Protective effects of L-carnitine on behavioral alterations and neuroinflammation in striatum of glutaryl-COA dehydrogenase deficient mice.

Glutaric acidemia type 1 (GA1) is caused by glutaryl-CoA dehydrogenase deficiency that leads to a blockage in the metabolic route of the amino acids lysine and tryptophan and subsequent accumulation of glutaric acid (GA), 3-hydroxyglutaric acids and glutarylcarnitine (C5DC). Patients predominantly manifest neurological symptoms, associated with acute striatal degeneration, as well as progressive cortical and striatum injury whose pathogenesis is not yet fully established. Current treatment includes protein/lysine restriction and l-carnitine supplementation of (L-car). The aim of this work was to evaluate behavior parameters and pro-inflammatory factors (cytokines IL-1ß, TNF-α and cathepsin-D levels), as well as the anti-inflammatory cytokine IL10 in striatum of knockout mice (Gcdh-/-) and wild type (WT) mice submitted to a normal or a high Lys diet. The potential protective effects of L-car treatment on these parameters were also evaluated. Gcdh-/- mice showed behavioral changes, including lower motor activity (decreased number of crossings) and exploratory activity (reduced number of rearings). Also, Gcdh-/- mice had significantly higher concentrations of glutarylcarnitine (C5DC) in blood and cathepsin-D (CATD), interleukin IL-1ß and tumor factor necrosis alpha (TNF-α) in striatum than WT mice. Noteworthy, L-car treatment prevented most behavioral alterations, normalized CATD levels and attenuated IL-1ß levels in striatum of Gcdh-/- mice. Finally, IL-1ß was positively correlated with CATD and C5DC levels and L-car was negatively correlated with CATD. Our results demonstrate behavioral changes and a pro-inflammatory status in striatum of the animal model of GA1 and, most importantly, L-car showed important protective effects on these alterations.

A Characterization of the Effects of Minocycline Treatment During Adolescence on Structural, Metabolic, and Oxidative Stress Parameters in a Maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders.

BACKGROUND: Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model. METHODS: On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue. RESULTS: MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen). CONCLUSIONS: MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.

Status and future directions of clinical trials in Parkinson's disease.

Novel therapies are needed to treat Parkinson's disease (PD) in which the clinical unmet need is pressing. Currently, no clinically available therapeutic strategy can either retard or reverse PD or repair its pathological consequences. l-DOPA (levodopa) is still the gold standard therapy for motor symptoms yet symptomatic therapies for both motor and non-motor symptoms are improving. Many on-going, intervention trials cover a broad range of targets, including cell replacement and gene therapy approaches, quality of life improving technologies, and disease-modifying strategies (e.g., controlling aberrant α-synuclein accumulation and regulating cellular/neuronal bioenergetics). Notably, the repurposing of glucagon-like peptide-1 analogues with potential disease-modifying effects based on metabolic pathology associated with PD has been promising. Nevertheless, there is a clear need for improved therapeutic and diagnostic options, disease progression tracking and patient stratification capabilities to deliver personalized treatment and optimize trial design. This review discusses some of the risk factors and consequent pathology associated with PD and particularly the metabolic aspects of PD, novel therapies targeting these pathologies (e.g., mitochondrial and lysosomal dysfunction, oxidative stress, and inflammation/neuroinflammation), including the repurposing of metabolic therapies, and unmet needs as potential drivers for future clinical trials and research in PD.

Challenges in the management of an ignored cause of hyperammonemic encephalopathy: pyruvate carboxylase deficiency.

Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive disease and provides clinics in three essential phenotypes. Type B PC deficiency is characterized by lactic acidosis and hyperammonemia. We report a Turkish patient who was diagnosed with type B PC deficiency. Despite the application of anaplerotic treatment with biotin, citrate and arginine-aspartate, continuous veno-venous hemodialysis (CVVHD) treatments were applied due to the failure to keep hyperammonemia and lactic acidosis under control. Ammonia values increasing to 860 µmol/L were observed. A homozygous novel variant was detected in PC gene analyses containing a 12-base pair deletion on exon 8. Although the mutation found was not reported previously, it was accepted as a pathogenic variant due to its presence in a functional region of the protein. In type B PC deficiency, although a high level of ammonia is expected, it rarely exceeds 200 µmol/L. As far as we know, the present case has the highest ammonia values in the literature. This paper has been shared to highlight to keep PC deficiency in mind regarding the differential diagnosis of hyperammonemia, particularly in the presence of lactic acidosis, and to serve as a model for the use of different modalities in the management process of PC deficiency.

