Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2–33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.     

Consensus recommendations on lymphedema in Phelan-McDermid syndrome

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by deletions 22q13.3 or pathogenic variants in the SHANK3 gene. Lymphedema can be a clinical feature in 10–25% of individuals with PMS due to a deletion 22q13.3, but is not observed in those with a SHANK3 variant. This paper forms a part of the European consensus guideline for PMS and focuses on what is known regarding lymphedema in PMS in order to present clinical recommendations.The mechanism causing lymphedema in PMS is unknown. Lymphedema can be suggested by pitting oedema of the extremities or, in later stages, non-pitting swelling. It can occur already at a young age and be progressive if untreated, impacting daily functioning. Lymphedema can be treated using existing general multidisciplinary management guidelines, taking the functioning of the individual with PMS into account. Furthermore, well-known risk factors for the development of lymphedema as lack of physical activities and weight gain/obesity should be addressed. Diagnosis and treatment are best performed in a multidisciplinary centre of expertise.     

Consensus recommendations on counselling in Phelan-McDermid syndrome,with special attention to recurrence risk and to ring chromosome 22

This paper focuses on genetic counselling in Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder caused by a deletion 22q13.3 or a pathogenic variant in SHANK3. It is one of a series of papers written by the European PMS consortium as a consensus guideline. We reviewed the available literature based on pre-set questions to formulate recommendations on counselling, diagnostic work-up and surveillance for tumours related to ring chromosome 22. All recommendations were approved by the consortium, which consists of professionals and patient representatives, using a voting procedure. PMS can only rarely be diagnosed based solely on clinical features and requires confirmation via genetic testing. In most cases, the family will be referred to a clinical geneticist for counselling after the genetic diagnosis has been made. Family members will be investigated and, if indicated, the chance of recurrence discussed with them. Most individuals with PMS have a de novo deletion or a pathogenic variant of SHANK3. The 22q13.3 deletion can be a simple deletion, a ring chromosome 22, or the result of a parental balanced chromosomal anomaly, influencing the risk of recurrence. Individuals with a ring chromosome 22 have an increased risk of NF2-related schwannomatosis (formerly neurofibromatosis type 2) and atypical teratoid rhabdoid tumours, which are associated with the tumour-suppressor genes NF2 and SMARCB1, respectively, and both genes are located on chromosome 22. The prevalence of PMS due to a ring chromosome 22 is estimated to be 10–20%. The risk of developing a tumour in an individual with a ring chromosome 22 can be calculated as 2–4%. However, those individuals who do develop tumours often have multiple. We recommend referring all individuals with PMS and their parents to a clinical geneticist or a comparably experienced medical specialist for genetic counselling, further genetic testing, follow-up and discussion of prenatal diagnostic testing in subsequent pregnancies. We also recommend karyotyping to diagnose or exclude a ring chromosome 22 in individuals with a deletion 22q13.3 detected by molecular tests. If a ring chromosome 22 is found, we recommend discussing personalised follow-up for NF2-related tumours and specifically cerebral imaging between the age of 14 and 16 years.     

Parental perspectives on Phelan-McDermid syndrome: Results of a worldwide survey

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder characterised by hypotonia, speech problems, intellectual disability and mental health issues like regression, autism and mood disorders. In the development, implementation and dissemination of a new clinical guideline for a rare genetic disorder like PMS, the parental experienced perspective is essential. As information from literature is scarce and often conflicting the European Phelan-McDermid syndrome guideline consortium created a multi-lingual survey for parents of individuals with PMS to collect their lived experiences with care needs, genotypes, somatic issues, mental health issues and parental stress. In total, we analysed 587 completed surveys from 35 countries worldwide. Based on parental reporting, PMS appeared to be caused by a deletion of chromosome 22q13.3 in 78% (379/486) of individuals and by a variant in the SHANK3 gene in 22% (107/486) of the individuals. Parents reported a wide variety of developmental, neurological, and other clinical issues in individuals with PMS. The most frequently experienced issues were related to speech and communication, learning disabilities/intellectual disability, and behaviour. While most reported issues were present across all age groups and genotypes, the prevalence of epilepsy, lymphoedema, and mental health issues do appear to vary with age. Developmental regression also appeared to begin earlier in this cohort than described in literature. Individuals with PMS due to a 22q13.3 deletion had a higher rate of kidney issues and lymphoedema compared to individuals with SHANK3 variants. Parental stress was high, with specific contributing factors being child and context related in accordance with the PMS phenotype. The survey results led to various validated recommendations in the European PMS guideline including an age specific surveillance scheme, specific genetic counselling, structured healthcare evaluations on sleep and communication and a focus on family well-being.     

