Brain Magnetic Resonance Imaging Abnormalities in Acute Flaccid Myelitis.

BACKGROUND: Acute flaccid myelitis (AFM) presents with acute onset of flaccid paralysis with involvement of the gray matter on magnetic resonance imaging (MRI) of the spinal cord. Studies have reported brain MRI abnormalities, but the characteristics have not been fully defined. In this multicenter study, we assessed the acute features and evolution of brain MRI abnormalities in AFM. METHODS: We reviewed brain MRIs of patients with AFM who presented to four referral hospitals between 2012 and 2018. Cases met established criteria for AFM. We analyzed the initial and follow-up brain MRIs. Areas were divided into supratentorial, infratentorial, and subdivisions within those regions. RESULTS: A total of 66 patients were included. Brain MRI abnormalities were present in 34 (52%). Infratentorial abnormalities were more common, occurring in 33 (97%) cases with the dorsal pons being the most frequently affected area (88%). Abnormalities were also present in the medulla (74%), cerebellum (41%), and midbrain (38%). Nine subjects (26%) exhibited both supratentorial and infratentorial abnormalities, whereas isolated supratentorial changes were present in only one (3%). Contrast-enhancing abnormalities were encountered in 9% of cases and meningeal involvement in 6%. On follow-up, most abnormalities, 20 of 24 (83%), were stable, improving, or had resolved. CONCLUSIONS: Brain MRI abnormalities occur in about half of the cases of AFM and commonly resolve with time. Dorsal pontine involvement is a characteristic MRI feature, whereas isolated supratentorial abnormalities are rare. Clinicians should consider that brain imaging abnormalities do not exclude a diagnosis of AFM in patients with typical presentations.

Primary oxidative phosphorylation defects lead to perturbations in the human B cell repertoire.

Introduction: The majority of studies on oxidative phosphorylation in immune cells have been performed in mouse models, necessitating human translation. To understand the impact of oxidative phosphorylation (OXPHOS) deficiency on human immunity, we studied children with primary mitochondrial disease (MtD). Methods: scRNAseq analysis of peripheral blood mononuclear cells was performed on matched children with MtD (N = 4) and controls (N = 4). To define B cell function we performed phage display immunoprecipitation sequencing on a cohort of children with MtD (N = 19) and controls (N = 16). Results: Via scRNAseq, we found marked reductions in select populations involved in the humoral immune response, especially antigen presenting cells, B cell and plasma populations, with sparing of T cell populations. MTRNR2L8, a marker of bioenergetic stress, was significantly elevated in populations that were most depleted. mir4485, a miRNA contained in the intron of MTRNR2L8, was co-expressed. Knockdown studies of mir4485 demonstrated its role in promoting survival by modulating apoptosis. To determine the functional consequences of our findings on humoral immunity, we studied the antiviral antibody repertoire in children with MtD and controls using phage display and immunoprecipitation sequencing. Despite similar viral exposomes, MtD displayed antiviral antibodies with less robust fold changes and limited polyclonality. Discussion: Overall, we show that children with MtD display perturbations in the B cell repertoire which may impact humoral immunity and the ability to clear viral infections.

Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.

BACKGROUND: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to pathogens and neurodegeneration. We sought to examine transcriptional changes between MtD patients and healthy controls to identify common gene signatures of immune dysregulation in MtD. METHODS: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways. RESULTS: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1ß and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction. CONCLUSIONS: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.

Epitope-level profiling in children with mitochondrial disease reveals limitations in the antibacterial antibody repertoire.

