Enhancing the accuracy of surgical wound excision following burns trauma via application of Rapid Evaporative IonisationMass Spectrometry (REIMS).

BACKGROUND: Surgical wound excision is a necessary procedure for burn patients that require the removal of eschar. The extent of excision is currently guided by clinical judgement, with excessinto healthy tissue potentially leading to excessive scar, or inadequate debridement increasing risk of infection. Thus, an objective real-time measure to facilitate accurate excision could support clinical judgement and improve this surgical procedure. This study was designed to investigate the potential use of Rapid evaporative ionisation mass spectrometry (REIMS) as a tool to support data-driven objective tissue excision. METHODS: Data were acquired using a multi-platform approach that consisted of both Rapid Evaporative Ionisation Mass Spectrometry (REIMS) performed on intact skin, and comprehensive liquid chromatography-mass spectrometry (LC-MS/MS) lipidomics performed on homogenised skin tissue extracts. Data were analysed using principal components analysis (PCA) and multivariate orthogonal projections to latent squares discriminant analysis (OPLS-DA) and logistic regression to determine the predictability of the models. RESULTS: PCA and OPLS-DA models of the REIMS and LC-MS/MS lipidomics data reported separation of excised and healthy tissue. Molecular fingerprints generated from REIMS analysis of healthy skin tissue revealed a high degree of heterogeneity, however, intra-individual variance was smaller than inter-individual variance. Both platforms indicated high levels of skin classification accuracy. In addition, OPLS-DA of the LC-MS/MS lipidomic data revealed significant differences in specific lipid classes between healthy control and excised skin samples; including lower free fatty acids (FFA), monoacylglycerols (MAG), lysophosphatidylglycerol (LPG) and lysophosphatidylethanolamines (LPE) in excised tissue and higher lactosylceramides (LCER) and cholesterol esters (CE) compared to healthy control tissue. CONCLUSIONS: Having established the heterogeneity in the biochemical composition of healthy skin using REIMS and LC-MS/MS, our data show that REIMS has the potential to distinguish between excied and healthy skin tissue samples. This pilot study suggests that REIMS may be an effective tool to support accurate tissue excision during burn surgery.

Rituximab in juvenile myasthenia gravis-an international cohort study and literature review.

Juvenile myasthenia gravis (JMG) is a rare, antibody-mediated disorder of the neuromuscular junction. Treatment strategies in JMG are largely informed by adult MG treatments as the pathophysiology is similar. Rituximab is increasingly considered as a treatment option in refractory JMG but has not yet been systematically investigated in this patient group We conducted a retrospective study from five international centres with expertise in paediatric myasthenia. 10 JMG patients treated with rituximab were identified. Following rituximab treatment all patients had a reduction in JMG-related hospital admissions. At 24 month follow up, 6 patients (60%) had achieved complete stable remission or pharmacological remission and 7 patients were able to reduce immunomodulatory treatment(s). The main side-effect was infusion-related reactions (30%) which resolved in all patients with symptomatic treatment. We compared our cohort to previously reported JMG cases treated with rituximab and noted similar response rates but a slightly higher side-effect profile. Rituximab is a safe and effective treatment option in moderate to severe JMG and most patients have an improvement in MG symptoms post treatment.

Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function.

Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child's clinical presentation.

The severe epilepsy syndromes of infancy: A population-based study.

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy characterised by generalised weakness and respiratory insufficiency. XLMTM is associated with pathogenic variants in MTM1; a gene encoding the lipid phosphatase myotubularin. Whole genome sequencing (WGS) of an exome-negative male proband with severe hypotonia, respiratory insufficiency and centralised nuclei on muscle biopsy identified a deep intronic MTM1 variant NG_008199.1(NM_000252.2):c.1468-577A>G, which strengthened a cryptic 5' splice site (A>G substitution at the +5 position). Muscle RNA sequencing was non-diagnostic due to low read depth. Reverse transcription PCR (RT-PCR) of muscle RNA confirmed the c.1468-577A>G variant activates inclusion of a pseudo-exon encoding a premature stop codon into all detected MTM1 transcripts. Western blot analysis establishes deficiency of myotubularin protein, consistent with the severe XLMTM phenotype. We expand the genotypic spectrum of XLMTM and highlight benefits of screening non-coding regions of MTM1 in male probands with phenotypically concordant XLMTM who remain undiagnosed following exome sequencing.

NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease.

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF's role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Energy metabolism and mitochondrial defects in X-linked Charcot-Marie-Tooth (CMTX6) iPSC-derived motor neurons with the p.R158H PDK3 mutation.