Neurofibromatosis type 2 in Phelan-McDermid syndrome: Institutional experience and review of the literature

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by rearrangements on chromosome 22q13.3 or sequence variants in SHANK3. Individuals with PMS caused by a 22q terminal deletion and a ring chromosome are at increased risk for Neurofibromatosis type 2 (NF2). However, the prevalence of NF2 in individuals with PMS and a r (22) is unknown.Individuals with PMS and a r (22) chromosome evaluated at the Greenwood Genetic Center (GGC) or by international collaborators, or identified through the PMS International Registry (PMSIR) were contacted and participated in a clinical questionnaire. Forty-four families completed the questionnaire and consented for the study. Of the individuals with a r (22), 7 (16%) carried a diagnosis of NF2. The average age of diagnosis of r (22) was 18 years old in individuals with NF2 and three years old in individuals without NF2 (p-value <0.001). Clinical findings were similar among all individuals in our sample with the exception of hearing loss, present in 57% of individuals with NF2 and 8% of individuals without NF2 (p-value <0.01).This is the largest clinical report of individuals with PMS and a r (22) chromosome. We show a diagnosis of NF2 in individuals with r (22) is not uncommon and may be under ascertained. Moreover, the presentation of NF2 in this cohort is variable and lifelong routine screening for features of NF2 in this population should be considered.     

Improvements in proprioceptive functioning influence multisensory-motor integration in 7- to 13-year-old children

Accurate and efficient sensorimotor behavior depends on precise localization of the body in space, which may be estimated using multiple sensory modalities (i.e., vision and proprioception). Although age-related differences in multisensory-motor integration across childhood have been previously reported, the extent to which age-related changes in unimodal functioning affect multisensory-motor integration is unclear. The purpose of the current study was to address this knowledge gap. Thirty-seven 7- to 13-year-old children moved their dominant hand in a target localization task to visual, proprioceptive, and concurrent visual and proprioceptive stimuli. During a subsequent experimental phase, we introduced a perturbation that placed the concurrent visual and proprioceptive stimuli in conflicting locations (incongruent condition) to determine the relative contributions of vision and proprioception to the multisensory estimate of target position. Results revealed age-related differences in the localization of incongruent stimuli in which the visual estimate of target position contributed more to the multisensory estimate in the younger children whereas the proprioceptive estimate was up-weighted in the older children. Moreover, above and beyond the effects of age, differences in proprioceptive functioning systematically influenced the relative contributions of vision and proprioception to the multisensory estimate during the incongruent trials. Specifically, improvements in proprioceptive functioning resulted in an up-weighting of proprioception, suggesting that the central nervous system of school-aged children utilizes information about unimodal functioning to integrate redundant sensorimotor inputs.     

Atypical central pain processing in sensory modulation disorder: absence of temporal summation and higher after-sensation

Sensory over-responsivity (SOR), a subtype of the proposed sensory modulation disorder (SMD), is characterized by over-responsiveness to stimuli in several sensory modalities. SMD individuals demonstrate abnormal responses to naturally occurring stimuli in a manner that interferes with daily life participation. Previous psychophysical testing of the somatosensory system revealed that SOR individuals rated pain sensations higher than controls, demonstrating hyperalgesia that can be centrally mediated. Temporal summation (TS) of second pain and after-sensation are manifestations of central sensitization; therefore, this study explored these measures for better characterization of central pain processing in SOR. Twelve SOR adults and 12 healthy controls participated. TS was produced by a train of fifteen repetitive heat pulses, 0.7 s duration each, and 2 s of inter-stimulus interval, applied to the thenar-eminence, while four pain ratings were obtained. An after-sensation was then measured for 5 min, obtaining six pain ratings. No TS of pain was indicated in the SOR group (SOR: p = 0.36; control: p < 0.001). Further, while controls reported a gradual disappearance of pain after-sensation, individuals with SOR continued to report pain for the duration of the 5 min measured (p = 0.002). These results demonstrate an atypical response pattern, suggesting alteration in pain processing and/or modulation at a central level in individuals with SOR. These possible neural changes may manifest themselves as interference with daily functioning as well as shed light on some of the between-subject variability seen in psychophysical testing in non-painful subjects.     

