Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma.

We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A>G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants.

Identifying encephalopathies from acute metabolic derangements.

Metabolic derangements, when acute and severe, affect brain function. This presents mostly with a marked decline in the level of consciousness, resulting in impaired responsiveness, abnormal receptivity, impaired content, and loss of memory retention. The term metabolic encephalopathy has been used but is conjecture that can be challenged in the age of modern neuroimaging. We now recognize that many metabolic encephalopathies may involve structural lesions and at an early stage. Common clinical conundrums are the evaluation of the degree of brain injury and its recoverability. This review discusses the appropriate terminology for these conditions, the diagnostic approach, therapy recommendations, and prediction of recovery potential. In evaluating a presumed metabolic cause for encephalopathy, we must (1) search for and rule out structural injury to the brain despite an obvious explanatory metabolic derangement, (2) recognize that several confounding conditions often co-exist, and (3) acknowledge that resolution of brain dysfunction may be protracted despite normalization of laboratory values.

Toxic-metabolic encephalopathy in adults: Critical discussion and pragmatical diagnostic approach.

Toxic-metabolic encephalopathy (TME) results from an acute cerebral dysfunction due to different metabolic disturbances including medications or illicit-drugs. It can lead to altered consciousness, going from delirium to coma, which may require intensive care and invasive mechanical ventilation. Even if it is a life-threatening condition, TME might have an excellent prognosis if its etiology is rapidly identified and treated adequately. This review summarizes the main etiologies, their differential diagnosis, and diagnostic strategy and management of TME with a critical discussion on the definition of TME.

[Neurological complications in haematopoietic stem cell transplant patients]. / Complicaciones neurológicas en pacientes sometidos a trasplante de progenitores hematopoyéticos.

INTRODUCTION: Neurological complications are some of the most important complications that can occur in a patient undergoing haematopoietic stem cell transplantation (HSCT), not only because of the high mortality rate, but also because of the sequelae that appear in survivors. The causes of such complications are manifold and very often coexist in the same patient: toxicity of the conditioning regimen, graft-versus-host disease and its treatment, infections and their treatment, platelets and coagulation disorders, liver failure or arterial hypertension with low platelet count. AIMS: The aim of the present study is to provide a clinical description and to describe the risk factors for complications involving the central nervous system that may occur during the course of HSCT, in order to assist in the early detection of these disorders that may have a negative influence on the morbidity and mortality of these patients. DEVELOPMENT: The following types of neurological complications are described: central nervous system infections, vascular complications, pharmacological toxicity, metabolic complications, immune-mediated disorders and post-HSCT carcinogenesis, and effects of graft-versus-host disease and thrombotic microangiopathy on the nervous system. CONCLUSIONS: The patient undergoing HSCT is at particular risk for the development of neurological complications. Early diagnosis and treatment are needed to try to reduce the high morbidity and mortality in these patients.

TITLE: Complicaciones neurológicas en pacientes sometidos a trasplante de progenitores hematopoyéticos.Introducción. Las complicaciones neurológicas son algunas de las más importantes que se pueden presentar en un paciente sometido a un trasplante de progenitores hematopoyéticos (TPH), no sólo porque conllevan una mortalidad elevada, sino también por las secuelas que aparecen en los supervivientes. Las causas de dichas complicaciones son múltiples y, muy frecuentemente, coexisten en el mismo paciente: toxicidad del régimen de acondicionamiento, enfermedad del injerto contra el hospedador y su tratamiento, infecciones y su tratamiento, plaquetopenia y trastornos de la coagulación, fallo hepático o hipertensión arterial con plaquetopenia. Objetivos. El objetivo del presente estudio es el de aportar una descripción clínica y de los factores de riesgo de las complicaciones sobre el sistema nervioso central que pueden presentarse en el curso de un TPH, para ayudar en la detección precoz de estos trastornos que pueden influir negativamente en la morbimortalidad de estos pacientes. Desarrollo. Se describen los siguientes tipos de complicaciones neurológicas: infecciones sobre el sistema nervioso central, complicaciones vasculares, toxicidad farmacológica, complicaciones metabólicas, trastornos inmunomediados y carcinogenia pos-TPH, y efectos de la enfermedad del injerto contra el hospedador y de la microangiopatía trombótica sobre el sistema nervioso. Conclusiones. El paciente sometido a TPH es de especial riesgo para el desarrollo de complicaciones neurológicas. Se precisan un diagnóstico y un tratamiento precoces para intentar disminuir la elevada morbimortalidad de estos pacientes.

