Congenital dyserythropoietic anemia type IV in the genetic era: A rare neonatal case report of rapid identification with a review of the literature.

Congenital dyserythropoietic anemia type IV (CDAIV) is a rare inherited hematological disorder, presenting with severe anemia due to altered erythropoiesis and hemolysis, with variable needs for recurrent transfusions. We present a case of a transfusion-dependent male newborn who presented at birth with severe hemolytic anemia, and required an intrauterine transfusion. Genetic testing rapidly identified a Kruppel-like factor 1 (KLF1) pathogenic variant (c.973G>A, p.E325K), known to be causative for CDAIV. This case highlights the advantages of next-generation sequencing testing for congenital hemolytic anemia: diagnostic speed, guidance on natural history, and optimized clinical management and anticipatory guidance for parents and clinicians. Additionally, we reviewed the literature for all CDAIV cases.

Resident Match During the COVID Pandemic: How Have Neurology Programs Adapted? - A Survey.

BACKGROUND: We aimed to evaluate the perceived effectiveness of interventions implemented by Canadian neurology residency programs for the 2020-2021 iteration of the Canadian Resident Matching Service (CaRMS). METHODS: A cross-sectional survey was distributed to Canadian neurology residency programs and final-year Canadian medical students who applied to at least one neurology program during the 2020-2021 match cycle. The surveys evaluated pre-interview and interview period interventions implemented by Canadian neurology residency programs and accessed by medical students. RESULTS: Thirty-five medical students and 13 out of 15 institutions in Canada with neurology residency programs responded to the survey. Multiple adaptations were implemented, including social media advertisement, web-based platforms, pre-interview information sessions, and teaching sessions, with all surveyed programs implementing at least two virtual interventions. We found that all interventions were perceived as adequate by a majority (>60%) of medical students, with pre-interview period virtual information sessions perceived as effective by the largest proportion of respondents. All Canadian neurology residency programs held virtual interviews for the 2020-2021 cycle, and most programs utilized the same interview structure as prior years. There was discordance between residency program stakeholders and medical students on the most helpful interview period modality. Medical students found the hospital tours and information sessions most valuable, whereas program stakeholders perceived the virtual socials and interviews as most helpful. CONCLUSION: The COVID-19 pandemic has led to innovative adaptations implemented by Canadian neurology residency programs, which were seen as effective by both medical students and program stakeholders.

Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants.

BACKGROUND: Nasal continuous positive airway pressure (NCPAP) is a strategy to maintain positive airway pressure throughout the respiratory cycle through the application of a bias flow of respiratory gas to an apparatus attached to the nose. Early treatment with NCPAP is associated with decreased risk of mechanical ventilation exposure and might reduce chronic lung disease. Nasal intermittent positive pressure ventilation (NIPPV) is a form of noninvasive ventilation delivered through the same nasal interface during which patients are exposed to short inflations, along with background end-expiratory pressure. OBJECTIVES: To examine the risks and benefits of early (within the first six hours after birth) NIPPV versus early NCPAP for preterm infants at risk of or with respiratory distress syndrome (RDS). Primary endpoints are respiratory failure and the need for intubated ventilatory support during the first week of life. Secondary endpoints include the incidence of mortality, chronic lung disease (CLD) (oxygen therapy at 36 weeks' postmenstrual age), pneumothorax, duration of respiratory support, duration of oxygen therapy, and intraventricular hemorrhage (IVH). SEARCH METHODS: Searches were conducted in January 2023 in CENTRAL, MEDLINE, Embase, Web of Science, and Dissertation Abstracts. The reference lists of related systematic reviews and of studies selected for inclusion were also searched. SELECTION CRITERIA: We considered all randomized and quasi-randomized controlled trials. Eligible studies compared NIPPV versus NCPAP treatment, starting within six hours after birth in preterm infants (< 37 weeks' gestational age (GA)). DATA COLLECTION AND ANALYSIS: We collected and analyzed data using the recommendations of the Cochrane Neonatal Review Group. MAIN RESULTS: We included 17 trials, enrolling 1958 infants in this review. NIPPV likely reduces the rate of respiratory failure (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.54 to 0.78; risk difference (RD) -0.08, 95% CI -0.12 to -0.05; 17 RCTs, 1958 infants; moderate-certainty evidence) and needing endotracheal tube ventilation (RR 0.67, 95% CI 0.56 to 0.81; RD -0.07, 95% CI -0.11 to -0.04; 16 RCTs; 1848 infants; moderate-certainty evidence) amongst infants treated with early NIPPV compared with early NCPAP. The meta-analysis demonstrated that NIPPV may reduce the risk of developing CLD compared to CPAP (RR 0.70, 95% CI 0.52 to 0.92; 12 RCTs, 1284 infants; low-certainty evidence) slightly. NIPPV may result in little to no difference in mortality (RR 0.82, 95% CI 0.62 to 1.10; 17 RCTs; 1958 infants; I2 of 0%; low-certainty evidence), the incidence of pneumothorax (RR 0.92, 95% CI 0.60 to 1.41; 16 RCTs; 1674 infants; I2 of 0%; low-certainty evidence), and rates of severe IVH (RR 0.98, 95% CI 0.53 to 1.79; 8 RCTs; 977 infants; I2 of 0%; low-certainty evidence). AUTHORS' CONCLUSIONS: When applied within six hours after birth, NIPPV likely reduces the risk of respiratory failure and the need for intubation and endotracheal tube ventilation in very preterm infants (GA 28 weeks and above) with respiratory distress syndrome or at risk for RDS. It may also decrease the rate of CLD slightly. However, most trials enrolled infants with a gestational age of approximately 28 to 32 weeks with an overall mean gestational age of around 30 weeks. As such, the results of this review may not apply to extremely preterm infants that are most at risk of needing mechanical ventilation or developing CLD. Additional studies are needed to confirm these results and to assess the safety of NIPPV compared with NCPAP alone in a larger patient population.

Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation.

BACKGROUND: Nasal continuous positive airway pressure (NCPAP) is a useful method for providing respiratory support after extubation. Nasal intermittent positive pressure ventilation (NIPPV) can augment NCPAP by delivering ventilator breaths via nasal prongs. OBJECTIVES: Primary objective To determine the effects of management with NIPPV versus NCPAP on the need for additional ventilatory support in preterm infants whose endotracheal tube was removed after a period of intermittent positive pressure ventilation. Secondary objectives To compare rates of abdominal distension, gastrointestinal perforation, necrotising enterocolitis, chronic lung disease, pulmonary air leak, mortality, duration of hospitalisation, rates of apnoea and neurodevelopmental status at 18 to 24 months for NIPPV and NCPAP. To compare the effect of NIPPV versus NCPAP delivered via ventilators versus bilevel devices, and assess the effects of the synchronisation of ventilation, and the strength of interventions in different economic settings. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was January 2023. SELECTION CRITERIA: We included randomised and quasi-randomised trials of ventilated preterm infants (less than 37 weeks' gestational age (GA)) ready for extubation to non-invasive respiratory support. Interventions were NIPPV and NCPAP. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. respiratory failure. Our secondary outcomes were 2. endotracheal reintubation, 3. abdominal distension, 4. gastrointestinal perforation, 5. necrotising enterocolitis (NEC), 6. chronic lung disease, 7. pulmonary air leak, 8. mortality, 9. hospitalisation, 10. apnoea and bradycardia, and 11. neurodevelopmental status. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 19 trials (2738 infants). Compared to NCPAP, NIPPV likely reduces the risk of respiratory failure postextubation (risk ratio (RR) 0.75, 95% confidence interval (CI) 0.67 to 0.84; number needed to treat for an additional beneficial outcome (NNTB) 11, 95% CI 8 to 17; 19 trials, 2738 infants; moderate-certainty evidence) and endotracheal reintubation (RR 0.78, 95% CI 0.70 to 0.87; NNTB 12, 95% CI 9 to 25; 17 trials, 2608 infants, moderate-certainty evidence), and may reduce pulmonary air leaks (RR 0.57, 95% CI 0.37 to 0.87; NNTB 50, 95% CI 33 to infinite; 13 trials, 2404 infants; low-certainty evidence). NIPPV likely results in little to no difference in gastrointestinal perforation (RR 0.89, 95% CI 0.58 to 1.38; 8 trials, 1478 infants, low-certainty evidence), NEC (RR 0.86, 95% CI 0.65 to 1.15; 10 trials, 2069 infants; moderate-certainty evidence), chronic lung disease defined as oxygen requirement at 36 weeks (RR 0.93, 95% CI 0.84 to 1.05; 9 trials, 2001 infants; moderate-certainty evidence) and mortality prior to discharge (RR 0.81, 95% CI 0.61 to 1.07; 11 trials, 2258 infants; low-certainty evidence). When considering subgroup analysis, ventilator-generated NIPPV likely reduces respiratory failure postextubation (RR 0.49, 95% CI 0.40 to 0.62; 1057 infants; I2 = 47%; moderate-certainty evidence), while bilevel devices (RR 0.95, 95% CI 0.77 to 1.17; 716 infants) or a mix of both ventilator-generated and bilevel devices likely results in little to no difference (RR 0.87, 95% CI 0.73 to 1.02; 965 infants). AUTHORS' CONCLUSIONS: NIPPV likely reduces the incidence of extubation failure and the need for reintubation within 48 hours to one-week postextubation more effectively than NCPAP in very preterm infants (GA 28 weeks and above). There is a paucity of data for infants less than 28 weeks' gestation. Pulmonary air leaks were also potentially reduced in the NIPPV group. However, it has no effect on other clinically relevant outcomes such as gastrointestinal perforation, NEC, chronic lung disease or mortality. Ventilator-generated NIPPV appears superior to bilevel devices in reducing the incidence of respiratory failure postextubation failure and need for reintubation. Synchronisation used to deliver NIPPV may be important; however, data are insufficient to support strong conclusions. Future trials should enrol a sufficient number of infants, particularly those less than 28 weeks' GA, to detect differences in death or chronic lung disease and should compare different categories of devices, establish the impact of synchronisation of NIPPV on safety and efficacy of the technique as well as the best combination of settings for NIPPV (rate, peak pressure and positive end-expiratory). Trials should strive to match the mean airway pressure between the intervention groups to allow a better comparison. Neurally adjusted ventilatory assist needs further assessment with properly powered randomised trials.

