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Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated, and clinically heterogeneous demyelinating disease affecting the nerve roots and peripheral nerves. We report a series of 4 patients who presented with early and progressive vision loss in the context of new-onset CIDP: 3 due to papilledema and 1 due to optic neuropathy without papilledema.This was a retrospective case series of 4 patients with vision loss as a presenting feature of CIDP evaluated at the Hospital of the University of Pennsylvania from January 2016 to August 2021. Demographic, clinical, diagnostic, and treatment data were collected via retrospective medical record review.Case 1 was a 51-year-old man with 2 months of progressive bilateral papilledema associated with reduced visual acuity (count fingers at 1 foot in each eye) and severely constricted visual fields. Case 2 was a 36-year-old man with 4 months of worsening headaches, reduced visual acuity (count fingers at 1 foot in each eye), severely constricted visual fields, and papilledema. Case 3 was a 39-year-old man with papilledema causing progressive vision loss (20/80 in both eyes), headaches, and relapsing limb sensorimotor deficits. Case 4 was a 19-year-old man with 3 months of progressive bilateral visual decline (20/400 in the right eye, 20/600 in the left eye), central scotoma, and optic disc pallor consistent with optic neuropathy without papilledema. All 4 patients met clinical and electrodiagnostic criteria of CIDP. Cases 3 and 4 each tested positive for serum neurofascin-155 IgG4 antibodies. All patients were managed with immunomodulatory therapy. Cases 1 and 2 also each required surgical intervention with bilateral optic nerve sheath fenestration and cerebrospinal fluid (CSF) shunting procedures.Vision loss from optic neuropathy with or without papilledema has rarely been reported in CIDP, and typically has been described in the context of longstanding disease. Our cases highlight how CIDP can present with early vision loss that may be profound and challenging to manage if diagnosis is delayed. CIDP should be considered in any patient with new progressive vision loss when associated with peripheral sensorimotor symptoms and elevated CSF protein. The small subgroup of CIDP patients with neurofascin-155 antibodies may be at particular risk of optic nerve involvement.

BACKGROUND: There has been a call by both patients and health professionals for the integration of palliative care with nephrology care, yet there is little evidence describing the effect of this approach. The objective of this paper is to report the feasibility and acceptability of a pilot randomized controlled trial testing the efficacy of integrated palliative and nephrology care. METHODS: English speaking patients with CKD stage 5 were randomized to monthly palliative care visits for 3 months in addition to their usual care, as compared with usual nephrology care. Feasibility of recruitment, retention, completion of intervention processes, and feedback on participation was measured. Other outcomes included differences in symptom burden change, measured by the Integrated Palliative Outcome Scale–Renal, and change in quality of life, measured by the Kidney Disease Quality of Life questionnaire and completion of advance care planning documents. RESULTS: Of the 67 patients approached, 45 (67%) provided informed consent. Of these, 27 patients completed the study (60%), and 14 (74%) of those in the intervention group completed all visits. We found small improvements in overall symptom burden (−2.92 versus 1.57) and physical symptom burden scores (−1.92 versus 1.79) in the intervention group. We did not see improvements in the quality-of-life scores, with the exception of the physical component score. The intervention group completed more advance care planning documents than controls (five health care proxy forms completed versus one, nine Medical Orders for Life Sustaining Treatment forms versus none). CONCLUSIONS: We found that pilot testing through a randomized controlled trial of an ambulatory integrated palliative and nephrology care clinical program was feasible and acceptable to participants. This intervention has the potential to improve the disease experience for those with nondialysis CKD and should be tested in other CKD populations with longer follow-up. CLINICAL TRIALS REGISTRY NAME AND REGISTRATION NUMBER: Pilot Randomized-controlled Trial of Integrated Palliative and Nephrology Care Versus Usual Nephrology Care, NCT04520984

We found a p.Ala406Val (c.1217C > T) mutation in MORC2 in three individuals, from two families. All three individuals were evaluated and clinical electrophysiology was completed. The neuropathy began in childhood to early adulthood, with distal weakness progressing to proximal weakness. Vinblastine (for Hodgkin lymphoma) acutely worsened the weakness in one patient. This finding confirms that that the p.Ala406Val mutation in MORC2 causes severe neuropathy. In addition, we report the first case of vinblastine neurotoxicity in Charcot-Marie-Tooth disease type 2Z.

