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Dawood Sayed,1 Timothy Ray Deer,2 Jonathan M Hagedorn,3 Asim Sayed,4 Ryan S D’Souza,3 Christopher M Lam,1 Nasir Khatri,5 Zohra Hussaini,1 Scott G Pritzlaff,6 Newaj Mohammad Abdullah,7 Vinicius Tieppo Francio,1 Steven Michael Falowski,8 Yussr M Ibrahim,9 Mark N Malinowski,10 Ryan R Budwany,2 Natalie Holmes Strand,11 Kamil M Sochacki,12 Anuj Shah,13 Tyler M Dunn,11 Morad Nasseri,14 David W Lee,15 Leonardo Kapural,16 Marshall David Bedder,17,18 Erika A Petersen,19 Kasra Amirdelfan,20 Michael E Schatman,21,22 Jay Samuel Grider23 1Department of Anesthesiology and Pain Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; 2Pain Services, Spine and Nerve Center of the Virginias, Charleston, WV, USA; 3Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA; 4Podiatry/Surgery, Susan B. Allen Memorial Hospital, El Dorado, KS, USA; 5Interventional Pain Medicine, Novant Spine Specialists, Charlotte, NC, USA; 6Department of Anesthesiology and Pain Medicine, University of California, Davis, Sacramento, CA, USA; 7Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA; 8Neurosurgery, Neurosurgical Associates of Lancaster, Lancaster, PA, USA; 9Pain Medicine, Northern Light Eastern Maine Medical Center, Bangor, ME, USA; 10OhioHealth Neurological Physicians, OhioHealth, Columbus, OH, USA; 11Anesthesiology and Pain Medicine, Mayo Clinic, Phoenix, AZ, USA; 12Department of Anesthesiology and Perioperative Medicine, Rutgers Robert Wood Johnson, New Brunswick, NJ, USA; 13Department of Physical Medicine and Rehabilitation, Detroit Medical Center, Detroit, MI, USA; 14Interventional Pain Medicine / Neurology, Boomerang Healthcare, Walnut Creek, CA, USA; 15Pain Management Specialist, Fullerton Orthopedic, Fullerton, CA, USA; 16Carolinas Pain Institute, Winston Salem, NC, USA; 17Chief of Pain Medicine Service, Augusta VAMC, Augusta, GA, USA; 18Associate Professor and Director, Addiction Medicine Fellowship Program, Department Psychiatry and Health Behavior, Medical College of Georgia at Augusta University, Augusta, GA, USA; 19Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 20Director of Clinical Research, Boomerang Healthcare, Walnut Creek, CA, USA; 21Department of Anesthesiology, Perioperative Care & Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 22Department of Population Health – Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USA; 23Anesthesiology, Division of Pain Medicine, University of Kentucky College of Medicine, Lexington, KY, USACorrespondence: Dawood Sayed, Anesthesiology and Pain Medicine, the University of Kansas Medical Center, Kansas City, KS, USA, Tel +1 785-550-5800, Email dsayed@kumc.eduIntroduction: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN.Objective: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN.Methods: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process.Results: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria.Conclusion: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.Keywords: diabetes, painful diabetic neuropathy, neuropathy, spinal cord stimulation, chronic pain, diabetic neuropathy

Sphingolipid homeostatic regulation is important for balancing plant life and death. Plant cells finely tune sphingolipid biosynthesis to ensure sufficient levels to support growth through their basal functions as major components of endomembranes and the plasma membrane. Conversely, accumulation of sphingolipid biosynthetic intermediates, long-chain bases (LCBs) and ceramides, is associated with programmed cell death. Limiting these apoptotic intermediates is important for cell viability, while overriding homeostatic regulation permits cells to generate elevated LCBs and ceramides to respond to pathogens to elicit the hypersensitive response in plant immunity. Key to sphingolipid homeostasis is serine palmitoyltransferase (SPT), an endoplasmic reticulum-associated, multi-subunit enzyme catalyzing the first step in the biosynthesis of LCBs, the defining feature of sphingolipids. Across eukaryotes, SPT interaction with its negative regulator Orosomucoid-like (ORM) is critical for sphingolipid biosynthetic homeostasis. The recent cryo-electron microscopy structure of the Arabidopsis SPT complex indicates that ceramides bind ORMs to competitively inhibit SPT activity. This system provides a sensor for intracellular ceramide concentrations for sphingolipid homeostatic regulation. Combining