Metabolic encephalopathy caused by nitrous oxide ('laughing gas') induced hyperammonaemia.

A 26-year-old man presented at the emergency department with confusion and decreased consciousness after several days of vomiting. In the preceding 6 months, he had used a 2-litre tank of nitrous oxide (N2O) weekly. His metabolic encephalopathy was caused by hyperammonaemia which probably resulted from interference of N2O-induced vitamin B12 deficiency with ammonia degradation. A catabolic state might have contributed to the hyperammonaemia in this case. After treatment with vitamin B12 and lactulose, both his consciousness and hyperammonaemia improved. He reported no residual complaints after 3 months of follow-up. Since N2O is increasingly used as a recreational drug, we recommend considering hyperammonaemia as a cause of metabolic encephalopathy in cases of N2O use and altered mental status.

Further Delineation of Pyridoxine-Responsive Pyridoxine Phosphate Oxidase Deficiency Epilepsy: Report of a New Case and Review of the Literature With Genotype-Phenotype Correlation.

In recent years, the clinical spectrum of pyridoxine phosphate oxidase (PNPO) deficiency has broadened. There are a growing number of patients with a transient or lasting response to pyridoxine in addition to cases that respond more traditionally to pyridoxal-phosphate. However, among pyridoxine-responsive patients with PNPO gene mutation, there are only a few reports on electroencephalogram (EEG) ictal/interictal patterns, and data regarding the outcomes are inconsistent. We describe a case of neonatal onset epilepsy with missense mutation c(674G>A) p(R225 H) in PNPO gene and pyridoxine responsiveness. Comparing this patient with 24 cases of previously described pyridoxine-responsive pyridoxine phosphate oxidase deficiency epilepsy, we found that patients carrying the missense mutation c(674G>A) p(R225 H) of the PNPO gene might have a more severe epileptic phenotype, possibly because of their lower residual PNPO activity. Indeed, pyridoxine-responsive pyridoxine phosphate oxidase deficiency epilepsy remains a challenge, with neurodevelopmental disabilities occurring in about half of the cases.

[Cerebral insulin resistance: current concepts of the pathogenesis and possible therapeutic strategies]. / Tserebral'naia insulinorezistentnost': sovremennye predstavleniia o patogeneze i vozmozhnye terapevticheskie strategii.

The review presents current concepts about the problem of cerebral insulin resistance (IR). It has now been established that cerebral IR plays a key role in the pathogenesis of degenerative and metabolic diseases of the brain. Based on literature data and own clinical experience, the authors recommend to use the standardized extract of ginkgo biloba EGb761 as a cellular protector, which increases insulin sensitivity of cells and reduces atherogenesis, in order to improve cognitive functions and quality of life in patients with diabetes mellitus.

[Valproate-induced hyperammonemic encephalopathy]. / Encefalopatia hiperamonemica inducida por acido valproico.

TITLE: Encefalopatia hiperamonemica inducida por acido valproico.

The radiological findings of hypoglycemic encephalopathy: A case report with high b value DWI analysis.