INTRODUCTION: Immunometabolic studies in mice have suggested the importance of oxidative phosphorylation (OXPHOS) in humoral immunity. However, there are important distinctions between murine and human immunity. Furthermore, translational studies on the role of OXPHOS in humoral immunity are nearly absent from the biomedical literature. Children with primary OXPHOS deficiency (i.e., mitochondrial disease, MtD), are an important patient population for demonstrating the functional effects of this bioenergetic defect on humoral immunity. METHODS: To define whether OXPHOS deficiency extended to human B cells, we performed extracellular flux analysis on lymphoblastoid B cell lines from children with MtD and controls (N = 4/group). To expand the immune phenotype of B cell OXPHOS deficiency, we conducted a cross-sectional multiplex serology study of the antibacterial antibody repertoire in children with MtD (N = 16) and controls (N = 16) using phage display and immunoprecipitation sequencing (PhIPseq). The PhIPseq library contained >3000 peptides (i.e., epitopes) covering >40 genera and > 150 species of bacteria that infect humans. RESULTS: B cell lymphoblastoid cell lines from children with MtD displayed depressed baseline oxygen consumption, ATP production and reserve capacity, indicating that OXPHOS deficiency extended to these key cells in humoral immunity. Characterization of the bacterial exposome revealed comparable bacterial species between the two groups, mostly Streptococcus and Staphylococcus. The most common species of bacteria was S. pneumoniae. By interrogating the antibacterial antibody repertoire, we found that children with MtD had less robust antibody fold changes to common epitopes. Furthermore, we also found that children with MtD failed to show a direct relationship between the number of bacterial epitopes recognized and age, unlike controls. OXPHOS deficiency extends to B cells in children with MtD, leading to limitations in the antibacterial antibody repertoire. Furthermore, the timing of bacterial exposures was asynchronous, suggesting different periods of increased exposure or susceptibility. CONCLUSIONS: Overall, the antibacterial humoral response is distinctive in children with MtD, suggesting an important role for OXPHOS in B cell function.

Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.

Background: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyperresponsiveness to pathogens and neurodegeneration. Methods: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways. Results: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1ß and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction. Conclusions: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.

Comprehensive profiling of the human viral exposome in households containing an at-risk child with mitochondrial disease during the 2020-2021 COVID-19 pandemic.

BACKGROUND: Viral infection is a major cause of morbidity in children with mitochondrial disease (MtD). As a result, families with children with MtD are highly adherent to risk mitigation behaviours (RMBs) advised by the Centers for Disease Control and Prevention during the COVID-19 pandemic that can modulate infection risk. METHODS: Deep serologic phenotyping of viral infections was performed via home-based sampling by combining SARS-CoV-2 serologic testing and phage display immunoprecipitation and sequencing. Samples were collected approximately 1 year apart (October 2020 to April 2021 and October 2021 to March 2022) on households containing a child with MtD. RESULTS: In contrast to our first collection in 2020-2021, SARS-CoV-2 antibody profiles for all participants in 2021-2022 were marked by greater isotype diversity and the appearance of neutralizing antibodies. Besides SARS-CoV-2, households (N = 15) were exposed to >38 different respiratory and gastrointestinal viruses during the study, averaging five viral infections per child with MtD. Regarding clinical outcomes, children with MtD (N = 17) experienced 34 episodes of illness resulting in 6 hospitalizations, with some children experiencing multiple episodes. Neurologic events following illness were recorded in five patients. Infections were identified via clinical testing in only seven cases. Viral exposome profiles were consistent with clinical testing and even identified infections not captured by clinical testing. CONCLUSIONS: Despite reported adherence to RMBs during the COVID-19 pandemic by families with a child with MtD, viral infection was pervasive. Not all infections resulted in illness in the child with MtD, suggesting that some were subclinical or asymptomatic. However, selected children with MtD did experience neurologic events. Our studies emphasize that viral infections are inexorable, emphasizing the need for further understanding of host-pathogen interactions through broad serologic surveillance.

Short report: Vaccine attitudes in the age of COVID-19 for a population of children with mitochondrial disease.

BACKGROUND: Children with developmental disabilities are vulnerable to morbidity associated with COVID-19. AIMS: To understand attitudes toward routine childhood vaccinations versus the COVID-19 vaccine in a population of families affected by mitochondrial disease (MtD), a form of developmental disability. METHODS AND PROCEDURES: An online survey was administered via several advocacy groups for children with MtD. OUTCOMES AND RESULT: Eighty-six percent of families reported being up to date with the childhood vaccine schedule and seventy percent reported that their affected child receives the annual flu shot. However, only fifty percent reported that the benefits of the COVID-19 vaccine outweighed the risk for their affected child. One quarter of families expressed concern that their child may become sick or deteriorate after the COVID-19 vaccine. In comparison to other routine childhood vaccines, families expressed less confidence in the COVID-19 vaccine. CONCLUSIONS AND IMPLICATIONS: Families affected by this population of developmental disabilities are more comfortable with the vaccines included in the routine childhood immunization schedule than with the newly introduced COVID-19 vaccine, even despite this group's vulnerability.

