Characterization of a novel heterozygous variant in the histidyl-tRNA synthetase gene associated with Charcot-Marie-Tooth disease type 2W.

Heterozygous pathogenic variants in the histidyl-tRNA synthetase (HARS) gene are associated with Charcot-Marie-Tooth (CMT) type 2W disease, classified as an axonal peripheral neuropathy. To date, at least 60 variants causing CMT symptoms have been identified in seven different aminoacyl-tRNA synthetases, with eight being found in the catalytic domain of HARS. The genetic data clearly show a causative role of aminoacyl-tRNA synthetases in CMT; however, the cellular mechanisms leading to pathology can vary widely and are unknown in the case of most identified variants. Here we describe a novel HARS variant, c.412T>C; p.Y138H, identified through a CMT gene panel in a patient with peripheral neuropathy. To determine the effect of p.Y138H we employed a humanized HARS yeast model and recombinant protein biochemistry, which identified a deficiency in protein dimerization and a growth defect which shows mild but significant improvement with histidine supplementation. This raises the potential for a clinical trial of histidine.

A Novel m.1636A > G Variant in Mitochondrial TV Gene Might Cause New Phenotype of Mitochondrial Disease in a 2-Year Old Chinese Boy.

Pathogenic variants of mitochondrial DNA (mtDNA) are associated with a large number of heterogeneous diseases involving multiple systems with which patients may present with a wide range of clinical phenotypes. Clinical data of the proband and his family members were gathered in a retrospective study. Whole-exome sequencing and full-length sequencing of the mitochondrial genome that was performed on peripheral blood, urine, and oral mucosa cells were applied for genetic analysis. In this study, we describe a 2-year-old Chinese boy with global developmental delay, Charcot-Marie-Tooth (CMT) disease, progressive myoclonic epilepsy, paroxysmal arrhythmia, and brain atrophy with elevated blood lactate levels. The clinical manifestations of the patient were improved after metabolic therapy, but the development regressed after infection. The molecular finding of whole-exome sequencing is unremarkable, but the mtDNA genome sequencing of the proband and his monther revealed a de novo novel heteroplasmic variant, m.1636A > G, located next to the highly conserved anticodon loop of tRNA Val (MT-TV) gene. Moreover, the higher levels of mutational load in urinary epithelial cells (19.05%) and oral mucosa cells (20.8%) were detected than that in blood (17.4%). Combined with the phenotypic and molecular genetics analysis of this family, this novel variation was currently considered to be a likely pathogenic variant. Our results added evidence that the de novo m.1636A > G variation in the highly conserved sequence of MT-TV appears to suggest a childhood-onset mitochondrial phenotype of a 2-year-old patient, thus broaden the genotypic interpretation of mitochondrial DNA-related disease.

Hereditary spastic paraplegia and extensive leukoencephalopathy: a case report of a unique phenotype associated with a GJB1/Cx32 p.Pro174Ser variant.

BACKGROUND: Pathogenic variants in Gap junction protein beta 1 (GJB1), which encodes Connexin 32, are known to cause X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT. CMTX presents with the following five central nervous systems (CNS) phenotypes: subclinical electrophysiological abnormalities, mild fixed abnormalities on neurological examination and/or imaging, transient CNS dysfunction, cognitive impairment, and persistent CNS manifestations. CASE PRESENTATION: A 40-year-old Japanese male showed CNS symptoms, including nystagmus, prominent spastic paraplegia, and mild cerebellar ataxia, accompanied by subclinical peripheral neuropathy. Brain magnetic resonance imaging revealed hyperintensities in diffusion-weighted images of the white matter, particularly along the pyramidal tract, which had persisted since childhood. Nerve conduction assessment showed a mild decrease in motor conduction velocity, and auditory brainstem responses beyond wave II were absent. Peripheral and central conduction times in somatosensory evoked potentials elicited by stimulation of the median nerve were prolonged. Genetic analysis identified a hemizygous GJB1 variant, NM_000166.6:c.520C > T p.Pro174Ser. CONCLUSIONS: The patient in the case described here, with a GJB1 p.Pro174Ser variant, presented with a unique CNS-dominant phenotype, characterized by spastic paraplegia and persistent extensive leukoencephalopathy, rather than CMTX. Similar phenotypes have also been observed in patients with GJC2 and CLCN2 variants, likely because of the common function of these genes in regulating ion and water balance, which is essential for maintaining white matter function. CMTX should be considered within the spectrum of GJB1-related disorders, which can include patients with predominant CNS symptoms, some of which can potentially be classified as a new type of spastic paraplegia.

