Protective down-regulated states in the human brain: A possible lesson from COVID-19.

The COVID-19 pandemic has created a large population of patients who are slow to recover consciousness following mechanical ventilation and sedation in the intensive care unit. Few clinical scenarios are comparable. Possible exceptions are the rare patients in post-cardiac arrest coma with minimal to no structural brain injuries who recovered cognitive and motor functions after prolonged delays. A common electroencephalogram (EEG) signature seen in these patients is burst suppression [8]. Biophysical modeling has shown that burst suppression is likely a signature of a neurometabolic state that preserves basic cellular function "during states of lowered energy availability." These states likely act as a brain protective mechanism [9]. Similar EEG patterns are observed in the anoxia resistant painted turtle [24]. We present a conceptual analysis to interpret the brain state of COVID-19 patients suffering prolonged recovery of consciousness. We begin with the Ching model and integrate findings from other clinical scenarios and studies of the anoxia-tolerant physiology of the painted turtle. We postulate that prolonged recovery of consciousness in COVID-19 patients could reflect the effects of modest hypoxic injury to neurons and the unmasking of latent neuroprotective mechanisms in the human brain. This putative protective down-regulated state appears similar to that observed in the painted turtle and suggests new approaches to enhancing coma recovery [12].

Spatiotemporal topological correspondence between blood oxygenation and glucose metabolism revealed by simultaneous fPET-fMRI in brain's white matter.

White matter (WM) makes up half of the human brain. Compelling functional MRI evidence indicates that white matter exhibits neural activation and synchronization via a hemodynamic window. However, the neurometabolic underpinnings of white matter temporal synchronization and spatial topology remain unknown. By leveraging concurrent [18F]FDG-fPET and blood-oxygenation-level-dependent-fMRI, we demonstrated the temporal and spatial correspondences between blood oxygenation and glucose metabolism in the human brain white matter. In the temporal scale, we found that blood-oxygenation-level-dependent signals shared mutual information with FDG signals in the default-mode, visual, and sensorimotor-auditory networks. For spatial distribution, the blood-oxygenation-level-dependent functional networks in white matter were accompanied by substantial correspondence of FDG functional connectivity at different topological scales, including degree centrality and global gradients. Furthermore, the content of blood-oxygenation-level-dependent fluctuations in the white matter default-mode network was aligned and liberal with the FDG graph, suggesting the freedom of default-mode network neuro-dynamics, but the constraint by metabolic dynamics. Moreover, the dissociation of the functional gradient between blood-oxygenation-level-dependent and FDG connectivity specific to the white matter default-mode network revealed functional heterogeneities. Together, the results showed that brain energy metabolism was closely coupled with blood oxygenation in white matter. Comprehensive and complementary information from fMRI and fPET might therefore help decode brain white matter functions.

Hyperornithinemia-hyperammonemia-homocitrullinuria: a rare neurometabolic disorder in two siblings.

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is an extremely rare disorder of urea cycle, with few patients reported worldwide. Despite hyperammonemia control, the long-term outcome remains poor with progressive neurological deterioration. We report the clinical, biochemical, and molecular features of two Lebanese siblings diagnosed with this disorder and followed for 8 and 15 years, respectively. Variable clinical manifestations and neurological outcome were observed. The patient with earlier onset of symptoms had a severe neurological deterioration while the other developed a milder form of the disease at an older age. Diagnosis was challenging in the absence of the complete biochemical triad and the non-specific clinical presentations. Whole exome sequencing revealed a homozygous variant, p.Phe188del, in the SLC25A15 gene, a French- Canadian founder mutation previously unreported in Arab patients. Hyperammonemia was controlled in both patients but hyperonithinemia persisted. Frequent hyperalaninemia spikes and lactic acidosis occured concomitantly with the onset of seizures in one of the siblings. Variable neurological deterioration and outcome were observed within the same family. This is the first report from the Arab population of the long-term outcome of this devastating neurometabolic disorder.