Although almost everyone knows the feeling of fatigue, few people experience it as often as patients with ESKD on maintenance hemodialysis (HD). A majority of HD patients report feeling fatigued on a regular basis ([1][1]), affecting their ability to accomplish the tasks they want and need to do

BACKGROUND: Despite having high comorbidity rates and shortened life expectancy, patients with ESKD may harbor unrealistically optimistic expectations about their prognoses. Whether this affects resuscitation orders is unknown. METHODS: To determine whether do-not-resuscitate (DNR) orders differ among patients with ESKD compared with other critically ill patients, including those with diseases of other major organs, we investigated DNR orders on admission to intensive care units (ICUs) among 106,873 patients in the United States. RESULTS: Major organ disease uniformly associated with increased risk of hospital mortality, particularly for cirrhosis (adjusted odds ratio [aOR], 2.67; 95% confidence interval [95% CI], 2.30 to 3.08), and ESKD (aOR, 1.47; 95% CI, 1.31 to 1.65). Compared with critically ill patients without major organ disease, patients with stroke, cancer, heart failure, dementia, chronic obstructive pulmonary disease, and cirrhosis were statistically more likely to have a DNR order on ICU admission; those with ESKD were not. Findings were similar when comparing patients with a single organ disease with those without organ disease. The disconnect between prognosis and DNR use was most notable among Black patients, for whom ESKD (compared with no major organ disease) was associated with a 62% (aOR, 1.62; 95% CI, 1.27 to 2.04) higher odds of hospital mortality, but no appreciable difference in DNR utilization (aOR, 1.06; 95% CI, 0.66 to 1.62). CONCLUSIONS: Unlike patients with diseases of other major organs, critically ill patients with ESKD were not more likely to have a DNR order than patients without ESKD. Whether this reflects a greater lack of advance care planning in the nephrology community, as well as a missed opportunity to minimize potentially needless patient suffering, requires further study.

We found a p.Gly327Arg mutation in GARS in two unrelated women, both of whom had a similar phenotype - motor weakness that began in late childhood, distal weakness in the arms and legs, a motor greater than sensory neuropathy with slowing of motor and not sensory conduction velocities. A de novo mutation was proven in one patient and suspected in the other. The p.Gly327Arg GARS variant did not support yeast growth in a complementation assay, showing that this variant severely impairs protein function. Thus, the p.Gly327Arg GARS mutation causes a distal motor neuropathy.

BACKGROUND AND OBJECTIVES: AKI is a common complication of coronavirus disease 2019 (COVID-19) and is associated with high mortality. Palliative care, a specialty that supports patients with serious illness, is valuable for these patients but is historically underutilized in AKI. The objectives of this paper are to describe the use of palliative care in patients with AKI and COVID-19 and their subsequent health care utilization. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective analysis of New York University Langone Health electronic health data of COVID-19 hospitalizations between March 2, 2020 and August 25, 2020. Regression models were used to examine characteristics associated with receiving a palliative care consult. RESULTS: Among patients with COVID-19 (n=4276; 40%), those with AKI (n=1310; 31%) were more likely than those without AKI (n=2966; 69%) to receive palliative care (AKI without KRT: adjusted odds ratio, 1.81; 95% confidence interval, 1.40 to 2.33; P