The recovery cycle of excitability assessed by a conventional electrodiagnostic machine: A study in healthy volunteers and in Charcot-Marie-Tooth 1A patients.

OBJECTIVE: To validate the 'paired pulses' technique with a conventional electrodiagnostic machine (CEM) for studying the axonal excitability recovery cycle (ERC). METHODS: Paired pulses, with a variable inter-stimulus interval, were delivered at the wrist along the median nerve. The CEM repeatability was verified in a group of 15 healthy volunteers (test/retest analysis). ERC was then applied in 40 healthy volunteers and 10 patients with Charcot-Marie-Tooth type 1A (CMT1A), using both the threshold tracking (TT) reference method and CEM (basal condition, during and after ischemia). RESULTS: CEM parameters evaluating absolute refractory and supernormal periods were reproducible (interclass correlation coefficient > 0.75). CEM results were consistent with TT method and literature data. In CMT1A, refractory and superexcitable periods were significantly reduced. According to receiving operator characteristic analysis, the CEM supernormal period area was the most relevant parameter for discriminating CMT1A from healthy volunteers (area under the curve = 0.98). CONCLUSIONS: CEM was a valid procedure for studying ERC. CMT1A patients exhibited ERC alterations due to modifications in passive membrane properties and of nodal ion channel distribution resulting from demyelination. SIGNIFICANCE: Studying ERC with CEM could be performed in routine practice in patients with peripheral neuropathies to provide information on motor axonal excitability.

A Case of Charcot-Marie-Tooth Disease Causing Colitis and Electrolyte Imbalances.

Peripheral nerve injury is a result of the rare and crippling Charcot-Marie-Tooth (CMT) disease. Although it can happen at any age, progressive muscle weakening is most obvious in adolescence or the early stages of adulthood. We present a case of an 81-year-old female with recurrent urinary tract infections (UTIs), complaints of abdominal pain and constipation, as well as dysuria with abnormal electrolyte levels. This case serves as an effective symptomatic treatment plan for a patient with this rare neuromuscular disorder.

Optical Genome Mapping Identifies a Second Xq27.1 Rearrangement Associated With Charcot-Marie-Tooth Neuropathy CMTX3.

BACKGROUND: X-linked recessive type 3 Charcot-Marie-Tooth (CMTX3) is a rare subtype of childhood-onset CMT. To date, all reported CMTX3 patients share a common founder 78 kb insertion from chromosome 8 into the Xq27.1 palindrome region. METHODS: We conducted patient-parent trio optical genome mapping (OGM) on a male patient presenting with clinically diagnosed Dejerine-Sottas disease for whom initial standard diagnostic genetic tests, including whole-genome sequencing (WGS), yielded negative results. RESULTS: OGM analysis revealed a maternally inherited interchromosomal insertion from chromosome region 7q31.1 into Xq27.1. Coupled with manual reassessment of WGS data, this confirmed the molecular diagnosis of atypical CMTX3 and showed that the 122.4 kb inserted fragment contained DLD and partially LAMB1. Subsequent analyses confirmed that the rearrangement had arisen de novo in the proband's mother. CONCLUSION: We report the second Xq27.1 rearrangement associated with CMTX3, providing novel clinical insights into its phenotypic and genotypic spectrum. Our findings highlight the importance of including genomic rearrangement analysis of Xq27.1 in standard diagnostic pipelines for childhood-onset CMT. Given the overlap in polyneuropathy phenotypes resulting from insertions from chromosomes 7 and 8 into the same Xq27.1 palindrome region, the pathogenic mechanism underlying peripheral neuropathy in CMTX3 likely involves dysregulation of genes within this region.

The effect of ankle-foot orthoses on gait characteristics in people with Charcot-Marie-Tooth disease: A systematic review and meta-analysis.