Clinical and biochemical footprints of inherited metabolic diseases. XV. Epilepsies.

We provide a comprehensive overview of inherited metabolic disorders (IMDs) in which epilepsy is a prominent manifestation. Our unique database search has identified 256 IMDs associated with various types of epilepsies, which we classified according to the classic pathophysiology-based classification of IMDs, and according to selected seizure-related factors (neonatal seizures, infantile spasms, myoclonic seizures, and characteristic EEG patterns) and treatability for the underlying metabolic defect. Our findings indicate that inherited metabolic epilepsies are more likely to present in the neonatal period, with infantile spasms or myoclonic seizures. Additionally, the ∼20% of treatable inherited metabolic epilepsies found by our search were mainly associated with the IMD groups of "cofactor and mineral metabolism" and "Intermediary nutrient metabolism." The information provided by this study, including a comprehensive list of IMDs with epilepsy stratified according to age of onset, and seizure type and characteristics, along with an overview of the key clinical features and proposed diagnostic and therapeutic approaches, may benefit any epileptologist and healthcare provider caring for individuals with metabolic conditions.

Secretin modulates appetite via brown adipose tissue-brain axis.

PURPOSE: Secretin activates brown adipose tissue (BAT) and induces satiation in both mice and humans. However, the exact brain mechanism of this satiety inducing, secretin-mediated gut-BAT-brain axis is largely unknown. METHODS AND RESULTS: In this placebo-controlled, single-blinded neuroimaging study, firstly using [18F]-fluorodeoxyglucose (FDG) PET measures (n = 15), we established that secretin modulated brain glucose consumption through the BAT-brain axis. Predominantly, we found that BAT and caudate glucose uptake levels were negatively correlated (r = -0.54, p = 0.037) during secretin but not placebo condition. Then, using functional magnetic resonance imaging (fMRI; n = 14), we found that secretin improved inhibitory control and downregulated the brain response to appetizing food images. Finally, in a PET-fMRI fusion analysis (n = 10), we disclosed the patterned correspondence between caudate glucose uptake and neuroactivity to reward and inhibition, showing that the secretin-induced neurometabolic coupling patterns promoted satiation. CONCLUSION: These findings suggest that secretin may modulate the BAT-brain metabolic crosstalk and subsequently the neurometabolic coupling to induce satiation. The study advances our understanding of the secretin signaling in motivated eating behavior and highlights the potential role of secretin in treating eating disorders and obesity. TRIAL REGISTRATION: EudraCT no. 2016-002373-35, registered 2 June 2016; Clinical Trials no. NCT03290846, registered 25 September 2017.

Establishment and validation of a clinical severity scoring system for succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder with a variable phenotype and rate of progression. We aimed to develop and validate a clinical severity scoring (CSS) system applicable to the clinical setting and composed of five domains reflecting the principal manifestations of this disorder: cognitive, communication, motor, epilepsy, and psychiatry. A prospectively characterized cohort of 27 SSADHD subjects (55% females, median [IQR] age 9.2 [4.6-16.2] years) who enrolled in the SSADHD Natural History Study were included. The CSS was validated by comparison to an objective severity scoring (OSS) system based on comprehensive neuropsychologic and neurophysiologic assessments, which mirror and complement the domains of the CSS. The total CSS was sex and age-independent, and 80% of its domains lacked interdependence. With increasing age, there was a significant improvement in communication abilities (p = 0.05) and a worsening of epilepsy and psychiatric manifestations (p = 0.004 and p = 0.02, respectively). There was a significant correlation between all the CSS and OSS domain scores, as well as between the total CSS and OSS (R = 0.855, p < 0.001). Additionally, there were no significant demographic or clinical differences in the ratio of individuals in the upper quartile to the lower three quartiles of the CSS and OSS. The SSADHD CSS is validated using objective measures and offers a reliable condition-specific instrument universally applicable in clinical settings. This severity score may be utilized for family and patient counseling, genotype-phenotype correlations, biomarker development, clinical trials, and objective descriptions of the natural history of SSADHD.