the newly elucidated Arabidopsis SPT structure and mutant characterization, we present a model for the role of the 2 functionally divergent Arabidopsis ceramide synthase classes to produce ceramides that form repressive (trihydroxy LCB-ceramides) or nonrepressive (dihydroxy LCB-ceramides) ORM interactions to influence SPT activity. We describe how sphingolipid biosynthesis is regulated by the interplay of ceramide synthases with ORM-SPT when "enough is enough" and override homeostatic suppression when "enough is not enough" to respond to environmental stimuli such as microbial pathogen attack., Competing Interests: Conflict of interest statement: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: To assess the degree to which quantitative foveal structural measurements account for variation in best-corrected visual acuity (BCVA) in human albinism., Methods: BCVA was measured and spectral domain optical coherence tomography (SD-OCT) images were acquired for 74 individuals with albinism. Categorical foveal hypoplasia grades were assessed using the Leicester Grading System for Foveal Hypoplasia. Foveal anatomical specialization (foveal versus parafoveal value) was quantified for inner retinal layer (IRL) thickness, outer segment (OS) length, and outer nuclear layer (ONL) thickness. These metrics, participant sex, and age were used to build a multiple linear regression of BCVA. This combined linear model's predictive properties were compared to those of categorical foveal hypoplasia grading., Results: The cohort included three participants with type 1a foveal hypoplasia, 23 participants with type 1b, 33 with type 2, ten with type 3, and five with type 4. BCVA ranged from 0.08 to 1.00 logMAR (mean ± SD: 0.53 ± 0.21). IRL ratio, OS ratio, and ONL ratio were measured in all participants and decreased with increasing severity of foveal hypoplasia. The best-fit combined linear model included all three quantitative metrics and participant age expressed as a binary variable (divided into 0-18 years and 19 years or older; adjusted R2 = 0.500). This model predicted BCVA more accurately than a categorical foveal hypoplasia model (adjusted R2 = 0.352)., Conclusions: A quantitative model of foveal specialization accounts for more variance in BCVA in albinism than categorical foveal hypoplasia grading. Other factors, such as optical aberrations and eye movements, may account for the remaining unexplained variance.

The homeostatic regulation of serine palmitoyltransferase (SPT) activity in yeast involves N-terminal phosphorylation of Orm proteins, while higher eukaryotes lack these phosphorylation sites. Although recent studies have indicated a conserved ceramide-mediated feedback inhibition of the SPT-ORM/ORMDL complex in higher eukaryotes, its conservation and relationship with phosphorylation regulation in yeast remain unclear. Here, we determine the structure of the yeast SPT-Orm2 complex in a dephosphomimetic state and identify an evolutionarily conserved ceramide-sensing site. Ceramide stabilizes the dephosphomimetic Orm2 in an inhibitory conformation, facilitated by an intramolecular β-sheet between the N- and C-terminal segments of Orm2. Moreover, we find that a phosphomimetic mutant of Orm2, positioned adjacent to its intramolecular β-sheet, destabilizes the inhibitory conformation of Orm2. Taken together, our findings suggest that both Orm dephosphorylation and ceramide binding are crucial for suppressing SPT activity in yeast. This highlights a distinctive regulatory mechanism in yeast involving the collaborative actions of phosphorylation and ceramide., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells. They are especially abundant within the lipid portion of myelin. In this review, we will focus on our current understanding of disease phenotypes in three monogenic, neuromuscular diseases associated with pathogenic variants in components of serine palmitoyltransferase, the first step in sphingolipid biosynthesis. These include hereditary sensory and autonomic neuropathy type 1 (HSAN1), a sensory predominant peripheral neuropathy, and two neurodegenerative disorders: juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons, and a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration. We will also review our current understanding of disease pathomechanisms, therapeutic approaches, and the unanswered questions to explore in future studies.

