Open access peer-reviewed chapter

Personalized Management of Selected Neurological Disorders

Written By

Shirley Ekvall, Tuomas Westermarck, Mari Havia and Faik Atroshi

Reviewed: 05 March 2020 Published: 14 October 2020

DOI: 10.5772/intechopen.92002

From the Monograph

Personalized Medicine, in Relation to Redox State, Diet and Lifestyle

Edited by Faik Atroshi

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Neurological disorders are medically complex diseases that affect the central and peripheral nervous systems. They can affect an entire neurological pathway or a single neuron. Some neurological problems can present years after a causative event. The World Health Organization reports that various types of neurological disorders affect millions of people around the world. So far, there are no therapies available to cure these disorders. Pharmacological and non-pharmacological interventions can at best relieve symptoms and perhaps delay the progression of the disease. However, there are a wide variety of helpful treatments for different disorders that may help an individual to learn better social skills and communication cues, in order to help them be able to interact socially, in a more natural fashion. For some neurological issues, the outlook can be quite good with treatment and adequate rehabilitation. Diet also plays an important role in the prevention of late-life cognitive decline. Deficits in cognition, low dietary quality and physical functioning, and cardio-metabolic risk factors are frequently reported in patients with neurological disorders. In this chapter we will briefly discuss research, as well as current opportunities and future prospects towards personalized medicine in relation to selected neurological disorders and diseases such as Down syndrome, neuronal ceroid lipofuscinoses (NCLs), and multiple sclerosis (MS).


  • neurological disorders
  • free radicals
  • antioxidants
  • personalized medicine

1. Introduction

Genes are responsible for forming all of the neurons. However, they are certainly not the only factor determining how our brain develops and forms its inner connections. A combination of hereditary factors and environmental factors plays an important role in determining a neuron’s final location [1]. Studies confirm that an active lifestyle maintains brain function [2]; thus, new research aims to develop lifestyle behaviors and medications that could improve normal brain development as well as repair damaged brains. Many neurological disorders emerge during the early years of development and may be diagnosed at birth or later, and their causes include congenital, chromosomal, and gene abnormalities, infections, immune disorders, and environmental factors such as nutritional deficiencies and toxins. The effectiveness of self-management interventions for people with long-term neurological conditions, in particular, Down syndrome (DS), neuronal ceroid lipofuscinosis (NCL), Duchenne muscular dystrophy (DMD), and multiple sclerosis (MS), has been reported. The effectiveness of various antioxidants on several neurodegenerative diseases in clinical trials has increasingly demonstrated that reactive oxygen species (ROS) and oxidative damage are important factors in the processes involved. Imbalanced defense mechanism of antioxidants and overproduction of free radicals from environment to living system lead to serious penalty resulting in neurodegeneration [3]. The current need for better interventions is highlighted, particularly the importance of providing condition-specific information. As the overall life expectancy across the globe has increased, the global community is now facing new challenges of improving quality of life and healthcare; however, advancements in medical technology have benefits and improved healthcare [4, 5]. This chapter provides an overview of the evidence of current findings; research limitations and future directions of research efforts are discussed in some neurological conditions such as DS, DMD, NCL, and MS.


2. Free radicals in the brain

Unlike many other tissues, the brain is a highly aerobic and totally oxygen-dependent tissue. Oxygen reduction produces reactive radical intermediates, such as superoxide and hydroxyl radicals which are thought to be the major agents of oxygen toxicity [6, 7]. Hydrogen peroxide is formed through dismutation of superoxide anion catalyzed by Cu-Zn and Mn forms of superoxide dismutase (SOD), both found in the central nervous system. In addition to Cu-Zn SOD (SOD-1), the activity of which is increased in DS, and hydrogen peroxide (H2O2) is generated in association with D- and L-amino acid oxidase, monoamine oxidase, α-hydroxyacid oxidase, xanthine oxidase, and cytochrome P-450 system.

Unlike charged oxygen radicals, H2O2, being rather unreactive and stable, rapidly crosses cell membranes. Cellular damage is accomplished when H2O2 decomposes to the highly reactive hydroxyl radical in reactions catalyzed by iron (II) or copper (I). If the scavenging of H2O2 and the contemporaneous prevention of hydroxyl radical formation do not take place, the hydroxyl radical may attack, e.g., fatty acid side chains, and start a chain reaction of lipid peroxidation. Lipid peroxidation causes gradual loss of membrane fluidity and membrane potential and increases membrane permeability to ions [6, 7]. Abnormalities in the fatty acid composition found in fetal DS brain phospholipids suggest that from the early stage of ontogenesis, lipoperoxidation may have a pathological significance [8, 9]. Oxidative degradation and polymerization of lipids lead to the accumulation of lipofuscin, the age pigment. Current evidence permits the interpretation that a high proportion of DS subjects later develop the neuropathological changes resembling Alzheimer’s disease [10, 11, 12].

Considerable evidence has emerged in recent years implicating a role for oxygen free radicals in the initiation of cellular injury that leads to the development of several neurological disorders. The neonatal brain, with its high concentrations of unsaturated fatty acids (lipid content), high rate of oxygen consumption, and low concentrations of antioxidants, is particularly vulnerable to oxidative damage. Thus, increased oxidative stress has been implicated in various neurological disorders such as seizures, ischemia-reperfusion injury, and neurodegenerative diseases [13] such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease). Free radical damage has been implicated in the initiation and propagation of seizure activity as well as the accompanying seizure-induced neuronal damage [14]. Therefore, antioxidants could play an important role in modulating susceptibility to seizure activity and seizure-induced neuronal injury.

Radical attack may also destroy membrane-bound enzymes and receptors, e.g., the binding of serotonin is decreased. However, the brain tends to need radical reactions for the generation of physiological responses. Cellular redox adjustments generally regulate functional sulfhydryl groups of proteins. There is evidence supporting the suggestion that free radical intermediates are involved, e.g., in the coupling between depolarization of the plasma membrane Ca2+ fluxes and neurotransmitter release [15, 16]. It has also been hypothesized that the elimination of neurofilaments at nerve terminals is regulated by oxygen radicals and that a contact of a growing neurite with a neighboring neuron induces the production of oxygen radicals. Rapid elimination of oxygen radicals during synaptogenesis would result in a reduced number of synaptic connections [17]. Accordingly, transgenic mice bearing the human SOD gene develop abnormalities in neuromuscular junctions of the tongue which closely resemble those of DS patients [18]. However, these abnormalities may be explained by a decreased level of superoxide anion as well as by increased formation of highly active and toxic hydroxyl radicals and singlet oxygen.

The regulation of glutathione (GSH) level (GSH/GSSG) through pentose phosphate pathway producing nicotinamide adenine dinucleotide phosphate (NADPH), GSH reductase, and glutathione peroxidase (GSHPx) contributes to the overall redox state of cells in brain [19]. The brain tends to need radical reactions as well as to possess specific or high endogenous levels of free radical scavengers such as dopamine, norepinephrine, catechol estrogens, taurine, and carnosine [20] in neurons. Carnosine is involved with GABA activity in the brain, and brain tissue contains high levels of carnosine, which is capable of reducing the oxidative, nitrosative, and glycemic stress to which the brain is especially vulnerable [21, 22, 23]. Oxidation and glycation produce inflammation and also contribute to cross-linking of proteins, including the Alzheimer’s disease protein called amyloid-beta [24]. A study by Takahashi [25] demonstrated that homocarnosine levels were high in patients who responded to antileptic drugs. The functional balance between various free radical scavenger systems in the brain seems reasonable. Significant positive correlations between catalase and SOD levels have been reported in tissues of normal subjects excluding erythrocytes. Factors concomitantly influencing the variation of the activities of SOD, catalase, and GSHPx have been reported. Enzymes frequently called protective should rather be envisaged as being regulatory, controlling the levels of different states of oxygen reduction, phorbol esters, and strong superoxide producers through NADPH oxidase activation [26, 27, 28, 29], inducing biosynthesis of polyamines [30, 31]. The role of polyamines is also associated with the architectural modeling of brain regions and generation of synaptic connections [32, 33, 34]. Thus effective scavenging of superoxide by excess SOD-1 may contribute even to the polyamine biosynthesis.

In addition to the complex enzyme systems, biochemical defenses include low molecular weight free radical scavengers and antioxidants. Lipid soluble vitamin E lowers the steady-state concentrations of many free radical species [35, 36, 37, 38, 39]. Ubiquinone may exert, similarly to vitamin E, a protective effect against lipid peroxidation [40]. The concentration of vitamin E in a fetal DS brain does not significantly differ from that of controls [41]. We have found the serum vitamin E concentrations of Down syndrome patients to be normal (1.01 + 0.35 vs. 1.13 + 0.39 mg/100 ml) [42]. In addition to conventional antioxidant systems, the brain has been found to contain specific or high endogenous levels of free radical scavengers such as dopamine, norepinephrine [43, 44, 45], catechol estrogens [20], carnosine [46], and taurine [47, 48]. The transport of taurine to platelets is impaired in DS [49]. Taurine and hypotaurine, found in high concentrations in the brain [50], could act as intracellular superoxide scavengers which would inhibit not only lipid peroxidation but also inactivation of SOD by both superoxide and H2O2 [51, 52]. The presence of 1–10 mM taurine protects cultured lymphoblastoid cells from the injurious effect of iron-ascorbate [48].

The role of dietary beta-carotene in the central nervous system is not elucidated. Beta-carotene acts as an antioxidant at low oxygen pressures [53, 54, 55]. Being converted to retinol or retinoic acid, it causes a marked decrease in superoxide generation. Through a still unknown mechanism, retinoic acid induces human neuroblastoma cell differentiation in vitro [56, 57, 58], and it also contributes to neural differentiation of embryonal carcinoma cells in vitro [59].

Serum β-carotene and vitamin A levels are generally normal in DS, although vitamin A levels lower than in normal subjects have also been reported. Relatively high carotene/vitamin A ratio suggests decreased efficiency in converting carotene to vitamin A. In addition the utilization of vitamin A in DS may be impaired at its site of action [60, 61, 62].

Thyroid hormones improve the cleaving of beta-carotene to vitamin A. This conversion to retinol is decreased in hypothyroidism. Thus, in hypothyroidism the vitamin A concentration decreases even when the dietary β-carotene remains the same or rises [63, 64].


3. Down syndrome

Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21 [65]. It is one of the most common chromosome abnormalities in humans [66]. Globally, as of 2010, DS occurs in about 1 per 1000 births [67] and results in about 17,000 deaths [68].

In spite of the intensified antenatal diagnostics and termination of affected pregnancies, the prevalence of DS, first described in 1866, is still so high that it constitutes an important healthcare problem. DS phenotype is readily recognized at birth. Karyotype analysis confirms the diagnosis of DS associated with trisomy of chromosome 21. Since the further development of the child is predestined to be hampered by a multitude of clinical symptoms including mental retardation, premature aging, and immunological disorders such as hypothyroid states, attempts have been made to increase the understanding of the etiopathogenesis of the syndrome and to influence its progress.

The genetic imbalance due to an extra set of normal genes located in chromosome 21 means that the expression of these or actually of only some genes in the q arm leads to the disturbed development. Cumulative effects of increased amounts of primary gene products may be deleterious if no compensatory mechanisms exist. Genes of the q arm in chromosome 21, which may contribute to the DS pathology, include α/β interferon receptor, phosphoribosylglycinamide synthetase [69, 70, 71, 72], cystathionine beta synthase [73], and cytoplasmic Cu-Zn superoxide dismutase (SOD-1) [74, 75].

DS, described in a karyotypically normal 18-month-old boy, has been explained by a microduplication of a chromosome 21 fragment (not exceeding 2000–3000 kilobase pairs) containing the SOD-1 gene [76, 77]. Further evidence of the involvement of additional SOD-1 gene in the neuropathological symptoms of DS has been derived from studies performed with transgenic cell lines and from mice carrying the human SOD gene [18, 78].

Consistent with the gene dosage effect, SOD-1 activity is increased in the cerebral cortex of DS fetuses as well as in erythrocytes, blood platelets, leukocytes, and fibroblasts of DS patients [79] (Thilakavathy et al. 2008). According to Sinet [75], elevated SOD-1 activity may constitute an oxygen free radical “stress.” Usually SOD-1 protects cells from the harmful effects of oxygen radicals by catalyzing formation of H2O2 from O2 enzymes that remove excessive peroxides like catalase and glutathione peroxidase (GSHPx) [74]. NADPH is needed for the regeneration by glutathione reductase of glutathione (GSH), the utilization of which is increased via GSHPx as a defense against peroxide formation. Thus several enzymes with structural loci other than those of chromosome 21, including glutathione reductase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase, show elevated activity in erythrocytes of DS patients [80, 81].

