Background Heterozygous variants in SLC12A6 have recently been shown to cause dominant Charcot-Marie-Tooth disease (CMT). We aim to characterise the phenotype of patients with previously reported and novel heterozygous variants in the gene and understand any genotype-phenotype correlation.Methods Patients were clinically and genetically assessed in sites from Europe, Australia, Brazil and the USA. All patients underwent whole exome or whole genome sequencing. Variants were classified using American College of Medical Genetics and Genomics criteria.Results Twenty-three individuals from 13 families carried nine variants classified either as pathogenic/likely pathogenic or variants of uncertain significance segregating in multiple family members, including five novel variants. Forty-eight percent (11/23) were male with a mean age of disease onset of 15.7 years (range 1-45 years). Clinical phenotype varied dramatically with genotype; Arg207His and Ser647Pro caused a severe childhood-onset, sensory and motor, conduction-slowing neuropathy, whereas Gly552Asp caused a mild, adult-onset, sensory-predominant neuropathy, Thr991Ala an infantile-onset motor neuropathy, and the Met282Lys/Gly286Cys locus a complex, axonal neuropathy.Conclusions Heterozygous variants in SLC12A6 can cause CMT of all clinical phenotypes, severity and age of onset, depending on the genotype. Such phenotypic diversity has not been described for any other CMT gene, and more work is needed to understand disease mechanisms to guide future therapeutic options.

Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant peripheral neuropathy caused by missense variants, deletions, and truncations within the peripheral myelin protein-22 (PMP22) gene. CMT1E phenotypes vary depending on the specific variant, ranging from mild to severe, and there is little natural history and phenotypic progression data on individuals with CMT1E. Patients with CMT1E were evaluated during initial and follow-up visits at sites within the Inherited Neuropathy Consortium. Clinical characteristics were obtained from history, neurological exams, and nerve conduction studies. Clinical outcome measures were used to quantify baseline and longitudinal changes, including the Rasch-modified CMT Examination Score version 2 (CMTESv2-R) and the CMT Pediatric Scale (CMTPedS). The trafficking of PMP22 variants in transfected cells was correlated to disease severity. Twenty-four, presumed disease-causing PMP22 variants were identified in 50 individuals from 35 families, including 19 missense variants, three in-frame deletions, and two truncations. Twenty-nine patients presented with delayed walking during childhood. At their baseline evaluation, the mean CMTESv2-R in 46 patients was 16 ± 7.72 (out of 32), and the mean CMTPedS from 17 patients was 28 ± 6.35 (out of 44). Six individuals presented with hearing loss, eleven with scoliosis, three with hip dysplasia, and one with both scoliosis and hip dysplasia. Twenty variants were localized within in transmembrane domains; 31 of 35 individuals with these variants had moderate to severe phenotypes. Three variants were found in the extracellular domain and were associated with milder phenotypes. Reduced expression of PMP22 at the cell surface, and the location of missense variants within in the transmembrane domain correlated with disease severity. Pathogenic PMP22 variants located within the transmembrane regions usually cause a moderate to severe clinical phenotype, beginning in early childhood, and have impaired trafficking to the plasma membrane.

BACKGROUND AND AIMS:SCO2 encodes a mitochondrial copper chaperone required for cytochrome c oxidase (COX) assembly and is classically associated with severe multisystem mitochondrial disease. We characterize a motor-predominant axonal neuropathy presentation associated with biallelic SCO2 variants. METHODS:Clinical, genetic, and functional studies were performed in a 15-year-old female presenting with axonal neuropathy. Functional studies were conducted in patient-derived fibroblasts, including Western blot analysis and spectrophotometric cytochrome c oxidation assay. Structural modeling was performed using ChimeraX. RESULTS:The patient presented with a motor-predominant axonal neuropathy consistent with Charcot-Marie-Tooth (CMT) disease. Clinical genetic testing identified compound heterozygous SCO2 variants of uncertain significance: a missense variant (p.Arg120Trp) and a frameshift variant (p.Asp252ValfsTer24). Structural modeling predicted disruption of protein stability for both variants. Functional studies in patient-derived fibroblasts demonstrated complete absence of SCO2 protein and reduced mitochondrial complex IV activity, supporting a loss-of-function mechanism. INTERPRETATION:These findings demonstrate that SCO2-related disease can present as an isolated axonal neuropathy, a phenotype that remains rarely reported. Our study also highlights the value of integrating in silico prediction tools with functional assays to establish pathogenicity in rare sporadic cases of inherited neuropathy.