Central and peripheral delivered AAV9-SMN are both efficient but target different pathomechanisms in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of the SMN1 gene and low SMN protein levels. Although lower motor neurons are a primary target, there is evidence that peripheral organ defects contribute to SMA. Current SMA gene therapy and clinical trials use a single intravenous bolus of the blood-brain-barrier penetrant scAAV9-cba-SMN by either systemic or central nervous system (CNS) delivery, resulting in impressive amelioration of the clinical phenotype but not a complete cure. The impact of scAAV9-cba-SMN treatment regimens on the CNS as well as on specific peripheral organs is yet to be described in a comparative manner. Therefore, we injected SMA mice with scAAV9-cba-SMN either intravenously (IV) for peripheral SMN restoration or intracerebroventricularly (ICV) for CNS-focused SMN restoration. In our system, ICV injections increased SMN in peripheral organs and the CNS while IV administration increased SMN in peripheral tissues only, largely omitting the CNS. Both treatments rescued several peripheral phenotypes while only ICV injections were neuroprotective. Surprisingly, both delivery routes resulted in a robust rescue effect on survival, weight, and motor function, which in IV-treated mice relied on peripheral SMN restoration but not on targeting the motor neurons. This demonstrates the independent contribution of peripheral organs to SMA pathology and suggests that treatments should not be restricted to motor neurons.

Survival motor neuron protein deficiency alters microglia reactivity.

Survival motor neuron (SMN) protein deficiency results in loss of alpha motor neurons and subsequent muscle atrophy in patients with spinal muscular atrophy (SMA). Reactive microglia have been reported in SMA mice and depleting microglia rescues the number of proprioceptive synapses, suggesting a role in SMA pathology. Here, we explore the contribution of lymphocytes on microglia reactivity in SMA mice and investigate how SMN deficiency alters the reactive profile of human induced pluripotent stem cell (iPSC)-derived microglia. We show that microglia adopt a reactive morphology in spinal cords of SMA mice. Ablating lymphocytes did not alter the reactive morphology of SMA microglia and did not improve the survival or motor function of SMA mice, indicating limited impact of peripheral immune cells on the SMA phenotype. We found iPSC-derived SMA microglia adopted an amoeboid morphology and displayed a reactive transcriptome profile, increased cell migration, and enhanced phagocytic activity. Importantly, cell morphology and electrophysiological properties of motor neurons were altered when they were incubated with conditioned media from SMA microglia. Together, these data reveal that SMN-deficient microglia adopt a reactive profile and exhibit an exaggerated inflammatory response with potential impact on SMA neuropathology.

