is a rare genetic disorder of the peripheral nervous system caused by biallelic mutations in the N-Myc Downstream Regulated 1 gene (NDRG1). Patients present with an early onset demyelinating peripheral neuropathy causing severe distal muscle weakness and sensory loss, leading to loss of ambulation and progressive sensorineural hearing loss. The disorder was initially described in the Roma community due to a common founder mutation, and only a handful of disease-causing variants have been described in this gene so far. Here, we present genetic and clinical findings from a large Bulgarian cohort of demyelinating CMT patients harboring recurrent and novel variants in the NDRG1 gene. Notably, two splice-site variants are exclusive to Bulgarian Muslims and reside in ancestral haplotypes, suggesting a founder effect. Functional characterization of these novel variants implicates a loss-of-function mechanism due to shorter gene products. Our findings contribute to a deeper understanding of the genetic and clinical heterogeneity of CMT4D and highlight novel founder mutations in the ethnic minority of Bulgarian Muslims.

BACKGROUND: Potassium ion channels play a crucial role in maintaining cellular electrical stability and are implicated in various epilepsies. Heterozygous pathogenic variants in KCNK4 cause a recognizable neurodevelopmental syndrome with facial dysmorphism, hypertrichosis, epilepsy, intellectual disability (ID), and gingival overgrowth (FHEIG). To date, no more than nine patients with FHEIG have been described worldwide and still little is known about epileptic phenotype in KCNK4-related disease.
METHODS: We identified a novel de novo p.(Gly139Arg) variant in KCNK4 in a patient with drug-resistant nocturnal seizures, mild ID, and dysmorphic features. In silico analyses of the variant strongly suggest a gain-of-function effect. We conducted a retrospective review of previously published cases, focusing on the epileptic features and response to various treatments.
RESULTS: To date, epilepsy has been reported in 8/10 patients with KCNK4-related disease. The mean age of seizure onset was 1.8 years, and the most common seizure type was focal to bilateral tonic-clonic (5/8). Sodium channel blockers and valproate were effective in the majority of patients, but in 3/8 the epilepsy was drug-resistant. Our patient showed improved seizure control after treatment with the carbonic anhydrase inhibitor sulthiame. Interestingly, the patient showed features of peripheral nerve hyperexcitability syndrome, a phenomenon not previously described in potassium channelopathies caused by increased K+ conductance.
CONCLUSIONS: Gain-of-function variants in KCNK4 cause a spectrum of epilepsies, ranging from benign isolated epilepsy to epileptic encephalopathy, with focal to bilateral tonic-clonic seizures being the most commonly observed. Importantly, a subgroup of patients present with a mild extra-neurological phenotype without characteristic facial dysmorphism or generalized hypertrichosis. This report expands the phenotypic spectrum of KNCK4-associated disease and provides new insights into the clinical heterogeneity of this rare neurodevelopmental syndrome.

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Elevated plasma concentrations of neural cell adhesion molecule 1 (NCAM1) and p75 neurotrophin receptor (p75) in patients with peripheral neuropathy have been reported. This study aimed to determine the specificity of plasma concentration elevation of either NCAM1 or p75 in a subtype of Charcot-Marie-Tooth disease (CMT) and its correlation with pathologic nerve status and disease severity.
Blood samples were collected from 138 patients with inherited peripheral neuropathy and 51 healthy controls. Disease severity was measured using Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), and plasma concentrations of NCAM1 and p75 were analyzed by enzyme-linked immunosorbent assay. Eight sural nerves from CMT patients were examined to determine the relation of histopathology and plasma NCAM1 levels.
Plasma concentration of NCAM1, but not p75, was specifically increased in demyelinating subtypes of CMT (median = 7100 pg/mL, p < 0.001), including CMT1A, but not in axonal subtype (5964 pg/mL, p > 0.05), compared to the control (3859 pg/mL). CMT1A patients with mild or moderate severity (CMTNSv2 < 20) showed higher levels of plasma NCAM1 than healthy controls. Immunofluorescent NCAM1 staining for the sural nerves of CMT patients showed that NCAM1-positive onion bulb cells and possible demyelinating Schwann cells might be associated with the specific increase of plasma NCAM1 in demyelinating CMT.
The plasma NCAM1 levels in demyelinating CMT might be a surrogate biomarker reflecting pathological Schwann cell status and disease progression.

The myelin sheath is an essential structure for the rapid transmission of electrical impulses through axons, and peripheral myelination is a well-programmed postnatal process of Schwann cells (SCs), the myelin-forming peripheral glia. SCs transdifferentiate into demyelinating SCs (DSCs) to remove the myelin sheath during Wallerian degeneration after axonal injury and demyelinating neuropathies, and macrophages are responsible for the degradation of myelin under both conditions. In this study, the mechanism by which DSCs acquire the ability of myelin exocytosis was investigated. Using serial ultrastructural evaluation, we found that autophagy-related gene 7-dependent formation of a \"secretory phagophore (SP)\" and tubular phagophore was necessary for exocytosis of large myelin chambers by DSCs. DSCs seemed to utilize myelin membranes for SP formation and employed p62/sequestosome-1 (p62) as an autophagy receptor for myelin excretion. In addition, the acquisition of the myelin exocytosis ability of DSCs was associated with the decrease in canonical autolysosomal flux and was demonstrated by p62 secretion. Finally, this SC demyelination mechanism appeared to also function in inflammatory demyelinating neuropathies. Our findings show a novel autophagy-mediated myelin clearance mechanism by DSCs in response to nerve damage.