Some reports suggest that Both SOD GSHPx activities are increased in Down syndrome children [82]. It remains to be seen whether oxidative damage will still be related to the accumulation of aluminum silicates in the brain as well as to that of the senile plaques and tangles. Experiments have indicated that aluminum salts may not only accelerate Fe (II)-induced peroxidation of membrane lipids but do this especially in the brain [83]. Interestingly a high proportion of Down syndrome patients develop the neuropathological and clinical changes of AD suggesting a close pathogenetic relationship between these disorders. Thus the correction of antioxidant balance in AD by Se supplementation should be demonstrated by other means so as to direct it preventatively to those with a high risk of developing AD.

Balazs and Brooksbank [8] noticed that the adaptive response to elevated SOD-1 activity, i.e., increased GSHPx activity found in other tissues, is not detected in the fetal DS brain. The level of GSHPx activity in neural tissues seems to be as such too low to provide protection from peroxide-induced lesions [84]. Furthermore, if H2O2 production is high, catalase might be a superior scavenger, because restoration of glutathione becomes a limiting factor for the activity of GSHPx [85]. However, catalase level is normal in DS erythrocytes [72, 86], and its activity is practically absent in the brain tissue [87]. Consequently brain cells may be extremely susceptible to oxygen free radicals.

3.1. The pathophysiology of Down syndrome and the role of the thyroid gland

Thyroid hormone has a regulatory function on mitosis and differentiation of neural cells; hence, it is intimately involved in normal brain maturation [88, 89, 90, 91]. Experimentally trijodothyronine enhances neural outgrowth in vitro [92, 94]. Even subclinical hypothyreosis during the postnatal period may contribute to the delayed and incomplete maturation of the cerebral and cerebellar cortices.

Increased prevalence of thyroid dysfunction is associated with DS in infants as well as in older children and adults [95, 96, 97, 98]. Hypothyroidism is reported in 17–50% of the DS patients studied depending on the age and sex distribution of the population [98]. The relatively high incidence of autoimmune thyroiditis suggests that impaired immune surveillance is the primary mechanism in hypothyroidism [99]. Pueschel and Pezullo [98] conducted a study which showed that approximately 28% of their 151 DS patients had elevated antimicrosomal antibodies, and a highly significant correlation of antimicrosomal antibodies to T4 and to TSH was found. Recent studies indicate that antimicrosomal antibodies are mainly, if not exclusively, against thyroid peroxidase [100].

Thyroid peroxidase is a membrane-bound enzyme associated with the endoplasmic reticulum and the apical membrane of the thyroid cell. lmmunoelectron microscopical observations of the thyroid microsomal antigen in the apical plasma membrane are compatible with the notion that microsomal antigen is identical with thyroid peroxidase [101, 102, 103, 104].

SOD-1 system, which generates H2O2, is essential in the iodination and coupling reactions catalyzed by thyroid peroxidase [105, 106, 107]. However, an excess of H2O2 may inactivate the peroxidase complex [105, 106, 107, 108]. The irreversible loss of catalytic activity, caused by H2O2 or by the reactive oxygen species generated, may result from oxidation of functionally important amino acid residues to carbonyl derivatives. This may also render the protein susceptible to proteolytic attack and to detachment of its cellular compartment. If so, the maintenance of the thyroid peroxidase function and its integrity would require correct steady-state production of H2O2 and strict control of its level. This requirement is mainly met with by GSHPx and catalase.

Antigenicity of the modified and disintegrated thyroid peroxidase should be recognized by helper lymphocytes only in the context of MHC Class 11 products coded by genes in the HLA-D region. This region normally expressed only by a restricted variety of cell types is found in autoimmune disorders in target cells. Thus an aberrant expression of HLA-DR antigen found on thyrocytes in Graves’ and Hashimoto’s disease indicates its potential importance in antigen presentation of thyroid autoimmune disorders [109, 110].

The presence and intensity of DR expression in Graves’ thyroids correlate positively with the titer of microsomal antibodies. Curiously, in cultured thyroid cells, plant lectins are able to induce the expression of HLA-DR by a mechanism unrelated to the known mitogenic effects. On the other hand, the inducing effect of gamma-interferon (IFN-γ) could have a physiological significance (IFN-α and IFN-β did not induce Class II expression in thyrocytes) [111, 112, 113]:

  • Release of IFNs and lymphokines, best candidates for inducers, must be triggered by other factors [111, 112, 113].

On the basis of the gene dosage effect, we suggest possible mechanisms for the sensitization of DS thyroids to autoimmunization:

  • Viral challenge including enhanced production of oxygen radicals due to macrophage and neutrophil activity may exert additional requirement for GSHPx and selenium. If these needs are not met with overproduction of oxygen radicals and constitutive excess of both LFA-1 and its beta-chain, it may hinder normal immune response [111, 112, 113, 114].

  • Excess H2O2 causes fragmentation of thyroid peroxidase which detaches from the cell membrane and turns into an autoantigen.

  • Increased expression of IFN-α/IFN-P receptors, the gene of which is found in chromosome 21, may sensitize thyrocytes to the induction of HLA-DR antigen by γ-IFN [111, 112, 113].

3.2. The impact of early hearing loss on language

Down syndrome occurs in approximately 1 in 600–800 live births [115] and remains the most common genetic abnormality seen in most otolaryngology practices. Down syndrome has a number of clinical problems associated with it [116, 117, 118]. The symptoms of DS vary from person to person, and people with the syndrome may have different problems at different times of their lives [119]. Hearing loss will affect many people with Down syndrome at some point in their lives. It has been reported that children with Down syndrome are at particular risk of some degree of hearing impairment due to a number of physiological differences. The authors concluded that there are a range of middle ear problems that can be treated successfully if the children are taken for routine cleaning and examination from birth [120]. Hearing losses affect 40–80% of individuals with DS [121, 122, 123, 124]. In young children, the most common cause is conductive loss due to episodes of ear infection and otitis media with effusion (OME).

To determine the prevalence of hearing loss in newborn with Down syndrome, Tedeschi et al. [125] reported that newborn with Down syndrome have a higher prevalence of congenital hearing loss than the total neonatal population (15 vs. 0.25%). Individuals with Down syndrome are prone to otolaryngologic anomalies that complicate the diagnosis and classification of hearing impairment [126]. In children, hearing loss can affect educational, language-related, and emotional development. Even mild hearing loss can affect a child’s articulation. It is reported that as many as 80% of people with Down syndrome will have some problem with hearing [127]. A retrospective and cross-sectional analysis was performed to evaluate the prevalence of OME in children with DS for consecutive age categories between 6 months and 12 years [128]. The authors concluded that a high prevalence of OME was found at the age of 1 year (66.7%), with a second peak prevalence of 60% at 6–7 years. A declining trend was seen in older children [128].

As with children, adults with DS may experience hearing loss due to glue ear. Picciotti et al. [129] assessed auditory function in adults with DS to evaluate the prevalence of hearing loss. The authors concluded that hearing loss is common in adults with DS and shows a pattern compatible with precocious aging of the hearing system.

3.3. Hearing and spoken language

Disorders impairing a patient’s communication abilities may involve voice, speech, language, hearing, and/or cognition [130]. The effect of hearing difficulties on spoken language development has been demonstrated in many studies of the speech and language skills of children and teenagers with Down syndrome [131, 132].

Most individuals with DS also experience speech and language impairments although the severity of these is variable [133, 134]. Researchers studying language development in DS have measured hearing either directly tested or using pure tone audiometry to establish hearing thresholds [135] or, indirectly, using speech discrimination tasks [136, 137, 138]. Therefore, it suggested that speech and language therapy should be provided when children are found to have ongoing hearing difficulties and that joint audiology and speech and language therapy clinics could be considered for preschool children [138].


4. Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is one of the most severe myopathies, usually obvious by the age of 5, and evolves progressively until it causes disablement and death, around the age of 20 [139]. In young boys, DMD is caused by deletions or point mutations in the pre-mRNA for dystrophin that result in out-of-frame transcripts and hence a nonfunctional truncated dystrophin protein [140]. It is recessively inherited, linked to sex, and the gene determining DMD has been mapped in the Xp-21 locus [141]. It has an incidence of 1/3000–1/3500 male births and 1/3 of the cases coming from new mutation. Some affected individuals may develop intellectual disturbance due to unknown mechanism, so far. The sister of an affected individual has a 50% chance of carrying the defective gene [141]. The result of the dystrophic locus on the gene is the absence of dystrophin, a rod-shaped protein that is part of the muscle cytoskeleton. Death commonly results from involvement of the respiratory muscles. Dystrophin is present in the muscle of normal individuals and has been rarely, or not at all, detected in patients with DMD [142, 143]. The genetic alteration produces abnormality in the membrane of the muscular fibers that consists of a disturbance in the calcium transport (Ca2+), inside the muscular fibers, which is the base mechanism of cellular degeneration and necrosis. There is fiber necrosis and replacement of fibers by fat. A nucleotide degradation and decreased muscle ATP and ADP content have been reported. The ATP is necessary to drive the Na+/K+ pump which maintains ionic gradients across the sarcolemma; resequester the Ca++ into the cisternae; and power contraction [144, 145, 146]. The production of ATP can be the result of anaerobic respiration, which breaks glucose down into ATP and lactic acid, or aerobic respiration when ATP, carbon dioxide, and water are formed. A second immediate reserve of energy exists in the form of creatine phosphate, which can donate phosphate to ADP to form ATP, becoming itself a creatine. In the resting muscle, glucose is stored as glycogen, and in such a muscle aerobic respiration synthesizes ATP from glucose or fatty acids.

Muscle dystrophy and mitochondrial dysfunction give rise to an amplification of stress-induced cytosolic calcium signals and an amplification of stress-induced reactive oxygen species (ROS) production, and increased oxidative stress within the cell damages the sarcolemma and eventually results in the death of the cell. Muscle fibers undergo necrosis and are ultimately replaced with adipose and connective tissue. In recent years, synthetic splice-switching oligonucleotides (SSO) have been developed as new treatments for DMD whereby an SSO is targeted to the pre-mRNA and mediates splicing redirection to restore the reading frame of the dystrophin gene via exon skipping and thus to generate a shorter but functional dystrophin protein isoform [140, 147, 148, 149, 150, 151, 152, 153, 154, 155]. Several SSO chemistries have been developed for exon skipping in DMD and other neuromuscular diseases [156, 157], but of these only two SSO chemical types have been used in clinical trials, namely, 2′-O-methyl phosphorothioates (2′-OMe/PS) [158] and phosphorodiamidate morpholino oligonucleotides (PMO) [159, 160].

Therapy of DMD has been an elusive goal. Studies with isolated myocytes have shown that lipid peroxidation with an enhanced free radical production can be activated by increasing Ca concentration [161, 162, 163]. Thus, several kinds of antioxidants have been proposed as a treatment since increased levels of thiobarbituric acid (TBA) reactive material has been found in the muscles and blood of DMD males [164]. We have previously reported that the biological half-life of 75Se in DMD patients was significantly shorter than in healthy controls [165]. Low oxygen saturation in the muscle tissue may stimulate the Il-6 production, a cytokine, which is produced by contracting muscles and released into the blood. The blood circulation of the older Duchenne patients is particularly disturbed. Pedersen et al. [166] have demonstrated that Il-6 affects the metabolic genes, induction of lipolysis, inhibition of insulin resistance, and stimulation of cortisol production. In addition, carbohydrate supplementation during exercise was shown to inhibit the release of Il-6 from contracting muscles. Thus carnitine supplementation is indicated to the Duchenne patients, to make sure that the energy supply will be good [167].

Shimomura et al. [168] observed that a group of trained animals, part of which were coenzyme Q10 (CoQ10)-treated, had to exercise for 30 min on treadmill, in downhill position. CoQ10-treated animals had a higher level of CoQ10 in their muscles, and the early rise in creatine kinase and lactic dehydrogenase plasma levels, due to the exercise, was evident at a remarkably significant lower extent, in the treated ones. Similar observations were also made in humans [169, 170]. Therefore we have been treating the Duchenne patients with CoQ10. In our earlier work, we gave DMD patients sodium selenite, 0.05–0.1 mg Se kg−1 BW day−1; α-tocopherol, 10–20 mg kg−1 BW day−1; vitamin B2, 0.2 mg kg−1 BW day−1; vitamin B6, 5 mg kg−1 BW day−1; carnitine, 10–20 mg kg−1 BW day−1; and ubiquinone-10 (CoQ10), 3 mg kg−1 BW day−1 [171]. We reported two siblings of whom the elder one got practically no antioxidants and the younger one has antioxidant treatment starting at the age of 6 years. The first one was wheelchair bound at the age of 8 years and deceased at the age of 17 years. However, at the age of 15 years, the younger brother was still able to walk without any assistance. At the age 19 years, he was to be a graduate student with the best scores of all seven subjects that he participated. At the age of 21 years, he was still able to swim a distance of 50 m without any assistance. At age of 30 years, he is still able to make computer art and to have art exhibitions of his own. There are also mothers who have made observations that the odor of lard characteristic of their DMD sons was cured during the antioxidant supplementation. Potential future developments therapy may be to produce functional amounts of dystrophin by skipping the mutated exon like what has been done in mdx dystrophic mouse [172, 173, 174].


5. Neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinoses (NCLs) are clinically heterogeneous neurodegenerative lysosomal diseases [175, 176, 177, 178, 179]. NCLs are recessively inherited neurodegenerative lysosomal storage diseases. The neuronal ceroid lipofuscinoses are with a prevalence of 1 in 12,500 in some populations such as the USA and Northern Europe. Currently the classification is based on genetic defects, with 14 clinical subtypes and genetically separate neurodegenerative disorders that result from excessive accumulation of lipopigments (lipofuscin) in the body’s tissues, and the most prevalent NCLs are CLN3 disease, classic juvenile and CLN2 disease, and classic late infantile [39, 176, 180, 181, 182]. Characteristics of the diseases are deposits of ceroid and lipofuscin pigments in the tissues, particularly in the neural tissue, visual failure, and progressive mental retardation; depending on the age of onset and clinical, electrophysiological, and neuropathological features, the NCLs can be subdivided into the infantile the late infantile, the juvenile and the adult type of NCL; however, the pathogenesis of NCL is still unknown.

5.1. Management of neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinoses are a group of hereditary diseases caused by mutations in at least eight genes (CLN1-CLN8) [183, 184]. They are characterized by massive accumulation of autofluorescent lysosomal storage bodies in most cells and associated severe degeneration of the CNS [183]. There is no single, standard treatment for neuronal ceroid lipofuscinoses (NCLs), as there is currently no cure; however, a number of different treatments can be used to ease symptoms and encourage independence and better standards of general health [185]. Also there are certain medical problems that can affect someone with neuronal ceroid lipofuscinosis. However, a number of different treatments can be used to ease the symptoms and encourage independence and better standards of general health. These treatments are based on each individual’s physical and intellectual needs as well as their personal strengths and limitations: enzyme replacement therapy, gene therapy, stem cells including tissue engineering, and medicine or metabolic therapy such as dietary restriction and immune biotherapy [186, 187, 188, 189, 190]. These modes of treatments have been used in many genetic diseases. Acetyl-L-carnitine (ALC) has been shown to be therapeutic in treatment of NCLs [191]. It was reported that ALC might rebalance the disorders underlying neuronal ceroid lipofuscinosis disease which are related to a disturbance in pH homeostasis [191].

The polyenic acid level with low levels of linoleic acid and an inverse relationship between GSHPx activity and the level of eicosatrienoic acid have been observed in juvenile neuronal ceroid lipofuscinosis (JNCL) [192]. The occurrence of the fluorescent pigments suggested the peroxidation of lipids in the etiology of NCL. It is likely that the diseased tissues peroxidized cause secondary damage more rapidly than normal tissues and cytotoxic end products of lipoperoxidation. On a weight basis, ceroid seen in JNCL patients binds five times more iron than the lipofuscin seen in normal elderly individuals. The increased levels of aluminum salts greatly enhance iron-dependent damage to membranes. Heiskala et al. [193] has confirmed the presence of complexable iron and copper in the CSF of patients with NCL and other neurological disorders, and when the pH value of the assay for iron was lowered, the NCL group had substantially more complexable iron in their CSFs. Interestingly aluminum has been observed in CSF and in ceroid lipofuscin pigments of the brain of NCL patients [194]. It is well established that damaged tissue release metals from protein-bound sites and these metals stimulate peroxidative damage to lipids and other biomolecules.

One of the most essential enzymes counteracting lipoperoxidation is the selenium-containing GSHPx. Two independent reports have demonstrated that erythrocyte GSHPx activity is decreased in JNCL patients [195]. This low GSHPx activity was reversed to normal level by selenium supplementation. The evaluation of sodium selenite absorption and losses before supplementation of JNCL patients has been studied by using total body counting for 75Se detection. These studies showed that in three JNCL patients, about 55% of the administered 75Se was eliminated during the first 11 days in the feces and about 10% in the urine [39]. Compared to healthy controls (42 and 7%, respectively), findings indicate a reduced absorption of selenium in JNCL patients contrary to a previous report. The low GSHPx activity in NCL patients may indeed reflect a low selenium intake most probably due to a disturbed absorption of selenium and secondary phenomena due to an inborn error of metabolism. Apart from the low selenium status, also very low vitamin E levels are found in the serum of advanced and hospitalized NCL patients. This can be explained by the recent finding of a pronounced reduction of apolipoprotein B as well as the whole fraction of very low-density lipoprotein (VLDL) in JNCL patients.

JNCL patients (genetically subgroups) have been given daily supplementation of sodium selenite (0.05–0.1 mg/Se/kg of BW), vitamin E (α-tocopherol acetate 0.014–0.05 g/kg BW), and vitamins B2 (0.025–0.05 mg/kg BW) and B6 (0.63–0.8 mg/kg BW). The benefits of the therapy are corroborated by the significant negative correlation of GSHPx activity with neurological dysfunction of motor performance, balance, coordination, and speech [196]. The mean age at death has been extended by 4 years as compared to that at the beginning of the century. As the best responders to antioxidant therapy show no neurological dysfunction at the age of over 20 years, there is no doubt that the life expectancy of JNCL patients receiving antioxidants, including selenium, will be significantly prolonged in the future [197]. Complications of the antioxidant therapy have been few and not severe. Six patients have experienced vomiting and nausea when the serum concentration of selenium reached the level of 0.45 to 0.5 mM. Serum levels up to 4.0 mM were usually well tolerated, as well as when the sodium selenite was changed to ebselen (2-phenyl-1,2,-benzisoselenazol-3(2H)-one).


6. Multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, where suspected autoimmune attack causes nerve demyelination and progressive neurodegeneration and should benefit from both anti-inflammatory and neuroprotective strategies [198]. MS affects an estimated 4.3 cases per 100,000 in Europe with a higher rate in Northern Europe [199]. Often it appears in individuals between 20 and 40 years of age and has a strong genetic component [200]. The disease course is benign in 10–15% of patients, and they do not need an assistive device for walking even after 20 years of MS [201, 202]. Low levels of polyenic acids are involved in the pathogenesis of both MS and JNCL. Earlier a decrease level of serum linoleate as well as unsaturated fatty acids of brain phospholipids in MS patients was shown [203, 204]. It has also been argued that supplementation with essential fatty acids may improve the clinical status of MS patients [205]. And as in NCL, the selenium may, by activating GSHPx (scavenger of organic peroxides), regulate the metabolic transformation of essential fatty acids and biotransformation of these to prostaglandins, thromboxanes, and leukotrienes [206]. Curiously decreased GSHPx activities in erythrocytes have been found in female but not in male MS patients [207]. A significant association between the two haplotypes of the dopamine D2 receptor gene (DRD2) and the age of onset and/or diagnosis of MS was reported [208].

Current treatments for MS mainly target inflammatory processes, and there has been scant progress in treatments that enhance neuronal or glial regeneration. Can we predict the risk of serious side effects? This asks for the development of biomarkers, clinical, genetic, imaging, or immunological, that allow for a better stratification of patients [209]. The need for tailored therapeutics is especially imperative, as the consequences of an ineffective medication might be irreversible dysfunction. However, it is obvious that treatment decisions in clinical practice must be made on an individual basis. This requires a personalized medicine approach in predicting disease activity in multiple sclerosis. Biomarkers that could predict disease course, treatment response, and risk of side effects would be highly appreciated. Despite extensive research over the last years, few biomarkers have made their way into clinical practice.


7. Advances in the development of novel antioxidant therapies

Earlier, through intervention efforts, patients with DS have received medical treatment and stimulation of sensory, motor, and cognitive areas [210]. In 1981, Harrell et al. [211] reported that the administration of a megavitamin mineral supplement to a heterogenous group of 16 mentally retarded children, 4 of which had DS, had led to encouraging results. However, controlled double-blind studies on somewhat larger groups using similar megadoses of vitamins and minerals but no thyroid supplementation did not result in any beneficial effects [212, 213, 214, 215, 216]. However, these studies were devoid of a detailed theory of the mechanism of action, and the age distribution of the patients was disadvantageous in relation to possible targets in the developing brains.

Our primary survey and theory of antioxidant therapy in DS [42, 217] rest on the present concepts of the etiopathogenesis of DS [8, 79]. Earlier, selected antioxidants have been used, e.g., in the therapy of neuronal ceroid lipofuscinosis [218]. Prevention of free radical damage should be executed by agents focused on the tissue and cellular compartments and processes where the generation of free radicals is critical. In DS, elevated cytoplasmic SOD-1 activity causes free radical stress through H2O2. An excess of H2O2 may be activated in iron- or copper-catalyzed reactions to generate highly reactive hydroxyl radical (–OH) or singlet oxygen. The extent and nature of the damage depend on the precise site of the •OH production, which in turn depends on the intra- or extracellular location of the critical metal ions [7, 219].

However, GSHPx, which gives protection against elevated H2O2, is low in brains with intensive oxygen metabolism. Histochemical studies by Slivka and co-workers [220] are indicative of the relative absence of GSH in neuronal somata and locate GSH to non-neuronal elements and fibrous and terminal regions of neurons. Furthermore, in normal newborn infants, the activity of GSHPx is physiologically low [221, 222]. Just a reflection of this condition could be the low blood selenium level found in neonates [223]. Controversial results have been published on the level of selenium in plasma and erythrocytes of DS patients [79]. Peripherally decreased GSHPx activity may be corrected by selenium supplementation [224, 225]. Unlike catalase, benefit of optimal GSHPx activity is gained through its capability to reduce both H2O2 and organic hydroperoxides including lipid peroxides. The mean plasma selenium concentration in DS patients has been shown not to differ significantly from that of the control subjects although the GSHPx activity is 130% of the normal [226]. Neve and co-workers [227] reported normal erythrocyte but significantly decreased plasma selenium levels in 29 DS patients. These discrepancies may be explained by the differences in the population groups studied and by the distribution of the blood selenium pool. Only 10–15% of the erythrocyte selenium in man is reported to be incorporated into the GSHPx, whereas the corresponding value in rat is 75–85% [228].

We noticed in DS patients of different ages that the mean compensatory increase of erythrocyte GSHPx was lower than expected, 33.4 vs. 50%. The finding that the erythrocyte SOD/GSHPx ratio was higher than in healthy controls confirmed our belief of insufficient compensation [42, 217]. In DS the whole body retention of 5–8 kBq, 75Se-sodium selenite, with 0.4 ug Se as carrier/kg BW, is estimated to be 53.3 ± 21.1%. Stable selenium supplementation increased 75Se elimination indicating a saturated selenium pool in the body [229]. Selenium supplementation 0.025 mg Se/kg/d in the form of sodium selenite increased E-GSHPx activity by 28 (59.9% above normal). This was also demonstrated by the 23.9% decrease of SOD/GSHPx ratio (P < 0.01) [42, 217].

The consequences of selenium supplementation on the brain antioxidant balance, and thus its therapeutic value, are difficult to monitor. However, certain clinical, experimental, and in vitro observations may be indicative [230]. A highly positive correlation has been reported between erythrocyte GSHPx values and IQ in DS [231]. The plasma selenium concentration and erythrocyte GSHPx activity were found to be higher in DS girls than in DS boys, which is consistent with the finding of significantly higher IQ scores for female than for male DS patients. The positive correlation of E-GSHPx activity between DS subjects and their siblings suggests the influence of environmental and/or additional genetic factors [26, 230].

Estimates of the amount of selenium in the rat brain indicate that the GSHPx may account for only ⅕ of the total selenium in the brain [232]. The finding that selenoproteins other than GSHPx are distributed mainly in the brain and endocrine organs raises a question of their physiological role. After the administration of very small amounts of selenium, severely depleted rats retained in the brain and in the reproductive and several endocrine organs (including thyroid) a dose which was 20–50 times the dose found in adequately fed control animals. This indicates the existence of regulatory mechanisms which ensure a sufficient level of selenium in critical organs, above all in the brain and the thyroid even during depletion [91, 233].

In concentrations of 6 x 10-7 M, selenite induces a 30-fold increase of GSHPx activity in neuroblast cells in vitro [234]. Earlier studies on the rat liver suggested that selenium regulates the level of GSHPx mRNA as well as GSHPx protein concentration and GSHPx activity [235]. Concentrations of 10-5 M exert obvious toxic effects on nerve fibers in vitro [236]. Trace elements, as “doping impurities” in organic material, could be key variables that regulate conductivity in biological semiconduction structures [237]. We suggest that the abnormally high levels of copper and iron and the low level of zinc ion in erythrocytes and blood mononuclear cells are reflections of disturbed oxygen radical metabolism in DS. However, increased concentration of copper can be explained as gene dosage evident by the increased activity of SOD-1 [238]. Except for the decreased iron content in erythrocytes, the results were in accordance with an earlier study [239]. Ferrous-ion (Fe II) and copper-ion (Cu I) react with H2O2 producing •OH radicals [240, 241]. Titanium in erythrocytes may indicate insufficient protection by GSHPx. If titanium is present as Ti (IV), stable compounds may be formed with hydrogen peroxides and probably with superoxide anions to give 1:1 adducts [238]. The low plasma zinc concentration in DS children has been recognized in earlier studies as well [242, 243]. The homeostasis of zinc is regulated by the intestine. The absorption of zinc seems to be decreased in DS, mean retention of zinc being 30% compared with 58% in healthy adults. Stable zinc supplementation in one DS patient did not increase the 65Zn elimination, indicating an unsaturated zinc pool [229].