Younger Age at Onset Is Associated With Worse Long-term Behavioral Outcomes in Anti-NMDA Receptor Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-NMDA receptor encephalitis (anti-NMDARE) is one of the most common causes of encephalitis. It typically presents in adolescence and young adulthood, but little is known about its potential long-term consequences across the lifespan. Adaptive behavior describes an individual's ability to respond and adapt to environmental demands and unanticipated changes in daily routines. In this study, we evaluate the relationship between features from clinical presentation, including age, and long-term adaptive behavior in participants with anti-NMDARE. METHODS: Cross-sectional informant-reported data were collected between 2017 and 2019 from 41 individuals/caregivers of individuals with anti-NMDARE treated at 3 major academic hospitals. Neurologic disability was assessed by record review using the modified Rankin Scale (mRS). Functional outcomes were assessed using the validated Adaptive Behavior Assessment System, Third Edition (ABAS-3). RESULTS: The mean age at the time of study enrollment was 23.4 years (SD 17.0 years), and the mean time from symptom onset to study enrollment was 4.0 years. Seventeen participants were aged <12 years at symptom onset, 19 participants were aged 12-30 years, and 5 participants were aged >30 years. Mean ABAS-3 scores at study enrollment for all participants were in the average range (mean general adaptive composite standard score 92.5, SD 18.7). Individuals aged <12 years at symptom onset had lower mean ABAS-3 scores and were in the below average range compared with those aged 12-30 years at symptom onset, whose mean scores were in the average range (87 vs 99, p < 0.05). Similar differences were seen in 3 of the individual subscales (functional academics, health and safety, and self-care). There were no significant differences in mRS scores between age groups (p > 0.05). DISCUSSION: Although anti-NMDARE is associated with an overall favorable outcome, younger age at onset associates with worse long-term adaptive behavior despite no differences in neurologic disability. These findings suggest that the disease may have distinct consequences on the early developing brain. Future studies should evaluate behavioral recovery and quality of life after anti-NMDARE and identify additional factors associated with differential recovery.

Undiagnosed COVID-19 in households with a child with mitochondrial disease.

Background: The impact of the COVID-19 pandemic on medically fragile populations, who are at higher risk of severe illness and sequelae, has not been well characterized. Viral infection is a major cause of morbidity in children with mitochondrial disease (MtD), and the COVID-19 pandemic represents an opportunity to study this vulnerable population. Methods: A convenience sampling cross-sectional serology study was conducted (October 2020 to June 2021) in households (N = 20) containing a child with MtD (N = 22). Samples (N = 83) were collected in the home using a microsampling apparatus and shipped to investigators. Antibodies against SARS-CoV-2 nucleocapsid (IgG), spike protein (IgG, IgM, IgA), and receptor binding domain (IgG, IgM, IgA) were determined by enzyme linked immunosorbent assay. Results: While only 4.8% of participants were clinically diagnosed for SARS-CoV-2 infection, 75.9% of study participants were seropositive for SARS-CoV-2 antibodies. Most samples were IgM positive for spike or RBD (70%), indicating that infection was recent. This translated to all 20 families showing evidence of infection in at least one household member. For the children with MtD, 91% had antibodies against SARS-CoV-2 and had not experienced any adverse outcomes at the time of assessment. For children with recent infections (IgM+ only), serologic data suggest household members as a source. Conclusions: COVID-19 was highly prevalent and undiagnosed in households with a child with MtD through the 2020-2021 winter wave of the pandemic. In this first major wave, children with MtD tolerated SARS-CoV-2 infection well, potentially due to household adherence to CDC recommendations for risk mitigation.

Risk mitigation behaviors to prevent infection in the mitochondrial disease community during the COVID-19 pandemic.

