Dendritic cells (DCs) are the sentinel innate immune cells that initiate antigen-specific adaptive immune responses. On the one hand, DCs have been extensively analyzed because of their roles in immune response against pathogens, and on the other hand, there are numerous other studies that have investigated their role in immune tolerance of autoimmune disorders such as type 1 diabetes, systemic lupus erythematosus, multiple sclerosis (MS), and psoriasis. The presence, recruitment, and activation of DCs in the cerebral spinal fluids of experimental allergic encephalomyelitis and MP models, initiated the long array of studies of pathogenic and the potential therapeutic role of DCs in MS. Many classic disease-modifying therapies that are employed have used strategies to alter the maturation and function of DCs; several other novel therapeutic strategies are currently under investigations, which we aim to briefly review in this article. We have focused on reviewing the role of DCs in the central nervous system (CNS), underlying their pathogenesis involvement, and proposing targeting therapies for autoimmune CNS disorders.

Free radicals (FRs) are continuously produced during aerobic metabolism and are characterized by high reactivity. They participate in many important physiological processes, but if produced in high concentrations, they lead to oxidative stress (OS) development and disturb pro-oxidative/antioxidative balance toward the oxidation of lipids, proteins, carbohydrates, or nucleic acids.[1] Each of these reactions may have deleterious consequences and differential effects on the distinct cell populations of the body, with certain specific cell types being particularly vulnerable in perinatal period.[2] Pathologies resulting from oxidative damage are grouped together and categorized as “free radical disease in the neonate” (FRD). Such pathologies include retinopathy of prematurity (which in severe cases may lead to blindness), bronchopulmonary dysplasia (a particularly debilitating pulmonary lesion in the preterm infant), periventricular leukomalacia (an important cause of severe neurodisability in premature infants), and necrotizing enterocolitis.

During fetal life, a right balance between oxidants and antioxidants is required for survival and growth of the fetus. At birth, an overproduction of free radicals (FRs) together with poor antioxidant defenses may be detrimental for developing organs and tissues. Protecting the newborn infant against perinatal oxidative stress (OS) is a health care priority, and therefore the search for new, safe, and efficacious antioxidants has been a major quest during the last decade. Due to its antioxidant and anti-inflammatory properties, lutein, a compound belonging to the xanthophyll family of carotenoids, is one of the most promising molecules with clinical application during neonatal age. Lutein is not synthesized by humans, hence the intake primarily depends on diet. In the neonatal period, fresh human milk is the main source of lutein, though lutein-enriched infant formulas are now available. Oral supplementation represents an alternative source of lutein, and it has been demonstrated to decrease plasma biomarkers of OS and increase antioxidant capacity in the first days of life.

Systemic organic acidemias are intoxication-type inborn errors of metabolism which can present in the neonatal period and beyond with metabolic acidosis, vomiting, and lethargy, and progress to coma and without adequate treatment ultimately death. There should be a low threshold for consideration of this family of disorders in individuals that present with the above symptoms, present with a sepsis-like picture, have developmental delay or intellectual disability, or develop disease-specific long term complications (e.g., cardiomyopathy seen in propionic acidemia, renal failure seen in the methylmalonic acidemias). Late diagnosis with intellectual disabilities or disease-specific complications are thought to becoming less common in areas with universal newborn screening since it includes many of these disorders and allows for early treatment and avoidance of severe presentations. In general, treatment in the acute setting focuses on decreasing toxin production by reversal of catabolism, removal of toxin precursors, use of toxin scavengers (e.g., levocarnitine to bind propionic acid in propionic acidemia) and attempting to improve enzyme function by using supra-physiologic doses of cofactors. Long term therapy has similar approaches.