INTRODUCTION: Ankle-foot orthoses (AFOs) are commonly prescribed for people with Charcot-Marie-Tooth disease (CMT) to improve gait efficiency and reduce the occurrence of tripping and falls. The aim of this study was to systematically review evidence on the effects of AFOs on gait kinematics and kinetics and postural stability/balance in people with CMT. METHODS: Studies were identified from electronic databases and screened for inclusion online using Rayyan. Data from all eligible studies were extracted into a standardised Excel spreadsheet. Methodological quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklists. Where available, continuous outcomes were pooled to estimate standardised mean differences in random-effects meta-analyses. RESULTS: A total of 15 studies were included with variable methodological quality. Sample sizes ranged from 1 to 32 with significant variability in participant characteristics, AFO designs and testing procedures. Data from eight studies were available for meta-analysis. Although AFOs impacted walking velocity, stride length, step length, cadence, ankle dorsiflexion, plantarflexion, knee and hip flexion and ankle plantarflexion and dorsiflexion moments, the effect sizes were small-to-moderate and non-significant. There were insufficient data available for pooled analyses of outcomes related to postural stability/balance. CONCLUSION: Although AFOs positively affect a number of gait and balance parameters, the small participant numbers, variability in participant characteristics, AFO designs and testing procedures adopted by the available studies resulted in the absence of statistically significant effects when data were pooled. The results from this review also highlight the importance of device customisation based on the individual needs of people with CMT and their degree of gait impairment.

Pharmacological Doses of Thiamine Benefit Patients with the Charcot-Marie-Tooth Neuropathy by Changing Thiamine Diphosphate Levels and Affecting Regulation of Thiamine-Dependent Enzymes.

Charcot-Marie-Tooth (CMT) neuropathy is a polygenic disorder of peripheral nerves with no effective cure. Thiamine (vitamin B1) is a neurotropic compound that improves neuropathies. Our pilot study characterizes therapeutic potential of daily oral administration of thiamine (100 mg) in CMT neuropathy and its molecular mechanisms. The patient hand grip strength was determined before and after thiamine administration along with the blood levels of the thiamine coenzyme form (thiamine diphosphate, ThDP), activities of endogenous holo-transketolase (without ThDP in the assay medium) and total transketolase (with ThDP in the assay medium), and transketolase activation by ThDP [1 - (holo-transketolase/total transketolase),%], corresponding to the fraction of ThDP-free apo-transketolase. Single cases of administration of sulbutiamine (200 mg) or benfotiamine (150 mg) reveal their effects on the assayed parameters within those of thiamine. Administration of thiamine or its pharmacological forms increased the hand grip strength in the CMT patients. Comparison of the thiamin status in patients with different forms of CMT disease to that of control subjects without diagnosed pathologies revealed no significant differences in the average levels of ThDP, holo-transketolase, or relative content of holo and apo forms of transketolase. However, the regulation of transketolase by thiamine/ThDP differed in the control and CMT groups: in the assay, ThDP activated transketolase from the control individuals, but not from CMT patients. Thiamine administration paradoxically decreased endogenous holo-transketolase in CMT patients; this effect was not observed in the control group. Correlation analysis revealed sex-specific differences in the relationship between the parameters of thiamine status in both the control subjects and patients with the CMT disease. Thus, our findings link physiological benefits of thiamine administration in CMT patients to changes in their thiamine status, in particular, the blood levels of ThDP and transketolase regulation.

Charcot-Marie-Tooth Disease With Leukodystrophy: An Atypical Presentation.

This case report presents a 23-year-old male diagnosed with Charcot-Marie-Tooth (CMT) disease, who exhibited additional neurological symptoms suggestive of leukodystrophy. The patient experienced recurrent episodes of slurred speech, imbalance, and a recent tonic-clonic seizure, prompting admission. Neurological examination and imaging revealed bilateral white matter changes, raising suspicion of leukoencephalopathy. Further investigations confirmed a nonsense mutation c.64C>T (p.Arg22*) in the gap junction beta 1 (GJB1) gene. This case underscores the complexity of Charcot-Marie-Tooth disease type 1 (CMTX1) with atypical central nervous system (CNS) manifestations, highlighting the importance of comprehensive diagnostic evaluations and a multidisciplinary approach to management.

