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L-Carnitine supplementation improves the behavioral symptoms in autistic children
Abstract
l-Carnitine was proposed as a potential treatment for patients diagnosed with autism to ameliorate the behavioral symptoms associated with the disease. Thirty children diagnosed with autism were randomly assigned to receive (100 mg/kg bodyweight/day) of liquid l-carnitine (n = 16) or placebo (n = 14) for 6 months. Measurements included changes in childhood autism rating scale (CARS) form and free and total carnitine levels using tandem mass spectrometry. Results showed significant improvement in CARS scores (P-groups <0.001) and (P-overtime = 0.006), with statistically significant differences in free carnitine levels (P = 0.027) and total carnitine levels (P = 0.036). There was no correlation between baseline free and total carnitine levels with changes in CARS scores from zero to 6 months (r > 0.5, P > 0.05) and generally l-carnitine therapy was well tolerated. In conclusion, l-carnitine therapy (100 mg/kg bodyweight/day) administered for 6 months significantly improved the autism severity, but subsequent studies are recommended.
... Hamedi-kalajahi et al. [41] did a randomized clinical trial and found no significant change in serum albumin levels after 10 wk of supplementation. Fahmy et al. [42] did a study on L-carnitine supplementation in autistic children and found significant improvement in the severity of the conditions after 6 mo of supplementation with the same dose as ours (100 mg/kg/d). Al-Biltagi et al. [43] did a study on children with moderate persistent asthma and found significant improvement after 6 mo of supplementation. ...
... Al-Biltagi et al. [43] did a study on children with moderate persistent asthma and found significant improvement after 6 mo of supplementation. Our study administered supplementation for 15 d, whereas a longer duration of supplementation resulted in significant improvement, according to other studies [42,43]. Our result showed improvement in weight gain at NRU, but their condition remains unimproved at home. ...
... In our study, after 15 d of supplementation, there was a comparable change in the carnitine concentration in both groups. Like ours, Fahmy et al. [42] reported finding no significant changes in carnitine levels in autistic children receiving the L-carnitine group compared with placebo after 3 mo of supplementation. In our study, we gave supplementation for 15 d only. ...
... Fahmy, S.F.;El-hamamsy, M.H.;Zaki, O.K.;Badary, 2013). Goin-Kochel et al. conducted an 8-week study in which 10 boys with ASD (including a patient with hereditary ASD with a TMLHE gene deficit) were given carnitine in three separate dosages starting at 200 mg/kg and escalating to 400 mg/kg/day, up to a maximum of 6 g daily. ...
... Fahmy, S.F.;El-hamamsy, M.H.;Zaki, O.K.;Badary, 2013). Goin-Kochel et al. conducted an 8-week study in which 10 boys with ASD (including a patient with hereditary ASD with a TMLHE gene deficit) were given carnitine in three separate dosages starting at 200 mg/kg and escalating to 400 mg/kg/day, up to a maximum of 6 g daily. ...
... Fahmy, S.F.;El-hamamsy, M.H.;Zaki, O.K.;Badary, 2013). Goin-Kochel et al. conducted an 8-week study in which 10 boys with ASD (including a patient with hereditary ASD with a TMLHE gene deficit) were given carnitine in three separate dosages starting at 200 mg/kg and escalating to 400 mg/kg/day, up to a maximum of 6 g daily. ...
Carnitine is a medically needful nutrient that contributes in the production of energy and the metabolism of fatty acids. Bioavailability is higher in vegetarians than in people who eat meat. Deficits in carnitine transporters occur as a result of genetic mutations or in combination with other illnesses such like hepatic or renal disease. Carnitine deficit can arise in diseases such endocrine maladies, cardiomyopathy, diabetes, malnutrition, aging, sepsis, and cirrhosis due to abnormalities in carnitine regulation. The exogenously provided molecule is obviously useful in people with primary carnitine deficits, which can be life-threatening, and also some secondary deficiencies, including such organic acidurias: by eradicating hypotonia, muscle weakness, motor skills, and wasting are all improved L-carnitine (LC) have reported to improve myocardial functionality and metabolism in ischemic heart disease patients, as well as athletic performance in individuals with angina pectoris. Furthermore, although some intriguing data indicates that LC could be useful in a variety of conditions, including carnitine deficiency caused by long-term total parenteral supplementation or chronic hemodialysis, hyperlipidemias, and the prevention of anthracyclines and valproate-induced toxicity, such findings must be viewed with caution.