Salt-bearing passive margin basins offshore SE Brazil have been and remain attractive for hydrocarbon exploration and production. In the Campos Basin, major reservoir types include post-salt turbidites, which are located in structural traps related to thin-skinned faulting above salt anticlines and rollers. Classic models of gravity-driven salt tectonics commonly depict kinematically linked zones of deformation, characterised by updip extension and downdip contraction, separated by a weakly deformed zone associated with downdip translation above a relatively smooth base-salt surface. We use 2D and 3D seismic reflection and borehole data from the south-central Campos Basin to show that this does not adequately capture the styles of salt-detached gravity-driven deformation above relict, rift-related relief. The base-salt surface is composed of elongated, broadly seaward-dipping ramps with structural relief reaching c. 2 km. These ramps define the boundary between the External High and the External Low, basement structures related to the rift tectonics. Local deformation associated with the base-salt ramps can overprint and/or influence regional, margin-scale patterns of deformation producing kinematically-variable and multiphase salt deformation. We define three domains of thin-skinned deformation: an updip extensional domain, subdivided into subdomains E1 and E2, an intermediate multiphase domain and a downdip contractional domain. The multiphase domain is composed of three types of salt structures with a hybrid extensional-contractional origin and evolution. These are: (i) contractional anticlines that were subjected to later extension and normal faulting; (ii) diapirs with passive and active growth later subjected to regional extension, developing landward-dipping normal faults on the landward flank; and, lastly, (iii) an extensional diapir that was subsequently squeezed. We argue that this multiphase style of deformation occurs as a consequence of base-salt geometry and relief creating local variations of salt flow that localize extension at the top and along the ramps, and contraction at the base. Translation and extension of salt and its overburden across major base-salt ramps resulted in three ramp syncline basins northeast of the study area, partially bounded by salt-detached listric faults. The temporal and spatial distribution and evolution of these and other key salt and overburden structures, and their relationship to base-salt relief, suggest 30 to 60 km of horizontal gravity-driven translation of salt and overburden.

Context In spring 2020, New York experienced a surge of patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or COVID-19) disease, as part of a global pandemic. There are limited data on populations of COVID-19–infected patients seen by palliative care services. Objective To describe a palliative care population at one New York hospital system during the initial pandemic surge. Methods This repeated cross-sectional, observational study collected data on palliative care patients in a large health system seen during the COVID-19 outbreak and compared it with pre-COVID data. Results Palliative service volume surged from 678 (4% of total admissions) before COVID-19 to 1071 (10% of total admissions) during the COVID-19 outbreak. During the outbreak, 695 (64.9%) of the total palliative patients tested positive for the virus. Compared with a preoutbreak group, this COVID-19–positive group had higher rates of male (60.7% vs. 48.6%, P

Bioluminescent imaging (BLI) is one of the most powerful and widely used preclinical imaging modalities. However, the current technology relies on the use of transgenic luciferase-expressing cells and animals and therefore can only be applied to a limited number of existing animal models of human disease. Here, we report the development of a "portable bioluminescent" (PBL) technology that overcomes most of the major limitations of traditional BLI. We demonstrate that the PBL method is capable of noninvasive measuring the activity of both extracellular (e.g., dipeptidyl peptidase 4) and intracellular (e.g., cytochrome P450) enzymes in vivo in non-luciferase-expressing mice. Moreover, we successfully utilize PBL technology in dogs and human cadaver, paving the way for the translation of functional BLI to the noninvasive quantification of biological processes in large animals. The PBL methodology can be easily adapted for the noninvasive monitoring of a plethora of diseases across multiple species. Bioluminescence imaging tends to rely on transgenic luciferase-expressing cells and animals. Here the authors report a portable bioluminescent system to non-invasively measure intra- and extracellular enzymes in vivo in non-transgenic animals which do not express luciferase.