Charcot-Marie-Tooth (CMT) is a group of inherited diseases clinically and genetically heterogenous, characterised by length dependent degeneration of axons of the peripheral nervous system. A missense mutation (p.R158H) in the pyruvate dehydrogenase kinase 3 gene (PDK3) has been identified as the genetic cause for an X-linked form of CMT (CMTX6) in two unrelated families. PDK3 is one of four PDK isoenzymes that regulate the activity of the pyruvate dehydrogenase complex (PDC). The balance between kinases (PDKs) and phosphatases (PDPs) determines the extend of oxidative decarboxylation of pyruvate to generate acetyl CoA, critically linking glycolysis and the energy producing Krebs cycle. We had shown the p.R158H mutation causes hyperactivity of PDK3 and CMTX6 fibroblasts show hyperphosphorylation of PDC, leading to reduced PDC activity and ATP production. In this manuscript we have generated induced pluripotent stem cells (iPSCs) by re-programming CMTX6 fibroblasts (iPSCCMTX6). We also have engineered an isogenic control (iPSCisogenic) and demonstrated that genetic correction of the p.R158H mutation reverses the CMTX6 phenotype. Patient-derived motor neurons (MNCMTX6) show increased phosphorylation of the PDC, energy metabolism defects and mitochondrial abnormalities, including reduced velocity of trafficking mitochondria in the affected axons. Treatment of the MNCMTX6 with a PDK inhibitor reverses PDC hyperphosphorylation and the associated functional deficits founds in the patient motor neurons, demonstrating that the MNCMTX6 and MNisogenic motor neurons provide an excellent neuronal system for compound screening approaches to identify drugs for the treatment of CMTX6.

Cerebellar ataxia with normal intellect associated with a homozygous truncating variant in CA8.

Biallelic pathogenic variants in CA8 cause cerebellar ataxia, mental retardation and dysequilibrium syndrome 3 (CAMRQ3), a rare form of hereditary ataxia characterised by cerebellar hypoplasia/atrophy, variable intellectual disability and often quadrupedal gait. The few cases reported in the medical literature are all caused by pathogenic homozygous or compound heterozygous missense variants in CA8. We report a 9 year-old boy with marked gross motor delay, ataxia and progressive cerebellar atrophy with limited bipedal gait, but without intellectual disability. Singleton whole exome sequencing was performed. A novel homozygous truncating variant in CA8 (c.232C>T) with a predicted premature termination codon at position 78 (p.Arg78*) was identified. Both parents and the proband's healthy sister are heterozygous for the variant. This variant is likely pathogenic and the cause of the condition in this child. Functional evidence in the form of a spontaneous mouse model involving homozygous intragenic deletion of the mouse analogue of CA8 with nonsense-mediated decay and similar clinical features to the proband support pathogenicity. Identification of this truncating variant broadens the genotypic and phenotypic spectrum of CA8-related cerebellar ataxia.

Importance of muscle biopsy to establish pathogenicity of DMD missense and splice variants.

A precise genetic diagnosis of a dystrophinopathy has far-reaching implications for affected boys and their families. We present three boys with DMD single nucleotide variants associated with Becker muscular dystrophy presenting with myalgia, reduced exercise capacity, neurodevelopmental symptoms and elevated creatine kinase. The DMD variants were difficult to classify: AIII:1 a synonymous variant in exon 13 c.1602G>A, p.Lys534Lys; BIII:1 an essential splice-site variant in intron 33 c.4674+1G>A, and CII:1 a missense mutation within the cysteine-rich domain, exon 66 c.9619T>C, p.Cys3207Arg. Complementary DNA (cDNA) analysis using muscle-derived mRNA established splice-altering effects of variants for AIII:1 and BIII:1, and normal splicing in CII:1. Western blot analysis demonstrated mildly to moderately reduced dystrophin levels (17.6 - 36.1% the levels of controls), supporting dystrophinopathy as a probable diagnosis. These three cases highlight the diagnostic utility of muscle biopsy for mRNA studies and western blot to investigate DMD variants of uncertain pathogenicity, by exploring effects on splicing and dystrophin protein levels.

Peripheral nerve disease secondary to systemic conditions in children.

