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 CMT type 1A (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.

Objectives We present a case of cortical laminar necrosis after severe hydrocephalus to highlight considerations for multimodal cerebral autoregulation monitoring to determine mean arterial pressure (MAP) thresholds during neurological emergencies, as well as postoperative head imaging for patients with ventriculoperitoneal shunts (VPS).Methods A 40-year-old woman with a history of Chiari II malformation and non-communicating hydrocephalus with VPS presented in septic shock from a sacral wound. One week after colostomy for fecal diversion, the patient became comatose and had progressive slowing to full suppression on electroencephalogram (EEG).Results CT imaging revealed hydrocephalus, most likely due to VPS distal obstruction from intraperitoneal surgery. Despite neurosurgical and neurocritical care management, MRI confirmed diffuse cortical hypoxic ischemic injury.Discussion The Neurocritical Care Society's Emergency Neurological Life Support (ENLS) protocol for neurological emergencies focuses on managing increased intracranial pressure (ICP) but does not set MAP goals. As ICP may be very high during brain herniation, our case demonstrates that higher MAP may be required to maintain adequate circulation. To determine the optimal MAP target, bedside multimodality monitoring, including ICP monitors, transcranial doppler, and near infrared spectroscopy, can help establish individualized cerebral autoregulation guided thresholds. Outside of a neurological intensive care unit, EEG can monitor cerebral blood flow and indicate windows for intervention before exam or imaging changes. Additionally, our case demonstrates how a post-operative surveillance CT head should be considered for patients with VPS.

Objective: Clinical trials for transient receptor potential vanilloid 4 (TRPV4)-associated neuromuscular disease have been limited by the lack of natural history data and clearly defined endpoints to assess treatment response. We sought to characterize the natural history of TRPV4-associated neuromuscular disease through a standardized patient questionnaire and neurologic exam. Background: Mutations in TRPV4 cause a spectrum of neuromuscular disease, including Charcot-Marie-Tooth disease type 2C and related forms of spinal muscular atrophy. Case reports demonstrate a diversity in the age of onset, disease severity, and phenotype, including pure neuromuscular disease or mixed neuromuscular and skeletal disease. Design/Methods: Twenty-seven patients with TRPV4-associated neuromuscular disease completed a questionnaire that assessed motor, sensory, respiratory, and skeletal symptoms and underwent a neurologic exam, including calculation of the validated CMT Exam Score (CMTES). Descriptive statistics were used to assess phenotypic patterns, frequency of disease manifestations, and disease progression. Pearson correlation coefficients were used to describe association. Results: The median age of onset was 1 year (range 0–50 years), with 19 congenital-onset (70%) and 8 adult-onset (30%) patients. Stridor and vocal cord weakness were reported by 59.3% and 40.7% of patients, respectively. Diagnoses of skeletal dysplasia (25.9%), scoliosis (70.4%), and arthrogryposis (33.3%) were also common. Patients reported weakness primarily in the hands (74.1%) and feet (70.4%) with lower frequencies noted in the shoulders (59.3%) and hips (48.2%). CMTES was found to have a weak positive association with age (r = 0.34). Conclusions: This represents the largest study of TRPV4-associated neuromuscular disease using a patient questionnaire. Promising therapeutic possibilities for TRPV4-associated neuromuscular disease are being explored in mouse models, increasing the need for clinical trial readiness. The initial data suggest that CMTES, along with respiratory and skeletal symptoms, may provide a meaningful endpoint for congenital and adult-onset patients. This questionnaire represents part of a larger study that will include ongoing yearly longitudinal follow-up. Disclosure: Mr. Donohue has nothing to disclose. Dr. Peyton has nothing to disclose. Mrs. Thomas has received personal compensation for serving as an employee of Foundation of Peripheral Neuropathy. Mr. Ben-Davies has nothing to disclose. Dr. Sumner has received personal compensation for serving as an employee of Biogen. Dr. Sumner has received personal compensation for serving as an employee of Avexis. Dr. Sumner has received personal compensation for serving as an employee of Roche/Genentech. Dr. Sumner has received personal compensation for serving as an employee of Ionis Pharmaceuticals. Dr. Sumner has received personal compensation for serving as an employee of Sarepta. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avexis/Novartis. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche/Genentech. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Proneurotech. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for CMTRF. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal Clinical Investigation. Dr. Sumner has received research support from Roche. Dr. Sumner has received intellectual property interests from a discovery or technology relating to health care. Dr. Sumner has received publishing royalties from a publication relating to health care. The institution of Dr. McCray has received research support from NIH. The institution of Dr. McCray has received research support from Johns Hopkins Merkin Peripheral Neuropathy and Nerve Regeneration Center. The institution of Dr. McCray has received research support from Muscular Dystrophy Association. Inherited Neuropathies Consortium Rare Disease Clinical Research Network has nothing to disclose.