... Carnitine levels in ASD are important because they show potential mitochondrial dysfunction and abnormal fatty acid metabolism [16]. Although in their studies of Filipek et al. [17], and Mostafa et al. [18], low carnitine levels in ASD children, besides, in their studies of Geier et al. [19], and Fahmy et al. [20], improvement in cases administrated L-carnitine in ASD symptoms have been demonstrated, there are not many studies on this subject. For all these reasons, in this study, in ASD children carnitine levels in dried blood spot samples were evaluated and compared with the control group. ...
... Similarly, Fahmy et al. [18] have been reported that 30 cases diagnosed with autism were randomly assigned to receive of liquid l-carnitine (n=16) or placebo (n=14) for 6 months, and after 6 months, liquid l-carnitine therapy administered significantly improved the autistic behavior and decreased the severity of autism. Total and free carnitine levels were examined in the studies [19,20]. Based on the data obtained from these studies and our study, it is obvious that carnitine levels are important for ASD and it should be emphasized that carnitine levels should be examined in terms of ASD treatment protocols. ...
... Adams et al. [26] demonstrated that carnitine results in 67 cases with ASD in both groups with and without carnitine administration started at levels similar to neurotypical controls, and that treatment led to a significant increase in L-carnitine and non-significant increase in acetyl-L-carnitine. In this study, in cases with ASD, it has been stated that administered L-carnitine can be absorbed better than acetyl-L-carnitine in other studies [19,20] and therefore might be more effective. They also reported that the benefit from carnitine was very limited in cases with ASD [26]. ...
Objectives
Autism Spectrum Disorder is a neurodevelopmental disease with an average diagnosis age of over 3 years. Carnitine levels in ASD are important because they show potential mitochondrial dysfunction and abnormal fatty acid metabolism. In this study, in ASD children carnitine levels in dried blood spot samples were evaluated and compared with the control group.
Methods
Twentythree children diagnosed with ASD in Research and Training Hospital (19 boys, 4 girls) and age and gender matched 24 children without ASD were enrolled in this study. 17 carnitines in dried blood samples were measured with LC-MS/MS.
Results
C0, C2, C4-OH, C5, C5-OH, C6, C16, C18 carnitines were lower (p value 0.037, 0.010, 0.005, 0.032, 0.005, 0.003, 0.043, 0.003, respectively) and C18:1 carnitine was higher (p<0.025) in ASD group compared with control group.
Conclusions
Comprehensive carnitine levels for ASD are important to establish a treatment protocol for the treatment of ASD behavior and severity. C18:1 carnitine, detected for the first time in the cases with ASD, is important for its high levels and for being a glycine transporter two inhibitor. In ASD cases, the molecular analysis might be suggested for enzymes involved in carnitine metabolism and for glycine transporter 2.
... Controlled studies have examined carnitine. [9][10][11][12] Open label and observational studies have examined carnitine 13 NAD and ribose, 14 ubiquinol, 15 ubiquinone 16 and thiamine tetrahydrofurfuryl disulfide. 17 Only one open-label trial treated 11 children with ASD and mitochondrial dysfunction with carnitine, coenzyme Q10 and alpha-lipoic acid. ...
... Two DPBC studies using higher carnitine doses (N=30, 100mg/kg/d, 10 ; N=30, 50mg/k/d 9 ) than the current study (10-25mg/kg/d) found improvement in the CARS. Two DBPC studies which added carnitine to risperidone, found improvements in ABC subscales (hyperactivity, social withdrawal, inappropriate speech) similar to the current study. ...
Autism spectrum disorder (ASD) is associated with mitochondrial dysfunction but studies demonstrating the efficacy of treatments are scarce. We sought to determine whether a mitochondrial-targeted dietary supplement designed for children with ASD improved mitochondrial function and ASD symptomatology using a double-blind placebo-controlled cross-over design. Sixteen children [Mean Age 9y 4m; 88% male] with non-syndromic ASD and mitochondrial enzyme abnormalities, as measured by MitoSwab (Religen, Plymouth Meeting, PA), received weight-adjusted SpectrumNeeds (NeuroNeeds, Old Lyme, CT) and QNeeds (NeuroNeeds) and placebos matched on taste, texture and appearance during two separate 12-week blocks. Which product received first was randomized. The treatment significantly normalized citrate synthase and complex IV activity as measured by the MitoSwab. Mitochondrial respiration of peripheral blood mononuclear cell respiration, as measured by the Seahorse XFe96 (Agilent, Santa Clara, CA) with the mitochondrial oxidative stress test, became more resilient to oxidative stress after the treatment, particularly in children with poor neurodevelopment. The mitochondrial supplement demonstrated significant improvement in standardized parent-rated scales in neurodevelopment, social withdrawal, hyperactivity and caregiver strain with large effect sizes (Cohens d = 0.77-1.25), while changes measured by the clinical and psychometric instruments were not significantly different. Adverse effects were minimal. This small study on children with ASD and mitochondrial abnormalities demonstrates that a simple, well-tolerated mitochondrial-targeted dietary supplement can improve mitochondrial physiology, ASD symptoms and caregiver wellbeing. Further larger controlled studies need to verify and extend these findings. These findings are significant as children with ASD have few other effective treatments.