Interestingly, the primarily high blood mononuclear cell levels of copper decreased, whereas the concentration of iron and zinc was not affected during selenium supplementation [244]. No significant alterations were observed in the erythrocyte concentrations of magnesium, calcium, iron, copper, zinc, sulfur, titanium, and manganese. Aluminum was not found in erythrocytes nor in neutrophils of DS patients [238].


8. Brain antioxidant homeostasis in relation to selenium and GSHPx

In nature the availability of selenium, as a trace element, may be limited. GSHPx activity has been shown to reflect selenium status in deficient and adequate states [245]. On the other hand, protection against toxicity is likely to involve the alterations in GSH metabolism that occur in nutritional Se deficiency. A high concentration of erythrocyte glutathione in patients with neurological disorders has been reported [246, 247, 248]. However, regulatory mechanisms apparently exist which ensure that during periods of insufficient selenium intake, the content of the element is kept up above all in the brain and the reproductive and the endocrine organs.

Selenium seems to be somehow involved in the regulation of oxygen metabolism through its influence on a variety of enzymes. In concentrations of 6 × 10−7 to ×10−6 M, selenite induces a 30-fold increase of GSHPx activity in neuroblast cells in vitro. Other studies with the rat liver have suggested that Se status regulates the level of GSHPx mRNA as well as GSHPx protein concentration and GSHPx activity [235]. In concentrations of 0.7 − 2 × 10−5 M, Se in the rat liver increases the activities of γ-glutamylcysteine synthetase, the first rate-limiting enzyme in GSH biosynthesis, and GSSG reductase, which catalyzes the reduction of GSSG to GSH [249]. In some species the induction of GSH S-transferase has been shown to occur as a result of Se deficiency. Hydrogen peroxide as the most stable and diffusible of the oxygen reduction intermediates may exert an influence on the expression of SOD, catalase, and GSHPx activities. The homeostasis in the oxidative metabolism and oxygen reduction may be distorted by different means either inherent or acquired. Depending on the spatial and temporal occurrence of the distortion, various neurological states are expressed. The developing brain is particularly susceptible to oxidative stress more so than the mature brain [250]. H2O2 accumulation has also been associated with increased injury in the superoxide dismutase-overexpressing neonatal murine brain, and greater cell death is seen when immature neurons are exposed to H2O2 than with mature neurons. Increased H2O2 accumulation may be the result of relative insufficiency of the endogenous enzyme GSHPx.

Under physiologic circumstances, the brain has efficient antioxidant defense mechanisms, including GSHPx, which converts potentially harmful H2O2 to oxygen and water at the expense of reduced GSH. Under oxidative stress, in the immature brain, endogenous levels of GSHPx may be inadequate for converting excess H2O2. Transgenic mice that overexpress GSHPx (hGPx-tg), when subjected to hypoxia-ischemia (HI), have less histologic brain injury than their WT littermates [19]. In addition, the cortex exhibits increased GSHPx enzyme activity at 24 h, whereas GSHPx activity remains unaltered in the WT brain. In addition, neurons cultured from the hGPx-tg brain are resistant to injury from exogenously applied H2O2 [251]. Neurons cultured from the hippocampus and cortex that are transfected (transfection describes the introduction of foreign material into eukaryotic cells) with genes for catalase and GSHPx also show protection from neurotoxic insults and a corresponding decrease in H2O2 accumulation [252]. These findings indicate that adequate GSHPx activity can ameliorate injury to the immature brain from oxidative stress due to H2O2.

It is well established that a previous stress to the brain can induce tolerance to subsequent injury, a phenomenon called personality change (PC). In neonatal rodents, protection against HI brain injury has been induced by PC with a period of hypoxia before the induction of HI [253]. The mechanisms of this protection have yet to be fully determined, but it has been established that a large number of genes are induced in response to hypoxia [254]. Many of these genes are regulated by the transcription factor hypoxia-inducible factor-1α (HIF-1α), perhaps most importantly vascular endothelial growth factor (VEGF) and erythropoietin (EPO). VEGF is upregulated after focal ischemic injury in the neonatal rat, in parallel with the induction of HIF-1α [255].


9. Current opportunities and future prospects towards personalized medicine

Neurological disorders are diseases that affect the central and peripheral nervous systems. They can affect an entire neurological pathway or a single neuron; the neurodegeneration describes the loss of neuronal structure and function [256]. They are caused by genetic mutations present during embryo or fetal development, although they may be observed later in life [257, 258, 259]. The mutations may be inherited from a parent’s genome, or they may be acquired in utero. The risk factors for the diseases are diverse, including age, genetics, lifestyle, etc. Inflammatory conditions represent a major causative factor in numerous medically significant disorders. It can result from a range of stimuli from outside or within the body. However, these stimuli trigger cells and physiological processes within a host environment. It is believed that environmental exposures increase the risk of developing the disease. Even in inherited cases, exposure to toxins or other environmental factors may influence when symptoms of the disease appear or how the disease progresses [258, 260, 261].

With an increase in life span and decrease in death rate, the prevalence of these chronic recurring condition are rising all over the world. Moreover, no direct therapy/treatment is available now, which can reverse or retard the pathophysiological processes permanently. The medication (drug) regimen needs to be well integrated with healthy diet and lifestyle to attain high-quality and longer lives [262]. Therefore, the complex physiopathological mechanisms must now be clarified, and the immunological and genetical causes to neurological diseases must be investigated. New research on gene changes linked and gene therapy to neurological disorders is helping scientists better understand the disease, in which DNA or RNA is used as the pharmacological agent, defined as gene therapy [263]. Both genetic and environmental factors are known to influence susceptibility to diseases. Therefore, environmental factors may also have a protective effect.

The role of free radicals is well established in etiopathogenesis of neurological disorders. Some of the known antioxidants, which can prevent oxidation chronic recurring condition, have been studied [38, 39]. Recent developments in basic research have confirmed the relationship between etiopathogenesis and supplementation therapy with vitamins and trace elements. Supplementation therapy studies should be conducted. We need more clinical experience and a longer follow-up period with our neurological disorder patients receiving antioxidant therapy to reach more final conclusions concerning efficacy in the control of optimal development. Studies are now looking at the possible effects of these compounds more closely to develop related compounds that are even more potent and might be used as dietary supplements. However, so far, most research suggests that a balanced diet is of greater benefit than taking these substances as dietary supplements.


10. Personalized medicine approaches

Neurological diseases cannot be managed by using one single approach. These disorders, like all chronic diseases, are a complex metabolic system that is related to the way a patient’s genes interact with their individual environment. Therefore, precise and reliable testing methods are needed including patient biomarkers, age, and genetic history. Oxidative stress has been linked to dozens of chronic conditions [264, 265]. Identifying the cause of oxidative stress such as emotional stressors, poor diet, smoking, metal toxicity [266], chemical exposure, and pesticides can be of help [266, 267]. To balance free radicals may require lifestyle and diet modifications such as antioxidant supplementation [268, 269].

There is no doubt that the nervous system is involved in the etiopathogenesis of various pathological states and diseases. Interactions between the nervous, endocrine, and immune systems might represent the anatomical and functional basis for understanding the pathways and mechanisms that enable the brain to modulate the progression of disease. For example, an increasing number of pharmacogenetic association studies in DS are being reported [270, 273]. Personalized medicine is an evidence-based, individualized medicine that delivers the right care to the right patient at the right time and results in measurable improvements in outcomes and a reduction on healthcare costs. However, in order to make personalized medicine effective, genomic techniques must be standardized and integrated into health systems and clinical workflow. Though personalizing drug treatment on the basis of individual genotype rather than ethnicity may be more appropriate, differences in allele frequencies across continents should be considered when designing clinical trials of new drugs [270]. For example, new therapies for treating DS require quality of life measurement, such as the use of stem cells in order to develop treatments which may improve the intelligence of those affected with the syndrome [274]. Other methods being studied include the use of antioxidants, gamma secretase inhibition, adrenergic agonists, and memantine [275, 276, 277, 278, 279].