Metabolic Dysfunction in Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense oligonucleotide treatment and gene therapy have made it possible for SMA patients to benefit from improvements in many aspects of the once devastating natural history of the disease. How the depletion of survival motor neuron (SMN) protein, the product of the gene implicated in the disease, leads to the consequent pathogenic changes remains unresolved. Over the past few years, evidence toward a potential contribution of gastrointestinal, metabolic, and endocrine defects to disease phenotype has surfaced. These findings ranged from disrupted body composition, gastrointestinal tract, fatty acid, glucose, amino acid, and hormonal regulation. Together, these changes could have a meaningful clinical impact on disease traits. However, it is currently unclear whether these findings are secondary to widespread denervation or unique to the SMA phenotype. This review provides an in-depth account of metabolism-related research available to date, with a discussion of unique features compared to other motor neuron and related disorders.

Immune dysregulation may contribute to disease pathogenesis in spinal muscular atrophy mice.

Spinal muscular atrophy (SMA) has long been solely considered a neurodegenerative disorder. However, recent work has highlighted defects in many other cell types that could contribute to disease aetiology. Interestingly, the immune system has never been extensively studied in SMA. Defects in lymphoid organs could exacerbate disease progression by neuroinflammation or immunodeficiency. Smn depletion led to severe alterations in the thymus and spleen of two different mouse models of SMA. The spleen from Smn depleted mice was dramatically smaller at a very young age and its histological architecture was marked by mislocalization of immune cells in the Smn2B/- model mice. In comparison, the thymus was relatively spared in gross morphology but showed many histological alterations including cortex thinning in both mouse models at symptomatic ages. Thymocyte development was also impaired as evidenced by abnormal population frequencies in the Smn2B/- thymus. Cytokine profiling revealed major changes in different tissues of both mouse models. Consistent with our observations, we found that survival motor neuron (Smn) protein levels were relatively high in lymphoid organs compared to skeletal muscle and spinal cord during postnatal development in wild type mice. Genetic introduction of one copy of the human SMN2 transgene was enough to rescue splenic and thymic defects in Smn2B/- mice. Thus, Smn is required for the normal development of lymphoid organs, and altered immune function may contribute to SMA disease pathogenesis.

Oligodendrocyte development and CNS myelination are unaffected in a mouse model of severe spinal muscular atrophy.

The childhood neurodegenerative disease spinal muscular atrophy (SMA) is caused by loss-of-function mutations or deletions in the Survival Motor Neuron 1 (SMN1) gene resulting in insufficient levels of survival motor neuron (SMN) protein. Classically considered a motor neuron disease, increasing evidence now supports SMA as a multi-system disorder with phenotypes discovered in cortical neuron, astrocyte, and Schwann cell function within the nervous system. In this study, we sought to determine whether Smn was critical for oligodendrocyte (OL) development and central nervous system myelination. A mouse model of severe SMA was used to assess OL growth, migration, differentiation and myelination. All aspects of OL development and function studied were unaffected by Smn depletion. The tremendous impact of Smn depletion on a wide variety of other cell types renders the OL response unique. Further investigation of the OLs derived from SMA models may reveal disease modifiers or a compensatory mechanism allowing these cells to flourish despite the reduced levels of this multifunctional protein.

Myogenic program dysregulation is contributory to disease pathogenesis in spinal muscular atrophy.

Mutations in the survival motor neuron (SMN1) gene lead to the neuromuscular disease spinal muscular atrophy (SMA). Although SMA is primarily considered as a motor neuron disease, the importance of muscle defects in its pathogenesis has not been fully examined. We use both primary cell culture and two different SMA model mice to demonstrate that reduced levels of Smn lead to a profound disruption in the expression of myogenic genes. This disruption was associated with a decrease in myofiber size and an increase in immature myofibers, suggesting that Smn is crucial for myogenic gene regulation and early muscle development. Histone deacetylase inhibitor trichostatin A treatment of SMA model mice increased myofiber size, myofiber maturity and attenuated the disruption of the myogenic program in these mice. Taken together, our work highlights the important contribution of myogenic program dysregulation to the muscle weakness observed in SMA.