Consensus recommendations on organization of care for individuals with Phelan-McDermid syndrome

The manifestations of Phelan-McDermid syndrome (PMS) are complex, warranting expert and multidisciplinary care in all life stages. In the present paper we propose consensus recommendations on the organization of care for individuals with PMS. We indicate that care should consider all life domains, which can be done within the framework of the International Classification of Functioning, Disability and Health (ICF). This framework assesses disability and functioning as the outcome of the individual's interactions with other factors. The different roles within care, such as performed by a centre of expertise, by regional health care providers and by a coordinating physician are addressed. A surveillance scheme and emergency card is provided and disciplines participating in a multidisciplinary team for PMS are described. Additionally, recommendations are provided for transition from paediatric to adult care. This care proposition may also be useful for individuals with other rare genetic neurodevelopmental disorders.     

PMS2 monoallelic mutation carriers: the known unknown

Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors’ research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance.     

Consensus recommendations on mental health issues in Phelan-McDermid syndrome

Phelan-McDermid syndrome is a rare genetic condition caused by a deletion encompassing the 22q13.3 region or a pathogenic variant of the gene SHANK3. The clinical presentation is variable, but main characteristics include global developmental delay/intellectual disability (ID), marked speech impairment or delay, along with other features like hypotonia and somatic or psychiatric comorbidities. This publication delineates mental health, developmental and behavioural themes across the lifetime of individuals with PMS as informed by parents/caregivers, experts, and other key professionals involved in PMS care. We put forward several recommendations based on the available literature concerning mental health and behaviour in PMS. Additionally, this article aims to improve our awareness of the importance of considering developmental level of the individual with PMS when assessing mental health and behavioural issues. Understanding how the discrepancy between developmental level and chronological age may impact concerning behaviours offers insight into the meaning of those behaviours and informs care for individuals with PMS, enabling clinicians to address unmet (mental health) care needs and improve quality of life.     

Does physical anhedonia play a role in depression? A 20-year longitudinal study

BackgroundAnhedonia towards physical or sensory experiences (i.e., physical anhedonia) has most often been examined as a differentia of schizophrenia and not depression, despite the fact that general anhedonia is a core feature of many models of Major Depressive Disorder (MDD).MethodsForty-nine participants with non-psychotic MDD were recruited from inpatient settings and followed-up six times over 20 years. The three aims of the study was to assess a) the stability of physical anhedonia over time, b) whether physical anhedonia relates to the course of depressive symptoms over time, and c) whether physical anhedonia relates to three domains of functioning — work, social functioning, or re-hospitalizations.ResultsWe found that over time physical anhedonia was relatively stable and related to depressive symptoms (both between and within person). Physical anhedonia was also related to certain aspects of functioning, though less robustly than depressive symptoms.LimitationsBecause depressive symptoms, functioning, and physical anhedonia were measured concurrently at each follow-up, the direction of causality among these variables could not be assessed. Additionally, because our sample was recruited from inpatient settings, our findings may not generalize to individuals with less severe depression.ConclusionsA trait tendency to experience decreased pleasure to positive physical stimuli is a clinically meaningful variable for those with MDD and may be a behavioral endophenotype for a more severe form of depression.     

Tactile/proprioceptive integration during arm localization is intact in individuals with Parkinson's disease

It has been theorized that sensorimotor processing deficits underlie Parkinson's disease (PD) motor impairments including movement under proprioceptive control. However, it is possible that these sensorimotor processing deficits exclude tactile/proprioception sensorimotor integration: prior studies show improved movement accuracy in PD with endpoint tactile feedback, and good control in tactile-driven precision-grip tasks. To determine whether tactile/proprioceptive integration in particular is affected by PD, nine subjects with PD (off-medication, UPDRS motor = 19–42) performed an arm-matching task without visual feedback. In some trials one arm touched a static tactile cue that conflicted with dynamic proprioceptive feedback from biceps brachii muscle vibration. This sensory conflict paradigm has characterized tactile/proprioceptive integration in healthy subjects as specific to the context of tactile cue mobility assumptions and the intention to move the arm. We found that the individuals with PD had poorer arm-matching acuracy than age-matched control subjects. However, PD-group accuracy improved with tactile feedback. Furthermore, sensory conflict conditions were resolved in the same context-dependent fashion by both subject groups. We conclude that the somatosensory integration mechanism for prioritizing tactile and proprioception feedback in this task are not disrupted by PD, and are not related to the observed proprioceptive deficits.     