OBJECTIVE:Distinct dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically cause nonoverlapping diseases of either the neuromuscular or skeletal systems. However, accumulating evidence suggests that some patients develop mixed phenotypes that include elements of both neuromuscular and skeletal disease. We sought to define the genetic and clinical features of these patients.METHODS:We report a 2-year-old with a novel R616G mutation in TRPV4 with a severe neuropathy phenotype and bilateral vocal cord paralysis. Interestingly, a different substitution at the same residue, R616Q, has been reported in families with isolated skeletal dysplasia. To gain insight into clinical features and potential genetic determinants of mixed phenotypes, we perform in-depth analysis of previously reported patients along with functional and structural assessment of selected mutations.RESULTS:We describe a wide range of neuromuscular and skeletal manifestations and highlight specific mutations that are more frequently associated with overlap syndromes. We find that mutations causing severe, mixed phenotypes have an earlier age of onset and result in more marked elevations of intracellular calcium, increased cytotoxicity, and reduced sensitivity to TRPV4 antagonism. Structural analysis of the two mutations with the most dramatic gain of ion channel function suggests that these mutants likely cause constitutive channel opening through disruption of the TRPV4 S5 transmembrane domain.INTERPRETATION:These findings demonstrate that the degree of baseline calcium elevation correlates with development of mixed phenotypes and sensitivity to pharmacologic channel inhibition, observations that will be critical for the design of future clinical trials for TRPV4 channelopathies.

In this narrative medicine essay, a medical student learns of her inherited disease during a genetics class in which she sees an image of a foot that matches her own, a DNA missense stemming from her biological father who left her life when she was an infant.

The Pediatric Emergency Care Applied Research Network (PECARN) Head Injury/Trauma Algorithm is a well-validated decision rule used to identify patients at low risk of clinically important traumatic brain injuries who may not need head CT. In adult patients with mild head trauma, elevated serum glucose and white cell count (WCC) have been associated with abnormal head CT findings. Currently, glucose or WCC is not considered in pediatric patients. The objective of this study was to determine if elevations in glucose or WCC could be used as additional tools to risk-stratify pediatric trauma patients for intracranial injury (ICI). Data were abstracted from the Maryland Trauma Registry and from electronic medical records for patients at the Johns Hopkins Children's Center from 2017 to 2020. We evaluated 145 encounters that met the inclusion criteria. There were 33 cases of ICI on CT. In addition to higher median glucose and WCC, we found that patients with ICI had a younger median age and were less likely to have other clinically significant injuries than patients without ICI. Following multiple logistic regression analysis, WCC (OR 1.113, 95% CI 1.02 to 1.21), younger age (OR 0.89, 95% CI 0.8 to 0.98), and absence of other injuries (OR 0.41, 95% CI 0.23 to 0.73) were found to be associated with risk of ICI. The area under the curve for our model was 0.79. When used with the PECARN algorithm, our model could help determine which patients may avoid head CT or undergo a shorter observation period.