MD/PhD Training in Canada: Results from a national trainee and program director review.

PURPOSE: There has been limited examination of clinician scientist training in Canada, particularly regarding training integration and funding. This study assessed program structure, funding, tuition and mentorship structures available at Canadian MD/PhD programs. METHODS: Clinician Investigator Trainee Association of Canada administered an anonymous survey to current trainees and program directors that captured program structure, trainee funding, tuition and mentorship opportunities and needs across institutions. RESULTS: In June 2015, 101/228 (44%) trainees and 9/13 (69%) program directors completed the online survey. In all programs, students completed the PhD degree prior to clerkship training. Seven programs offered research training upon completion of pre-clerkship, four offered concurrent clinical and research training, and three offered alternative structures. Nine held seminars exposing students to clinical and research integration and two offered clinician scientist skills courses. Stipend funding and tuition varied, especially during clinical training years. Regarding mentorship, all programs held regular meetings, though eight programs do not have formal mentorship opportunities. Both trainees and program directors identified the need for further career planning and development support as a student priority. CONCLUSION: MD/PhD programs varied by program structure, funding, tuition and mentorship opportunities. Mechanisms to share and spread program innovations should be instated. Students may benefit from concurrent research and clinical training as well as courses specific to clinician scientist skill development. Decreasing debt burden may attract and retain trainees in this demanding path. To ensure mentorship programs align with trainee priorities, program directors should directly collaborate with students in their development and evaluation.

Suppression of the necroptotic cell death pathways improves survival in Smn 2B/- mice.

Spinal muscular atrophy (SMA) is a monogenic neuromuscular disease caused by low levels of the Survival Motor Neuron (SMN) protein. Motor neuron degeneration is the central hallmark of the disease. However, the SMN protein is ubiquitously expressed and depletion of the protein in peripheral tissues results in intrinsic disease manifestations, including muscle defects, independent of neurodegeneration. The approved SMN-restoring therapies have led to remarkable clinical improvements in SMA patients. Yet, the presence of a significant number of non-responders stresses the need for complementary therapeutic strategies targeting processes which do not rely solely on restoring SMN. Dysregulated cell death pathways are candidates for SMN-independent pathomechanisms in SMA. Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 have been widely recognized as critical therapeutic targets of necroptosis, an important form of programmed cell death. In addition, Caspase-1 plays a fundamental role in inflammation and cell death. In this study, we evaluate the role of necroptosis, particularly RIPK3 and Caspase-1, in the Smn 2B/- mouse model of SMA. We have generated a triple mutant (TKO), the Smn 2B/-; Ripk3 -/-; Casp1 -/- mouse. TKO mice displayed a robust increase in survival and improved motor function compared to Smn 2B/- mice. While there was no protection against motor neuron loss or neuromuscular junction pathology, larger muscle fibers were observed in TKO mice compared to Smn 2B/- mice. Our study shows that necroptosis modulates survival, motor behavior and muscle fiber size independent of SMN levels and independent of neurodegeneration. Thus, small-molecule inhibitors of necroptosis as a combinatorial approach together with SMN-restoring drugs could be a future strategy for the treatment of SMA.

SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn2B/- mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn2B/- mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn2B/- mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH). METHODS: Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used. RESULTS: The Smn2B/- mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to non-esterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced ß-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn2B/- mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia. CONCLUSIONS: The Smn2B/- mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.

Blood Flow to the Spleen is Altered in a Mouse Model of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disorder affecting young children. While pre-clinical models of SMA show small spleens, the same is not true in humans. Here, we show by doppler ultrasonography decreased splenic blood flow in Smn2B/- mice. Further, AAV9-SMN gene therapy does not rescue the distal ear and tail necrosis nor the spleen size in these mice, suggesting that the latter may be linked to a cardiovascular defect. Absence of smaller spleens in human patients is likely due to differences in presentation of defects in SMA between pre-clinical mouse models and human patients, particularly the susceptibility to cardiovascular issues.

Motor transmission defects with sex differences in a new mouse model of mild spinal muscular atrophy.