Update current understanding of neurometabolic disorders related to lysine metabolism.

Lysine, as an essential amino acid, predominantly undergoes metabolic processes through the saccharopine pathway, whereas a smaller fraction follows the pipecolic acid pathway. Although the liver is considered the primary organ for lysine metabolism, it is worth noting that lysine catabolism also takes place in other tissues and organs throughout the body, including the brain. Enzyme deficiency caused by pathogenic variants in its metabolic pathway may lead to a series of neurometabolic diseases, among which glutaric aciduria type 1 and pyridoxine-dependent epilepsy have the most significant clinical manifestations. At present, through research, we have a deeper understanding of the multiple pathophysiological mechanisms related to these diseases, including intracerebral accumulation of neurotoxic metabolites, imbalance between GABAergic and glutamatergic neurotransmission, energy deprivation due to metabolites, and the dysfunction of antiquitin. Because of the complexity of these diseases, their clinical manifestations are also diverse. The early implementation of lysine-restricted diets and supplementation with arginine and carnitine has reported positive impacts on the neurodevelopmental outcomes of patients. Presently, there is more robust evidence supporting the effectiveness of these treatments in glutaric aciduria type 1 compared with pyridoxine-dependent epilepsy.

Recent advances in neurometabolic diseases: The genetic role in the modern era.

The global birth prevalence of all inborn errors of metabolism (IEMs) in children (49 studies, 1980-2017) is approximately 50.9/100,000 live births. Regional pooled birth prevalence showed higher rates in Eastern Mediterranean regions (75.7/100,000 live births) and highest in Saudi Arabia (169/100,000) with higher parental consanguinity rates of ∼60%. Case fatality rates globally are estimated to be 33% or higher. IEMs are a group of >600 heterogeneous disorders often presenting in newborns and infants with drug-resistant seizures and/or encephalopathy. Early diagnosis and treatments are key in the prevention of morbidity, early mortality, and high lifetime health care costs, such as the early recognition of the newborn with pyridoxine- or pyridoxal-L-phosphate-dependent seizures which do not respond to standard antiepileptic drugs. The earlier the recognition and intervention in the specific cofactor- or vitamin-responsive epilepsies, the better the outcome and prevention of intractable seizures and encephalopathy leading to irreversible neurologic injury. In recent years, the genetics of IEMs has been transformed by the emergence of new molecular genetic technologies. Depending upon the clinical phenotype, current genetic testing may include chromosomal microarray (deletion/duplication analysis), single target gene sequencing, gene panels (sequencing and deletion/duplication analysis), DNA methylation analysis, mitochondrial nuclear gene panel, and mtDNA sequencing and/or trio WES or WGS (which have reduced in costs). A meta-analysis, showed WES and epilepsy gene panels to be the most cost-effective genetic tests for unknown epilepsies versus chromosomal microarray. Most recently, rapid genomic sequencing (RGS) has been associated with a shorter time to diagnosis (3 days) and increased diagnostic yield when compared with standard-of-care testing, including gene panels and microarrays. A randomized controlled trial (RCT) of rapid(r) WGS or rWES in acutely ill infants with diseases of unknown etiology in pediatric ICUs in San Diego, California found RGS to be highly clinically useful for 77% of 201 infants. RGS changed clinical management in 28% of infants and outcomes in 15%. An Australian study of ultra-rapid (ur) exome sequencing (mean time to genomic test report of 3.3 days) in 108 critically ill infants and children with suspected monogenic conditions, had a molecular diagnostic yield of 51% with 20% requiring further genetic analysis. In 42/55 (76%), ur exome sequencing was felt to have influenced clinical management for targeted treatments, surveillance, or palliative care, however, the study was not designed or powered to measure differences in major clinical outcomes compared to standard care of critically ill patients. Further research is needed to understand this tool's clinical value and generalizability balanced against its high costs. A paradigm shift is evolving from pattern- and evidence-based medicine toward algorithm-based, precision medicine targeted to individual mutations. Meticulous clinical phenotyping and pedigree analysis, combined with advances in high-throughput metabolomics, proteomics, transcriptomics (RNAseq in clinically relevant tissues), and genomics, have expedited the identification of novel pathomechanisms and new therapeutic targets. Evaluation of these therapies in IEMs, many of which manifest with encephalopathy and epilepsy, will depend on international registries of well-characterized phenotypes in RCTs and measurement of clinically relevant endpoints. The earlier the recognition and diagnosis and intervention with targeted therapies, the better the overall outcome in terms of the impact on intellectual disability and the effective management of the associated epilepsy.