... Children with ASD were observed to have unique plasma acyl-carnitine profiles and elevations in both lactate and long-chain fatty acids [21,22]. Carnitine is important for transporting fatty acids in and out of the mitochondrial cell membrane, and two randomized double-blind placebo-controlled studies have found that carnitine therapy improves ASD symptoms in some children with ASD [23,24]. ...
... So, this suggests that children with ASD may also have a decreased ability to conjugate carnitine, consistent with this study finding higher levels of l-carnitine and acetyl-l-carnitine. Furthermore, two randomized, double-blind, placebo-controlled studies found that carnitine supplementation was beneficial to children with ASD, as additional carnitine would increase the rate of carnitine conjugation [23,24]. This is also consistent with reports of abnormal mitochondrial function in children with autism [14]. ...
There have been promising results regarding the capability of statistical and machine-learning techniques to offer insight into unique metabolomic patterns observed in ASD. This work re-examines a comparative study contrasting metabolomic and nutrient measurements of children with ASD (n = 55) against their typically developing (TD) peers (n = 44) through a multivariate statistical lens. Hypothesis testing, receiver characteristic curve assessment, and correlation analysis were consistent with prior work and served to underscore prominent areas where metabolomic and nutritional profiles between the groups diverged. Improved univariate analysis revealed 46 nutritional/metabolic differences that were significantly different between ASD and TD groups, with individual areas under the receiver operator curve (AUROC) scores of 0.6–0.9. Many of the significant measurements had correlations with many others, forming two integrated networks of interrelated metabolic differences in ASD. The TD group had 189 significant correlation pairs between metabolites, vs. only 106 for the ASD group, calling attention to underlying differences in metabolic processes. Furthermore, multivariate techniques identified potential biomarker panels with up to six metabolites that were able to attain a predictive accuracy of up to 98% for discriminating between ASD and TD, following cross-validation. Assessing all optimized multivariate models demonstrated concordance with prior physiological pathways identified in the literature, with some of the most important metabolites for discriminating ASD and TD being sulfate, the transsulfuration pathway, uridine (methylation biomarker), and beta-amino isobutyrate (regulator of carbohydrate and lipid metabolism).
... However, only about 3% of men with TMLHE gene deficiency developed autism. The risk of nondysmorphic autism connected with TMLHE mutation may be diminished by appropriate carnitine supplementation during the early stages of child brain development [11,12,96,106]. Butyrobetaine dioxygenase (BBD) is the next false enzyme participating in carnitine biosynthesis, coded by the BBOX1 gene, which may induce autism [98]. Symptoms of carnitine deficiency (small head, delay in speech, tenuous growth, and presence of some dysmorphic traits) in a girl with a homozygous deletion of BBOX1 were described by Rashidi-Nezhad et al. [107]. ...
... The influence of higher L-carnitine dose (100 mg/kg body mass/day) over 6 months in 35 patients with ASD was evaluated in the next randomized clinical trial, and a significant improvement in ASD symptoms was observed. Concentrations of free and total L-carnitine in dry blood drop increased more significantly after six months than after three months of L-carnitine treatment; a positive correlation of the applied carnitine doses with cognitive and behavioral status in autistic children during six months of L-carnitine therapy was demonstrated [106]. An 8 week experiment of oral supplementation with a suspension or pills of carnitine in three divided doses starting from 200 mg/kg increasing to 400 mg/kg day, to a maximum of 6 g daily in 10 boys with ASD (including one patient with genetic ASD with a deficiency in TMLHE gene) was described in Goin-Kochel et al. [126]. ...