BACKGROUND: Mouse models of mild spinal muscular atrophy (SMA) have been extremely challenging to generate. This paucity of model systems has limited our understanding of pathophysiological events in milder forms of the disease and of the effect of SMN depletion during aging. METHODS: A mild mouse model of SMA, termed Smn2B/-;SMN2+/-, was generated by crossing Smn-/-;SMN2 and Smn2B/2B mice. This new model was characterized using behavioral testing, histology, western blot, muscle-nerve electrophysiology as well as ultrasonography to study classical SMA features and extra-neuronal involvement. FINDINGS: Smn2B/-;SMN2+/- mice have normal survival, mild but sustained motor weakness, denervation and neuronal/neuromuscular junction (NMJ) transmission defects, and neurogenic muscle atrophy that are more prominent in male mice. Increased centrally located nuclei, intrinsic contractile and relaxation muscle defects were also identified in both female and male mice, with some male predominance. There was an absence of extra-neuronal pathology. INTERPRETATION: The Smn2B/-;SMN2+/- mouse provides a model of mild SMA, displaying some hallmark features including reduced weight, sustained motor weakness, electrophysiological transmission deficit, NMJ defects, and muscle atrophy. Early and prominent increase central nucleation and intrinsic electrophysiological deficits demonstrate the potential role played by muscle in SMA disease. The use of this model will allow for the understanding of the most susceptible pathogenic molecular changes in motor neurons and muscles, investigation of the effects of SMN depletion in aging, sex differences and most importantly will provide guidance for the currently aging SMA patients treated with the recently approved genetic therapies. FUNDING: This work was supported by Cure SMA/Families of SMA Canada (grant numbers KOT-1819 and KOT-2021); Muscular Dystrophy Association (USA) (grant number 575466); and Canadian Institutes of Health Research (CIHR) (grant number PJT-156379).

Low fat diets increase survival of a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disorder leading to paralysis and death. Recent evidence shows increased susceptibility to dyslipidemia and liver steatosis in patients. Here, we provide evidence that low fat diets nearly double survival in Smn2B/- mice, a model for SMA, independent of changes in SMN levels, liver steatosis, or enhanced hepatic functions. Liver damage and ketone levels were reduced, implying a lower reliance on fatty acid oxidation. This preclinical proof of concept study provides grounds for controlled clinical investigation of dietary needs and offers evidence to inform nutritional guidelines specific to SMA.

Impaired kidney structure and function in spinal muscular atrophy.

OBJECTIVE: To determine changes in serum profiles and kidney tissues from patients with spinal muscular atrophy (SMA) type 1 compared with age- and sex-matched controls. METHODS: In this cohort study, we investigated renal structure and function in infants and children with SMA type 1 in comparison with age- and sex-matched controls. RESULTS: Patients with SMA had alterations in serum creatinine, cystatin C, sodium, glucose, and calcium concentrations, granular casts and crystals in urine, and nephrocalcinosis and fibrosis. Nephrotoxicity and polycystic kidney disease PCR arrays revealed multiple differentially expressed genes, and immunoblot analysis showed decreased calcium-sensing receptors and calbindin and increased insulin-like growth factor-binding proteins in kidneys from patients with SMA. CONCLUSIONS: These findings demonstrate that patients with SMA type 1, in the absence of disease-modifying therapies, frequently manifest impaired renal function as a primary or secondary consequence of their disease. This study provides new insights into systemic contributions to SMA disease pathogenesis and the need to identify coadjuvant therapies.

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy.

OBJECTIVE: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra-neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease. METHODS: We analyzed clinical data collected from a large cohort of pediatric SMA type I-III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA. RESULTS: We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/- mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non-alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation. INTERPRETATION: This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.

Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice.

The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn-/-;SMN2 and Smn2B/- mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling.

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation.

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by motor neuron degeneration, although defects in multiple cell types and tissues have also been implicated. Three independent laboratories recently identified immune organ defects in SMA. We therefore propose a novel pathogenic mechanism contributory to SMA, resulting in higher susceptibility to infection and exacerbated disease progression caused by neuroinflammation. Overall, compromised immune function could significantly affect survival and quality of life of SMA patients. We highlight the recent findings in immune organ defects, their potential consequences on patients, our understanding of neuroinflammation in SMA, and new research hypotheses in SMA pathogenesis.