Epidermal nerve fiber involvement in chronic inflammatory demyelinating neuropathy (CIDP) has been reported in a limited number of patients. We quantified small-fiber involvement in a mixed cohort of patients with typical CIDP and CIDP variants to evaluate relationships with clinical outcome measures at different disease stages.
Intraepidermal nerve fiber densities (IENFDs) were evaluated by skin punch biopsies of 23 patients with CIDP and 13 healthy controls at the forearm, thigh, and distal leg. Skin sections were optimally interpreted in all three regions in 16 CIDP patients and 10 age- and sex-matched healthy controls. Statistical analysis was performed in these subjects.
The IENFDs in forearm, thigh, and distal leg were similar among seven typical CIDP and nine CIDP variants. IENFDs in those regions were significantly reduced in CIDP compared with healthy controls, with a moderate negative correlation with scores on the International Neuropathy Cause and Treatment (INCAT) Upper Limb Functional Disability Scale. The reduction in IENFD compared with controls was more remarkable in the distal leg. In clinically unstable CIDP patients, the IENFDs of distal leg and forearm were significantly reduced compared with stable CIDP patients and controls. Stable CIDP patients had significantly reduced IENFDs in distal leg and forearm compared with controls.
In this exploratory study, we confirm that small fibers are also affected in CIDP. Larger studies are needed to explore longitudinal changes of IENFD in CIDP and its relation to disease stage.

Demyelinating forms of Charcot-Marie-Tooth disease (CMT) are genetically and phenotypically heterogeneous and result from highly diverse biological mechanisms including gain of function (including dominant negative effects) and loss of function. While no definitive treatment is currently available, rapid advances in defining the pathomechanisms of demyelinating CMT have led to promising pre-clinical studies, as well as emerging clinical trials. Especially promising are the recently completed pre-clinical genetic therapy studies in PMP-22, GJB1, and SH3TC2-associated neuropathies, particularly given the success of similar approaches in humans with spinal muscular atrophy and transthyretin familial polyneuropathy. This article focuses on neuropathies related to mutations in PMP-22, MPZ, and GJB1, which together comprise the most common forms of demyelinating CMT, as well as on select rarer forms for which promising treatment targets have been identified. Clinical characteristics and pathomechanisms are reviewed in detail, with emphasis on therapeutically targetable biological pathways. Also discussed are the challenges facing the CMT research community in its efforts to advance the rapidly evolving biological insights to effective clinical trials. These considerations include the limitations of currently available animal models, the need for personalized medicine approaches/allele-specific interventions for select forms of demyelinating CMT, and the increasing demand for optimal clinical outcome assessments and objective biomarkers.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies, which are subdivided into demyelinating and axonal forms. Biallelic mutations in POLR3B are the well-established cause of hypomyelinating leukodystrophy, which is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. To date, only one study has reported the demyelinating peripheral neuropathy phenotype caused by heterozygous POLR3B variants.
METHODS: A 19-year-old male patient was referred to our hospital for progressive muscle weakness of the lower extremities. Physical examination showed muscle atrophy, sensory loss and deformities of the extremities. Nerve conduction studies and electromyography tests revealed sensorimotor demyelinating polyneuropathy with secondary axonal loss. Trio whole-exome sequencing revealed a de novo variant in POLR3B (c.3137G > A).
CONCLUSIONS: In this study, we report the case of a Chinese patient with a de novo variant in POLR3B (c.3137G > A), who manifested demyelinating CMT phenotype without additional neurological or extra-neurological involvement. This work is the second report on POLR3B-related CMT.

This article focuses on principles of nerve conduction studies and needle electromyography applied to the electrodiagnosis of polyneuropathy. The components of the electrodiagnostic evaluation of polyneuropathy and the electrophysiological characteristics of axonal and demyelinating neuropathies and nodo-paranodopathies are reviewed.

BACKGROUND: Point mutations in the Peripheral Myelin Protein 22 (PMP22) gene comprise less than 5% of the Charcot-Marie-Tooth (CMT) type 1 cases, and individualize either the CMT 1E subtype, or Hereditary Neuropathy with Liability to Pressure Palsy. The phenotype of CMT 1E presents with a severe early-onset polyneuropathy associated with deafness, although the clinical spectrum is broad.
METHODS: We describe a novel PMP22 gene point mutation (c.84G>T;p.(Trp28Cys)) in three patients of a Portuguese family with variable phenotypes, ranging from asymptomatic to mild complaints of distal limb numbness and gait difficulties, with the age of onset of symptoms ranging from mid-twenties to late-sixties, and no associated disability. In all affected patients, there was evidence of diffuse demyelinating sensorimotor polyneuropathy. Hearing loss does not seem to be associated with this variant, albeit neuropathic pain was reported.
CONCLUSIONS: These findings suggest that this particular point mutation in the PMP22 gene is associated with a mild phenotype, further emphasizing that there are still unknown mechanisms (genetic and/or epigenetic) that may play a role in the clinical spectrum of CMT1E patients. Next generation sequencing panels including commonly mutated genes in CMT should be considered in CMT1 cases negative for PMP22 gene duplication.