This review is an overview of systemic conditions that can be associated with peripheral nervous system dysfunction. Children may present with neuropathic symptoms for which, unless considered, a causative systemic condition may not be recognized. Similarly, some systemic conditions may be complicated by comorbid peripheral neuropathies, surveillance for which is indicated. The systemic conditions addressed in this review are critical illness polyneuropathy, chronic renal failure, endocrine disorders such as insulin-dependent diabetes mellitus and multiple endocrine neoplasia type 2b, vitamin deficiency states, malignancies and reticuloses, sickle cell disease, neurofibromatosis, connective tissue disorders, bowel dysmotility and enteropathy, and sarcoidosis. In some disorders presymptomatic screening should be undertaken, while in others there is no benefit from early detection of neuropathy. In children with idiopathic peripheral neuropathies, systemic disorders such as celiac disease should be actively excluded. While management is predominantly focused on symptomatic care through pain control and rehabilitation, some neuropathies improve with effective control of the underlying etiology and in a small proportion a more targeted approach is possible. In conclusion, peripheral neuropathies can be associated with a diverse range of medical conditions and unless actively considered may not be recognized and inadequately managed.

Recessive MYH7-related myopathy in two families.

Myopathies due to recessive MYH7 mutations are exceedingly rare, reported in only two families to date. We describe three patients from two families (from Australia and the UK) with a myopathy caused by recessive mutations in MYH7. The Australian family was homozygous for a c.5134C > T, p.Arg1712Trp mutation, whilst the UK patient was compound heterozygous for a truncating (c.4699C > T; p.Gln1567*) and a missense variant (c.4664A > G; p.Glu1555Gly). All three patients shared key clinical features, including infancy/childhood onset, pronounced axial/proximal weakness, spinal rigidity, severe scoliosis, and normal cardiac function. There was progressive respiratory impairment necessitating non-invasive ventilation despite preserved ambulation, a combination of features often seen in SEPN1- or NEB-related myopathies. On biopsy, the Australian proband showed classical myosin storage myopathy features, while the UK patient showed multi-minicore like areas. To establish pathogenicity of the Arg1712Trp mutation, we expressed mutant MYH7 protein in COS-7 cells, observing abnormal mutant myosin aggregation compared to wild-type. We describe skinned myofiber studies of patient muscle and hypertrophy of type II myofibers, which may be a compensatory mechanism. In summary, we have expanded the phenotype of ultra-rare recessive MYH7 disease, and provide novel insights into associated changes in muscle physiology.

Pediatric Neuroschistosomiasis: A Case Report and Review of the Literature.

Neuroschistosomiasis is a rare but severe manifestation of Schistosoma infection. Diagnosis is challenging and surgical biopsy is often required to confirm diagnosis and exclude malignancy. We present a pediatric case of presumed pseudotumoral cerebral schistosomiasis secondary to Schistosoma mansoni with an excellent therapeutic response to empirical praziquantel and corticosteroid treatment.

Infantile-Onset Myelin Protein Zero-Related Demyelinating Neuropathy Presenting as an Upper Extremity Monoplegia.

We describe an infant with an early-onset demyelinating neuropathy who presented with an upper extremity monoplegia and progressive asymmetric weakness. Neurophysiologic testing revealed a generalized severe neuropathy with marked slowing of nerve conduction. The disproportionate severity and asymmetry of upper extremity involvement at presentation was atypical of inherited neuropathies, and an initial diagnosis of chronic inflammatory demyelinating polyneuropathy was considered. Nerve biopsy showed severe depletion of large myelinated fibers without inflammatory cells, and focally folded myelin sheaths were seen on electron microscopy. Genetic testing revealed a de novo heterozygous mutation in the myelin protein zero gene.

Investigation of the activation of the temporalis and masseter muscles in voluntary and spontaneous smile production.

INTRODUCTION: Masticatory muscles or their nerve supply are options for facial reanimation surgery, but their ability to create spontaneous smile has been questioned. This study assessed the percentage of healthy adults who activate the temporalis and masseter muscles during voluntary and spontaneous smile. METHODS: Healthy volunteer adults underwent electromyography (EMG) studies of the temporalis and masseter muscles during voluntary and spontaneous smile. Responses were repeated three times and recorded as negative, weakly positive, or strongly positive according to the activity observed. The best response was used for analysis. RESULTS: Thirty healthy adults (median age: 34 years, range: 25-69 years) participated. Overall, 92% of the masseter muscles were activated during voluntary smile (22% strong, 70% weak). Seventy-seven percent of the masseter muscles were activated in spontaneous smile (12% strong, 65% weak). The temporalis muscle was activated in 62% of responses in voluntary smile (15% strong, 47% weak) and in 45% of responses in spontaneous smile (13% strong, 32% weak). No significant difference was found for males vs females or closed vs open mouth smiles. There was no significant difference in responses between voluntary and spontaneous smiles for the temporalis and masseter muscles, and their use in voluntary smile did not predict activity in spontaneous smile. CONCLUSIONS: Our study has shown that masseter and temporalis are active in a high proportion of healthy adults during voluntary and spontaneous smiles. Further work is required to determine the relationship between preoperative donor muscle activation and postoperative spontaneous smile, and whether masticatory muscle activity can be upregulated with appropriate training.