Deterioration of visual quality and acuity as the first sign of ceroid lipofuscinosis type 3 (CLN3), a rare neurometabolic disease.

Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic disease. Typical clinical symptoms include progressive visual loss, epilepsy of unknown etiology and dementia. Presence of lipofuscin deposits with typical pattern of 'fingerprints' and vacuolized lymphocytes suggest the diagnosis of CLN3. Cause of CLN3 are mutations in the CLN3 gene, among which the most frequently found is the large deletion 1.02 kb spreading on exons 7 and 8. We present 4 patients from 2 families, in whom the deterioration of visual quality and acuity was observed as first clinical sign, when they were a few years old and it was successively accompanied by symptoms of neurologic deterioration (like generalized convulsions with consciousness impairment). In all patients the 1.02 kb deletion in the CLN3 gene was detected in homo- or heterozygosity with other CLN3 pathogenic variant. Ultrastructural studies revealed abnormal structures corresponding to 'fingerprint' profiles (FPPs) in conjunctival endothelial cells. It should be emphasized that in patients with blindness of unknown cause the diagnosis of ceroid lipofuscinosis should be considered and in older children-especially CLN3. The facility of the analysis for the presence of 1.02 kb deletion and economic costs are a solid argument for intensive use of this test in the diagnostic procedure of CLN3.

Knowledge and experiences of healthcare workers in managing children with neurometabolic disorders in a developing country: a cross-sectional study.

OBJECTIVE: To evaluate the knowledge and experiences of healthcare workers in the management of neurometabolic disorders. METHODS: A cross-sectional study was carried out among the 132 participants of a continued medical education program conducted in the Department of Pediatrics at a tertiary-care teaching hospital. A questionnaire-based feedback form was circulated among the participants, and their responses were analyzed. RESULTS: Ninety-three responses were analyzed. The most common pediatric illnesses identified were infections (91%), nutritional (91%), birth-related injuries (44.4%) and metabolic disorders (44.4%). Consanguinity (81.5%) and genetic heterogeneity (42.4%) were recognized as most important causes of neurometabolic disorders. Important steps identified for prevention were prenatal testing (65.6%) and newborn screening at birth (61%); while for improving the diagnosis were routine availability of metabolic investigations (65.3%) and screening at birth (46.6%). Most respondents (58.7%) expressed discomfort in managing a case with inherited metabolic defect due to a lack of knowledge (46.8%) and diagnostic facilities (44.6%). Despite access to testing in the majority, a high cost of testing was noticed for biochemical and genetic investigations. The majority of participants (73%) considered some of the inherited metabolic disorders as treatable. Dietary substitution (89.3%), enzyme replacement (69%), cofactor replacement (53.6%), gene therapy (35.7%) and regular dialysis (16.7%) were considered the treatment options. CONCLUSION: In spite of growing awareness of inherited metabolic disorders, there are still gaps in knowledge among healthcare workers. It is challenging to diagnose and manage these disorders. Cost-reduction of diagnostic tests, routine newborn screening and increased educational activities are key challenges to be addressed.

NAXE deficiency: A neurometabolic disorder of NAD(P)HX repair amenable for metabolic correction.