Urea cycle disorders (UCDs) are a group of autosomal or X-linked, recessively inherited errors of metabolism that lead to severe neurological disease due to insufficient detoxification of excess nitrogen. The resulting hyperammonemia is the key feature of UCDs, but at the same time only a surrogate marker. In the majority of cases, a sole biochemical analysis is indicative but not diagnostic. Therefore, additional means are required and mutation analysis is the method of choice for con- firmation in most cases of UCD. In addition to confirming the diagnosis, mutation analysis enables genetic counseling and prenatal testing and contributes to new research approaches. All genes involved in any of the enzymatic (namely the genes for N-acetylglutamate synthase, NAGS; carbamoylphosphate synthetase, CPS1; ornithine transcarbamylase, OTC; argininosuccinate synthetase, ASS1; argininosuccinate lyase, ASL; arginase, ARG1) or transporter steps (namely the genes for the ornithine/ citrulline antiporter ORNT1, SLC25A15; glutamate/aspartate antiporter citrin, SLC25A13) of the urea cycle are known and thus accessible for genetic testing. In most situations, direct Sanger sequencing using DNA from peripheral blood cells can be done but there are exceptions to this such as in the case of the relatively large CPS1 gene which renders RNA based mutation analysis an attractive alternative. With this review, we provide an overview on the current methods used for mutation analysis of each UCD gene, we mention possible pitfalls and their solutions, and discuss alternative methods which may become standard in the future.

Metabolic myopathies refer to a group of heterogeneous hereditary muscle disorders associated with known enzymatic defects. These conditions affect the ability of muscle fibers to maintain adequate energy and adenosine triphosphate (ATP) concentrations. Conventionally these diseases are grouped into abnormalities of lipid, glycogen, purine or mitochondrial metabolism. This review will focus on current diagnosis and management of pediatric patients presenting with a suspected metabolic myopathy.

In the clinical management of inborn errors of metabolism (IEMs) a central focus is on protecting the central nervous system (CNS) from the toxic effects of the metabolic dysfunction. Despite our ability to screen for and detect many of these conditions in the newborn period, making early treatment possible, cognitive abnormalities may still result because of our inability to identify and alter the early steps in brain pathology. A key in preventing neurological imaging is the understanding the steps in the brain injury and the time course of injury in order that physicians may intervene. Since the infant who is comatose does not give us clues as to whether it is due to infection, inborn errors of metabolism and which one, seizures or other causes based on examination alone. Therefore, neuroimaging may provide biomarkers for diagnosis and prognosis. This review will discuss use of neuroimaging in inborn errors of metabolism of acutely ill infants.

Lysosomes are cytoplasmic organelles that play a major role in cellular metabolic salvage, necessary for cellular homeostasis. Besides, degrading several macromolecules in metabolic salvage process, lysosomes also involve in several cellular processes e.g. cell apoptosis and intracellular signaling. Lysosomal storage disorder (LSD) is a group of inherited metabolic disorders, which can present at any age from prenatal to adult. Pathology/pathophysiology usually engages several organ systems. Majority of diseases in this group involve neurological system causing neurodegenerative manifestation. Biomarkers are not only available but also useful for disease screening and monitoring. Diagnosis should be confirmed by enzyme analysis and/or molecular analysis. Although treatment is available in some diseases, the outcomes are not favorable in selected patients, especially when present with neurological symptoms. Understanding the complexity of LSD is important for patients' care and development of new treatment. Appropriate genetic counseling should be provided to every patient.

Nephrocalcinosis (NC) describes the deposition of calcium-oxalate or calcium-phosphate crystals in the tubuli or interstitial kidney parenchyma. Whereas kidney stones are formed in every age NC is most frequently seen during the first years of life. Because of multiple causative factors NC is a diagnostic challenge. A mostly metabolic reason for the development of nephrocalcinosis can be identified in up to 75% of patients and hence adequately be treated. An imbalance of lithogenic and inhibitory substances is the pathophysiologic basis for the development of nephrocalcinosis. This imbalance is either transient, for example in patients with alimentary hyperoxaluria or short term immobilization induced hypercalciuria, or ongoing, e.g., in tubulopathies or inborn errors of metabolism. Hypercalciuria is the most prominent promotor for the development of nephrocalcinosis, either accompanied by hypercalcemia or not. Both hyperoxaluria, in its primary or secondary forms, as well as hypocitraturia, e.g., in renal tubular acidosis, or in the premature infant, are further specific risk factors. Of course, although mostly clinically silent, early diagnosis is mandatory to start treatment, which may help not only to prevent progression of NC but end stage renal failure relying on the underlying diseases.