DCC Is Required for the Development of Nociceptive Topognosis in Mice and Humans.

Avoidance of environmental dangers depends on nociceptive topognosis, or the ability to localize painful stimuli. This is proposed to rely on somatotopic maps arising from topographically organized point-to-point connections between the body surface and the CNS. To determine the role of topographic organization of spinal ascending projections in nociceptive topognosis, we generated a conditional knockout mouse lacking expression of the netrin1 receptor DCC in the spinal cord. These mice have an increased number of ipsilateral spinothalamic connections and exhibit aberrant activation of the somatosensory cortex in response to unilateral stimulation. Furthermore, spinal cord-specific Dcc knockout animals displayed mislocalized licking responses to formalin injection, indicating impaired topognosis. Similarly, humans with DCC mutations experience bilateral sensation evoked by unilateral somatosensory stimulation. Collectively, our results constitute functional evidence of the importance of topographic organization of spinofugal connections for nociceptive topognosis.

Pathogenic mechanisms underlying X-linked Charcot-Marie-Tooth neuropathy (CMTX6) in patients with a pyruvate dehydrogenase kinase 3 mutation.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. An X-linked form of CMT (CMTX6) is caused by a missense mutation (R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. PDK3 is one of 4 isoenzymes that negatively regulate the activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation of its first catalytic component pyruvate dehydrogenase (designated as E1). Mitochondrial PDC catalyses the oxidative decarboxylation of pyruvate to acetyl CoA and links glycolysis to the energy-producing Krebs cycle. We have previously shown the R158H mutation confers PDK3 enzyme hyperactivity. In this study we demonstrate that the increased PDK3 activity in patient fibroblasts (PDK3(R158H)) leads to the attenuation of PDC through hyper-phosphorylation of E1 at selected serine residues. This hyper-phosphorylation can be reversed by treating the PDK3(R158H) fibroblasts with the PDK inhibitor dichloroacetate (DCA). In the patient cells, down-regulation of PDC leads to increased lactate, decreased ATP and alteration of the mitochondrial network. Our findings highlight the potential to develop specific drug targeting of the mutant PDK3 as a therapeutic approach to treating CMTX6.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.

Neurologic Melioidosis: Case Report of a Rare Cause of Acute Flaccid Paralysis.

Acute flaccid paralysis is associated with inflammation, infection, or tumors in the spinal cord or peripheral nerves. Melioidosis (Burkholderia pseudomallei infection) can rarely cause this presentation. We describe a case of spinal melioidosis in a 4-year-old boy presenting with flaccid paralysis, and review the literature on this rare disease.

An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels.

Friedreich ataxia (FRDA) is due to a triplet repeat expansion in FXN, resulting in deficiency of the mitochondrial protein frataxin. Resveratrol is a naturally occurring polyphenol, identified to increase frataxin expression in cellular and mouse models of FRDA and has anti-oxidant properties. This open-label, non-randomized trial evaluated the effect of two different doses of resveratrol on peripheral blood mononuclear cell (PBMC) frataxin levels over a 12-week period in individuals with FRDA. Secondary outcome measures included PMBC FXN mRNA, oxidative stress markers, and clinical measures of disease severity. Safety and tolerability were studied. Twenty-four participants completed the study; 12 received low-dose resveratrol (1 g daily) and 12 high-dose resveratrol (5 g daily). PBMC frataxin levels did not change in either dosage group [low-dose group change: 0.08 pg/µg protein (95% CI -0.05, 0.21, p = 0.21); high-dose group change: 0.03 pg/µg protein (95% CI -0.10, 0.15, p = 0.62)]. Improvement in neurologic function was evident in the high-dose group [change in Friedreich Ataxia Rating Scale -3.4 points, 95% CI (-6.6, -0.3), p = 0.036], but not the low-dose group. Significant improvements in audiologic and speech measures, and in the oxidative stress marker plasma F2-isoprostane were demonstrated in the high-dose group only. There were no improvements in cardiac measures or patient-reported outcome measures. No serious adverse events were recorded. Gastrointestinal side-effects were a common, dose-related adverse event. This open-label study shows no effect of resveratrol on frataxin levels in FRDA, but suggests that independent positive clinical and biologic effects of high-dose resveratrol may exist. Further assessment of efficacy is warranted in a randomized placebo-controlled trial.