The NAD(P)HX repair system is a metabolite damage repair mechanism responsible for restoration of NADH and NADPH after their inactivation by hydration. Deficiency in either of its two enzymes, NAD(P)HX dehydratase (NAXD) or NAD(P)HX epimerase (NAXE), causes a fatal neurometabolic disorder characterized by decompensations precipitated by inflammatory stress. Clinical findings include rapidly progressive muscle weakness, ataxia, ophthalmoplegia, and motor and cognitive regression, while neuroimaging abnormalities are subtle or nonspecific, making a clinical diagnosis challenging. During stress, nonenzymatic conversion of NAD(P)H to NAD(P)HX increases, and in the absence of repair, NAD(P)H is depleted, and NAD(P)HX accumulates, leading to decompensation; however, the contribution of each to the metabolic derangement is not established. Herein, we summarize the clinical knowledge of NAXE deficiency from 30 cases and lessons learned about disease pathogenesis from cell cultures and model organisms and describe a metabolomics signature obtained by untargeted metabolomics analysis in one case at the time of crisis and after initiation of treatment. Overall, biochemical findings support a model of acute depletion of NAD+, signs of mitochondrial dysfunction, and altered lipidomics. These findings are further substantiated by untargeted metabolomics six months post-crisis showing that niacin supplementation reverses primary metabolomic abnormalities concurrent with improved clinical status.

Eye motor manifestations in children with neurometabolic disorders.

Neurometabolic diseases are complex group of rare neurogenetic disorders, which are difficult to diagnose. Patients may have toxic metabolite accumulation, inadequate energy supply, or neurotransmitter deficiency, resulting in a variety of clinical manifestations and severity with enzyme activity or transporter function defects. Multiple organ involvement is frequently seen, among which neurological symptoms and signs are one of the most encountered problems. Ocular motor problems deserve special attention for it occurs in some inborn error of metabolism. Furthermore, some are early signs or characteristic findings of certain diseases, such as the gaze palsy in Niemann-Pick disease type C and Gaucher disease or oculogyric crisis in neurotransmitter diseases. Early recognition and intervention are important for better prognosis in treatable neurometabolic disorders. In addition, ways to evaluate and describe eye movement problems also help to demonstrate the severity or clinical progression for those diagnosed with certain neurometabolic diseases. However, the complexity of eye movement and ocular motor control renders our clinical observation, recording and even anatomic localization of abnormal eye movements. Clinicians are more likely to detect early signs and unravel problems by gaining awareness of abnormal eye movement. This study amied to approach neurometabolic diseases in children via eye motor manifestations.

Aperiodic measures of neural excitability are associated with anticorrelated hemodynamic networks at rest: A combined EEG-fMRI study.

The hallmark of resting EEG spectra are distinct rhythms emerging from a broadband, aperiodic background. This aperiodic neural signature accounts for most of total EEG power, although its significance and relation to functional neuroanatomy remains obscure. We hypothesized that aperiodic EEG reflects a significant metabolic expenditure and therefore might be associated with the default mode network while at rest. During eyes-open, resting-state recordings of simultaneous EEG-fMRI, we find that aperiodic and periodic components of EEG power are only minimally associated with activity in the default mode network. However, a whole-brain analysis identifies increases in aperiodic power correlated with hemodynamic activity in an auditory-salience-cerebellar network, and decreases in aperiodic power are correlated with hemodynamic activity in prefrontal regions. Desynchronization in residual alpha and beta power is associated with visual and sensorimotor hemodynamic activity, respectively. These findings suggest that resting-state EEG signals acquired in an fMRI scanner reflect a balance of top-down and bottom-up stimulus processing, even in the absence of an explicit task.

Dual molecular diagnoses in a neurometabolic specialty clinic.