L-carnitine plays an important role in the functioning of the central nervous system, and especially in the mitochondrial metabolism of fatty acids. Altered carnitine metabolism, abnormal fatty acid metabolism in patients with autism spectrum disorder (ASD) has been documented. ASD is a complex heterogeneous neurodevelopmental condition that is usually diagnosed in early childhood. Patients with ASD require careful classification as this heterogeneous clinical category may include patients with an intellectual disability or high functioning, epilepsy, language impairments, or associated Mendelian genetic conditions. L-carnitine participates in the long-chain oxidation of fatty acids in the brain, stimulates acetylcholine synthesis (donor of the acyl groups), stimulates expression of growth-associated protein-43, prevents cell apoptosis and neuron damage and stimulates neurotransmission. Determination of L-carnitine in serum/plasma and analysis of acylcarnitines in a dried blood spot may be useful in ASD diagnosis and treatment. Changes in the acylcarnitine profiles may indicate potential mitochondrial dysfunctions and abnormal fatty acid metabolism in ASD children. L-carnitine deficiency or deregulation of L-carnitine metabolism in ASD is accompanied by disturbances of other metabolic pathways, e.g., Krebs cycle, the activity of respiratory chain complexes, indicative of mitochondrial dysfunction. Supplementation of L-carnitine may be beneficial to alleviate behavioral and cognitive symptoms in ASD patients.
... Many in vitro studies [22][23][24][25][26][27][28][29], and in vivo studies of animals [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] and humans [48][49][50][51][52][53][54][55][56][57][58][59] have reported different beneficial functions for carnitine. In the following, the main activities observed are reported. ...
... An up-to-date picture of studies conducted in humans is presented in Table 3. [57] Clinical trial Anti-autism effect Administration of l-carnitine (100 mg/kg/day body weight) in children An enhancement of total and free carnitine levels, a reduction of autism severity and an improvement of autistic behavior [58] Clinical trial Anti-autism effect Administration of l-carnitine (200 mg/kg/day) in male subjects aged 5 years for 4.5 months A gradual improvement of autism symptoms [59] The findings of a recent systematic review and meta-analysis of randomized clinical trials regarding l-carnitine supplementation showed an amelioration of muscle soreness and an improvement in muscle damage biomarkers, due to a decrease in lactate dehydrogenase, myoglobin and creatine kinase [97]. In a study by Chae et al. [98], daily administration of two or three 500-mg/ l-carnitine tablets reduced imatinib-induced muscle cramps in gastrointestinal stromal tumor (GIST) patients. ...
Carnitine can be considered a conditionally essential nutrient for its importance in human physiology. This paper provides an updated picture of the main features of carnitine outlining its interest and possible use. Particular attention has been addressed to its beneficial properties, exploiting carnitine’s properties and possible use by considering the main in vitro, in animal, and human studies. Moreover, the main aspects of carnitine-based dietary supplements have been indicated and defined with reference to their possible beneficial health properties.
... Abnormalities in fatty acid metabolism may help account for the relative deficiency in carnitine associated with ASD [58,70], and the fact that mutations in the trimethyllysine hydroxylase epsilon (TMLHE) gene, the first enzyme in carnitine biosynthesis, is a risk factor for ASD [71]. In addition, children with ASD in general [72][73][74] and those with the TMLHE mutations specifically [75] benefit from supplementation with L-carnitine. Clearly, further research will be needed to better understand the significance of these fatty acid abnormalities in ASD and whether they are truly linked to disruptions in the enteric microbiome. ...
... For example, carnitine deficiency appears to be common in children with ASD [58,70]. Two double-blind, placebo-controlled studies demonstrated improvement in ASD symptoms with carnitine supplementation [74], with some improvements directly related to the change in blood carnitine levels [72]. In another study, reduced NAD and ribose appeared to improve metabolic biomarkers in children with ASD and symptoms of mitochondrial dysfunction [222]. ...