Corrigendum: Case report: Chronic inflammatory demyelinating polyneuropathy superimposed on Charcot-Marie-tooth type 1A disease after SARS-CoV-2 vaccination and COVID-19 infection.

[This corrects the article DOI: 10.3389/fneur.2024.1358881.].

Noninvasive ventilation and laser-assisted unilateral posterior cordotomy as novel multidisciplinary approaches for Charcot-Marie-Tooth disease 4B vocal cord paralysis: a case report.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neuropathies. The disease is generally characterized by sensory loss most prominent in distal extremities, muscle weakness, and muscle wasting. There is still no effective therapy for Charcot-Marie-Tooth disease. CASE PRESENTATION: The patient is a 6-year-old Iranian girl, of Fars ethnicity, who was admitted with a chief complaint of hoarseness and an impression of Charcot-Marie-Tooth disease type 4B. She was initially treated with noninvasive ventilation and, after a year, electively underwent cordotomy as a novel therapeutic approach. CONCLUSIONS: Charcot-Marie-Tooth disease type 4B is a less common but important cause of stridor. Noninvasive ventilation treatment and unilateral posterior cordotomy can be utilized for hereditary neuropathies.

Rotating Hinge Knee Arthroplasty for Charcot Joints of the Knees in Patients With Charcot-Marie-Tooth Disease: A Report of Two Cases.

We report two cases wherein rotating hinge knee (RHK) arthroplasty was performed for Charcot joints that developed secondary to Charcot-Marie-Tooth disease (CMT).  Case 1 was of a 74-year-old woman with CMT. She presented with muscle weakness and sensory disturbances of the distal lower limbs, deformity, and significant medial instability of the bilateral knees. She was then diagnosed with Charcot joints of the knees secondary to CMT, which were treated with RHK arthroplasty. Five years postoperatively, there was no instability, and she was able to stand unassisted without pain. Case 2 was a 90-year-old woman with CMT who presented with muscle weakness and sensory disturbances of the distal lower limbs, deformity, and significant medial instability of the bilateral knees. She was then diagnosed with Charcot joints of the knees secondary to CMT, which were also treated with RHK arthroplasty. One year postoperatively, there was no instability, and she was able to walk smoothly using a walker. These clinical cases indicate that RHK arthroplasty can be a good therapeutic option for Charcot joints of the knees in patients with CMT.

Roles for PMP22 in Schwann cell cholesterol homeostasis in health and disease.

Underexpression, overexpression, and point mutations in peripheral myelin protein 22 (PMP22) cause most cases of Charcot-Marie-Tooth disease (CMTD). While its exact functions remain unclear, PMP22 is clearly essential for formation and maintenance of healthy myelin in the peripheral nervous system. This review explores emerging evidence for roles of PMP22 in cholesterol homeostasis. First, we highlight dysregulation of lipid metabolism in PMP22-based forms of CMTD and recently-discovered interactions between PMP22 and cholesterol biosynthesis machinery. We then examine data that demonstrates PMP22 and cholesterol co-traffic in cells and co-localize in lipid rafts, including how disease-causing PMP22 mutations result in aberrations in cholesterol localization. Finally, we examine roles for interactions between PMP22 and ABCA1 in cholesterol efflux. Together, this emerging body of evidence suggests that PMP22 plays a role in facilitating enhanced cholesterol synthesis and trafficking necessary for production and maintenance of healthy myelin.

Insights into phenotypic variability caused by GARS1 pathogenic variants.