  1. 1. Eliot L. What’s Going on in There? How the Brain and Mind Develop in the First Five Years of Life. New York: Bantam Books; 1999
  2. 2. Ornstein R, Thompson RF. The Amazing Brain. Boston: Houghton Mifflin; 1984. pp. 23-27
  3. 3. Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proceedings of the Society for Experimental Biology and Medicine. 1999;222(3):236-245
  4. 4. Dillon K, Prokesch S. Global challenges in health care: Is rationing in our future? Harvard Business Review. 2010
  5. 5. Yager P, Domingo GJ, Gerdes J. Point-of-care diagnostics for global health. Annual Review of Biomedical Engineering. 2008;10:107-144
  6. 6. Gutteridge JM, Westermarck T, Halliwell B. Oxygen radical damage in biological systems. In: Johnson JE Jr, Walford R, Harman O, Miquel J, editors. Free Radicals. Aging and Degenerative Diseases. New York: Alan R. Liss; 1985. pp. 99-139
  7. 7. Halliwell B, Gutteridge JM. The importance of free radicals and catalytic metal ions in human diseases. Molecular Aspects of Medicine. 1985;8(2):89-193
  8. 8. Balazs R, BWL B. Neurochemical approaches to the pathogenesis of Down’s syndrome. Journal of Mental Deficiency Research. 1985;29:1-14
  9. 9. Brooksbank BW, Balazs R. Superoxide dismutase and lipoperoxidation in down’s syndrome fetal brain. Developmental Brain Research. 1984;16:37-44
  10. 10. Mann DMA. Alzheimer’s disease and Down’s syndrome. Histopathology. 1988;13(2):125-137
  11. 11. Ness S, Rafii M, Aisen P, Krams M, Silverman W, Manji H. Down’s syndrome and Alzheimer’s disease: Towards secondary prevention. Nature Reviews. Drug Discovery. 2012;11(9):655-656
  12. 12. Rafii MS, Aisen PS. Advances in Alzheimer’s disease drug development. BMC Medicine. 2015;13:62
  13. 13. Bains JS, Shaw CA. Neurodegenerative disorders in humans: The role of glutathione in oxidative stress-mediated neuronal death. Brain Research. Brain Research Reviews. 1997;25(3):335-358
  14. 14. Halliwell B. Role of free radicals in the neurodegenerative diseases: Therapeutic implications for antioxidant treatment. Drugs & Aging. 2001;18(9):685-716
  15. 15. Chaudhari N, Roper SD. The cell biology of taste. The Journal of Cell Biology. 2010;190(3):285-296
  16. 16. Zoccarato F, Pandolfo M, Deana R, Alexandre A. Inhibition by some phenolic antioxidants of Ca2+ uptake and neurotransmitter release from brain synaptosomes. Biochemical and Biophysical Research Communications. 1987;146(2):603-610
  17. 17. Elomaa E, Virtanen I. Is the mental deterioration In Down’s syndrome linked to impaired terminal degradation of neurofilaments? Med. Hypotheses. 1985;16:171-172
  18. 18. Avraham KB, Schickler M, Sapoznikov D, Yarom R, Groner Y. Down’s syndrome: Abnormal neuromuscular junction in tongue of transgenic mice with elevated levels of human Cu/Zn-superoxide dismutase. Cell. 1988;54(6):823-829
  19. 19. Sheldon R, Jiang X, Francisco C, Christen S, Vexler ZS, Tauber MG, et al. Manipulation of antioxidant pathways in neonatal murine brain. Pediatric Research. 2004;56(4):656-662
  20. 20. Nakano M, Sugioka K, Naito I, Takekoshi S, Niki E. Novel and potent antioxidants on membrane phospholipid peroxidation: 2-hydroxyestrone and 2-hydroxyestradiol. Biochemical and Biophysical Research Communications. 1987;142:919-924
  21. 21. Calabrese V, Colombrita C, Guagliano E, Sapienza M, Ravagna A, Cardile V, et al. Protective effect of carnosine during nitrosative stress in astroglial cell cultures. Neurochemical Research. 2005;30(6-7):797-807
  22. 22. Guiotto A, Calderan A, Ruzza P, Borin G. Carnosine and carnosine-related antioxidants: A review. Current Medicinal Chemistry. 2005;12(20):2293-2315
  23. 23. Reddy VP, Garrett MR, Perry G, Smith MA. Carnosine: A versatile antioxidant and antiglycating agent. Science of Aging Knowledge Environment. 2005;2005(18):pe12
  24. 24. Dukic-Stefanovic S, Schinzel R, Riederer P, Münch G. AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs? Biogerontology. 2001;2(1):19-34
  25. 25. Takahashi H. Studies on homocarnosine in cerebrospinal fluid in infancy and childhood. Part I. Homocarnosine level in cerebrospinal fluid of normal infants and children. Brain & Development. 1981;3(3):255-261
  26. 26. Björnsdottir H, Granfeldt D, Welin A, Bylund J, Karlsson A. Inhibition of phospholipase A(2) abrogates intracellular processing of NADPH-oxidase derived reactive oxygen species in human neutrophils. Experimental Cell Research. 2013;319(5):761-774
  27. 27. Dechatelet LR, Shirley PS, Johnston RB. Effect of phorbol myristate acetate on the oxidative metabolism of human polymorphonuclear leukocytes. Blood. 1976;47:545-5543
  28. 28. Suzuki Y, Lehrer RI. NAD(P)H oxidase activity in human neutroph1ls stimulated by phorbol myristate acetate. Journal of Clinical Investigation. 1980;66:1409-1418
  29. 29. Tepperman BL, Soper BD, Chang Q. Effect of protein kinase C activation on intracellular Ca2+ signaling and integrity of intestinal epithelial cells. European Journal of Pharmacology. 2005;518(1):1-9
  30. 30. Han NR, Kim HM, Jeong HJ. Thymic stromal lymphopoietin is regulated by the intracellular calcium. Cytokine. 2012;59(2):215-217
  31. 31. O’Brien TG, Simsiman RC, Boutwell RK. Induction of the polyamine-biosynthetic enzymes in mouse epidermis by tumorpromoting agents. Cancer Research. 1975;35:1662
  32. 32. Greenwood MP, Greenwood M, Paton JF, Murphy D. Control of polyamine biosynthesis by Antizyme inhibitor 1 is important for transcriptional regulation of arginine vasopressin in the male rat hypothalamus. Endocrinology. 2015;156(8):2905-2917
  33. 33. Jasper TW, Luttge WG, Benton TB, Garnica AD. Polyamines in the developing mouse brain. Developmental Neuroscience. 1982;5:233-242
  34. 34. Slotkin TA, Bartolome J. Role of ornithine decarboxylase and the polyamines in nervous system development: A review. Brain Research Bulletin. 1986;17:307-320
  35. 35. Niki E, Traber MG. A history of vitamin E. Annals of Nutrition & Metabolism. 2012;61:207-212
  36. 36. Niki E. Lipid peroxidation: Physiological levels and dual biological effects. Free Radical Biology & Medicine. 2009;47:469-484
  37. 37. Nishikimi M, Yamada H, Yagi K. Oxidation by superoxide of tocopherol dispersed in aqueous media with deoxycholate. Biochimica et Biophysica Acta. 1980;627(1):101-108
  38. 38. Płonka-Półtorak E, Zagrodzki P, Nicol F, Kryczyk J, Bartoń H, Westermarck T, et al. Antioxidant agents and physiological responses in adult epileptic patients treated with lamotrigine. Pharmacological Reports. 2013;65(1)
  39. 39. Westermarck T, Johansson E, Atroshi F. Antioxidants may slow down the progress of neuronal ceroid lipofuscinosis (NCL, BATTEN’S disease) including epilepsy. Epileptologia. 2006;14(Suppl 1):119
  40. 40. Ernster L. Ubiquinone: Redox coenzyme, hydrogen carrier, antioxidant. In: Folkers K, Yamamura Y, editors. Biomedical and Clinical Aspects of Coenzyme A. Vol. 4. Amsterdam: Biomedical Press; 1984. pp. 3-13
  41. 41. Metcalfe T, Bowen DM, Muller DPR. Vitamin E concentrations in human brain of patients with Alzheimer’s disease, fetuses with Down’s syndrome, centenarians, and controls. Neurochemical Research. 1989;14:1209
  42. 42. Antila E, Nordberg UR, Westermarck T. Antioxidant therapy in Down syndrome (OS). A theory and primary survey. In: Selenium in Biology and Medicine. Fourth International Symposium, July 18-21, 1988. W-Germany: University of TUbingen; 1988
  43. 43. Feeney DM, Sutton RL. Pharmacotherapy for recovery of function after brain injury. Critical Reviews in Neurobiology. 1987;3:135-197
  44. 44. Goldstein LB. Effects of amphetamines and small related molecules on recovery after stroke in animals and man. Neuropharmacology. 2000;39:852-859
  45. 45. Misra HP, Fridovich I. The role of superox1de anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. Journal of Biological Chemistry. 1972;247:3170-3175
  46. 46. Kohen R, Yamamoto Y, Cundy KC, Ames BN. Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain. Proceedings of the National Academy of Sciences of the United States of America. 1988;85(9):3175-3179
  47. 47. Oja SS, Kontro P. Taurine. In: Lajtha A, editor. Handbook of Neurochemistry. Vol. 3. New York: Plenum Press; 1983. pp. 501-553
  48. 48. Pasantes-Morales H, Wright CE, Gaull GE. Taurine protection of lymphoblastoid cells from iron-ascorbate induced damage. Biochemical Pharmacology. 1985;34(12):2205-2207
  49. 49. Boullin DJ, Airaksinen EM, Paasonen M. Platelet taurine in Down’s syndrome. Medical Biology. 1975;53:184-186
  50. 50. Perry TL, Hansen S, Berry K, Mok C, Lesk D. Free amino acids and related compounds in b1ops1es of human brain. Journal of Neurochemistry. 1971;18:521-528
  51. 51. Alvarez JG, Storey BT. Taurine, hypotaurine, epinephrine and albumin inhibit lipid peroxidation in rabbit spermatozoa and protect against loss of motility. Biology of Reproduction. 1983;29:548-555
  52. 52. Sinet PM, Garber P. Inactivation of the human CuZn superoxide dismutase during exposure to O-2, and H2O2. Archives of Biochemistry and Biophysics. 1981;212:411-416
  53. 53. Britton G. Structure and properties of carotenoids in relation to function. The FASEB Journal. 1995;9:1551-1558
  54. 54. Burton GW, Ingolod KU. Beta-carotene: An unusual type of lipid antioxidant. Science. 1984;224:569-573
  55. 55. Chen CH, Han RM, Liang R, Fu LM, Wang P, Ai XC, et al. Direct observation of the β-carotene reaction with hydroxyl radical. The Journal of Physical Chemistry. B. 2011;115(9):2082-2089
  56. 56. Maden M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nature Reviews. Neuroscience. 2007;8:755-765
  57. 57. Mey J. New therapeutic target for CNS injury? The role of retinoic acid signaling after nerve lesions. Journal of Neurobiology. 2006;66:757-779
  58. 58. Sidell N, Sarafian T, Kelly M, Tsuchida T, Hausler M. Retinoic acid-induced differentiation of human neuroblastoma: a cell variant system showing two distinct responses. Experimental Cell Biology. 1986;54:287-300
  59. 59. Jetten AM. Induction of differentiation of embryonal carcinoma cells by retinoids. In: Sherman MI, editor. Retinoids and Cell Differentiation. Boca Raton, Florida: CRC Press Inc.; 1986. pp. 105-136
  60. 60. Pueschel SM, Hillemeier C, Caldwell M, Senft K, Mevs C, Pezzullo JC. Vitamin a gastrointestinal absorption in persons with Down’s syndrome. Journal of Mental Deficiency Research. 1990;34(Pt 3):269-275
  61. 61. Roizen NJ. Complementary and alternative therapies for Down syndrome. Mental Retardation and Developmental Disabilities Research Reviews. 2005;11:149-155
  62. 62. Underwood BA. Vitamin A deficiency disorders: International efforts to control a preventable “pox”. The Journal of Nutrition. 2004;134:S231-S236
  63. 63. Mandal SK, Dastidar AG. Carotene and retinol levels in the diagnosis of hypothyroidism. The Journal of the Association of Physicians of India. 1985;33(10):654-655
  64. 64. Mondul AM, Weinstein SJ, Bosworth T, Remaley AT, Virtamo J, Albanes D. Circulating thyroxine, thyroid-stimulating hormone, and hypothyroid status and the risk of prostate cancer. PLoS One. 2012;7(10):e47730. DOI: 10.1371/journal.pone.0047730. Epub October 30, 2012
  65. 65. Patterson D. Molecular genetic analysis of Down syndrome. Human Genetics. 2009;126(1):195-214
  66. 66. Malt EA, Dahl RC, Haugsand TM, Ulvestad IH, Emilsen NM, Hansen B, et al. Health and disease in adults with Down syndrome. Tidsskrift for den Norske laegeforening: Tidsskrift for Praktisk Medicin, NY Raekke. 2013;133(3):290-294
  67. 67. Weijerman ME, de Winter JP. Clinical practice. The care of children with Down syndrome. European Journal of Paediatrics. 2010;169(12):1445-1452
  68. 68. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095-2128
  69. 69. Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and Down syndrome: From genomics to pathophysiology. Nature Reviews. Genetics. 2004;5:725-738
  70. 70. Epstein CJ, Cox DR, Epstein LB. Mouse trisomy 16: An animal model of human trisomy 21 (Down syndrome). Annals of the New York Academy of Sciences. 1985;450:157-168
  71. 71. Lott IT, Dierssen M. Cognitive deficits and associated neurological complications in individuals with Down’s syndrome. Lancet Neurology. 2010;9:623-633
  72. 72. Mccoy EE, Sneddon JM. Cell biological aspects of Down’s syndrome. In: Fedoroff S, Hertz L, editors. Advances in Cellular Neurobiology. Vol. 4. New York: Academic Press; 1983. pp. 249-266
  73. 73. Chadefaux B, Rethore MO, Raoul O, Ceballos I, Poisson-Nier M, Gilgenkranz S, et al. Cystathionine beta synthase. gene dosage effect in trisomy 21. Biochemical and Biophysical Research Communications. 1985;128:40-44
