Journal of Pediatric Biochemistry - Volume 2, issue 4

Authors: Frye, Richard E. | Rossignol, Daniel A.

Article Type: Other

DOI: 10.3233/JPB-120059

Citation: Journal of Pediatric Biochemistry, vol. 2, no. 4, pp. 177-180, 2012

Authors: Frye, Richard E. | Rossignol, Daniel A.

Article Type: Research Article

Abstract: Recent research has implicated systematic physiological and metabolic abnormalities, such as immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and other metabolic disorders that transcend organ specific dysfunction in ASD. In this context, ASD may arise from, or at least involve, systemic physiological abnormalities. In this review, common, and not so common, metabolic abnormalities associated with ASD are outlined. Mitochondrial dysfunction and cerebral folate abnormalities are the most prevalent metabolic disorders affecting children …with ASD. Other potentially important metabolic disorders that have been reported in ASD include urea cycle disorders, succinic semialdehyde dehydrogenase deficiency, adenylosuccinate lyase deficiency, phenylketonuria, creatine deficiency syndromes, pyridoxine dependent and responsive seizures, biotinidase deficiency and Smith-Lemli-Opitz syndrome. Other metabolic abnormalities that appear to be associated with ASD are disorders of general cholesterol metabolism and tetrahydrobiopterin metabolism. Although detailed cases of children with ASD and these latter two metabolic abnormalities have not been formally described, there is evidence that some children with ASD may manifest these metabolic abnormalities. Lastly, an algorithm for systematically approaching the diagnosis of metabolic disease in ASD is provided. Show more

Keywords: Autism spectrum disorder, mitochondrial disease, cerebral folate deficiency, folate receptor autoantibodies, metabolic disease

DOI: 10.3233/JPB-120060

Citation: Journal of Pediatric Biochemistry, vol. 2, no. 4, pp. 181-191, 2012

Authors: Kendall, Fran D.

Article Type: Research Article

Abstract: Mitochondrial disorders typically present with widespread, clinical features in all age groups and ethnicities and are often progressive and degenerative in nature. Because their clinical presentation is so variable and typically leads to widespread multisystem problems, diagnosis based on history and physical findings alone is often difficult, particularly for physicians unfamiliar with this group of diseases. Traditional diagnostic tools, which include invasive muscle biopsies for a variety of histological studies, functional assays, …and enzymology, are costly, typically require a surgical procedure, are not definitively diagnostic in all cases and generate data that for the non-mitochondrial specialist is often difficult to interpret. Recent advances with expanded gene testing, in some cases utilizing easily obtainable urine samples, and noninvasive enzymatic testing are proving to increase patient accessibility to testing modalities and will likely lead to more rapid and accurate diagnosis, and ultimately improve management and treatment of affected individuals. Show more

Keywords: Mitochondrial, disease, diagnose, test, symptom, gene, buccal swab, muscle biopsy, next gen sequencing

DOI: 10.3233/JPB-120061

Citation: Journal of Pediatric Biochemistry, vol. 2, no. 4, pp. 193-203, 2012

Authors: van den Heuvel, Lambertus P. | Smeitink, Jan A.M. | Rodenburg, Richard J.T.

Article Type: Research Article

Abstract: The clinical heterogeneity of mitochondrial disorders often makes it a challenge to establish a diagnosis in suspected mitochondrial patients. The classical approach to the diagnostic examination usually involves a muscle biopsy to evaluate mitochondrial function by measuring enzyme activities of the OXPHOS enzymes complex I to V, and to determine flux parameters such as oxygen consumption, the oxidation of various substrates, and ATP production. Based on the combination of clinical features and biochemical parameters, candidate …genes are selected for subsequent molecular genetic studies in the conventional diagnostic work-flow. The procedures for diagnostic molecular genetic analysis of mitochondrial patients are rapidly evolving, due to the introduction of next generation sequencing (NGS) technologies in diagnostic laboratories. In addition to the application to mtDNA sequence analysis, NGS is used for the sequence analysis of multiple nuclear genes. The new technological possibilities for molecular genetic testing will result in a change in the diagnostic work-up of suspected mitochondrial patients. Because of the often poor genotype-phenotype correlation in mitochondrial disease, NGS analysis will often require functional follow up testing to confirm pathogenicity of genetic variants. This will create a demand for more specific diagnostic functional tests; not only for mitochondrial oxidative phosphorylation, but also for other mitochondrial processes like substrate transport, nucleotide homeostasis, mtDNA transcription/translation, and so on. The development of a collection of sophisticated and preferably non-invasive diagnostic tests for functional follow-up of NGS molecular genetics results is the next challenge in the diagnostic examination of suspected mitochondrial patients. Show more