BACKGROUND AND PURPOSE: Pathogenic variants of the glycyl-tRNA synthetase 1 (GARS1) gene have been described as a cause of Charcot-Marie-Tooth disease type 2D, motor axonal neuropathy with upper limb predominance (distal hereditary motor neuropathy [dHMN] type V), and infantile spinal muscular atrophy. METHODS: This cross-sectional, retrospective, observational study was carried out on 12 patients harboring the c.794C>T (p.Ser265Phe) missense pathogenic variant in GARS1. The patients' clinical data, nerve conduction studies, magnetic resonance imaging (MRI), and intraepidermal nerve fiber density in skin biopsies were reviewed. RESULTS: The mean age at onset was 9.5 years; the intrinsic hand muscles were affected before or at the same time as the distal leg musculature. The clinical examination revealed greater weakness of the distal muscles, with a more pronounced involvement of the thenar complex and the first dorsal interosseous in upper limbs. Electrophysiological studies were concordant with an exclusively motor axonal neuropathy. A pathologic split hand index was found in six patients. Muscle MRI showed predominant fatty infiltration and atrophy of the anterolateral and superficial posterior compartment of the legs. Most patients reported distal pinprick sensory loss. A reduced intraepidermal nerve fiber density was evident in skin biopsies from proximal and distal sites in nine patients. CONCLUSIONS: GARS1 variants may produce a dHMN phenotype with "split hand" and sensory disturbances, even when sensory nerve conduction studies are normal. This could be explained by a dysfunction of sensory neurons in the dorsal ganglion that is reflected as a reduction of dermal nerve endings in skin biopsies without a distal gradient.

Combined clinical, structural, and cellular studies discriminate pathogenic and benign TRPV4 variants.

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias, and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear. Here, we used a combination of clinical information and experimental structure-function analyses to evaluate 30 TRPV4 variants across various functional protein domains. We report clinical features of seven patients with TRPV4 variants of unknown significance and provide extensive functional characterization of these and an additional 17 variants, including structural position, ion channel function, subcellular localization, expression level, cytotoxicity, and protein-protein interactions. We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity. We further identify a cluster of gain-of-function variants within the intracellular intrinsically disordered region that may cause toxicity via altered interactions with membrane lipids. In contrast, assessed variants in the transmembrane domain and other regions of the intrinsically disordered region do not cause gain of function and are likely benign. Clinical features associated with gain of function and cytotoxicity include congenital onset of disease, vocal cord weakness, and motor predominant disease, whereas patients with likely benign variants often demonstrated late-onset and sensory-predominant disease. These results provide a framework for assessing additional TRPV4 variants with respect to likely pathogenicity, which will yield critical information to inform patient selection for future clinical trials for TRPV4 channelopathies.

Spatial selectivity of ATase inhibition in mouse models of Charcot-Marie-Tooth disease.

The endoplasmic reticulum acetylation machinery has emerged as a new branch of the larger endoplasmic reticulum quality control system. It regulates the selection of correctly folded polypeptides as well as reticulophagy-mediated removal of toxic protein aggregates with the former being a particularly important aspect of the proteostatic functions of endoplasmic reticulum acetylation. Essential to this function is the Nε-lysine acetyltransferase activity of acetyltransferase 1 and acetyltransferase 2, which regulates the induction of endoplasmic reticulum-specific autophagy through the acetylation of the autophagy-related protein 9A. Here, we used three mouse models of Charcot-Marie-Tooth disease, peripheral myelin protein 22/Tr-J, C3-peripheral myelin protein 22 and myelin protein zero/ttrr, to study spatial and translational selectivity of endoplasmic reticulum acetyltransferase inhibitors. The results show that inhibition of the endoplasmic reticulum acetyltransferases selectively targets misfolding/pro-aggregating events occurring in the lumen of the organelle. Therefore, they establish acetyltransferase 1 and acetyltransferase 2 as the first proven targets for disease-causing proteotoxic states that initiate within the lumen of the endoplasmic reticulum/secretory pathway.

Identification of a Novel Homozygous Mutation in MTMR2 Gene Causes Very Rare Charcot-Marie-Tooth Disease Type 4B1.