  74. 74. Marucci G, Morandi L, Bartolomei I, Salvi F, Pession A, Righi A, et al. Amyotrophic lateral sclerosis with mutation of the Cu/Zn superoxide dismutase gene (SOD1) in a patient with Down syndrome. Neuromuscular Disorders. 2007;17:673-676
  75. 75. Sinet PM. Metabolism of oxygen derivatives in Down’s syndrome. Annals of the New York Academy of Sciences. 1982;396:83-94
  76. 76. Eckmann-Scholz C, Bens S, Kolarova J, et al. DNA-methylation profiling of fetal tissues reveals marked epigenetic differences between chorionic and amniotic samples. PLoS One. 2012;7(6):e39014
  77. 77. Huret JL, Delabar JM, Marlhens F, Aurias A, Nicole A, Berthier M, et al. Down syndrome with duplication of a region of chromosome 21 containing the CuZn superoxide dismutase gene without detectable karyotypic abnormality. Human Genetics. 1987;75(3):251-257
  78. 78. Elroy-Stein O, Groner Y. Impaired neurotransmitter uptake in PC12 cells overexpressing human Cu/Zn-superoxide dismutase—Implication for gene dosage effects in Down syndrome. Cell. 1988;52:259-267
  79. 79. Kedziora J, Bartosz G. Down’s syndrome. A pathology involving the lack of balance of reactive oxygen species. Free Radical Biology and Medicine. 1988;4:317-330
  80. 80. Francke U. Gene dosage studies in Down syndrome. A review. In Trisomy 21 (Down syndrome) F.F. de la Cruz, P.S. Gerald, editors. University Park Press, Baltimore, 1981, 237-251
  81. 81. Ordonez FJ, Rosety M, Rosety-Rodriguez M. Regular exercise did not modify significantly superoxide dismutase activity in adolescents with Down’s syndrome. British Journal of Sports Medicine. 2006;40(8):717-718
  82. 82. Sulthana MS, Kumar NS, Sridhar MG, Bhat VB, Rao RK. Antioxidant enzyme activity in children with Down syndrome. Current Pediatric Research. 2012;16(1):43-47
  83. 83. Kuroda Y, Kobayashi K, Ichikawa M, Kawahara M, Muramoto K. Application of long-term cultured neurons in aging and neurological research: Aluminum neurotoxicity, synaptic degeneration and Alzheimer’s disease. Gerontology. 1995;41(Suppl 1):2-6
  84. 84. De Marchena O, Guarnieri M, McKhann G. Glutathione peroxidase levels in brain. Journal of Neurochemistry. 1974;22(5):773-776
  85. 85. Brawn K, Fridovich I. Superoxide radical and superoxide dismutases: Threat and defence. Acta Physiologica Scandinavica. 1980;492(Suppl):9-18
  86. 86. Mattiei JF, Baeteman MA, Baret A, Ardissone JP, Rebuffel P, Giraud F. Erythrocyte superoxide dismutase and redox enzymes in trisomy 21. Acta Paediatrica Scandinavica. 1982;71:589-591
  87. 87. Sailer N. Enzymes. In: Lajtha A, editor. Handbook of Neuro-chemistry. Vol. 1. New York: Plenum Press; 1969. pp. 325-468
  88. 88. Ahmed RG. Hypothyroidism and brain developmental players. Thyroid Research. 2015;8:2
  89. 89. Andersen SL, Olsen J, Wu CS, Laurberg P. Psychiatric disease in late adolescence and young adulthood. Foetal programming by maternal hypothyroidism? Clinical Endocrinology. 2014;81:126-133
  90. 90. Bass NH, Pelton EW, Young E. Defective maturation of cerebral cortex: An inevitable consequence of dysthyroid states during early postnatal life. In: Grave GD, editor. Thyroid Hormones and Brain Development. New York: Raven Press; 1977. pp. 199-214
  91. 91. Moog NK, Entringer S, Heim C, Wadhwa PD, Kathmann N, Buss C. Influence of maternal thyroid hormones during gestation on fetal brain development. Neuroscience. 2017;342:68-100
  92. 92. Anderson RB, Newgreen DF, Young HM. Neural crest and the development of the enteric nervous system. Advances in Experimental Medicine and Biology. 2006;589:181-196
  93. 93. Barakat-Walter I. Role of thyroid hormones and their receptors in peripheral nerve regeneration. Journal of Neurobiology. 1999;40:541-559
  94. 94. Romijn HJ, Habets AM, Mud MT, Wolters PS. Nerve outgrow the synaptogenes is and bioelectric activity in fetal rat cerebral cortex tissue cultured in serum-free chemically defined medium. Developmental Brain Research. 1982;2:583-589
  95. 95. Fort P, Lifshitz F, Bellisario R, Davis J, Lanes R, Pugliese M, et al. Abnormalities of thyroid function in infants with Down syndrome. The Journal of Pediatrics. 1984;104(4):545-549
  96. 96. Karlsson B, Gustafsson J, Hedov G, Ivarsson S, Anneren G. Thyroid dysfunction in Down syndrome: Related to age and thyroid autoimmunity. Archives of Disease in Childhood. 1998;73:242-245
  97. 97. Kennedy RL, Jonest TH, Cukle HS. Down’s syndrome and the thyroid. Clinical Endocrinology. 1992;37:471-476
  98. 98. Pueschel SM, Pezzullo JC. Thyroid dysfunction in Down syndrome. American Journal of Diseases of Children. 1985;139:636-639
  99. 99. Tuysuz B, Beker DB. Thyroid dysfunction in children with Down’s syndrome. Acta Paediatrica. 2001;90:1389-1393
  100. 100. Ruf J, Czarnocka B, De Micco C, Dutoit C, Ferrand M, Carayon P. Thyroid peroxidase is the organ-specific ‘microsomal’ autoantigen involved in the thyroid autoimmunity. Acta Endocrinologica. 1987;281:49-56
  101. 101. Karakosta P, Alegakis D, Georgiou V, Roumeliotaki T, Fthenou E, Vassilaki M, et al. Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. The Journal of Clinical Endocrinology and Metabolism. 2012;97:4464-4472
  102. 102. McLachlan SM, Rapoport B. The molecular biology of thyroid peroxidase: Cloning, expression and role as autoantigen in autoimmune thyroid disease. Endocrine Reviews. 1992;13:192-206
  103. 103. Nilsson M, Molne J, Karlsson FA, Ericson LE. lmmunoelectron microscopic studies on the cell surface location of the thyroid microsomal antigen. Molecular and Cellular Endocrinology. 1987;53:177-186
  104. 104. Weetman AP, McGregor AM. Autoimmune thyroid disease: Further developments in our understanding. Endocrine Reviews. 1994;15:788-830
  105. 105. Boelaert K, Horacek J, Holder RL, Watkinson JC, Sheppard MC, Franklyn JA. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. The Journal of Clinical Endocrinology & Metabolism. 2006;91(11):4295-4301
  106. 106. Corvilain B, Van Sande J, Laurent E. The H2O2-generating system modulates protein iodination and the activity of the pentose phosphate pathway in dog thyroid. Endocrinology. 1991;128:779-785
  107. 107. Nunez J, Pommier J. Formation of thyroid hormones. In: Munson PL, Diczfalusy E, Glover J, Olson RE, editors. Vitamins and Hormones. Advances in Research and Applications. New York: Academic Press; 1982. pp. 175-229
  108. 108. Stanley JA, Neelamohan R, Suthagar E, Vengatesh G, Jayakumar J, Chandrasekaran M, et al. Lipid peroxidation and antioxidants status in human malignant and non-malignant thyroid tumours. Human and Experimental Toxicology. 2016;35(6):585-597
  109. 109. Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of graves’ disease and ophthalmopathy. Endocrine Reviews. 2003;24:802-835
  110. 110. Weetman AP. Autoimmune thyroid disease: Propagation and progression. European Journal of Endocrinology. 2003;148:1-9
  111. 111. Bonmort M, Ullrich E, Mignot G, Jacobs B, Chaput N, Zitvogel L. Interferon-gamma is produced by another player of innate immune responses: The interferon-producing killer dendritic cell (IKDC). Biochimie. 2007;89(6-7):872-877
  112. 112. Pujol-Borrell R, Todd I. Inappropriate HLA class II in autoimmunity: is it the primary event? In: Doniach D, Botazzo GF, editors. Bai/liere Clinical Immunology and Allergy. London: Batlliere Tindal; 1987. pp. 1-27
  113. 113. Tatsuta T, Sugawara S, Takahashi K, Ogawa Y, Hosono M, Nitta K. Leczyme: A new candidate drug for cancer therapy. BioMed Research International. 2014;2014:421415. DOI: 10.1155/2014/421415. Epub April 23, 2014
  114. 114. Taylor GM. Altered expression of lymphocyte functional antigen in Down syndrome. Immunology Today. 1987;8:366-369
  115. 115. Blaser S, Propst EJ, Martin D, Feigenbaum A, James AL, Shannon P, et al. Inner ear dysplasia is common in children with Down syndrome (trisomy 21). The Laryngoscope. 2006;116(12):2113-2119
  116. 116. Foresta C, Ferlin A, Gianaroli L, Dallapiccola B. Guidelines for the appropriate use of genetic tests in infertile couples. European Journal of Human Genetics. 2002;10:303-312
  117. 117. Gravholt CH, Juul S, Naeraa RW, Hansen J. Prenatal and postnatal prevalence of turner syndrome: A registry study. British Medical Journal. 1996;312:16-21
  118. 118. Moore SW. Down syndrome and the enteric nervous system. Pediatric Surgery International. 2008;24:873-883
  119. 119. Bull MJ, the Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics. 2011;128:393-406
  120. 120. Sacks B, Wood A. Hearing disorders in children with Down syndrome. Down Syndrome News and Update. 2003;3(2):38-41
  121. 121. Dahle AJ, McCollister FP. Hearing and otologic disorders in children with Down syndrome. American Journal of Mental Deficiency. 1986;90(6):636-642
  122. 122. Davies B. Auditory disorders. In: Stratford B, Gunn P, editors. New Approaches to Down Syndrome. London: Cassell; 1996. pp. 100-121
  123. 123. Marcell MM, Cohen S. Hearing abilities of Down syndrome and other mentally handicapped adolescents. Research in Developmental Disabilities. 1992;13(6):533-551
  124. 124. Roizen N. Hearing loss in children with Down syndrome: A review. Down Syndrome Quarterly. 1997;1997(2):1-4
  125. 125. Tedeschi AS, Roizen NJ, Taylor HG, Murray G, Curtis CA, Parikh AS. The prevalence of congenital hearing loss in neonates with Down syndrome. The Journal of Pediatrics. 2015;166(1):168-171
  126. 126. McPherson B, Lai SP, Leung KK, Ng IH. Hearing loss in Chinese school children with Down syndrome. International Journal of Pediatric Otorhinolaryngology. 2007;71:1905-1915
  127. 127. Shott SR. Down syndrome: Common paediatric ear, nose and throat problems. Down Syndrome Quarterly. 2000;5(2):1-6
  128. 128. Maris M, Wojciechowski M, Van de Heyning P, Boudewyns A. A cross-sectional analysis of otitis media with effusion in children with Down syndrome. European Journal of Pediatrics. 2014;173(10):1319-1325
  129. 129. Picciotti PM, Carfì A, Anzivino R, Paludetti G, Conti G, Brandi V, et al. Audiologic assessment in adults with Down syndrome. American Journal on Intellectual and Developmental Disabilities. 2017;122:333-341
  130. 130. Miller RM, Groher ME, Yorkston KM, et al. Speech, language, swallowing, and auditory rehabilitation. In: JA DL, Gans BM, editors. Rehabilitation Medicine: Principles and Practice. 3rd ed. Philadelphia, PA: Lippincott-Raven; 1998
  131. 131. Buckley SJ. The significance of hearing loss for children with Down syndrome. Down Syndrome News and Update. 2003;3(2):37-37
  132. 132. Miller JF, Leddy M, Leavitt LA, editors. Improving the Communication of People with Down Syndrome. Baltimore: Paul Brookes Publishing; 1999
  133. 133. Abbeduto L, Brady N, Kover ST. Language development and fragile X syndrome: Profiles, syndrome-specificity, and within-syndrome differences. Mental Retardation and Developmental Disabilities Research Reviews. 2007;13(1):36-46
  134. 134. Abbeduto L, Murphy MM, Cawthon SW, Richmond EK, Weissman MD, Karadottir S, et al. Receptive language skills of adolescents and young adults with down or fragile X syndrome. American Journal of Mental Retardation. 2003;108(3):149-160
  135. 135. Chapman RS, Schwartz SE, Bird EK. Language skills of children and adolescents with Down syndrome: I. Comprehension. Journal of Speech and Hearing Research. 1991;34(5):1106-1120
  136. 136. Jarrold C, Baddeley AD. Short-term memory for verbal and Visuospatial information in Down’s syndrome. Cognitive Neuropsychiatry. 1997;2(2):101-122
  137. 137. Keller-Bell Y, FOX RA. A preliminary study of speech discrimination in youth with Down syndrome. Clinical Linguistics & Phonetics. 2007;21:305-317
  138. 138. Laws G, Hall A. Early hearing loss and language abilities in children with Down syndrome. International Journal of Language & Communication Disorders. 2014;49(3):333-342
  139. 139. Rowland LP. Clinical perspective: Phenotypic expression. In: Strohman RC, Wolf S, editors. Muscular Dystrophy, Gene Expression in Muscle. New York, NY: Plenum Press; 1985. pp. 3-5
  140. 140. O’Donovan L, Okamoto I, Arzumanov AA, Williams DL, Deuss P, Gait MJ. Parallel synthesis of cell-penetrating peptide conjugates of PMO toward exon skipping enhancement in Duchenne muscular dystrophy. Nucleic Acid Therapeutics. 2015;25(1):1-10
  141. 141. Swash M, Heathfield KW. Quadriceps myopathy: A variant of the limb-girdle dystrophy syndrome. Journal of Neurology, Neurosurgery, and Psychiatry. 1983;46:355-357
  142. 142. Beam KG. Duchenne muscular dystrophy. Localizing the gene product. Nature. 1988;333(6176):798-799