Keywords: Mitochondrial disorders, biochemical diagnosis, respiratory chain, molecular genetic diagnosis, mtDNA, next generation sequencing

DOI: 10.3233/JPB-120062

Citation: Journal of Pediatric Biochemistry, vol. 2, no. 4, pp. 205-212, 2012

Authors: Chauhan, Abha | Gu, Feng | Chauhan, Ved

Article Type: Research Article

Abstract: Mitochondrial respiratory electron transport chain (ETC) consists of five multi-subunit enzymes, i.e., complex I-V, which differs not only in structure but also in function, and plays an important role in adenosine triphosphate (ATP) generation by mitochondria. Each of these complexes participates in the generation of proton gradient in the mitochondrial intermembrane space, which is necessary for converting adenosine diphosphate (ADP) into ATP by ATP synthase. Brain has a high demand for energy, and neurons …generate energy in the form of ATP through the respiratory chain in the mitochondria. Almost 90% of this energy is provided by mitochondrial ETC. ETC also generates most of the endogenous free radicals, i.e., reactive oxygen species (ROS) of the cell. The normal functions of ETC are essential to maintain physiological function and plasticity of neurons. Therefore, abnormalities in ETC during development, i.e., in utero, infancy and childhood, may be involved in the etiology of neurodevelopmental disorders. The abnormalities in mitochondrial ETC pertaining to neurodevelopmental disorders include mtDNA mutations, altered gene expression, decreased activities and protein expression levels of ETC complexes, and oxidative stress. Here, we review these mitochondrial ETC defects in autism spectrum disorders (ASDs) and other neurodevelopmental disorders, i.e., attention deficit hyperactivity disorder, schizophrenia, Down syndrome and Fragile X syndrome. Show more

Keywords: Autism, attention deficit hyperactivity disorder, Down syndrome, electron transport chain, Fragile X syndrome, mitochondria, neurodevelopment, oxidative stress, schizophrenia

DOI: 10.3233/JPB-120063

Citation: Journal of Pediatric Biochemistry, vol. 2, no. 4, pp. 213-223, 2012

Authors: El-Ansary, Afaf

Article Type: Research Article

Abstract: An unavoidable consequence of aerobic respiration is the generation of reactive oxygen species (ROS). ROS is a collective term that includes both oxygen radicals and certain oxidizing agents that are easily converted into radicals. They can be produced from both endogenous and exogenous substances. ROS play a dual role in biological systems, since they can be either harmful or beneficial to living systems. They can be considered a double-edged sword: oxygen-dependent reactions and aerobic respiration have …significant advantages but overproduction of ROS, a consequence of oxygen-dependent reactions, has the potential to cause damage. Overproduction of ROS may negatively impact neonatal growth and contribute to the aetiology of many developmental disorders. During mitochondrial respiration, an inability to neutralize reactive oxygen species and free radicals leads to oxidative stress. The inner membrane of the mitochondria contains a large number of free radical scavengers including glutathione, vitamin C, and vitamin E, as well as anti-oxidant enzymes such as superoxide dismutase. The brain is particularly vulnerable to free radical attack for several reasons, including exposed to high oxygen concentrations, relatively low antioxidant protection, membranes with high levels of polyunsaturated fatty acids, and high iron and ascorbate content. The brain's high energy demand is primarily supplied by oxidative phosphorylation, the major producer of free radicals. When the level of free radicals overwhelms the cellular antioxidant defense system, a deleterious condition known as oxidative stress occurs. ROS has an intimate relationship with mitochondrial function and oxidative stress is believed to result from mitochondrial dysfunction. This review highlights the role of oxidative stress and mitochondrial dysfunction as key players in the neurodevelopmental pathophysiology. The mechanisms associating these two disease states can lead to neuronal death, neuroinflammation and impairment of energy metabolism. Biomarkers related to both aspects will be highlighted to demonstrate their importance in the early diagnosis of neurodevelopmental disorders like autism, cerebral palsy and others. Treatments trials for oxidative stress or mitochondrial dysfunction using nutritional supplements and antioxidants are reviewed in order to shed light on recent strategies for the early intervention for neurodevelopmental disorders. Show more

Keywords: Oxidative stress, mitochondrial dysfunction, neurodevelopmental disorders, antioxidants, melatonin, hyperbaric oxygen therapy

DOI: 10.3233/JPB-120064

Citation: Journal of Pediatric Biochemistry, vol. 2, no. 4, pp. 225-239, 2012

Authors: Frye, Richard E. | Rossignol, Daniel A.