Pott's puffy tumor (PPT) describes forehead swelling with associated frontal bone osteomyelitis and a subperiosteal abscess (SPA) requiring a high suspicion index for optimal outcomes. PPT is a life-threatening complication of frontal sinusitis typically found in adolescents. Our case is one of the youngest in the literature. This report describes a 3-year-old patient who developed multifocal abscesses in the epidural space with frontal and orbital SPA, requiring surgical intervention. Additionally, her course was complicated by a superior sagittal venous thrombosis, a complication commonly associated with PPT. We present an unusual case of orbital SPA and aim to highlight a life-threatening pediatric condition that is often underrecognized., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The number of prenatal genetic screening options, including aneuploidy screening and carrier screening, has drastically increased with rapid advancements in DNA sequencing technologies. Noninvasive prenatal screening analyzing cell-free DNA has quickly been integrated into routine prenatal care as it is the most sensitive and specific screening method for pregnancies at increased and average risk of fetal aneuploidy. The aim of this article is to outline current recommendations for cell-free DNA screening and carrier screening, important aspects of pretest and posttest counseling for obstetric providers, and which patients should be referred to a genetic specialist., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)

The serine palmitoyltransferase (SPT) complex catalyzes the first and rate-limiting step in sphingolipid biosynthesis in all eukaryotes. ORM/ORMDL proteins are negative regulators of SPT that respond to cellular sphingolipid levels. However, the molecular basis underlying ORM/ORMDL-dependent homeostatic regulation of SPT is not well understood. We determined the cryo-electron microscopy structure of Arabidopsis SPT-ORM1 complex, composed of LCB1, LCB2a, SPTssa, and ORM1, in an inhibited state. A ceramide molecule is sandwiched between ORM1 and LCB2a in the cytosolic membrane leaflet. Ceramide binding is critical for the ORM1-dependent SPT repression, and dihydroceramides and phytoceramides differentially affect this repression. A hybrid β sheet, formed by the amino termini of ORM1 and LCB2a and induced by ceramide binding, stabilizes the amino terminus of ORM1 in an inhibitory conformation. Our findings provide mechanistic insights into sphingolipid homeostatic regulation via the binding of ceramide to the SPT-ORM/ORMDL complex that may have implications for plant-specific processes such as the hypersensitive response for microbial pathogen resistance.

Background: Dystroglycanopathies are a heterogeneous group of membrane-related muscular dystrophies. The dystroglycanopathy phenotype includes a spectrum of severity ranging from severe congenital muscular dystrophy to adult-onset limb-girdle muscular dystrophy (LGMD). LGMDR9 is a dystroglycanopathy caused by mutations in the FKRP gene. Previous studies have characterized electroretinogram findings of dystroglycanopathy mouse models but have not been reported in humans., Purpose: This study set out to characterize the electroretinogram in eight participants with LGMDR9., Methods: Eight participants were recruited from an ongoing dystroglycanopathy natural history study at the University of Iowa (NCT00313677). Inclusion criteria for the current study were children and adults > 6 years old with confirmed LGMDR9. Age similar controls were identified from our electrophysiology service normative control database. Full-field electroretinograms were recorded using ISCEV standards. Six of the eight participants underwent light-adapted ON/OFF testing., Results: The electronegative electroretinogram was not seen in any participants with LGMDR9. An unusual sawtooth pattern in the 30 Hz flicker with faster rise than descent was noted in all 8 participants. Our cases showed a decreased b-wave amplitude in light-adapted ON responses (p = 0.011) and decreased d-wave amplitude in light-adapted OFF responses (p = 0.015). Decreased b-wave amplitude in light-adapted 3.0 testing (p = 0.015) and decreased flicker ERG amplitudes were also detected (p = 0.0018). Additionally, compared to controls, participants with LGMDR9 had decreased a-wave amplitudes on dark-adapted 10 testing (p = 0.026)., Conclusions: Abnormal ON/OFF bipolar cell responses and sawtooth 30 Hz flicker waveforms on full-field electroretinogram may be specific for LGMDR9. If confirmed in a larger population and if related to disease stage, these tests are potential biomarkers which could be useful as endpoints in clinical treatment