  143. 143. Hoffman EP, Fischbeck KH, Brown RH, Johnson M, Medori R, Loike JD, et al. Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne’s or Becker’s muscular dystrophy. The New England Journal of Medicine. 1988;318(21):1363-1368
  144. 144. Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415:198-205
  145. 145. Fabiato A. Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. The Journal of General Physiology. 1985;85:247-289
  146. 146. Terentyev D, Viatchenko-Karpinski S, Gyorke I, Terentyeva R, Gyorke S. Protein phosphatases decrease sarcoplasmic reticulum calcium content by stimulating calcium release in cardiac myocytes. The Journal of Physiology. 2003;552:109-118
  147. 147. Dominski Z, Kole R. Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proceedings of the National Academy of Sciences of the United States of America. 1993;90:8673-8677
  148. 148. Douglas AGL, Wood MJA. Splicing therapy for neuromuscular disease. Molecular and Cellular Neurosciences. 2013;56:169-185
  149. 149. Kole R. Modification of pre-mRNA splicing by antisense oligonucleotides. Acta Biochimica Polonica. 1997;44:231-237
  150. 150. Kole R, Vacek M, Williams T. Modification of alternative splicing by antisense therapeutics. Oligonucleotides. 2004;14:65-74
  151. 151. Lacerra G, Sierakowska H, Carestia C, Fucharoen S, Summerton J, Weller D, et al. Restoration of hemoglobin a synthesis in erythroid cells from peripheral blood of thalassemic patients. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(17):9591-9596
  152. 152. Muntoni F, Wood MJA. Targeting RNA to treat neuromuscular disease. Nature Reviews. 2011;10:621-637
  153. 153. Suwanmanee T, Sierakowska H, Lacerra G, Svasti S, Kirby S, Walsh CE, et al. Restoration of human beta-globin gene expression in murine and human IVS2-654 thalassemic erythroid cells by free uptake of antisense oligonucleotides. Molecular Pharmacology. 2002;62(3):545-553
  154. 154. Wilton SD, Fall AM, Harding PL, McClorey G, Coleman C, Fletcher S. Antisense oligonucleotide-induced exon skipping across the human dystrophin gene transcript. Molecular Therapy. 2007;15(7):1288-1296
  155. 155. Wilton SD, Lloyd F, Carville K, Fletcher S, Honeyman K, Agrawal S, et al. Specific removal of the nonsense mutation from the mdx dystrophin mRNA using antisense oligonucleotides. Neuromuscular Disorders. 1999;9(5):330-338
  156. 156. Järver P, O’Donovan L, Gait MJ. A chemical view of oligonucleotides for exon skipping and related drug applications. Nucleic Acid Therapeutics. 2014;24:37-47
  157. 157. Koo T, Wood MJA. Clinical trials using antisense oligonucleotides in Duchenne muscular dystrophy. Human Gene Therapy. 2013;24:479-488
  158. 158. Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, et al. Systemic administration of PRO051 in Duchenne’s muscular dystrophy. New England Journal of Medicine. 2011;364:1513-1522
  159. 159. Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study. Lancet. 2011;378(9791):595-605
  160. 160. Mendell J, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Annals of Neurology. 2013;74:637-647
  161. 161. Hunter MI, Brzeski MS, De Vane PJ. Superoxide dismutase, glutathione peroxidase and thiobarbituric acid-reactive compounds in erythrocytes in Duchenne muscular dystrophy. Clinica Chimica Acta. 1981;115:93-98
  162. 162. Hunter MI, Mohamed JB. Plasma antioxidants and lipid peroxidation products in Duchenne muscular dystrophy. Clinica Chimica Acta. 1986;155(2):123-131
  163. 163. Jackson MJ, Coakley J, Stokes M, Edwards RH, Oster O. Selenium metabolism and supplementation in patients with muscular dystrophy. Neurology. 1989;39(5):655-659
  164. 164. Jackson M, Edwards RH. Free radicals and trials of antioxidant therapy in muscle disorders. Advances in Experimental Medicine and Biology. 1990;264:485-491
  165. 165. Westermarck T, Rahola T, Kallio AK, Suomela M. Long term turnover of selenite-Se in children with motor disorders. Klinische Pädiatrie. 1982;194:301-302
  166. 166. Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P, et al. Searching for the exercise factor: Is IL-6 a candidate? Journal of Muscle Research and Cell Motility. 2003;24(2-3):113-119
  167. 167. Le Borgne F, Guyot S, Logerot M, Beney L, Gervais P, Demarquoy J. Exploration of lipid metabolism in relation with plasma membrane properties of duchenne muscular dystrophy cells: Influence of L-carnitine. PLoS One. 2012;7(11)
  168. 168. Shimomura Y, Suzuki M, Sugiyama S, Hanaki Y, Ozawa T. Protective effect of coenzyme Q10 on exercise-induced muscular injury. Biochemical and Biophysical Research Communications. 1991;176:349-355
  169. 169. Belardinelli R, Muçaj A, Lacalaprice F, Solenghi M, Seddaiu G, Principi F, et al. Coenzyme Q10 and exercise training in chronic heart failure. European Heart Journal. 2006;27(22):2675-2681
  170. 170. Littarru GP, Tiano L. Clinical aspects of coenzyme Q10: An update. Nutrition. 2010;26(3):250-254
  171. 171. Westermarck T, Atroshi F. Dietary approaches to patients with Duchenne muscular dystrophy (DMD), patients with spielmeyer-sergen disease, and patients with epilepsy. Trace Elements in Medicine. 2005;6(2):27-32
  172. 172. Lu A, Poddar M, Tang Y, Proto JD, Sohn J, Mu X, et al. Rapid depletion of muscle progenitor cells in dystrophic mdx/utrophin−/− mice. Human Molecular Genetics. 2014;23(18):4786-4800
  173. 173. Lu QL, Mann CJ, Lou F, Bou-Gharios G, Morris GE, Xue SA, et al. Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nature Medicine. 2003;9(8):1009-1014
  174. 174. van Deutekom JC, van Ommen GJ. Advances in Duchenne muscular dystrophy gene therapy. Nature Reviews. Genetics. 2003;4(10):774-783
  175. 175. Bennett MJ, Rakheja D. The neuronal ceroid-lipofuscinoses. Developmental Disabilities Research Reviews. 2013;17(3):254-259
  176. 176. Mole SE. Batten’s disease: Eight genes and still counting? Lancet. 1999;354:443-445
  177. 177. Pardo CA, Rabin BA, Palmer DN, Price DL. Accumulation of the adenosine triphosphate synthase subunit C in the mnd mutant mouse. A model for neuronal ceroid lipofuscinosis. The American Journal of Pathology. 1994;144(4):829-835
  178. 178. Persaud-Sawin DA, Mousallem T, Wang C, Zucker A, Kominami E, Boustany RM. Neuronal ceroid lipofuscinosis: A common pathway? Pediatric Research. 2007;61(2):146-152
  179. 179. Santavuori P, Haltia M, Rapola J, Raitta C. Infantile type of so-called neuronal ceroid lipofuscinosis part 1. A clinical study of 15 patients. Journal of the Neurological Sciences. 1973;18:257-267
  180. 180. Bäckman ML, Santavuori PR, Aberg LE, Aronen ET. Psychiatric symptoms of children and adolescents with juvenile neuronal ceroid lipofuscinosis. Journal of Intellectual Disability Research. 2005;49(Pt 1):25-32
  181. 181. Crystal RG, Sondhi D, Hackett NR, Kaminsky SM, Worgall S, Stieg P, et al. Clinical protocol. Administration of a replication-deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of children with late infantile neuronal ceroid lipofuscinosis. Human Gene Therapy. 2004;15:1131-1154
  182. 182. Narayan SB, Pastor JV, Mitchison HM, Bennett MJ. CLN3L, a novel protein related to the batten disease protein, is overexpressed in Cln3−/− mice and in batten disease. Brain. 2004;127(Pt 8):1748-1754
  183. 183. Mole SE, Williams RE, Goebel HH. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics. 2005;6:107-126
  184. 184. Winchester B, Vellodi A, Young E. The molecular basis of lysosomal storage diseases and their treatment. Biochemical Society Transactions. 2000;28(2):150-154
  185. 185. Hawkins-Salsbury JA, Cooper JD, Sands MS. Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease). Biochimica et Biophysica Acta. 2013;1832(11):1906-1909
  186. 186. Dhar S, Bitting RL, Rylova SN, Jansen PJ, Lockhart E, Koeberl DD, et al. Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons. Annals of Neurology. 2002;51(4):448-466
  187. 187. Kohan R, Cismondi IA, Oller-Ramirez AM, et al. Therapeutic approaches to the challenge of neuronal ceroid lipofuscinoses. Current Pharmaceutical Biotechnology. 2011;12(6):867-883
  188. 188. Lönnqvist T, Vanhanen SL, Vettenranta K, Autti T, Rapola J, Santavuori P, et al. Hematopoietic stem cell transplantation in infantile neuronal ceroid lipofuscinosis. Neurology. 2001;57(8):1411-1416
  189. 189. Neverman NJ, Best HL, Hofmann SL, Hughes SM. Experimental therapies in the neuronal ceroid lipofuscinoses. Biochimica et Biophysica Acta. 2015;1852(10 Pt B):2292-2300
  190. 190. Sands MS. Considerations for the treatment of infantile neuronal ceroid lipofuscinosis (infantile batten disease). Journal of Child Neurology. 2013;28(9):1151-1158
  191. 191. Traina G, Bernardi R, Cataldo E, Macchi M, Durante M, Brunelli M. In the rat brain acetyl-L-carnitine treatment modulates the expression of genes involved in neuronal ceroid lipofuscinosis. Molecular Neurobiology. 2008;38(2):146-152
  192. 192. Banerjee P, Dasgupta A, Siakotos AN, Dawson G. Evidence for lipase abnormality: High levels of free and triacylglycerol forms of unsaturated fatty acids in neuronal ceroid-lipofuscinosis tissue. American Journal of Medical Genetics. 1992;42:549-554
  193. 193. Heiskala H, Gutteridge J, Westermarck T, Alanen T, Santavuori P. Bleomycin-detectable iron and phenanthroline-detectable copper in the cerebrospinal fluid of patients with neuronal ceroid-lipofuscinoses. American Journal of Medical Genetics. Supplement. 1988;5:193-202
  194. 194. Johansson E, Lindh U, Westermarck T, Heiskala H, Santavuori P. Altered elemental profiles in neuronal ceroid lipofuscinosis. Journal of Trace Elements and Electrolytes in Health and Disease. 1990;4(3):139-142
  195. 195. Hall NA, Lake BD, Dewji NN, Patrick AD. Lysosomal storage of subunit c of mitochondrial ATP synthase in Batten’s disease (ceroid-lipofuscinosis). The Biochemical Journal. 1991;275:269-272
  196. 196. Piattella L, Cardinali C, Zamponi N, Papa O. Spielmeyer-Vogt disease: Clinical and neurophysiological aspects. Child’s Nervous System. 1991;7(4):226-230
  197. 197. Santavuori P, Heiskala H, et al. Experience over 17 years with antioxidant treatment in Spielmeyer-Sjogren’s disease. American Journal of Medical Genetics—Part A. 1988;5(Suppl):265-274
  198. 198. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221-1231
  199. 199. Pugliatti M, Rosati G, Carton H, Riise T, Drulovic J, Vécsei L, et al. The epidemiology of multiple sclerosis in Europe. European Journal of Neurology. 2006;13(7):700-722
  200. 200. Haegert DG, Marrosu MG. Genetic susceptibility to multiple sclerosis. Annals of Neurology. 1994;36(Suppl 2):S204-S210
  201. 201. Skoog B, Runmarker B, Winblad S, Ekholm S, Andersen O. A representative cohort of patients with non-progressive multiple sclerosis at the age of normal life expectancy. Brain. 2012;135:900-911
  202. 202. Skoog B, Tedeholm H, Runmarker B, Odén A, Andersen O. Continuous prediction of secondary progression in the individual course of multiple sclerosis. Multiple Sclerosis and Related Disorders. 2014;3(5):584-592
  203. 203. Belin J, Pettet N, Smith AD, Thompson RH, Zilkha KJ. Linoleate metabolism in multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry. 1971;34(1):25-29
  204. 204. Thompson RH. Fatty acid metabolism in multiple sclerosis. Biochemical Society Symposium. 1972;35:103-111
  205. 205. Schwarz S, Leweling H. Multiple sclerosis and nutrition. Multiple Sclerosis. 2005;11(1):24-32
  206. 206. Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. Journal of the American College of Nutrition. 2002;21(6):495-505
  207. 207. Clausen J, Jensen GE, Nielsen SA. Selenium in chronic neurologic diseases. Multiple sclerosis and Batten’s disease. Biological Trace Element Research. 1988;15:179-203
  208. 208. Gade-Andavolu R, MacMurray JP, Blake H, Muhleman D, Tourtellotte W, Comings DE. Association between the gamma-aminobutyric acid A3 receptor gene and multiple sclerosis. Archives of Neurology. 1998;55(4):513-516
  209. 209. Derfuss T. Personalized medicine in multiple sclerosis: Hope or reality? BMC Medicine. 2012;10:116
  210. 210. Pueschel SM. Therapeutic approaches in Down syndrome. In: Delacruz FF, Gerald PS, editors. Trisomy 21 (Down syndrome). Baltimore: University Park Press; 1981. pp. 217-224
  211. 211. Harrell RF, Capp RH, Davis DR, Peerless J, Ravitz LR. Can nutritional supplements help mentally retarded children? An exploratory study. Proceedings of the National Academy of Sciences of the United States of America. 1981;78(1):574-578
  212. 212. Anjos T, Altmäe S, Emmett P, Tiemeier H, Closa-Monasterolo R, Luque V, et al. Nutrition and neurodevelopment in children: Focus on NUTRIMENTHE project. European Journal of Nutrition. 2013;52(8):1825-1842