BACKGROUND: A challenge during the COVID-19 pandemic has been widespread adherence to risk-reducing behaviors. Individuals with mitochondrial disease (MtD) are special population with an increased risk of morbidity associated with infection. PURPOSE: To measure risk mitigation behaviors (RMBs) in families affected by MtD and identify factors that may influence these behaviors. METHODS: An online questionnaire was distributed in April and June 2020. Individuals with MtD or their caregivers completed the survey. RESULTS: We received 529 eligible responses with n = 312 completing all questions for our multivariate regression model. The most common RMBs were increased hand washing (96%), social distancing (94%), and avoiding public gatherings (93%). Higher numbers of recent healthcare visits (b = 0.62, p < 0.05) and expressed fear of the MtD patient contracting COVID-19 (b = 0.92, p < 0.05) were associated with more RMBs. Living in a rural community (b = -0.99,p < 0.05) and a history of COVID-19 testing (b = -2.14,p < 0.01) were associated with fewer RMBs. CONCLUSIONS: Our results suggest that during the COVID-19 pandemic, families affected by MtD have near universal adherence to basic RMBs. This may be motivated by fear of the severe morbidity associated with infection in MtD. Patients with frequent healthcare visits may be sicker and therefore take more precautions. Living in a rural community may also impact these behaviors. People who practice fewer RMBs may be more likely to seek testing. Our findings may generalize to other chronic diseases.

Progressive cerebellar atrophy in a patient with complex II and III deficiency and a novel deleterious variant in SDHA: A Counseling Conundrum.

BACKGROUND: Complex II is an essential component of the electron transport chain, linking it with the tricarboxylic acid cycle. Its four subunits are encoded in the nuclear genome, and deleterious variants in these genes, including SDHA (OMIM 600857), are associated with a wide range of symptoms including neurological disease, cardiomyopathy, and neoplasia (paraganglioma-pheochromocytomas (PGL/PCC), and gastrointestinal stromal tumors). Deleterious variants of SDHA are most frequently associated with Leigh and Leigh-like syndromes. METHODS AND RESULTS: Here, we describe a case of a 9-year-old boy with tremor, nystagmus, hypotonia, developmental delay, significant ataxia, and progressive cerebellar atrophy. He was found to have biallelic variants in SDHA, a known pathogenic variant (c.91C>T (p.R31*)), and a variant of unknown significance (c.454G>A (p.E152K)). Deficient activity of complexes II and III was detected in fibroblasts from the patient consistent with a diagnosis of a respiratory chain disorder. CONCLUSION: We, therefore, consider whether c.454G>A (p.E152K) is, indeed, a pathogenic variant, and what implications it has for family members who carry the same variant.

Prenatal cytomegalovirus, rubella, and Zika virus infections associated with developmental disabilities: past, present, and future.

Prenatal infections have long been recognized as important, preventable causes of developmental disabilities. The list of pathogens that are recognized to have deleterious effects on fetal brain development continues to grow, most recently with the association between Zika virus (ZIKV) and microcephaly. To answer clinical questions in real time about the impact of a novel infection on developmental disabilities, an historical framework is key. The lessons learned from three historically important pathogens: rubella, cytomegalovirus, and ZIKV, and how these lessons are useful to approach emerging congenital infections are discussed in this review. Congenital infections are preventable causes of developmental disabilities and several public health approaches may be used to prevent prenatal infection. When they cannot be prevented, the sequelae of prenatal infection may be treatable. WHAT THIS PAPER ADDS: The list of prenatal infections associated with developmental disabilities continues to increase. Lessons learned from rubella, cytomegalovirus, and Zika virus have implications for new pathogens. Severity of illness in the mother does not correlate with severity of sequelae in the infant.

Retinal measurements predict 10-year disability in multiple sclerosis.

Objective: Optical coherence tomography (OCT)-derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long-term disability is unknown. We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later. Methods: Between 2006 and 2008, 172 people with MS underwent Stratus time domain-OCT imaging [160 with measurement of total macular volume (TMV)] and high and low-contrast letter acuity (LCLA) testing (n = 150; 87%). All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10-year follow-up. We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10-year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status. Results: In multivariable models, lower baseline TMV was associated with higher 10-year EDSS scores (mean increase in EDSS of 0.75 per 1 mm3 loss in TMV (mean difference = 0.75; 95% CI: 0.11-1.39; P = 0.02). In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.86 higher EDSS scores at 10 years (mean difference = 0.86; 95% CI: 0.23-1.48) and had over 3.5-fold increased odds of clinically significant EDSS worsening relative to those in the highest tertile of baseline TMV (OR: 3.58; 95% CI: 1.30-9.82; P trend = 0.008). pRNFL and LCLA predicted the 10-year EDSS scores only in univariate models. Interpretation: Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status.