Using case vignettes, we highlight challenges in communication, prognostication, and medical decision-making that have been exacerbated by the coronavirus disease-19 (COVID-19) pandemic for patients with kidney disease. We include best practice recommendations to mitigate these issues and conclude with implications for interdisciplinary models of care in crisis settings.Certain biomarkers, demographics, and medical comorbidities predict an increased risk for mortality among patients with COVID-19 and kidney disease, but concerns related to physical exposure and conservation of personal protective equipment have exacerbated existing barriers to empathic communication and value clarification for these patients. Variability in patient characteristics and outcomes has made prognostication nuanced and challenging. The pandemic has also highlighted the complexities of dialysis decision-making for older adults at risk for poor outcomes related to COVID-19.The COVID-19 pandemic underscores the need for nephrologists to be competent in serious illness communication skills that include virtual and remote modalities, to be aware of prognostic tools, and to be willing to engage with interdisciplinary teams of palliative care subspecialists, intensivists, and ethicists to facilitate goal-concordant care during crisis settings.

Background Injury or compression of a sensory nerve is an under-reported source of disabling pain in the lower limb. It is known that peripheral nerve microsurgeons can reconstruct and rewire injured nerves to relieve chronic pain but this option remains not completely understood and ignored by most orthopaedic surgeons, neurologists, and pain therapists. In this paper, we describe our experience with knee and ankle peripheral nerve surgery to improve the condition of patients suffering from chronic, posttraumatic lower limb pain. Patients and Methods Between 2015 and 2018, a retrospective investigation was performed including patients who underwent ankle and knee nerve surgery for posttraumatic chronic pain with at least 1 year of follow-up. Previous surgeries or type of trauma, pain location and characteristics, type of operation (reconstruction, decompression, or denervation), and number of nerves operated were listed. Selective neuropathy was confirmed by ultrasound-guided nerve blocks. Outcome was assessed combining the visual analogue scale (VAS) score at rest and during movement, functional indexes, drug use, and ability to work. Results A total of 34 patients (14 knee and 20 ankle) were included in this study. A statistically significant difference (p Conclusion Peripheral nerve microsurgery is a useful and minimally invasive tool to be added in the algorithm of treatment of chronic knee and ankle pain. Physicians should be trained to suspect a neuropathic origin of pain in absence of musculoskeletal signs of pathology, especially following trauma or surgeries.

The COVID-19 pandemic created an unprecedented strain on hospitals in New York City. Although practitioners focused on the pulmonary devastation, resources for the provision of dialysis proved to be more constrained. To deal with these shortfalls, NYC Health and Hospitals/Bellevue, NYU Brooklyn, NYU Medical Center and the New York Harbor VA Healthcare System, put together a plan to offset the anticipated increased needs for kidney replacement therapy.Prior to the pandemic, peritoneal dialysis was not used for acute kidney injury at Bellevue Hospital. We were able to rapidly establish an acute peritoneal dialysis program at Bellevue Hospital for acute kidney injury patients in the intensive care unit. A dedicated surgery team was assembled to work with the nephrologists for bedside placement of the peritoneal dialysis catheters. A multi-disciplinary team was trained by the lead nephrologist to deliver peritoneal dialysis in the intensive care unit. Between April 8, 2020 and May 8, 2020, 39 peritoneal dialysis catheters were placed at Bellevue Hospital. 38 patients were successfully started on peritoneal dialysis. As of June 10, 2020, 16 patients recovered renal function. One end stage kidney disease patient was converted to peritoneal dialysis and was discharged. One catheter was poorly functioning, and the patient was changed to hemodialysis before recovering renal function. There were no episodes of peritonitis and nine incidents of minor leaking, which resolved. Some patients received successful peritoneal dialysis while being ventilated in the prone position.In summary, despite severe shortages of staff, supplies and dialysis machines during the COVID-19 pandemic, we were able to rapidly implement a de novo peritoneal dialysis program which enabled provision of adequate kidney replacement therapy to all admitted patients who needed it. Our experience is a model for the use of acute peritoneal dialysis in crisis situations.