Autism spectrum disorder (ASD) affects ~ 2% of children in the United States. The etiology of ASD likely involves environmental factors triggering physiological abnormalities in genetically sensitive individuals. One of these major physiological abnormalities is mitochondrial dysfunction, which may affect a significant subset of children with ASD. Here we systematically review the literature on human studies of mitochondrial dysfunction related to ASD. Clinical aspects of mitochondrial dysfunction in ASD include unusual neurodevelopmental regression, especially if triggered by an inflammatory event, gastrointestinal symptoms, seizures, motor delays, fatigue and lethargy. Traditional biomarkers of mitochondrial disease are widely reported to be abnormal in ASD, but appear non-specific. Newer biomarkers include buccal cell enzymology, biomarkers of fatty acid metabolism, non-mitochondrial enzyme function, apoptosis markers and mitochondrial antibodies. Many genetic abnormalities are associated with mitochondrial dysfunction in ASD, including chromosomal abnormalities, mitochondrial DNA mutations and large-scale deletions, and mutations in both mitochondrial and non-mitochondrial nuclear genes. Mitochondrial dysfunction has been described in immune and buccal cells, fibroblasts, muscle and gastrointestinal tissue and the brains of individuals with ASD. Several environmental factors, including toxicants, microbiome metabolites and an oxidized microenvironment are shown to modulate mitochondrial function in ASD tissues. Investigations of treatments for mitochondrial dysfunction in ASD are promising but preliminary. The etiology of mitochondrial dysfunction and how to define it in ASD is currently unclear. However, preliminary evidence suggests that the mitochondria may be a fruitful target for treatment and prevention of ASD. Further research is needed to better understand the role of mitochondrial dysfunction in the pathophysiology of ASD.
... The rst trial, randomized placebo-controlled with a dose of 50 mg/kg/day, lasted 3 months and demonstrated an improvement in symptoms, according to the CARS and CGIS, correlated with the level of carnitine in the serum 54 . The second trial, also randomized placebocontrolled but with a dose of 100 mg/kg/day, lasted 6 months and reported an improvement in symptoms according to the CARS criteria but did not observe a link with circulating carnitine levels ( 55 A lower abundance of ATP Our metabolomic data indicate a de ciency of adenine and adenosine diphosphate (ADP) in 8 and 6 ASD patients, respectively. No result being available for adenosine triphosphate (ATP), we measured its production with the Seahorse equipment and protocols. ...
In two previous studies, based on human olfactory ecto-mesenchymal stem cells (OE-MSC) of 11 patients with autism spectrum disorders (ASD) and 11 healthy individuals, we demonstrated that the lower abundance of the enzyme MOCOS (MOlybdenum COfactor Sulfurase) and its associated lower expression of the long non-coding RNA, COSMOC, induces neurotransmission and synaptic defects as well as an exacerbated oxidative stress sensitivity. To move a step further, we assessed whether these defects were associated to a disturbed mitochondrial homeostasis. For that purpose, we used cellular and molecular techniques to quantitfy mitochondrial metabolism and biogenesis, ATP production and cell respiration in OE-MSCs from the 8 ASD patients of the cohort that display the most severe symptoms. We show here that OE-MSCs from ASD patients, when compared to control individuals, display i) a reduced expression/abundance of glycolysis-associated transcripts and metabolites, ii) an overall reduced ATP, mainly due to the impaired glycolysis, iii) a reduced basal cell respiration and iv) a modified mitochondrial network. These results are in accordance with some of our previously published data and may explain some of the symptoms – stress, overarousal, seizures, increased or decreased muscle tone, fatigue - observed in autism spectrum disorders.
... For instance, we observed elevated levels of phenylpyruvate [14,15] and taurine [11,12,51,52], as noted earlier in several studies. We also show decreased levels of carnitine, similarly to what was reported in other biological samples [53,54]. However, direct comparisons with metabolomic studies using different biological samples should be critically evaluated due to lack of information about any correlations between such reports, as observed in other multifactorial pathologies [55]. ...
Currently, there are no reliable biomarkers for autism diagnosis. The heterogeneity of autism and several co-occurring conditions are key challenges to establishing these. Here, we used untargeted mass spectrometry-based urine metabolomics to investigate metabolic differences for autism diagnosis and autistic traits in a well-characterized twin cohort (N = 105). We identified 208 metabolites in the urine samples of the twins. No clear, significant metabolic drivers for autism diagnosis were detected when controlling for other neurodevelopmental conditions. However, we identified nominally significant changes for several metabolites. For instance, phenylpyruvate (p = 0.019) and taurine (p = 0.032) were elevated in the autism group, while carnitine (p = 0.047) was reduced. We furthermore accounted for the shared factors, such as genetics within the twin pairs, and report additional metabolite differences. Based on the nominally significant metabolites for autism diagnosis, the arginine and proline metabolism pathway (p = 0.024) was enriched. We also investigated the association between quantitative autistic traits, as measured by the Social Responsiveness Scale 2nd Edition, and metabolite differences, identifying a greater number of nominally significant metabolites and pathways. A significant positive association between indole-3-acetate and autistic traits was observed within the twin pairs (adjusted p = 0.031). The utility of urine biomarkers in autism, therefore, remains unclear, with mixed findings from different study populations.