RATIONALE: Hypoglycemic encephalopathy is a metabolic encephalopathy. Clinical risk is mixed with acute cerebrovascular disease, so it is critical to identify and make the correct diagnosis of the disease as early as possible. PATIENT CONCERNS: Here, we report a case of a 51-year-old male patient with hypoglycemic encephalopathy, who presented confusion and unconsciousness for 1 day. DIAGNOSES: In addition to blood-related indicators and medical histories, magnetic resonance imaging (MRI), especially diffusion-weighted imaging (DWI), can be valuable to the diagnosis of hypoglycemic encephalopathy, which showed diffuse high-signal intensity in the cerebral cortex, and also the hippocampus, head of the caudate nucleus, the lentiform nucleus, and corpus callosum. INTERVENTIONS: Intravenous glucose injection and drip was performed repeatedly. The blood glucose levels were gradually corrected, and the resulting blood glucose was 6.5 mmol/L. OUTCOMES: The prognosis depends on the degree of hypoglycemia, duration, and condition of the organism. Due to the long duration of hypoglycemia, unfortunately, the patient died. LESSONS: It is critical to diagnose hypoglycemic encephalopathy as early as possible. MRI reveals diffuse abnormal intensity in the cortex and basal ganglia region. DWI using high b values provides important information for diagnosis.

[Metabolic approach in epileptic encephalopathies in infants]. / Abordaje metabolico en las encefalopatias epilepticas del lactante.

INTRODUCTION: Although the overall incidence of inborn errors of metabolism is low, their early diagnosis is essential, since some of them have a specific treatment. DEVELOPMENT: We review the main treatable inborn errors of metabolism that can present as early-onset epileptic encephalopathies, together with their biochemical markers and their treatment. CONCLUSIONS: It is important to think about the possibility of an inborn error of metabolism with a specific therapy, since it is crucial for this to be started as soon as possible in order to prevent permanent neurological damage.

TITLE: Abordaje metabolico en las encefalopatias epilepticas del lactante.Introduccion. Aunque la incidencia global de los errores congenitos del metabolismo es baja, su diagnostico precoz es fundamental, ya que algunos de ellos tienen tratamiento especifico. Desarrollo. Se revisan los principales errores congenitos del metabolismo tratables que pueden cursar como encefalopatia epileptica de inicio precoz, asi como sus marcadores bioquimicos y su tratamiento. Conclusiones. Es importante pensar en la posibilidad de un error congenito del metabolismo con terapia especifica, ya que es fundamental que esta comience lo antes posible para evitar un daño neurologico permanente.

Pharmacological targeting of adenosine receptor signaling.

Adenosine receptor signaling plays important roles in normal physiology, but is also known to modulate the development or progression of several different diseases. The design of new, efficient, and safe pharmacological approaches to target the adenosine system may have considerable therapeutic potential, but is also associated with many challenges. This review summarizes the main challenges of adenosine receptor targeted treatment including tolerance, disease stage, cell type-specific effects, caffeine intake, adenosine level assessment and receptor distribution in vivo. Moreover, we discuss several potential ways to overcome these obstacles (i.e., the use of partial agonists, indirect receptor targeting, allosteric enhancers, prodrugs, non-receptor-mediated effects, neoreceptors, conditional knockouts). It is important to address these concerns during development of new and successful therapeutic approaches targeting the adenosine system.

Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision.

Glutaric aciduria type I (GA-I; synonym, glutaric acidemia type I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutaryl carnitine in body tissues, which can be reliably detected by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Most untreated individuals with GA-I experience acute encephalopathic crises during the first 6 years of life that are triggered by infectious diseases, febrile reaction to vaccinations, and surgery. These crises result in striatal injury and consequent dystonic movement disorder; thus, significant mortality and morbidity results. In some patients, neurologic disease may also develop without clinically apparent crises at any age. Neonatal screening for GA-I us being used in a growing number of countries worldwide and is cost effective. Metabolic treatment, consisting of low lysine diet, carnitine supplementation, and intensified emergency treatment during catabolism, is effective treatment and improves neurologic outcome in those individuals diagnosed early; treatment after symptom onset, however, is less effective. Dietary treatment is relaxed after age 6 years and should be supervised by specialized metabolic centers. The major aim of this second revision of proposed recommendations is to re-evaluate the previous recommendations (Kölker et al. J Inherit Metab Dis 30:5-22, 2007b; J Inherit Metab Dis 34:677-694, 2011) and add new research findings, relevant clinical aspects, and the perspective of affected individuals.