The Rare Diseases Clinical Research Network (RDCRN) was established to improve diagnosis, treatment, and research collaboration across rare diseases through collaborative, multi-site, translational, and clinical research. Its governance framework promotes efficient data sharing and collaboration among research consortia, NIH representatives, and patient advocacy groups (PAGs). This infrastructure facilitates coordinated efforts to advance rare disease research through shared resources and communication. Prompted by the COVID-19 pandemic's impact on rare disease patients, the RDCRN recognized cross-consortia collaboration as a priority. Its policies promote data sharing while protecting participant confidentiality. PAGs participate in governance, study design, and regulatory discussions, helping to identify patient-relevant priorities, improve recruitment and retention, and strengthen trust between researchers and patients. Cross-consortia efforts have addressed challenges like biomarker identification and harmonization of clinical measures, leading to new methods and standardized data collection that benefit multiple rare diseases. Studies by teams focusing on different diseases have led to improved diagnostic tools by addressing overlapping disease presentations. The RDCRN offers scholars cross-consortia opportunities for presentations, competitions, and NIH training collaborations, fostering growth and networking. Network meetings promote exchange and process standardization; pilot projects facilitate independent grant submissions, forming a pipeline of skilled investigators. The RDCRN fosters trust, shared vision, and open communication by cultivating a culture of mutual respect, shared learning, and collective problem solving. By engaging a wide range of stakeholders, it has aligned its research with patient needs, advancing innovation. Its high-impact publications, effective mentoring programs, and pioneering cross-consortia initiatives underscore the value of collaboration in rare disease research.

BACKGROUND AND AIMS:The HARS1 gene encodes cytoplasmic histidyl-tRNA synthetase, which catalyzes the ligation of histidine to tRNAHIS in the cytoplasm as an early step in protein biosynthesis and is essential for cell viability. Pathogenic variants in HARS1 have been associated with three phenotypes: autosomal dominant Charcot-Marie-Tooth (CMT) disease, a multisystem recessive syndrome with prominent ataxia, and autosomal recessive Usher syndrome. Here, we present a patient who is compound heterozygous for HARS1 variants and who has a complex recessive phenotype that includes a neuropathy with demyelinating features and active denervation. Our computational and functional analyses support the pathogenicity of these alleles, suggesting that our findings expand the allelic and clinical heterogeneity of HARS1-related disease. METHODS:The individual found to have pathogenic compound heterozygous HARS1 variants was evaluated in a neuromuscular clinic and was further investigated in research studies. Functional consequences of the HARS1 variants were tested in yeast complementation assays; the phase of these alleles was confirmed via long-range PCR and long-read sequencing on DNA isolated from the proband, the mother, and the father. RESULTS:A 25-year-old male with CMT1 and mild intellectual disability had a maternally inherited variant (p.Q410*) and a de novo variant in the HARS1 gene (p.R375C) identified via trio exome sequencing. Studies in yeast revealed ablated function for p.Q410* and reduced function for p.R375C. Of 2480 informative sequencing reads generated from the proband: (a) 1765 (71%) included only p.R375C or only p.Q410*; (b) 237 (10%) included both alleles; and (c) 478 (19%) included neither allele. INTERPRETATION:Studies in yeast revealed loss-of-function characteristics for both p.Q410* and p.R375C HARS1, consistent with these variants being pathogenic. Allele-specific sequencing analyses are consistent with the proband having a compound heterozygous genotype and with p.R375C being a de novo variant that arose on the chromosome 5 transmitted by the father. There is therefore moderate evidence that the two identified HARS1 variants are responsible for the recessive phenotype. This case report expands the allelic and phenotypic heterogeneity of biallelic HARS1 pathogenic variants.

Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicentre phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing. Diagnosing CMT-SORD will become imperative when disease-modifying therapies become available. In this cross-sectional multicentre study, we identified 144 patients from 126 families, including 99 males (69%) and 45 females (31%). Patients represented multiple ancestries, including European, Hispanic, Chinese, Near Eastern and Northern African. We confirmed c.757delG (p.Ala253GlnfsTer27) as the most common pathogenic allele, followed by c.458C>A (p.Ala153Asp), while other variants were identified, mostly in single cases. The average sorbitol level in CMT-SORD patients was significantly higher compared to controls and heterozygous carriers, independently from serum storage duration, sex or variant type. Two-thirds of cases were diagnosed with CMT2 while one-third had distal hereditary motor neuropathy. Disease onset was usually in the second decade of life. Although foot dorsiflexion was the most affected muscle group, dorsal and plantar flexion had a similar degree of weakness in most cases (difference of Medical Research Council score <= 1). One-fourth of patients used ankle foot orthoses, usually in their 30s, but most patients maintained independent ambulation later in life. Nerve conduction studies were suggestive of a motor predominant axonal neuropathy, with reduced conduction velocities in the intermediate range in a quarter of the cases. Sensory conductions in the upper limbs appeared more frequently affected than in the lower limbs. Foot dorsiflexion and plantar flexion decreased significantly with age. Male sex was significantly associated with the severity of distal lower limb weakness (plantar flexion) and a larger change over time (dorsiflexion). In conclusion, CMT-SORD is a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsiflexion and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition that can be utilized for pathogenicity assessment of identified rare SORD variants.

ABSTRACT Background and Aims In 2019, we conducted a cross‐sectional study, collecting information on 50 patients with CMT4B, an ultrarare CMT subtype, to better define the clinical phenotype. We now aimed at investigating disease progression in 26 patients with CMT4B1/CMT4B2, recruited from the previous study and among the Inherited Neuropathy Consortium. Materials and Methods We retrospectively analysed disease progression in patients with CMT4B1/CMT4B2, collecting MRC scores from nine muscle pairs, Charcot‐Marie‐Tooth Examination Score (CMTES), and a minimal dataset of clinical information (walking difficulties, aids dependency, upper limb impairment, cranial nerves involvement) at baseline and follow‐up visits. Thirteen centres from four continents were involved. Results Thirteen CMT4B1 and 13 CMT4B2 patients were followed up for 7.1 ± 4.9 and 7.9 ± 4.5 years, respectively. During follow‐up, walking aid dependency increased: two CMT4B1 patients adopted AFOs (overall 11/12 at follow‐up), and one started using wheelchair (6/12 at follow‐up) at the age of 19; among CMT4B2 patients, two more required unilateral support in walking (4/11 at follow‐up) by the age of 33 and 49 years, respectively. We found that disease progression, as measured by CMTES, was faster in CMT4B1 as compared to CMT4B2 patients (ΔCMTES/year 0.7 vs. 0.3, p = 0.037) but tended to slow down over time as burden of disease increased. At the end of follow‐up, CMT4B1 was associated to higher disability. Conclusions This international collective effort enabled collection of relevant data for characterizing natural history and estimating disease progression of CMT4B1/CMT4B2 ultrarare diseases, aiming at improving their management and paving the way for designing future clinical trials.

Background:NIH requires NIH-funded studies to use historical race and ethnicity categories-originally put forth by the Office of Management and Budget in 1997-for demographics collection. These historical categories were only designed for use within the United States (US). We speculated on the adequacy of these categories in capturing the true diversity of participants enrolled in the Inherited Neuropathy Consortium (INC), and their applicability for an international, broader rare disease population. Objectives:To determine the feasibility and outcomes of using updated categories for rare disease patients that can be collapsed into the required historical categories. Design:This was achieved by expanding on existing government categories from countries with INC sites to create categories that reached 100% consensus of the research team. Quantitative cross-sectional analysis was performed in two cohorts. Methods:Common government census categories among the US, the United Kingdom, Italy, and Australia were used to generate updated demographic categories capturing racial, ethnic, sex, and gender identities. We piloted the updated categories at three INC sites with participants who were participating in the INC. We made a minor update and sent the survey to anyone who had joined the Rare Disease Clinical Research Network's contact registry. Results:Both the pilot study and the contact registry saw an increase in diversity with the updated categories. The sex breakdown of the survey respondents was similar to that of the contact registry as a whole, but several participants were able to identify as nonbinary with the updated categories. Discussion:The updated categories allow researchers to provide a more inclusive race and ethnicity identification experience to participants. This may have implications for understanding differences in study populations that may translate to treatment response and has an overall aim to increase enrollment and adherence to observational research.