trials., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Since the term orthorexia nervosa (ON) was coined from the Greek (ὀρθός, right and ὄρεξις, appetite) in 1997 to describe an obsession with "correct" eating, it has been used worldwide without a consistent definition. Although multiple authors have proposed diagnostic criteria, and many theoretical papers have been published, no consensus definition of ON exists, empirical primary evidence is limited, and ON is not a standardized diagnosis. These gaps prevent research to identify risk and protective factors, pathophysiology, functional consequences, and evidence-based therapeutic treatments. The aims of the current study are to categorize the common observations and presentations of ON pathology among experts in the eating disorder field, propose tentative diagnostic criteria, and consider which DSM chapter and category would be most appropriate for ON should it be included., Methods: 47 eating disorder researchers and multidisciplinary treatment specialists from 14 different countries across four continents completed a three-phase modified Delphi process, with 75% agreement determined as the threshold for a statement to be included in the final consensus document. In phase I, participants were asked via online survey to agree or disagree with 67 statements about ON in four categories: A-Definition, Clinical Aspects, Duration; B-Consequences; C-Onset; D-Exclusion Criteria, and comment on their rationale. Responses were used to modify the statements which were then provided to the same participants for phase II, a second round of feedback, again in online survey form. Responses to phase II were used to modify and improve the statements for phase III, in which statements that met the predetermined 75% of agreement threshold were provided for review and commentary by all participants., Results: 27 statements met or exceeded the consensus threshold and were compiled into proposed diagnostic criteria for ON., Conclusions: This is the first time a standardized definition of ON has been developed from a worldwide, multidisciplinary cohort of experts. It represents a summary of observations, clinical expertise, and research findings from a wide base of knowledge. It may be used as a base for diagnosis, treatment protocols, and further research to answer the open questions that remain, particularly the functional consequences of ON and how it might be prevented or identified and intervened upon in its early stages. Although the participants encompass many countries and disciplines, further research will be needed to determine if these diagnostic criteria are applicable to the experience of ON in geographic areas not represented in the current expert panel., Level of Evidence: Level V: opinions of expert committees., (© 2022. The Author(s).)

Aims: SPTLC1-related disorder is a late onset sensory-autonomic neuropathy associated with perturbed sphingolipid homeostasis which can be improved by supplementation with the serine palmitoyl-CoA transferase (SPT) substrate, l-serine. Recently, a juvenile form of motor neuron disease has been linked to SPTLC1 variants. Variants affecting the p.S331 residue of SPTLC1 cause a distinct phenotype, whose pathogenic basis has not been established. This study aims to define the neuropathological and biochemical consequences of the SPTLC1 p.S331 variant, and test response to l-serine in this specific genotype., Methods: We report clinical and neurophysiological characterisation of two unrelated children carrying distinct p.S331 SPTLC1 variants. The neuropathology was investigated by analysis of sural nerve and skin innervation. To clarify the biochemical consequences of the p.S331 variant, we performed sphingolipidomic profiling of serum and skin fibroblasts. We also tested the effect of l-serine supplementation in skin fibroblasts of patients with p.S331 mutations., Results: In both patients, we recognised an early onset phenotype with prevalent progressive motor neuron disease. Neuropathology showed severe damage to the sensory and autonomic systems. Sphingolipidomic analysis showed the coexistence of neurotoxic deoxy-sphingolipids with an excess of canonical products of the SPT enzyme. l-serine supplementation in patient fibroblasts reduced production of toxic 1-deoxysphingolipids but further increased the overproduction of sphingolipids., Conclusions: Our findings suggest that p.S331 SPTLC1 variants lead to an overlap phenotype combining features of sensory and motor neuropathies, thus proposing a continuum in the spectrum of SPTLC1-related disorders. l-serine supplementation in these patients may be detrimental., (© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)