SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia.

Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia. The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila. Our results showed that two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals. The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila. These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function.

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.

The Pediatric Physiatric Posterior Fossa Symptoms scale (3PFSs): Impairments and outcome in pediatric inpatient rehabilitation for posterior fossa brain tumors.

BACKGROUND: Clinical recognition of the post-operative neurologic sequelae of posterior fossa tumors is inconsistent. This study aimed to characterize functional impairments and recovery trajectories in pediatric patients admitted to inpatient rehabilitation following surgical resection of posterior fossa brain tumors. This study also introduces the Pediatric Physiatric Posterior Fossa Symptom scale (3PFSs) for serial assessment of post-operative symptoms in pediatric posterior fossa brain tumors. METHODS: This retrospective cohort study included 49 patients aged 1.1 to 19.9 years admitted to a pediatric unit of a free-standing rehabilitation hospital following resection of a posterior fossa brain tumor. Functional Independence Measure for Children (WeeFIM) and 3PFSs scores at admission and discharge were the primary outcome measures. RESULTS: Across the group, WeeFIM score improved from 51.5±23.5 points at admission to 74.2±28.2 points at discharge (t=4.34, p<0.001). The 3PFSs score also showed improvement from 10[IQR=9-12] points at admission to 8[7-10] points at discharge (t=9.3, p<0.0001). While change in both the WeeFIM and 3PFSs captured statistically significant improvement in function, there was low inter-rating correlation (p>0.7). In addition, mortality was correlated with higher discharge 3PFSs score (p=0.007) but not discharge WeeFIM score. CONCLUSION: In pediatric patients with post-operative neurologic sequelae due to posterior fossa brain tumors, inpatient rehabilitation resulted in global and domain specific functional improvements. This initial application of the 3PFSs demonstrates potential applicability for stratifying patients to appropriate levels of rehabilitation, capturing functionally relevant response to rehabilitation treatment, and prognosticating long-term outcomes. These initial results are promising but require additional validation in a larger cohort.

Neuromuscular Scoliosis: When, Who, Why and Outcomes.

Scoliosis has a very high prevalence among patients with neuromuscular disease involving the thoracic spine and truncal muscles. Physical examination and radiographs are used to screen for presence of scoliosis and monitor progression. Management includes therapy participation, optimizing equipment and orthotic use, and possible surgical intervention. Unlike idiopathic adolescent scoliosis, curves tend to progress despite orthotic use compliance. Associated pelvic obliquity creates risk for pressure sores and pain. As such, education of caregivers is a key point of optimizing management.