Article Type: Research Article

Abstract: Mitochondrial disease (MD) and dysfunction are associated with autism spectrum disorder (ASD) and most likely affect a substantial number of children with ASD. The mitochondrion is the powerhouse of the body's cells which supports and is supported by many metabolic systems, so mitochondrial dysfunction can have widespread consequences on cellular metabolism, especially in high energy cells like the brain, gastrointestinal tract and immune system, and especially during critical periods of high energy demand like childhood. …This article reviews the treatments for MD as applied to children with ASD. We discuss supportive measures which aim at preventing further damage from occurring due to malfunctioning mitochondria, treatment with high dose vitamins that can support metabolism in light of dysfunctional mitochondria, dietary changes that can be useful in mitochondrial disease, and secondary organ systems to investigate due to mitochondrial dysfunction. We also discuss several treatments that have been reported to be of benefit in children with ASD which are also treatments that are standard of care for MD. This review provides a guide for appropriate treatments for children with ASD/MD and children with ASD that have mitochondrial dysfunction. Show more

Keywords: Autism spectrum disorder, mitochondrial disease, oxidative stress, treatment

DOI: 10.3233/JPB-120065

Citation: Journal of Pediatric Biochemistry, vol. 2, no. 4, pp. 241-249, 2012

Authors: DeSoto, M. Catherine | Hitlan, Robert T.

Article Type: Research Article

Abstract: Persons in developed countries are getting large amounts of folates in the form of folic acid. Folates are now ingested in three ways: as natural folates from food, as synthetic folic acid added to processed grains, and synthetic vitamin supplements. As a result of the supplementation, the circulating level of unmetabolized folic acid as well as total folates has greatly increased over the past generation, probably to levels largely unprecedented in human history. Folic acid has …been shown to be able to epigenetically alter the functioning of the genome and to have long term effects on gene expression. The Centers for Disease Control Vaccine Safety Datalink data set compared children with autism to control children on several variables. Here, we report that folic acid supplementation during gestation is associated with an increased risk for autism. The effect remains even when health seeking behaviors and other variables are controlled. Show more

Keywords: Folic acid, excess vitamins, autism, folate, synthetic vitamins

DOI: 10.3233/JPB-120066

Citation: Journal of Pediatric Biochemistry, vol. 2, no. 4, pp. 251-261, 2012

Authors: Rossignol, Daniel A. | Frye, Richard E.

Article Type: Research Article

Abstract: Cerebral folate deficiency (CFD) is a neurometabolic syndrome characterized by low levels of 5-methyltetrahydrofolate (5MTHF) in the brain despite normal systemic folate levels. Notably, CFD represents one of a few progressive neurological disorders that is treatable and potentially reversible. One common cause of CFD is an autoantibody that binds to the folate receptor-α (FRα) making it non-functional and blocking the transportation of 5MTHF from the blood into the central nervous system. Cow's …milk contains soluble FRα antigen, which is 91% similar to human FRα. Autoantibodies to the FRα cross-react with the soluble FRα antigen in cow's milk, increasing the concentration of autoantibodies and resulting in worsen of CFD, while elimination of cow's milk lowers the autoantibody concentration and improves CFD symptoms. Notably, some cases of CFD are due to mitochondrial disease (MD). To date, three studies have reported an association between CFD and Rett syndrome, seven studies have reported that CFD is associated with autism spectrum disorders (ASD) in some children, and five studies have reported FRα autoantibodies in children with ASD, some of whom also had CFD. One study of 93 children with ASD reported that FRα autoantibodies were found in 75.3%. From these studies of children with concomitant ASD and CFD, treatment with oral folinic acid (leucovorin, 0.5 to 2 mg/kg/day) resulted in various improvements ranging from partial improvements in communication, social interaction, attention and stereotypical behavior to complete recovery of both neurological and ASD symptoms. Notably, an overlap between ASD, MD and CFD is found in some children with ASD, and therefore we recommend testing for MD and CFD/FRα autoantibodies in all individuals with ASD. Further studies examining FRα autoantibodies and CFD in children with ASD are warranted. Show more

Keywords: Autism, cerebral folate deficiency, folate, methylfolate, folinic acid

DOI: 10.3233/JPB-120067

Citation: Journal of Pediatric Biochemistry, vol. 2, no. 4, pp. 263-271, 2012

Article Type: Other

Citation: Journal of Pediatric Biochemistry, vol. 2, no. 4, pp. 273-275, 2012