Evidence of generalised mechanical hyperalgesia in patients with advanced knee osteoarthritis undergoing total knee arthroplasty

Background and objective

Persistent pain is reported in up to 34% of patients following total knee arthroplasty (TKA) for management of knee osteoarthritis (KOA). Persistent pain in this group is thought to be at least partly reflective of pain sensory hypersensitivity. The objective of this study was to evaluate sensory hypersensitivity, using mechanical and thermal quantitative sensory testing, in patients about to undergo TKA.

Personality disorders in women with severe premenstrual syndrome

Premenstrual syndrome (PMS) and its more severe form, premenstrual dysphoric disorder, affect up to 18% of women. Both are commonly associated with other mood-related disorders such as major depression, and cause significant life impairment, but their relationship with personality disorders is less clear. After completing the Structured Clinical Interview for DSM-IV-TR disorders, 33 women with severe PMS and 26 asymptomatic women, counterbalanced for menstrual cycle phase, were administered the Structured Interview for DSM-IV Personality Disorders, a diagnostic interview with low transparency, strong inter-rater reliability, and good diagnostic clarity. Women with severe PMS had a higher prevalence of personality disorders (p = 0.003) than asymptomatic women (27% versus 0%), and were more likely to have odd–eccentric, dramatic–erratic, and anxious–fearful personality disorder traits (p < 0.05). Obsessive–compulsive personality disorder (OCPD) was the most common character pathology in the PMS group (n = 6, 18%). OCPD, although not necessarily associated with greater severity of premenstrual symptoms, was related to poorer life functioning in women with PMS. The comorbidity of a personality disorder and severe PMS places an additive burden on general life functioning and may have implications for psychiatric treatment or medication given to those with severe premenstrual symptoms.     

Updated consensus guidelines on the management of Phelan–McDermid syndrome

Phelan–McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype–phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.     

Inhibition of sensory neuronal TRPs contributes to anti-nociception by butamben

Butamben (n-butyl-p-aminobenzoic acid) is a pain-relieving local anesthetic for topical use. Blockade of voltage-gated channel expressed in the peripheral sensory neurons has been suggested as a mechanism of action. Its effects on another sensory neuronal channel family, transient receptor potential (TRP) have remained unclear. In this study we attempted to address this question using six sensory neuronal TRP channel-expressing heterologous systems, cultured sensory neurons and TRP-mediated acute animal pain tests. In Ca²⁺ imaging and whole cell electrophysiology, TRPA1 and TRPV4 were blocked by micromolar butamben. Butamben also activated TRPA1 at millimolar concentrations. The inhibitory effects on the two TRP channels were reproducible in sensory neurons. Moreover, butamben attenuated acute animal pain behaviors in a TRPA1- or TRPV4-dependent manner. Para-aminobenzoic acid (PABA), an analog of a simpler chemical structure, displayed similar in vitro and in vivo properties, suggestive that chemical structure is important for the two TRP-specificity. Our findings suggest that inhibition of TRPA1 and TRPV4 contribute to the peripheral analgesic mechanisms of butamben.     

Single-cell persistent activity in anterodorsal thalamus

The phenotype of neurotrophin-3 (NT-3) null mutant mice is characterized by sensory ataxia and early postnatal death. Previous analysis revealed a severe depletion of peripheral sensory, sympathetic and parasympathetic neurons. Most of the deficits are established early during embryonic development. Whereas absence of proprioceptive afferents can explain the sensory ataxia, the reasons for early postnatal death are unclear. To circumvent the limitations imposed by early mortality of null mutants we generated mouse line expressing NT-3 transgenes driven by the platelet-derived growth factor β-chain (PDGF-β) promoter, which is known to be active in neurons and mesenchyme derivatives. Mice carrying one or two PDGF-NT3 transgenes on a background null for wildtype NT-3 were generated by crossing with an NT-3 null strain. Although still ataxic, mice from this cross could survive for periods longer than a year. Histological analysis revealed a limited rescue of muscle spindles and parvalbumin immunoreactive sensory neurons.     