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.

D-lactic acidosis presenting as metabolic encephalopathy in a patient with short bowel syndrome.

We present a case of D-lactic acidosis presenting as a metabolic encephalopathy secondary to small intestinal bacterial overgrowth. This patient had a known history of short bowel syndrome. Of note, this case required the alteration of treatment to promote a sustained clinical and biochemical improvement. We discuss the pathophysiological mechanisms thought to be involved. We also review the current therapies as well as potential future strategies. This case highlights the importance of the prompt clinical recognition of signs and symptoms as well as the rapid initiation of management strategies to ameliorate this condition.

Encephalopathy in cystic fibrosis.

Cystic fibrosis liver disease (CFLD) affects a large proportion of cystic fibrosis (CF) patients; however encephalopathy is a rare complication. While classical hepatic encephalopathy can be a feature of end-stage liver disease, "hyperammonemic encephalopathy" can be precipitated in previously stable CFLD by various triggers including systemic corticosteroids. We describe one such case and review the relevant literature.

Medical complications of anorexia nervosa.

Anorexia nervosa is a mental illness characterized by self-starvation, marked weight loss, and malnutrition. As the illness worsens, numerous medical complications develop throughout the body. Some of these resolve with effective nutritional rehabilitation and weight gain, whereas others can lead to permanent damage.

Electrolyte Disorders and the Nervous System.

PURPOSE OF REVIEW: This article provides an overview of the major electrolyte disorders and discusses in detail the homeostasis, etiologies, neurologic manifestations, and treatment of these disorders. RECENT FINDINGS: The diagnosis and management of hyponatremia continue to evolve. Diagnostic accuracy is improved by assessing serum and urine osmolality as well as urinary sodium. Avoiding overcorrection of hyponatremia is crucial to avoid osmotic demyelination syndrome, although even careful correction can cause osmotic demyelination syndrome in patients who have other risk factors. The clinical presentation of osmotic demyelination syndrome has expanded, with many patients presenting with extrapontine myelinolysis in addition to central pontine myelinolysis. SUMMARY: Electrolyte disorders often present with neurologic manifestations. Whereas disorders of some electrolytes, such as sodium, preferentially affect the central nervous system, disorders of others, such as potassium and calcium, have significant neuromuscular manifestations. An understanding of the pathophysiology of these disorders and recognition of these manifestations are crucial for the practicing neurologist as the symptoms are reversible with correct management.

Idiopathic brain calcification in a patient with hereditary hemochromatosis.

BACKGROUND: Detection of brain-MRI T2/T2* gradient echo images (T2*GRE)-hypointensity can be compatible with iron accumulation and leads to a differential diagnosis work-up including neurodegeneration with brain iron accumulation (NBIA) and Wilson Disease. Idiopathic or secondary brain calcification can be also associated with neurological involvement and brain-MRI T2/T2*GRE-hypointensity. Hereditary hemochromatosis (HH), characterized by systemic iron loading, usually does not involve the CNS, and only sporadic cases of neurological abnormalities or brain-MRI T2/T2*GRE-hypointensity have been reported. CASE PRESENTATION: A 59-year-old man came to our observation after a diagnosis of HH carried out in another hospital 2 years before. First-level genetic test had revealed a homozygous HFE p.Cys282Tyr (C282Y) mutation compatible with the diagnosis of HFE-related HH, thus phlebotomy treatment was started. The patient had a history of metabolic syndrome, type-2 diabetes, autoimmune thyroiditis and severe chondrocalcinosis. Brain-MRI showed the presence of bilateral T2*GRE hypointensities within globus pallidus, substantia nigra, dentate nucleus and left pulvinar that were considered expression of cerebral siderosis. No neurological symptoms or family history of neurological disease were reported. Neurological examination revealed only mild right-sided hypokinetic-rigid syndrome. Vitamin D-PTH axis, measurements of serum ceruloplasmin and copper, and urinary copper were within the normal range. A brain computed tomography (CT) was performed to better characterize the suspected and unexplained brain iron accumulation. On the CT images, the hypointense regions in the brain MRI were hyperdense. DNA sequence analysis of genes associated with primary familial brain calcification and NBIA was negative. CONCLUSIONS: This report highlights the importance of brain CT-scan in ambiguous cases of suspected cerebral siderosis, and suggests that HH patients with a severe phenotype, and likely associated with chondrocalcinosis, may display also brain calcifications. Further studies are needed to confirm this hypothesis. So far, we can speculate that iron and calcium homeostasis could be reciprocally connected within the basal ganglia.