NCAM-deficient mice show prominent abnormalities in serotonergic and BDNF systems in brain - Restoration by chronic amitriptyline.

Mood disorders are associated with alterations in serotonergic system, deficient BDNF (brain-derived neurotrophic factor) signaling and abnormal synaptic plasticity. Increased degradation and reduced functions of NCAM (neural cell adhesion molecule) have recently been associated with depression and NCAM deficient mice show depression-related behavior and impaired learning. The aim of the present study was to investigate potential changes in serotonergic and BDNF systems in NCAM knock-out mice. Serotonergic nerve fiber density and SERT (serotonin transporter) protein levels were robustly reduced in the hippocampus, prefrontal cortex and basolateral amygdala of adult NCAM(-)(/-) mice. This SERT reduction was already evident during early postnatal development. [(3)H]MADAM binding experiments further demonstrated reduced availability of SERT in cell membranes of NCAM(-)(/-) mice. Moreover, the levels of serotonin and its major metabolite 5-HIAA were down regulated in the brains of NCAM(-)(/-) mice. NCAM(-)(/-) mice also showed a dramatic reduction in the BDNF protein levels in the hippocampus and prefrontal cortex. This BDNF deficiency was associated with reduced phosphorylation of its receptor TrkB. Importantly, chronic administration of antidepressant amitriptyline partially or completely restored these changes in serotonergic and BDNF systems, respectively. In conclusion, NCAM deficiency lead to prominent and persistent abnormalities in brain serotonergic and BDNF systems, which likely contributes to the behavioral and neurobiological phenotype of NCAM(-/-) mice.

[Treatable neurometabolic diseases. Association with schizophrenia spectrum disorders]. / Maladies neurométaboliques traitables associées aux troubles du spectre de la schizophrénie.

Schizophrenia spectrum disorders are presented on 1% of subjects over general population. Organic pathologies prevalence in schizophrenia spectrum patients is not well determined, and it is probably underestimated. In the present update review, we are going to highlight seven treatable neurometabolic diseases (NMD) associated to sub-clinic neurological symptoms. It is not infrequent to witness the absence of any clinical neurological signs going along with the NMD. Psychiatric symptoms may be the only clinical alarm that can guide physicians to an acute diagnosis. This is why it is a challenging pathology, defying our clinical accuracy as psychiatrist or any other practitioners confronted to this population. Hereby we are going to expose a literature review and comprehensive tables in order to present in a glance the essential clinical features of disorders of homocysteine metabolism, urea cycle disorders, Niemann-Pick disease type C, acute porphyria, cerebrotendinous-xanthomatosis. These conditions are sensible to major improvement strongly correlated to the accuracy of diagnosis. Literature analysis led us to propose a comprehensive list of atypical psychiatric symptoms including highly predominant visual hallucinations, compared to auditory ones, as well as confusion, catatonia or progressive cognitive decline. We highlight the importance of considering antipsychotic treatment resistance as a crucial sign leading to suspect an organic factor beneath the psychiatric features.

Rare presentation of a treatable disorder: glutaric aciduria type 1.

A 32-year-old female patient presented with migraine and a bipolar disorder with frontal lobe dysfunction and bilateral pyramidal tract signs on examination. MRI brain revealed confluent bilateral symmetric white matter signal abnormality on T2 and FLAIR images with mild cerebral atrophy. Classic widening of Sylvian fissures and CSF space anterior to temporal lobes was seen. In view of the clinical and radiologic findings suggestive of a leukodystrophy, she was investigated for the same. Her investigations revealed an high level of urinary glutaric acid 857 mmol/mol creatinine (normal <4mmol/mol creatinine) and 3-hydroxyglutaric acid 44 mmol/mol creatinine (normal <1 mmol/mol creatinine) and plasma glutaryl carnitine 1.2 micromol/L; (normal <0.34 micromol/L). This was diagnostic of glutaric aciduria type 1. She was started on L-carnitine with which she showed clinical improvement. Testing for urinary organic acids is important when looking for treatable metabolic disorders (such as glutaric aciduria type I) in patients with leukodystrophy.