Reports of patients with concomitant diagnoses of two inherited genetic disorders, sometimes referred to as "double trouble," have appeared intermittently in the medical literature. We report eight additional cases with dual diagnoses of two genetic conditions. All cases had a phenotype atypical for their primary diagnosis, leading to the search for a second genetic diagnosis. These cases highlight the importance of the history, physical examination and continued work-up if the phenotype of the patient falls drastically outside what has been reported with their primary diagnosis. Some of the diagnoses of the patients presented here (e.g., Myotonic Dystrophy Type 1, fascioscapulohumeral muscular dystrophy) would not have been identified by genetic testing done on a next generation sequencing backbone (e.g., panel or exome sequencing). When the clinical picture is atypical or more severe than expected the possibility of a dual diagnosis (double trouble) should be considered. Identification of a second genetic condition can impact management and genetic counseling.

Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome.

Mutations in nuclear-encoded mitochondrial genes are responsible for a broad spectrum of disorders among which Leigh syndrome is the most common in infancy. No effective therapies are available for this severe disease mainly because of the limited capabilities of the standard adeno-associated viral (AAV) vectors to transduce both peripheral organs and the CNS when injected systemically in adults. Here, we used the brain-penetrating AAV-PHP.B vector to reinstate gene expression in the Ndufs4 knockout mouse model of Leigh syndrome. Intravenous delivery of an AAV.PHP.B-Ndufs4 vector in 1-month-old knockout mice restored mitochondrial complex I activity in several organs including the CNS. This gene replacement strategy extended lifespan, rescued metabolic parameters, provided behavioural improvement, and corrected the pathological phenotype in the brain, retina, and heart of Ndufs4 knockout mice. These results provide a robust proof that gene therapy strategies targeting multiple organs can rescue fatal neurometabolic disorders with CNS involvement.

Infantile onset Sandhoff disease: clinical manifestation and a novel common mutation in Thai patients.

BACKGROUND: Sandhoff disease (SD) is an autosomal recessive lysosomal storage disorder, resulting in accumulation of GM2 ganglioside, particular in neuronal cells. The disorder is caused by deficiency of ß-hexosaminidase B (HEX-B), due to pathogenic variant of human HEXB gene. METHOD: This study describes clinical features, biochemical, and genetic defects among Thai patients with infantile SD during 2008-2019. RESULTS: Five unrelated Thai patients presenting with developmental regression, axial hypotonia, seizures, exaggerated startle response to noise, and macular cherry red spot were confirmed to have infantile SD based on deficient HEX enzyme activities and biallelic variants of the HEXB gene. In addition, an uncommon presenting feature, cardiac defect, was observed in one patient. All the patients died in their early childhood. Plasma total HEX and HEX-B activities were severely deficient. Sequencing analysis of HEXB gene identified two variants including c.1652G>A (p.Cys551Tyr) and a novel variant of c.761T>C (p.Leu254Ser), in 90 and 10% of the mutant alleles found, respectively. The results from in silico analysis using multiple bioinformatics tools were in agreement that the p.Cys551Tyr and the p.Leu254Ser are likely pathogenic variants. Molecular modelling suggested that the Cys551Tyr disrupt disulfide bond, leading to protein destabilization while the Leu254Ser resulted in change of secondary structure from helix to coil and disturbing conformation of the active site of the enzyme. Genome-wide SNP array analysis showed no significant relatedness between the five affected individuals. These two variants were not present in control individuals. The prevalence of infantile SD in Thai population is estimated 1 in 1,458,521 and carrier frequency at 1 in 604. CONCLUSION: The study suggests that SD likely represents the most common subtype of rare infantile GM2 gangliosidosis identified among Thai patients. We firstly described a potential common variant in HEXB in Thai patients with infantile onset SD. The data can aid a rapid molecular confirmation of infantile SD starting with the hotspot variant and the use of expanded carrier testing.

Encephalopathy due to defective mitochondrial and peroxisomal fission 2 caused by a novel MFF gene mutation in a young child.