Patients with advanced chronic kidney disease (CKD) suffer from a substantial burden of physical and emotional symptoms that adversely affect their health-related quality of life. Their number of symptoms when systematically evaluated is comparable to cancer patients. Overall symptom burden and severity are correlated directly with impaired quality of life and depression. Among the most frequent are fatigue, pain, pruritus, sleep disturbances and poor appetite. This chapter highlights one of the most common and troublesome of these symptoms affecting advanced CKD patients, particularly those with end-stage kidney disease: uremic pruritus. The epidemiology, pathophysiology, and current evidence-based treatments are discussed as a way to provide a practical guide for diagnosis and treatment. Lastly, areas for future research to improve symptom management in this growing, chronically ill population are identified.

BACKGROUND AND AIMS: The CMT-FOM is a 13-item clinical outcome assessment (COA) that measures physical ability in adults with Charcot-Marie-Tooth disease (CMT). Test-retest reliability, internal consistency and convergent validity have been established for the CMT-FOM. This current study sought to establish inter-rater reliability. METHODS: Following an in-person training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18-74 years, 6 female). Participants were evaluated using the CMT-FOM over 2 days. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. RESULTS: Following the provision of training by master trainers, all 13 items of the CMT-FOM exhibited excellent inter-rater reliability for raw scores (ICC(1,1) 0.825 to 0.989) and z-scores (ICC(1,1) 0.762 to 0.969). Reliability of the CMT-FOM total score was excellent (ICC(1,1) 0.983, 95% CI 0.958-0.995). INTERPRETATION: The CMT-FOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMT-FOM in the Accelerate Clinical Trials in CMT (ACT-CMT) study.

Objective: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot–Marie–Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22. Methods: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. Results: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10 −7 ). Coimmunoprecipitation and mass spectroscopy studies identified β-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development. Interpretation: SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316–330.

Background Charcot-Marie-Tooth disease Type 2A (CMT2A) presents with optic atrophy in a subset of patients, but the prevalence and severity of optic nerve involvement in relation to other CMT subtypes has not been explored. Methods Patients with genetically confirmed CMT2A (n = 5), CMT1A (n = 9) and CMTX1 (n = 10) underwent high- and low-contrast acuity testing using Sloan letter charts, and circumpapillary retinal nerve fiber layer (RNFL) and macular total retinal, RNFL, and ganglion cell layer/inner plexiform layer thickness was measured using spectral domain optical coherence tomography (OCT). We used age- and gender-adjusted linear regression to compare contrast acuity and retinal thickness between CMT groups. Results One of 5 patients with CMT2A had optic nerve atrophy (binocular high-contrast acuity equivalent 20/160, mean circumpapillary RNFL 47.5 μm). The other patients with CMT2A had normal high- and low-contrast acuity and retinal thickness, and there were no significant differences between patients with CMT2A, CMT1A, and CMTX1. Conclusions Optic atrophy occurs in some patients with CMT2A, but in others, there is no discernible optic nerve involvement. This suggests that optic neuropathy is specific to certain MFN2 mutations in CMT2A and that low-contrast acuity or OCT is of limited value as a disease-wide biomarker.

Mutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring heterozygous (Tubb4aD249N/+) and the homozygous (Tubb4aD249N/D249N) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4aD249N/D249N mice have myelination deficits along with dramatic decrease in mature oligodendrocytes and their progenitor cells. Additionally, a significant loss occurs in the cerebellar granular neurons and striatal neurons in Tubb4aD249N/D249N mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4aD249N/D249N mice. Thus Tubb4aD249N/D249N mice demonstrate the complex cellular physiology of H-ABC, likely due to independent effects on oligodendrocytes, striatal neurons, and cerebellar granule cells in the context of altered microtubule dynamics, with profound neurodevelopmental deficits., eLife digest Inside human and other animal cells, filaments known as microtubules help support the shape of the cell and move proteins to where they need to be. Defects in microtubules may lead to disease. For example, genetic mutations affecting a microtubule component called TUBB4A cause a rare brain disease in humans known as H-ABC. Individuals with H-ABC display many symptoms including abnormal walking, speech defects, impaired swallowing, and several cognitive defects. Abnormalities in several areas of the brain, including the cerebellum and striatum contribute to these defects. . In these structures, the neurons that carry messages around the brain and their supporting cells, known as oligodendrocytes, die, which causes these parts of the brain to gradually waste away. At this time, there are no therapies available to treat H-ABC. Furthermore, research into the disease has been hampered by the lack of a suitable “model” in mice or other laboratory animals. To address this issue, Sase, Almad et al. generated mice carrying a mutation in a gene which codes for the mouse equivalent of the human protein TUBB4A. Experiments showed that the mutant mice had similar physical symptoms to humans with H-ABC, including an abnormal walking gait, poor coordination and involuntary movements such as twitching and reduced reflexes. H-ABC mice had smaller cerebellums than normal mice, which was consistent with the wasting away of the cerebellum observed in individuals with H-ABC. The mice also lost neurons in the striatum and cerebellum, and oligodendrocytes in the brain and spinal cord. Furthermore, the mutant TUBB4A protein affected the behavior and formation of microtubules in H-ABC mice. The findings of Sase, Almad et al. provide the first mouse model that shares many features of H-ABC disease in humans. This model provides a useful tool to study the disease and develop potential new therapies.

Background Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability. Objective We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A. Methods We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study. Results The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91×10-7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08×10-7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63×10-7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14×10-7, beta = 3.014). Conclusions While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.

ObjectiveTo determine the genetic cause of axonal Charcot-Marie-Tooth disease in a small family with 2 affected siblings, one of whom had cerebellar features on examination.MethodsWhole-exome sequencing of genomic DNA and analysis for recessively inherited mutations; PCR-based messenger RNA/complementary DNA analysis of transcripts to characterize the effects of variants identified by exome sequencing.ResultsWe identified compound heterozygous mutations in dystonin (DST), which is alternatively spliced to create many plakin family linker proteins (named the bullous pemphigoid antigen 1 [BPAG1] proteins) that function to bridge cytoskeletal filament networks. One mutation (c.250C>T) is predicted to cause a nonsense mutation (p.R84X) that only affects isoform 2 variants, which have an N-terminal transmembrane domain; the other (c.8283+1G>A) mutates a consensus splice donor site and results in a 22 amino acid in-frame deletion in the spectrin repeat domain of all BPAG1a and BPAG1b isoforms.ConclusionsThese findings introduce a novel human phenotype, axonal Charcot-Marie-Tooth, of recessive DST mutations, and provide further evidence that BPAG1 plays an essential role in axonal health.

Although mutations in more than 90 genes are known to cause CMT, the underlying genetic cause of CMT remains unknown in more than 50% of affected individuals. The discovery of additional genes that harbor CMT2-causing mutations increasingly depends on sharing sequence data on a global level. In this way—by combining data from seven countries on four continents—we were able to define mutations in ATP1A1, which encodes the alpha1 subunit of the Na+,K+-ATPase, as a cause of autosomal-dominant CMT2. Seven missense changes were identified that segregated within individual pedigrees: c.143T>G (p.Leu48Arg), c.1775T>C (p.Ile592Thr), c.1789G>A (p.Ala597Thr), c.1801_1802delinsTT (p.Asp601Phe), c.1798C>G (p.Pro600Ala), c.1798C>A (p.Pro600Thr), and c.2432A>C (p.Asp811Ala). Immunostaining peripheral nerve axons localized ATP1A1 to the axolemma of myelinated sensory and motor axons and to Schmidt-Lanterman incisures of myelin sheaths. Two-electrode voltage clamp measurements on Xenopus oocytes demonstrated significant reduction in Na+ current activity in some, but not all, ouabain-insensitive ATP1A1 mutants, suggesting a loss-of-function defect of the Na+,K+ pump. Five mutants fall into a remarkably narrow motif within the helical linker region that couples the nucleotide-binding and phosphorylation domains. These findings identify a CMT pathway and a potential target for therapy development in degenerative diseases of peripheral nerve axons.