... Several previous cross-sectional metabolomics studies show that children with autism have altered circulating levels of acylcarnitines [15,82,83] and free carnitine [15]. Carnitine supplementation in children with autism has resulted in improved behavioral scores [84], but larger studies are needed to confirm their efficacy. The directionality of the associations has not been completely consistent and one study indicates that the acylcarnitines in children with autism differ depending on the fatty acid side chain, where short-chain acylcarnitines generally were more abundant in autism compared to controls and vice versa for long-chain acylcarnitines [15]. ...
Background
The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth.
Methods
We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features.
Results
We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p < 0.05) and with variants near SLC22A4 and SLC22A5 (p < 5.0e − 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels.
Conclusions
Cyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.
... [106] About 35 patients who underwent six months of LC treatment showed notable enhancements in ASD symptoms. [107] • Depression Depression is a prevalent and devastating mental health disorder with unresolved etiology and pathophysiology. Numerous antidepressant drugs are available, but many people with depression do not respond to them, leading to the development of novel antidepressant medications with different mechanisms of action. ...
L-carnitine (LC), also known as β-hydroxy γ-trimethyl-amino-butyric acid, is a quaternary amine synthesized within the liver and kidneys from the amino acid lysine and methionine. It is the pharmacologically active form of carnitine that plays a crucial role in energy production and the metabolism of long-chain fatty acids (LCFAs) through β-oxidation. Deficiency in the organic cation transporter-2 (OCTN2) can arise due to genetic mutations or in conjunction with other illnesses like hepatic or renal disease. Deficits in carnitine regulation can result in various diseases including endocrine disorders, cardiomyopathy, diabetes, malnutrition, aging, sepsis, and cirrhosis. LC has been reported to have antioxidant and anti-inflammatory effects. Supplementation of LC has shown benefits in improving inflammatory conditions by reducing levels of inflammatory mediators such as C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Supplementation of LC is particularly useful for individuals with primary carnitine deficiencies, which can be life-threatening, as well as certain secondary deficiencies such as organic acidurias, muscle wasting, and weakness. Moreover, emerging evidence suggests that LC may hold therapeutic potential for various diseases including renal diseases, liver diseases, neurodegenerative disorders, cardiovascular diseases (CVDs), cancer, diabetes, cachexia, obesity, depression, epilepsy, and more.
... Carnitine was found to improve hyperactivity in this study. Carnitine has been found to improve core ASD symptoms in two DBPC studies [43,44] and hyperactivity on the ABC when combined with risperidone [45]. Carnitine may be particularly important to supplement in ASD since, as a group, carnitine is low in many children with ASD [46,47] and a subset of children with ASD may have a genetic deficiency in carnitine production [45,47,48]. ...
Autism spectrum disorder (ASD) affects up to 1 in 36 children in the United States. It is a heterogeneous neurodevelopmental disorder with life-long consequences. Patients with ASD and folate pathway abnormalities have demonstrated improved symptoms after treatment with leucovorin (folinic acid), a reduced form of folate. However, biomarkers for treatment response have not been well investigated and clinical trials are lacking. In this retrospective analysis, a cohort of prospectively collected data from 110 consecutive ASD clinic patients [mean (SD) age: 10.5 (6.2) years; 74% male] was examined. These patients all underwent testing for folate receptor alpha autoantibodies (FRAAs) and soluble folate binding proteins (sFBPs) biomarker and were treated with leucovorin, if appropriate. Analyses examined whether these biomarkers could predict response to leucovorin treatment as well as the severity of ASD characteristics at baseline. The social responsiveness scale (SRS), a measure of core ASD symptoms, and the aberrant behavior checklist (ABC), a measure of disruptive behavior, were collected at each clinic visit. Those positive for sFBPs had more severe ASD symptoms, and higher binding FRAA titers were associated with greater ABC irritability. Treatment with leucovorin improved most SRS subscales with higher binding FRAA titers associated with greater response. Leucovorin treatment also improved ABC irritability. These results confirm and expand on previous studies, underscore the need for biomarkers to guide treatment of folate pathways in ASD, and suggest that leucovorin may be effective for children with ASD.