Background: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders involving peripheral nervous system. Charcot-Marie-Tooth disease 4B1 (CMT4B1) is a rare subtype of CMT. CMT4B1 is an axonal demyelinating polyneuropathy with an autosomal recessive mode of inheritance. Patients with CMT4B1 usually manifested with dysfunction of the motor and sensory systems which leads to gradual and progressive muscular weakness and atrophy, starting from the peroneal muscles and finally affecting the distal muscles. Germline mutations in MTMR2 gene causes CMT4B1. Material and Methods: In this study, we investigated a 4-year-old Chinese boy with gradual and progressive weakness and atrophy of both proximal and distal muscles. The proband's parents did not show any abnormalities. Whole-exome sequencing and Sanger sequencing were performed. Results: Whole-exome sequencing identified a novel homozygous nonsense mutation (c.118A>T; p.Lys40*) in exon 2 of MTMR2 gene in the proband. This novel mutation leads to the formation of a truncated MTMR2 protein of 39 amino acids instead of the wild- type MTMR2 protein of 643 amino acids. This mutation is predicted to cause the complete loss of the PH-GRAM domain, phosphatase domain, coiled-coil domain, and PDZ-binding motif of the MTMR2 protein. Sanger sequencing revealed that the proband's parents carried the mutation in a heterozygous state. This mutation was absent in 100 healthy control individuals. Conclusion: This study reports the first mutation in MTMR2 associated with CMT4B1 in a Chinese population. Our study also showed the importance of whole-exome sequencing in identifying candidate genes and disease-causing variants in patients with CMT4B1.

A recurrent missense variant in ITPR3 causes demyelinating Charcot-Marie-Tooth with variable severity.

Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically ∼80-95%, of which at least 60% is due to the PMP22 gene duplication. The remainder of CMT1 is more genetically heterogeneous. We used whole exome and whole genome sequencing data included in the GENESIS database to investigate novel causal genes and mutations in a cohort of ∼2,670 individuals with CMT neuropathy. A recurrent heterozygous missense variant p.Thr1424Met in the recently described CMT gene ITPR3, encoding IP3R3 (inositol 1,4,5-trisphosphate receptor 3) was identified. This previously reported p.Thr1424Met change was present in 33 affected individuals from nine unrelated families from multiple populations, representing an unusual recurrence rate at a mutational hotspot, strengthening the gene-disease relationship (GnomADv4 allele frequency 1.76e-6). Sanger sequencing confirmed the co-segregation of the CMT phenotype with the presence of the mutation in autosomal dominant and de novo inheritance patterns, including a four-generation family with multiple affected second-degree cousins. Probands from all families presented with slow nerve conduction velocities, matching the diagnostic category of CMT1. Remarkably, we observed a uniquely variable clinical phenotype for age at onset and phenotype severity in p.Thr1424Met carrying patients, even within families. Finally, we present data supportive of a dominant-negative effect of the p.Thr1424Met mutation with associated changes in protein expression in patient-derived cells.

TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT examination scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT1A patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%), and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction, and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness, and respiratory disease.

INF2 formin variants linked to human inherited kidney disease reprogram the transcriptome, causing mitotic chaos and cell death.

Mutations in the human INF2 gene cause autosomal dominant focal segmental glomerulosclerosis (FSGS)-a condition characterized by podocyte loss, scarring, and subsequent kidney degeneration. To understand INF2-linked pathogenicity, we examined the effect of pathogenic INF2 on renal epithelial cell lines and human primary podocytes. Our study revealed an increased incidence of mitotic cells with surplus microtubule-organizing centers fostering multipolar spindle assembly, leading to nuclear abnormalities, particularly multi-micronucleation. The levels of expression of exogenous pathogenic INF2 were similar to those of endogenous INF2. The aberrant nuclear phenotypes were observed regardless of the expression method used (retrovirus infection or plasmid transfection) or the promoter (LTR or CMV) used, and were absent with exogenous wild type INF2 expression. This indicates that the effect of pathogenic INF2 is not due to overexpression or experimental cell manipulation, but instead to the intrinsic properties of pathogenic INF2. Inactivation of the INF2 catalytic domain prevented aberrant nuclei formation. Pathogenic INF2 triggered the translocation of the transcriptional cofactor MRTF into the nucleus. RNA sequencing revealed a profound alteration in the transcriptome that could be primarily attributed to the sustained activation of the MRTF-SRF transcriptional complex. Cells eventually underwent mitotic catastrophe and death. Reducing MRTF-SRF activation mitigated multi-micronucleation, reducing the extent of cell death. Our results, if validated in animal models, could provide insights into the mechanism driving glomerular degeneration in INF2-linked FSGS and may suggest potential therapeutic strategies for impeding FSGS progression.