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.

Divergent metabolic substrate utilization in brain during epileptogenesis precedes chronic hypometabolism.

Alterations in metabolism during epileptogenesis may be a therapy target. Recently, an increase in amino acid transport into the brain was proposed to play a role in epileptogenesis. We aimed to characterize alterations of substrate utilization during epileptogenesis and in chronic epilepsy. The lithium-pilocarpine post status epilepticus (SE) rat model was used. We performed longitudinal O-(2-[(18)F]fluoroethyl)-l-tyrosine (18F-FET) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and calculated 18F-FET volume of distribution (Vt) and 18F-FDG uptake. Correlation analyses were performed with translocator protein-PET defined neuroinflammation from previously acquired data. We found reduced 18F-FET Vt at 48 h after SE (amygdala: -30.2%, p = 0.014), whereas 18F-FDG showed increased glucose uptake 4 and 24 h after SE (hippocampus: + 43.6% and +42.5%, respectively; p < 0.001) returning to baseline levels thereafter. In chronic epileptic animals, we found a reduction in 18F-FET and 18F-FDG in the hippocampus. No correlation was found for 18F-FET or 18F-FDG to microglial activation at seven days post SE. Whereas metabolic alterations do not reflect higher metabolism associated to activated microglia, they might be partially driven by chronic neuronal loss. However, both metabolisms diverge during early epileptogenesis, pointing to amino acid turnover as a possible biomarker and/or therapeutic target for epileptogenesis.

Pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency in zebrafish results in fatal seizures and metabolic aberrations.

Pyridox(am)ine 5'-phosphate oxidase (PNPO) catalyzes oxidation of pyridoxine 5'-phosphate (PNP) and pyridoxamine 5'-phosphate (PMP) to pyridoxal 5'-phosphate (PLP), the active form of vitamin B6. PNPO deficiency results in neonatal/infantile seizures and neurodevelopmental delay. To gain insight into this disorder we generated Pnpo deficient (pnpo-/-) zebrafish (CRISPR/Cas9 gene editing). Locomotion analysis showed that pnpo-/- zebrafish develop seizures resulting in only 38% of pnpo-/- zebrafish surviving beyond 20 days post fertilization (dpf). The age of seizure onset varied and survival after the onset was brief. Biochemical profiling at 20 dpf revealed a reduction of PLP and pyridoxal (PL) and accumulation of PMP and pyridoxamine (PM). Amino acids involved in neurotransmission including glutamate, γ-aminobutyric acid (GABA) and glycine were decreased. Concentrations of several, mostly essential, amino acids were increased in pnpo-/- zebrafish suggesting impaired activity of PLP-dependent transaminases involved in their degradation. PLP treatment increased survival at 20 dpf and led to complete normalization of PLP, PL, glutamate, GABA and glycine. However, amino acid profiles only partially normalized and accumulation of PMP and PM persisted. Taken together, our data indicate that not only decreased PLP but also accumulation of PMP may play a role in the clinical phenotype of PNPO deficiency.

Lactic acidosis: a unique presentation of diffuse large B-cell lymphoma.

An elderly man in the seventh decade of life was brought to the hospital with worsening mental status. Blood tests revealed anaemia and thrombocytopenia with elevated lactate dehydrogenase and serum lactate levels. CT scan showed bulky thoracic and abdominal lymphadenopathy with splenomegaly. A positron emission tomography scan confirmed the above and in addition, revealed bilateral adrenal involvement. Bone marrow biopsy revealed non-germinal centre B-cell-like (non-GCB)-diffuse large B-cell lymphoma (DLBCL). Prompt treatment with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab with intrathecal methotrexate chemotherapy resulted in a dramatic improvement in the patient's condition. This vignette serves as a reminder to include aggressive lymphomas like DLBCL in the differential diagnoses of patients presenting with metabolic encephalopathy and lactic acidosis. Our patient was moribund at presentation with poor sensorium and failure to thrive. The dilemma was whether to take an aggressive stand and start chemotherapy urgently or whether to stabilise the patient first and then consider the treatment of DLBCL. We make a case for initiating therapy promptly in such patients irrespective of their performance status.