The Spectrum of Developmental Disability with Zika Exposure: What Is Known, What Is Unknown, and Implications for Clinicians.

Clinicians who treat children with neurodevelopmental disabilities may encounter infants with congenital Zika syndrome or those exposed to Zika virus (ZIKV), either in utero or postnatally, in their practice and may have questions about diagnosis, management, and prognosis. In this special report, we reviewed the current literature to provide a comprehensive understanding of the findings and needs of children exposed to ZIKV in utero and postnatally. The current literature is sparse, and thus, this review is preliminary. We found that infants and children exposed to ZIKV in utero have a variety of health and developmental outcomes that suggest a wide range of lifelong physical and developmental needs. Postnatal exposure does not seem to have significant long-lasting health or developmental effects. We provide a comprehensive examination of the current knowledge on health and developmental care needs in children exposed to Zika in utero and postnatally. This can serve as a guide for health care professionals on the management and public health implications of this newly recognized population.

Autoimmune encephalitis: A costly condition.

OBJECTIVE: To assess the inpatient hospitalization burden and costs of patients with autoimmune encephalitis (AE) at a tertiary care institution. METHODS: Adult inpatients with AE were identified retrospectively from July 1, 2005, to June 30, 2015. Demographic and clinical data were collected and analyzed. Billing data were compared to those of patients with herpes simplex encephalitis (HSE). Charges were adjusted for inflation. RESULTS: Of 244 admissions for encephalitis reviewed, 63 patients met criteria for probable or definite AE. Thirty-one (49%) patients were antibody positive, and 27 (43%) were admitted to the intensive care unit (ICU). Median hospital charges per patient with AE were more than $70,000; median length of stay (LOS) was 15 days; and in-hospital mortality was 6%. Patients admitted to the ICU had substantially higher median hospital charges (ICU $173,000 per admission vs non-ICU $50,000 per admission, p < 0.001). LOS was strongly associated with charges and was driven by delay in diagnosis of AE, prolonged treatment courses, and lack of response to therapy. Compared with HSE, median hospital charges per patient with AE were nearly 4 times higher, median AE LOS was 3 times higher, and total charges over the study period were nearly twice as high. CONCLUSIONS: Patients with AE used more inpatient health care resources per patient during a 10-year period than patients with HSE at our institution. ICU-admitted patients with AE were responsible for a substantially higher financial burden than non-ICU-admitted patients with AE. Our data underscore the need for the development of novel diagnostic and therapeutic modalities to improve patient outcomes and to decrease hospital burden in AE.

Clinical Subpopulations in a Sample of North American Children Diagnosed With Acute Flaccid Myelitis, 2012-2016.

Importance: Acute flaccid myelitis (AFM) is an emerging poliolike illness of children whose clinical spectrum and associated pathogens are only partially described. The case definition is intentionally encompassing for epidemiologic surveillance to capture all potential AFM cases. Defining a restrictive, homogenous subpopulation may aid our understanding of this emerging disease. Objective: To evaluate the extent to which the US Centers for Disease Control and Prevention (CDC) case definition of AFM incorporates possible alternative diagnoses and to assess the plausibility of a case definition that enriches the biological homogeneity of AFM for inclusion in research studies. Design, Setting, and Participants: Retrospective case analysis of children younger than 18 years diagnosed as having AFM between 2012 and 2016 using the CDC case definition. Group 1 included patients recruited from the United States and Canada based on the CDC case definition of AFM. Group 2 included patients referred to the Johns Hopkins Transverse Myelitis Center for evaluation of suspected AFM. Patients' records and imaging data were critically reviewed by 3 neurologists to identify those cases with definable alternative diagnoses, and the remaining patients were categorized as having restrictively defined AFM (rAFM). Clinical characteristics were compared between patients with rAFM (cases) and those with alternative diagnoses, and a case description distinguishing these AFM groups was identified. Interrater reliability of this description was confirmed for a subset of cases by a fourth neurologist. Data were analyzed between May 2017 and November 2018. Main Outcomes and Measures: Proportion of patients with possible alternative diagnosis. Results: Of the 45 patients who met the CDC AFM case definition and were included, the mean age was 6.1 years; 27 were boys (60%); and 37 were white (82%), 3 were Asian (7%), 1 was Hispanic (2%), and 4 were mixed race/ethnicity (9%). Of the included patients, 34 were classified as having rAFM, and 11 had alternate diagnoses (including transverse myelitis, other demyelinating syndromes, spinal cord stroke, Guillain-Barre syndrome, Chiari I myelopathy, and meningitis). Factors differing between groups were primarily asymmetry of weakness, lower motor neuron signs, preceding viral syndrome, symptoms evolving over hours to days, absence of sensory deficits, and magnetic resonance imaging findings. A case description was able to reliably define the rAFM group. Conclusions and Relevance: We present an approach for defining a homogeneous research population that may more accurately reflect the pathogenesis of the prototypical poliomyelitis-like subgroup of AFM. The definition of rAFM forms a blueprint for inclusion criteria in future research efforts, but more work is required for refinement and external validation.