... Several previous cross-sectional metabolomics studies show that children with autism have altered circulating levels of acylcarnitines 15,60,61 and free carnitine 15 . Carnitine supplementation in children with autism have resulted in improved behavioral scores 62 , but larger studies are needed to confirm their efficacy. The directionality of the associations have not been completely consistent and one study indicates that the acylcarnitines in children with autism differ depending on the fatty acid side chain, where short-chain acylcarnitines generally were more abundant in autism compared to controls and vice versa for long-chain acylcarnitines 15 . ...
The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental and prenatal factors, the molecular etiology of autism is largely unknown. Metabolomics has emerged as a tool to measure small molecules that reflect genetic, gut microbiome and dietary intake variations. Here, we apply untargeted metabolomics to over 1400 neonatal dried bloods spots, including neonates who later are diagnosed with autism and matching controls. Overall, we detect underlying molecular perturbations that precede autism related to metabolism of amino acids, acylcarnitines and peptides. In particular the cyclic dipeptide cyclo-leucine-proline and the carnitine-related 5-aminovaleric acid betaine (5-AVAB), were associated with an increased probability for autism. Analysis of genetic and dietary data in over 7000 adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy and with variants SLC22A5, coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. We identify 5-AVAB as a novel and potentially modifiable early biomarker for autism that may influence carnitine homeostasis.
... The experimental group showed significantly improved CARS scores overall, with statistically significant differences in free and total carnitine levels but no established link between the former and the latter. Overall, the study recommends a 6-month course of L-Carnitine supplementation to improve autism severity but also suggests further studies to concur with this recommendation [58]. ...
Autism spectrum disorder (ASD) is an umbrella term for developmental disorders characterized by social and communication impairments, language difficulties, restricted interests, and repetitive behaviors. Current management approaches for ASD aim to resolve its clinical manifestations based on the type and severity of the disability. Although some medications like risperidone show potential in regulating ASD-associated symptoms, a comprehensive treatment strategy for ASD is yet to be discovered. To date, identifying appropriate therapeutic targets and treatment strategies remains challenging due to the complex pathogenesis associated with ASD. Therefore, a comprehensive approach must be tailored to target the numerous pathogenetic pathways of ASD. From currently viable and basic treatment strategies, this review explores the entire field of advancements in ASD management up to cutting-edge modern scientific research. A novel systematic and personalized treatment approach is suggested, combining the available medications and targeting each symptom accordingly. Herein, summarize and categorize the most appropriate ways of modern ASD management into three distinct categories: current, promising, and prospective strategies.
... For instance, we observed elevated levels of phenylpyruvate (Noto et al., 2014;Timperio et al., 2022) and taurine (Ma et al., 2021;Mavel et al., 2013;Nadal-Desbarats et al., 2014;Yap et al., 2010), as noted earlier in several studies. We also show decreased levels of carnitine, similarly to what was reported in other biological samples (Fahmy et al., 2013;Filipek et al., 2004). However, direct comparisons with metabolomic studies using different biological samples should be critically evaluated due to lack of information about any correlations between such reports, as observed in other multifactorial pathologies (Erben et al., 2021). ...
Currently, there are no reliable biomarkers for autism diagnosis. The heterogeneity of autism and several co-occurring conditions are key challenges to establish these. Here, we used untargeted mass spectrometry-based urine metabolomics to investigate metabolic differences for autism diagnosis and autistic traits in a well-characterized twin cohort (N=105). We identified 208 metabolites in the urine samples of the twins. No clear, significant metabolic drivers for autism diagnosis were detected when controlling for other neurodevelopmental conditions. However, we identified nominally significant changes for several metabolites. For instance, phenylpyruvate (p=0.019) and taurine (p=0.032) were elevated in the autism group, while carnitine (p=0.047) was reduced. We furthermore accounted for the shared factors, such as genetics within the twin-pairs, and report additional metabolite differences. Based on the nominally significant metabolites for autism diagnosis, arginine and proline metabolism pathway (p=0.024) was enriched. We also investigated the association between quantitative autistic traits, as measured by the Social Responsiveness Scale 2nd Edition, and metabolite differences, identifying a greater number of nominally significant metabolites and pathways. A significant positive association between indole-3-acetate and autistic traits was observed within twin-pairs (adjusted p=0.031). The utility of urine biomarkers in autism, therefore, remains unclear, with mixed findings from different study populations.