ObjectivesThe primary objective of this paper was to present the establishment of the Spastic Paraplegia-Centers of Excellence Research Network (SP-CERN) aimed at promoting clinical trial readiness for hereditary spastic paraplegia (HSP). SP-CERN is unique in its approach to addressing the diagnostic and therapeutic challenges associated with HSP through a large-scale, collaborative effort.MethodsParticipants with HSP are identified through multicenter collaborations across 11 institutions in the United States. SP-CERN systematically collects longitudinal clinical data, biospecimens, and wearable device data from patients. Data are stored in a centralized REDCap database, facilitating shared access for analysis. Patients are evaluated using standardized assessment tools for motor function, biomarkers, and digital outcome measures.ResultsSP-CERN has established a biorepository, centralized data collection methods, and standardized clinical assessments. It is conducting natural history studies for all HSP subtypes, enabling the validation of biomarkers and development of gene-based therapies.DiscussionSP-CERN's collaborative approach bridges gaps in clinical care and research for HSP by improving diagnostic capabilities and promoting clinical trial readiness. This initiative represents a framework for rare disease research, accelerating the development of novel therapies and improving patient outcomes through standardized, multi-institutional collaboration.

Objectives:The primary objective of this paper was to present the establishment of the Spastic Paraplegia-Centers of Excellence Research Network (SP-CERN) aimed at promoting clinical trial readiness for hereditary spastic paraplegia (HSP). SP-CERN is unique in its approach to addressing the diagnostic and therapeutic challenges associated with HSP through a large-scale, collaborative effort. Methods:Participants with HSP are identified through multicenter collaborations across 11 institutions in the United States. SP-CERN systematically collects longitudinal clinical data, biospecimens, and wearable device data from patients. Data are stored in a centralized REDCap database, facilitating shared access for analysis. Patients are evaluated using standardized assessment tools for motor function, biomarkers, and digital outcome measures. Results:SP-CERN has established a biorepository, centralized data collection methods, and standardized clinical assessments. It is conducting natural history studies for all HSP subtypes, enabling the validation of biomarkers and development of gene-based therapies. Discussion:SP-CERN's collaborative approach bridges gaps in clinical care and research for HSP by improving diagnostic capabilities and promoting clinical trial readiness. This initiative represents a framework for rare disease research, accelerating the development of novel therapies and improving patient outcomes through standardized, multi-institutional collaboration.

Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 (Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.

Charcot-Marie-Tooth type 1B (CMT1B) is a demyelination neuropathy caused by over 200 mutations in the myelin protein zero (MPZ) gene. Here, we generated two induced pluripotent stem cell (iPSC) lines from fibroblasts isolated from the skin biopsies of CMT1B patients, each carrying a distinct MPZ mutation (Arg98Cys and Ser63del). The iPSC lines created in this work retained their respective MPZ mutation, exhibited normal karyotypes, expressed pluripotency markers, and demonstrated the ability to differentiate into three germ-layer cell types. These lines offer a valuable tool for exploring and modeling dominant CMT1B disease within a human cellular framework.

BACKGROUND:Many individuals with Charcot-Marie-Tooth disease (CMT) use ankle foot orthoses (AFOs) to address balance and functional deficits. OBJECTIVES:This study was conducted to further understand how individuals with CMT perceive the effects of AFO use on function. STUDY DESIGN:Cross-sectional online survey. METHODS:Individuals with CMT provided free text responses to 3 questions: (Q1) What would you change about your orthosis if you could? (Q2) What activities does your ankle foot orthosis improve? (Q3) What activities does your ankle foot orthosis limit? Two independent reviewers evaluated responses and used an inductive approach to identify primary themes. Percent agreement between reviewers was calculated for each primary theme. RESULTS:A total of 310 individuals participated, and 5 primary themes were identified for each question. Q1 primary themes included ease of use or functionality, compatibility with shoes, durability, appearance, and comfort or fit. Q2 primary themes included walking, standing, balance and stability, physical health, and activities of daily life. Q3 primary themes were related to shoes or clothing, balance or inclines, mobility, long-term use, and general activities. Average percent agreement between reviewers was 63% (17%). CONCLUSIONS:Study results align with previously reported data collected using patient-reported outcome surveys. In addition, participants highlighted concerns that are not usually addressed in orthosis-related questionnaires. These data emphasize areas of improvement for orthotic treatment relevant to individuals with CMT and which may help guide future research aiming to improve functional outcomes and compliance with orthotic interventions.