Comparative quantitative clinical, neuroimaging, and functional profiles in children with acute flaccid myelitis at acute and convalescent stages of disease.

AIM: To quantify characteristics in acute flaccid myelitis (AFM) at acute and convalescent stages. METHOD: This was a retrospective case series of children with AFM evaluated at a single institution in the USA (2014-2017). Acute inflammatory/ischemic myelopathies were excluded. Neurological assessments and segmental quantitative analysis of signal abnormalities on magnetic resonance imaging (MRI) of the brain and spinal cord were performed. RESULTS: Sixteen patients (11 males, five females) were evaluated. Median age at onset was 4 years (interquartile range [IQR] 3-6y). All had parainfectious acute-onset limb weakness, lower motor neuron examination, and spinal fluid pleocytosis. On acute spinal cord MRI, longitudinally extensive T2 hyperintensities were identified throughout the spinal cord mostly within grey matter; five out of 12 patients had dorsal brainstem T2 hyperintensities. At a median of 2 months follow-up (IQR 2-3mo), spinal cord MRI improved in seven out of nine patients although focal T2 hyperintensities persisted in cervical and lumbar grey matter. At a median follow-up of 4 months (IQR 2-6mo), Medical Research Council sum score rose from a median of 29 to 32; distal muscle groups improved more than proximal ones; four out of 16 patients were ventilator-dependent; and two out of 16 patients were quadriplegic. INTERPRETATION: While patients may show marked improvement on neuroimaging from acute to convalescent stages, the majority of children with AFM have limited motor recovery and continued disability. Clinicians should consider the timing of clinical and neuroimaging exams when assessing diagnosis and prognosis. WHAT THIS PAPER ADDS: During the 2014 to 2017 acute flaccid myelitis outbreak in the USA, clinical recovery was better in distal than proximal muscle groups. Lumbar spinal cord showed more residual abnormalities at convalescence.

ST3GAL5-Related Disorders: A Deficiency in Ganglioside Metabolism and a Genetic Cause of Intellectual Disability and Choreoathetosis.

GM3 synthase deficiency is due to biallelic pathogenic variants in ST3GAL5, which encodes a sialyltransferase that synthesizes ganglioside GM3. Key features of this rare autosomal recessive condition include profound intellectual disability, failure to thrive and infantile onset epilepsy. We expand the phenotypic spectrum with 3 siblings who were found by whole exome sequencing to have a homozygous pathogenic variant in ST3GAL5, and we compare these cases to those previously described in the literature. The siblings had normal birth history, subsequent developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment. Ichthyosis and self-injurious behavior are newly described in our patients and may influence clinical management. We conclude that GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. Other phenotypic features have variable expressivity, including failure to thrive, epilepsy, regression, vision impairment, and skin findings. Our analysis demonstrates a broader phenotypic range of this potentially under-recognized disorder.

Current Therapeutic Approaches in Leukodystrophies: A Review.

Leukodystrophies are a heterogeneous class of genetic diseases affecting the white matter in the central nervous system with a broad range of clinical manifestations and a frequently progressive course. An interest in precision medicine has emerged over the last several decades, and biomedical research in leukodystrophies has made exciting advances along this front through therapeutic target discovery and novel disease model systems. In this review, we discuss current and emerging therapeutic approaches in leukodystrophies, including gene therapy, antisense oligonucleotide therapy, CRISPR/CAS-based gene editing, and cell and stem cell based therapies.