Sleep disturbances in Phelan-McDermid syndrome: Clinical and metabolic profiling of 56 individuals

Phelan-McDermid Syndrome (PMS) is caused by deletions at chromosome 22q13.3 or pathogenic/likely pathogenic SHANK3 variants. The clinical presentation is extremely variable and includes global developmental delay/intellectual disability (ID), seizures, neonatal hypotonia, and sleep disturbances, among others. This study investigated the prevalence of sleep disturbances, and the genetic and metabolic features associated with them, in a cohort of 56 individuals with PMS. Sleep data were collected via standardized observer/caregiver questionnaires, while genetic data from array-CGH and sequencing of 9 candidate genes within the 22q13.3 region, and metabolic profiling utilized the Biolog Phenotype Mammalian MicroArray plates. Sleep disturbances were present in 64.3% of individuals with PMS, with the most common problem being waking during the night (39%). Sleep disturbances were more prevalent in individuals with a SHANK3 pathogenic variant (89%) compared to subjects with 22q13.3 deletions of any size (59.6%). Distinct metabolic profiles for individuals with PMS with and without sleep disturbances were also identified. These data are helpful information for recognizing and managing sleep disturbances in individuals with PMS, outlining the main candidate gene for this neurological manifestation, and highlighting potential biomarkers for early identification of at-risk subjects and molecular targets for novel treatment approaches.     

Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of lynch syndrome patients

Heterozygous mutations in PMS2 are involved in Lynch syndrome, whereas biallelic mutations are found in Constitutional mismatch repair‐deficiency syndrome patients. Mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL. We investigated the frequency of such events with a nonspecific polymerase chain reaction (PCR) strategy, coamplifying both PMS2 and PMS2CL sequences. This allowed us to score ratios between gene and pseudogene‐specific nucleotides at 29 PSV sites from exon 11 to the end of the gene. We found sequence transfer at all investigated PSVs from intron 12 to the 3′ end of the gene in 4 to 52% of DNA samples. Overall, sequence exchange between PMS2 and PMS2CL was observed in 69% (83/120) of individuals. We demonstrate that mutation scanning with PMS2‐specific PCR primers and MLPA probes, designed on PSVs, in the 3′ duplicated region is unreliable, and present an RNA‐based mutation detection strategy to improve reliability. Using this strategy, we found 19 different putative pathogenic PMS2 mutations. Four of these (21%) are lying in the region with frequent sequence transfer and are missed or called incorrectly as homozygous with several PSV‐based mutation detection methods. Hum Mutat 31:578–587, 2010. © 2010 Wiley‐Liss, Inc.     

Characterization of sensory deficits in TrkB knockout mice

The sensory deficit in TrkB deficient mice was evaluated by counting the neuronal loss in lumbar dorsal root ganglia (DRG), the absence of sensory receptors (cutaneous—associated to the hairy and glabrous skin - muscular and articular), and the percentage and size of the neurocalcin-positive DRG neurons (a calcium-binding protein which labels proprioceptive and mechanoceptive neurons). Mice lacking TrkB lost 32% of neurons, corresponding to the intermediate-sized and neurocalcin-positive ones. This neuronal lost was accomplished by the absence of Meissner corpuscles, and reduction of hair follicle-associated sensory nerve endings and Merkel cells. The mutation was without effect on Pacinian corpuscles, Golgi's organs and muscle spindles. Present results further characterize the sensory deficit of the TrkB−/− mice demonstrating that the intermediate-sized neurons in lumbar DRG, as well as the cutaneous rapidly and slowly adapting sensory receptors connected to them, are under the control of TrkB for survival and differentiation. This study might serve as a baseline for future studies in experimentally induced neuropathies affecting TrkB positive DRG neurons and their peripheral targets, and to use TrkB ligands in the treatment of neuropathies in which cutaneous mechanoreceptors are primarily involved.