  213. 213. Bennet FC, McClelland S, Kriegsmann EA, Andrus LB, Sells CJ. Vitamin and mineral supplementation in Down’s syndrome. Pediatrics. 1983;72:707-713
  214. 214. Kozlowski BW. Megavitamin treatment of mental retardation in children: A review of effects on behavior and cognition. Journal of Child and Adolescent Psychopharmacology. 1992;2(4):307-320
  215. 215. Schaevitz L, Berger-Sweeney J, Ricceri L. One-carbon metabolism in neurodevelopmental disorders: using broad-based nutraceutics to treat cognitive deficits in complex spectrum disorders. Neuroscience and Biobehavioral Reviews. 2014;46(Pt 2):270-284. DOI: 10.1016/j.neubiorev.2014.04.007. Epub April 23, 2014
  216. 216. Smith GF, Spiker D, Peterson CP, Cicchetii D, Justine P. Use of megadoses of vitamins and minerals in Down syndrome. The Journal of Pediatrics. 1984;105:228-234
  217. 217. Antila, E., Nordberg, U-R., Syvaosa, E-L. and Westermarck, T. Selenium therapy in Down syndrome (OS). A theory and a clinical trial. In Antioxidants in Therapy and Preventive Medicine (I. Emerit, L. Packer and C. Auclair ). Plenum Pub. Co., New York. 1989
  218. 218. Antila E, Westermarck T. On the etiopathogenesis and therapy of Down syndrome. The International Journal of Developmental Biology. 1989;33:183-188
  219. 219. Halliwell B, Gutteridge JM. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochemical Journal. 1984;9:1-14
  220. 220. Slivka A, Mytilineou C, Cohen G. Histochemical evaluation of glutathione in brain. Brain Research. 1987;409:275-284
  221. 221. Miller DS. Hereditary hemolytic anemias. Pediatric Clinics of North America. 1972;19:865-887
  222. 222. Rocha JC, Martins MJ. Oxidative stress in phenylketonuria: Future directions. Journal of Inherited Metabolic Disease. 2012;35(3):381-398
  223. 223. Westermarck T, Raunu P, Kirjarinta M, Lappalainen L. Selenium content of who le blood and serum in adults and children of different ages from different parts of Finland. Acta Pharmacologica et Toxicologica. 1977;40:465-475
  224. 224. Thompson CD, Robinson MF, Campbell DR, Rea HM. Effect of prolonged supplementation with daily supplements of selenomethionine and sodium selenite on glutathione peroxidase activity in blood of New Zealand residents. The American Journal of Clinical Nutrition. 1982;36:24-31
  225. 225. Westermarck T, Sandholm M. Decreased erythrocyte glutathione peroxidase activity in neuronal ceroid lipofuscinosis (NCL)-corrected with selenium supplementation. Acta Pharmacologica et Toxicologica. 1977;40:70-74
  226. 226. Anneren G. Down’s syndrome. A metabolic and endocrinological study. Acta Universitatis Upsaliensis. 1984;483(VI):1-15, Uppsala
  227. 227. Neve J, Sinet PM, Molle L, Nicole A. Selenium, zinc and copper in Down’s syndrome (trisomy 21): Blood levels and relations with glutathione peroxidase and superoxide dismutase. Clinica Chimica Acta. 1983;133:209-214
  228. 228. Beilstein MA, Butler IA, Whang ER. Metabolism of 70 Se-selenite by rhesus monkeys. In: Friberg L, Nordberg G, Falke GF, Vouk V, editors. Handbook on the Toxicology of Metals. Amsterdam: Biomedical Press; 1984. pp. 482-520
  229. 229. Westermarck T, Rahola T, Suomela M, Alanen T, Puhakainen M. Biological half-life of Se-selenite and Zn-chloride in Down syndrome patients. In: Mills CF, Bremner I, Chesters JK, editors. Proceedings of the Fifth International Symposium on Trace Elements in Man and Animals. Farnham Royal, Slough SL2 3BN, UK: Commonwealth Agricultural Bureaux; 1985. pp. 792-795
  230. 230. Ani C, Grantham-McGregor S, Muller D. Nutritional supplementation in Down syndrome: Theoretical considerations and current status. Developmental Medicine and Child Neurology. 2000;42(3):207-213
  231. 231. Sinet PM, Lejeune J, Jerome H. Trisomy 21 (Down’s syndrome). Glutathione peroxidase. Hexose monophosphate shunt and IQ. Life Sciences. 1979;24:29-34
  232. 232. Prohaska JR, Ganther HE. Selenium and glutathione peroxidase in developing rat brain. Journal of Neurochemistry. 1976;27:1379-1387
  233. 233. Behne O, Hilmert H, Scheid S, Gessner H, Elger W. Evidence for specific selenium target tissues and new biologically important selenoproteins. Biochimica et Biophysica Acta. 1988;966:12-21
  234. 234. Germain GS, Arneson RM. Selenium induced glutathione peroxidase activity in mouse neuroblastoma cells. Biochemical and Biophysical Research Communications. 1977;79:119-123
  235. 235. Saedi MS, Smith CG, Frampton J, Chambers I, Harrison PR, Sunde RA. Effect of selenium status on MRNA levels for glutathione peroxidase in rat liver. Biochemical and Biophysical Research Communications. 1988;153:855-861
  236. 236. Lindner G, Grosse G. Effect of a selenium compound (Na2SeO3) on nerve tissue in vitro. Zeitschrift für Mikroskopisch-Anatomische Forschung. 1985;99(4):627-638
  237. 237. Parantainen J, Atroshi F. Trace elements as possible keys to biological semiconduction. In: n1 Conf. on Medical. Biochemical and Chemical Aspects of Free Radicals. 1988. 1 (Abstr)
  238. 238. Antila E, Nordberg UR, Syvaoja EL, Westermarck T. Selenium therapy in Down syndrome (DS): A theory and a clinical trial. Advances in Experimental Medicine and Biology. 1990;264:183-186
  239. 239. Anneren G, Johansson E, Lindh U. Trace elemental profiles in individual blood cells from patients with Down’s syndrome. Acta Paediatrica Scandinavica. 1985;74:259-263
  240. 240. Adewuyi YG. Sonochemistry in environmental remediation. 1. Combinative and hybrid sonophotochemical oxidation processes for the treatment of pollutants in water. Environmental Science & Technology. 2005;39(10):3409-3420
  241. 241. Dunford HB. Free radicals in iron-containing systems. Free Radical Biology & Medicine. 1987;3(6):405-421
  242. 242. Halsted JA, Smith JC Jr. Plasma-zinc in health and disease. Lancet. 1970;1:322-324
  243. 243. Milunsky A, Hackley M, Halsted JA. Plasma erythrocyte and leucocyte zinc levels in Down’s syndrome. Journal of Mental Deficiency Research. 1970;14:99-105
  244. 244. Malakooti N, Pritchard MA, Adlard PA, Finkelstein DI. Role of metal ions in the cognitive decline of Down syndrome. Frontiers in Aging Neuroscience. 2014;6:136
  245. 245. Thomson CD. Assessment of requirements for selenium and adequacy of selenium status: A review. European Journal of Clinical Nutrition. 2004;58:391-402
  246. 246. Atroshi F, Westermarck T. High concentrations of erythrocyte glutathione in patients with neurological disorders: Possible clinical implications. In: Rice-Evans C, editor. Free Radical Oxidant Stress & Drug Action. London: Richelieu Press; 1987. pp. 419-424
  247. 247. Atroshi F, Parantainen J, Sankari S, Österman T. Prostaglandin and glutathione peroxidase in bovine mastitis. Research in Veterinary Science. 1986;40:361-366
  248. 248. Atroshi F, Sankari S, Työppönen J, Parantainen J. Inflammation related changes in trace elements, GSH-metabolism, prostaglandins and sialic acid. In: Hurly LS, Keen CL, Lonnerdal B, Rucker RB, editors. Trace Elements in Man and Animals 6. New York, London: Plenum Press; 1988. pp. 97-99
  249. 249. Chung A-S, Maines MD. Effect of selenium on glutathione metabolism. Induction of gamma-glutamylcysteine synthetase and glutathione reductase in the rat liver. Biochemical Pharmacology. 1981;30:3217-3223
  250. 250. LaFemina MJ, Sheldon RA, Ferriero DM. Acute hypoxia-ischemia results in hydrogen peroxide accumulation in neonatal but not adult mouse brain. Pediatric Research. 2006;59:680-683
  251. 251. McLean CW, Mirochnitchenko O, Claus CP, Noble-Haeusslein LJ, Ferriero DM. Overexpression of glutathione peroxidase protects immature murine neurons from oxidative stress. Developmental Neuroscience. 2005;27:169-175
  252. 252. Wang H, Cheng E, Brooke S, Chang P, Sapolsky R. Over-expression of antioxidant enzymes protects cultured hippocampal and cortical neurons from necrotic insults. Journal of Neurochemistry. 2003;87:1527-1534
  253. 253. Miller BA, Perez RS, Shah AR, Gonzales ER, Park TS, Gidday JM. Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia reperfusion. Neuroreport. 2001;12:1663-1669
  254. 254. Bernaudin M, Tang Y, Reilly M, Petit E, Sharp FR. Brain genomic response following hypoxia and re-oxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance. The Journal of Biological Chemistry. 2002;277:39728-39738
  255. 255. Mu D, Jiang X, Sheldon RA, Fox CK, Hamrick SE, Vexler ZS, et al. Regulation of hypoxia-inducible factor 1 alpha and induction of vascular endothelial growth factor in a rat neonatal stroke model. Neurobiology of Disease. 2003;14:524-534
  256. 256. Zellweger H. Genetic aspects of neurological disease. Archives of Internal Medicine. 1965;115:387-397
  257. 257. Boyer SH, Fainer DC. Genetics and diseases of muscle. The American Journal of Medicine. 1963;35:622-631
  258. 258. Cannon JR, Greenamyre JT. The role of environmental exposures in neurodegeneration and neurodegenerative diseases. Toxicological Sciences. 2011;124(2):225-250
  259. 259. Mckusick VA. Medical genetics 1962. Journal of Chronic Diseases. 1963;16:457-634
  260. 260. Hunter DJ. Gene-environment interactions in human diseases. Nature Reviews. Genetics. 2005;6:287-298
  261. 261. van der Mei IA, Otahal P, Simpson S Jr, Taylor B, Winzenberg T. Meta-analyses to investigate gene-environment interactions in neuroepidemiology. Neuroepidemiology. 2014;42(1):39-49
  262. 262. Kaipainen P, Westermarck T, Kaski M, Iivanainen M, Atroshi F. Determination of levetiracetam in patients with epilepsy and intellectual disability. European Journal of Pharmaceutical Sciences. 2006;28(Suppl 1):S38
  263. 263. Simonato M, Bennett J, Boulis NM, Castro MG, Fink DJ, Goins WF, et al. Progress in gene therapy for neurological disorders. Nature Reviews. Neurology. 2013;9(5):277-291
  264. 264. Poulsen HE. Oxidative DNA modifications. Experimental and Toxicologic Pathology. 2005;57(Suppl 1):161-169
  265. 265. Villamena FA. Chemistry of reactive species. In: Villamna FA, editor. Molecular Basis of Oxidative Stress–Chemistry, Mechanism, and Disease Pathogenesis. Hoboken: John Wiley & Sons, Inc.; 2013. pp. 1-48
  266. 266. Atroshi F, Tallberg T, Abdulla VM, Westermarck T. The impact of heavy metals on health with special emphasis on cadmium carcinogenesis. In: Behera B, Panda SP, editors. Natural Resource Conservation and Environment Management. New Delhi: APH Publishing Corporation; 2010. pp. 1-12
  267. 267. Antila E, Mussalo-Rauhamaa H, Kantola M, Atroshi F, Westermarck T. Association of cadmium with human breast cancer. Science of the Total Environment. 1996;186:251-256
  268. 268. Crohns M, Westermarck T, Atroshi F. Prostate cancer, inflammation and antioxidants. In: Hamilton G, editor. Advances in Prostate Cancer. Croatia: InTech; 2013. pp. 401-421
  269. 269. Tallberg T, Atroshi F. Prostate cancer, the long search for etiologic and therapeutic factors: Dietary supplementation avoiding invasive treatment. In: Spiess PE, editor. Prostate Cancer: From Bench to Bedside. Croatia: InTech Publisher; 2011. pp. 33-52
  270. 270. Daly AK. Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: Review of current knowledge and comparison with selected European populations. Drug Metabolism and Personalized Therapy. 2015;30(3):165-174
  271. 271. Mann MW, Pons G. Various pharmacogenetic aspects of antiepileptic drug therapy: A review. CNS Drugs. 2007;21(2):143-164
  272. 272. Rabin KR, Whitlock JA. Malignancy in children with trisomy 21. The Oncologist. 2009;14(2):164-173
  273. 273. Rieder MJ, Carleton B. Pharmacogenomics and adverse drug reactions in children. Frontiers in Genetics. 2014;5:78
  274. 274. Goodman MJ, Brixner DI. New therapies for treating Down syndrome require quality of life measurement. American Journal of Medical Genetics—Part A. 2013;161A(4):639-641
  275. 275. Costa AC, Scott-McKean JJ. Prospects for improving brain function in individuals with Down syndrome. CNS Drugs. 2013;27(9):679-702
  276. 276. Vosslamber S, van Baarsen LG, Verweij CL. Pharmacogenomics of IFN-beta in multiple sclerosis: Towards a personalized medicine approach. Pharmacogenomics. 2009;10(1):97-108
  277. 277. Weinshenker BG. Natural history of multiple sclerosis. Annals of Neurology. 1994;36(S1,Suppl):S6-S11
  278. 278. WHO. Genes and Human Disease, Genes and Chromosomal Diseases. 1211 Geneva 27, Switzerland: WHO PRESS; 2015
  279. 279. WHO. Neurological Disorders: Public Health Challenges. 1211 Geneva 27, Switzerland: WHO PRESS; 2006

Written By

Shirley Ekvall, Tuomas Westermarck, Mari Havia and Faik Atroshi

Reviewed: 05 March 2020 Published: 14 October 2020