Recurrent de novo SPTLC2 variant causes childhood-onset amyotrophic lateral sclerosis (ALS) by excess sphingolipid synthesis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons with varying ages of onset, progression and pathomechanisms. Monogenic childhood-onset ALS, although rare, forms an important subgroup of ALS. We recently reported specific SPTLC1 variants resulting in sphingolipid overproduction as a cause for juvenile ALS. Here, we report six patients from six independent families with a recurrent, de novo, heterozygous variant in SPTLC2 c.778G>A [p.Glu260Lys] manifesting with juvenile ALS. METHODS: Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigation of patients' blood and fibroblasts, was performed. RESULTS: All patients presented with early-childhood-onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration in multiple myotomes, without sensory neuropathy. These findings were supported on ancillary testing including nerve conduction studies and electromyography, muscle biopsies and muscle ultrasound studies. Biochemical investigations in plasma and fibroblasts showed elevated levels of ceramides and unrestrained de novo sphingolipid synthesis. Our studies indicate that SPTLC2 variant [c.778G>A, p.Glu260Lys] acts distinctly from hereditary sensory and autonomic neuropathy (HSAN)-causing SPTLC2 variants by causing excess canonical sphingolipid biosynthesis, similar to the recently reported SPTLC1 ALS associated pathogenic variants. Our studies also indicate that serine supplementation, which is a therapeutic in SPTLC1 and SPTCL2-associated HSAN, is expected to exacerbate the excess sphingolipid synthesis in serine palmitoyltransferase (SPT)-associated ALS. CONCLUSIONS: SPTLC2 is the second SPT-associated gene that underlies monogenic, juvenile ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Our findings also have important therapeutic implications: serine supplementation must be avoided in SPT-associated ALS, as it is expected to drive pathogenesis further.

Pharmacokinetics and Proposed Dosing of Levetiracetam in Children With Obesity.

OBJECTIVE: Characterize levetiracetam pharmacokinetics (PK) in children with obesity to inform dosing. METHODS: Children 2 to <21 years old receiving standard of care oral levetiracetam across two opportunistic studies provided blood samples. Levetiracetam plasma PK data were analyzed with a nonlinear mixed-effects modeling approach. Indirect measures for body size and covariates were tested for model inclusion. Individual empirical Bayesian estimates using the final model parameters were compared by obesity status. Monte Carlo simulation using total body weight was performed in children with normal estimated glomerular filtration rate to identify dosing for children with obesity that resulted in comparable exposures to normal weight adults and children after receiving label dosing. RESULTS: The population PK model was developed from 341 plasma concentrations from 169 children. A 1-compartment model best fit the data with fat-free mass as a significant covariate. Compared with children with normal weight, children with obesity had significantly lower body weight-normalized clearance (median [range], 4.77 [1.49-10.44] and 3.71 [0.86-13.55] L/h/70 kg, respectively). After label dosing with the oral formulation in children with obesity 4 to <16 years old, maximum and minimum steady-state concentrations were higher (25% and 41%, respectively [oral solution] and 27% and 19%, respectively [tablet]) compared with children with normal weight. Comparable exposures between children with and without obesity were achieved with weight-tiered dosing regimens of <75 kg or ≥75 kg. CONCLUSIONS: Weight-tiered dosing for levetiracetam oral solution and tablets for children with obesity 4 to <16 years old results in more comparable exposures to children of normal weight.

Leveraging ChatGPT in the Pediatric Neurology Clinic: Practical Considerations for Use to Improve Efficiency and Outcomes.

BACKGROUND: Artificial intelligence (AI) is progressively influencing healthcare sectors, including pediatric neurology. This paper aims to investigate the potential and limitations of using ChatGPT, a large language model (LLM) developed by OpenAI, in an outpatient pediatric neurology clinic. The analysis focuses on the tool's capabilities in enhancing clinical efficiency, productivity, and patient education. METHOD: This is an opinion-based exploration supplemented with practical examples. We assessed ChatGPT's utility in administrative and educational tasks such as drafting medical necessity letters and creating patient educational materials. RESULTS: ChatGPT showed efficacy in streamlining administrative work, particularly in drafting administrative letters and formulating personalized patient education materials. However, the model has limitations in performing higher-order tasks like formulating nuanced differential diagnoses. Additionally, ethical and legal concerns, including data privacy and the potential dissemination of misinformation, warrant cautious implementation. CONCLUSIONS: The integration of AI tools like ChatGPT in pediatric neurology clinics has demonstrated promising results in boosting efficiency and patient education, despite present limitations and ethical concerns. As technology advances, we anticipate future applications may extend to more complex clinical tasks like precise differential diagnoses and treatment strategy guidance. Careful, patient-centered implementation is essential for leveraging the potential benefits of AI in pediatric neurology effectively.

Be in the Digital Room Where it Happens, Part II: Social Media for Neurology Educators.

Social media has changed the way we communicate and interact. Unsurprisingly, it has also changed how we teach and learn. Younger generations of learners have transitioned from traditional educational sources to digital ones. Medical educators need to adapt to trends in medical education and develop fluency in the digital methods used by medical learners today. This is part two of a two-part series on social media and digital education in neurology. This article provides an overview of how social media can be used as a teaching tool in medical education and provides an overview in which it is grounded. We offer practical strategies on how social media can promote lifelong learning, educator development, educator support, and foster educator identity with accompanying neurology-specific examples. We also review considerations for incorporating social media into teaching and learning practices and future directions for integrating these tools in neurology education.

Be in the Digital Room Where it Happens, Part I: Tweeting & Technology for Career Development.

Social media has become a part of everyday life. It has changed the way we obtain and distribute information, connect, and interact with others. As the number of platforms and users grow, medical professionals have learned the value social media can have in education, research, advocacy, and clinical care initiatives. Platforms provide opportunities to network, build collaborations, and develop a reputation. This is part one of a two-part series. This article provides an overview on how social media can benefit professional career development for clinicians and researchers, as well as for advocacy to raise awareness against biases, disparities, and for patient benefit. We review challenges, limitations, and best practices for social media use by medical professionals with neurology-specific examples.

Rhabdomyosarcoma in a Patient With Duchenne Muscular Dystrophy: A Possible Association.

Duchenne muscular dystrophy (DMD), caused by a mutation in the DMD gene, is known to be associated with co-morbidities including cardiomyopathy, respiratory failure, neuromuscular scoliosis and intellectual disability. Animal studies have explored the susceptibility of dystrophin-deficient mice with the development of myogenic tumors. While there is adequate literature describing both DMD and rhabdomyosarcoma (RMS) separately, there has yet to be a comprehensive literature review investigating the possibility that patients with DMD may be at a higher risk of developing RMS and other myogenic tumors. We present the case of a pediatric patient with DMD who developed alveolar RMS and review the literature for susceptibility to development of myogenic tumors in cases of DMD gene mutation.

Aphasic Dystextia as Presenting Feature of Ischemic Stroke in a Pediatric Patient.

Aphasia is an important presenting symptom of acute stroke. With increasing reliance on electronic communication, incoherent texting or "dystextia," which is a subset of aphasia that is reflected in text messages, can be a useful tool for symptom recognition and analysis. It can be a red flag for the family and therefore can help in early identification of an acute neurological deficit. It is also useful for providers to reliably analyze the deficit as well as establish a timeline of evolution of symptoms. There have been case reports where dystextia has been the presenting feature of stroke or complicated migraine and in one case of meningioma. We present the case of a teenage patient that in our knowledge is the youngest reported case of dystextia, whose aphasia recorded in a text message assisted with stroke localization. This also adds to the literature of dystextia which so far has only seven other cases reported.