Encephalopathy due to defective mitochondrial and peroxisomal fission 2 caused by mitochondrial fission factor (MFF) gene mutation is a rare neurogenetic disorder. Pathogenic MFF mutations have been described in three reports in literature so far. We report a young child of Indian descent who presented to us with global developmental followed by regression of acquired milestones, spasticity, visual and auditory impairment, and was found to harbor a novel pathogenic homozygous MFF truncating variant c.433C>T; p.Arg145Ter. Cellular imaging of patient lymphoblastoid cell line had shown abnormal shapes of mitochondria due to fission defects. The patient has been started on mitochondrial cocktail with some improvement.

Confirmation of neurometabolic diagnoses using age-dependent cerebrospinal fluid metabolomic profiles.

Timely diagnosis is essential for patients with neurometabolic disorders to enable targeted treatment. Next-Generation Metabolic Screening (NGMS) allows for simultaneous screening of multiple diseases and yields a holistic view of disturbed metabolic pathways. We applied this technique to define a cerebrospinal fluid (CSF) reference metabolome and validated our approach with patients with known neurometabolic disorders. Samples were measured using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry followed by (un)targeted analysis. For the reference metabolome, CSF samples from patients with normal general chemistry results and no neurometabolic diagnosis were selected and grouped based on sex and age (0-2/2-5/5-10/10-15 years). We checked the levels of known biomarkers in CSF from seven patients with five different neurometabolic disorders to confirm the suitability of our method for diagnosis. Untargeted analysis of 87 control CSF samples yielded 8036 features for semiquantitative analysis. No sex differences were found, but 1782 features (22%) were different between age groups (q < 0.05). We identified 206 diagnostic metabolites in targeted analysis. In a subset of 20 high-intensity metabolites and 10 biomarkers, 17 (57%) were age-dependent. For each neurometabolic patient, ≥1 specific biomarker(s) could be identified in CSF, thus confirming the diagnosis. In two cases, age-matching was essential for correct interpretation of the metabolomic profile. In conclusion, NGMS in CSF is a powerful tool in defining a diagnosis for neurometabolic disorders. Using our database with many (age-dependent) features in CSF, our untargeted approach will facilitate biomarker discovery and further understanding of mechanisms of neurometabolic disorders.

The experience of allogeneic hematopoietic stem cell transplantation in a patient with X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD), a progressive neurometabolic disorder that is caused by a defect in the gene ABCD1 (ATP-binding cassette, subfamily D, member 1), which encodes the peroxisomal ABC half-transporter ALD protein. Recently, allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only therapy known to prevent disease progression. In this study, we would like to present our experience of alloHSCT for X-ALD from a HLA matched related sibling by the use of reduced intensity conditioning regimen composed of fludarabine, busulfan and ATG which allows us to reduce procedure-related toxicity and prevent mortality while achieving a curative effect.

Nonlinear Transfer Entropy to Assess the Neurovascular Coupling in Premature Neonates.

In the adult brain, it is well known that increases in local neural activity trigger changes in regional blood flow and, thus, changes in cerebral energy metabolism. This regulation mechanism is called neurovascular coupling (NVC). It is not yet clear to what extent this mechanism is present in the premature brain. In this study, we explore the use of transfer entropy (TE) in order to compute the nonlinear coupling between changes in brain function, assessed by means of EEG, and changes in brain oxygenation, assessed by means of near-infrared spectroscopy (NIRS). In a previous study, we measured the coupling between both variables using a linear model to compute TE. The results indicated that changes in brain oxygenation were likely to precede changes in EEG activity. However, using a nonlinear and nonparametric approach to compute TE, the results indicate an opposite directionality of this coupling. The source of the different results provided by the linear and nonlinear TE is unclear and needs further research. In this study, we present the results from a cohort of 21 premature neonates. Results indicate that TE values computed using the nonlinear approach are able to discriminate between neonates with brain abnormalities and healthy neonates, indicating a less functional NVC in neonates with brain abnormalities.