Lay Abstract
Earlier literature has suggested that there are chemical molecules (metabolites) in the urine samples of autistic individuals that could be linked with their diagnosis of autism. However, there are still mixed results and uncertainty if any of these metabolites could be used as biomarkers (chemical molecules that indicate a biological condition). In this study, we analysed urine samples of 105 twins from Sweden, of which 48 were identical or fraternal twins, and the analysed metabolite levels were compared between those twins diagnosed with autism and those without a diagnosis. Additionally, we tested if the metabolite levels were different in relation to the level of autistic behaviour. The metabolite levels were measured using mass spectrometry, allowing us to identify hundreds of chemical molecules present in a urine sample followed with testing their significance for autism diagnosis or autistic traits. No single metabolite was found to be highly associated with a diagnosis of autism. However, indole-3-acetate, a metabolite produced by the breakdown of the amino acid tryptophan, was associated with the level of autistic behaviour within the twins. Nevertheless, several metabolites showed some association with autism or the level of autistic behaviour, while revealing interesting pathways for studies in the future.
... Carnitine is the most commonly reported supplement. In independent studies, L-carnitine therapy for three months and six months significantly improved the clinical measurements of ASD severity (Fahmy et al, 2013;Geier et al, 2011). ASD children with genetic variations that reduce carnitine levels also showed positive response to L-carnitine supplementation (Guevara-Campos et al, 2019;Ziats et al, 2015). ...
Mitochondria have a crucial role in brain development and neurogenesis, both in embryonic and adult brains. Since the brain is the highest energy consuming organ, it is highly vulnerable to mitochondrial dysfunction. This has been implicated in a range of brain disorders including, neurodevelopmental conditions, psychiatric illnesses, and neurodegenerative diseases. Genetic variations in mitochondrial DNA (mtDNA), and nuclear DNA encoding mitochondrial proteins, have been associated with several cognitive disorders. However, it is not yet clear whether mitochondrial dysfunction is a primary cause of these conditions or a secondary effect. Our review article deals with this topic, and brings out recent advances in mitochondria-oriented therapies. Mitochondrial dysfunction could be involved in the pathogenesis of a subset of disorders involving cognitive impairment. In these patients, mitochondrial dysfunction could be the cause of the condition, rather than the consequence. There are vast areas in this topic that remains to be explored and elucidated.
... Several of the vitamins, minerals, and micronutrients in ANRC-EP have individually been investigated and found to be beneficial in children and/or adults with ASD in randomized, double-blind, placebo-controlled studies. These include studies of Methyl-B12, folinic acid, and trimethylglycine (TMG) [6,7,26], high dose folinic acid [27,28], high dose vitamin B6 with magnesium [29], vitamin D [30][31][32], high-dose carnitine [33,34], CoQ10 [35], and high-dose Vitamin C [13,36]. Similarly, Open-label trials of vitamin/ mineral supplementation for ASD have reported benefits for vitamin A [37], iron [16] and zinc [15], in children with ASD, and a case study of high dose biotin [38]. ...
Background
Vitamin and mineral supplements are widely used by children and adults diagnosed with autism spectrum disorder (ASD). Several studies have reported benefits of such supplements in resolving nutritional deficiencies, treating various metabolic problems and improving symptoms and overall quality of life.
Methods
This research survey collected evaluations from 161 people about the effectiveness of ANRC-Essentials Plus (ANRC-EP), a vitamin/mineral/micronutrient supplement designed for children and adults with autism. Although this was an open-label survey, results were compared with a three-month randomized double-blind placebo-controlled study of an earlier version of the supplement. Evaluations included the Parent Global Impressions of Autism (PGIA) and the Overall Benefit/Adverse Effect scale of the National Survey on Treatment Effectiveness for Autism (NSTEA).
Results
The participants reported substantially higher Average PGIA Scores than the placebo group in a similar previous study, with an estimated effect size of 0.66. Based on the NSTEA questionnaire, 73% of participants rated the Overall Benefit as Moderate, Good, or Great, with scores that were substantially higher than the NSTEA study found for multi-vitamins, the average of 58 nutraceuticals, and the average of 28 psychiatric and seizure medications. The Overall Adverse Effect score was low (0.25/3.0), similar or slightly higher than other nutraceuticals, and much lower than the average of 28 psychiatric and seizure medications (0.9/3.0). Sub-analysis found that the Overall Benefit of ANRC-EP was not significantly affected by gender, age, autism severity, diet quality, self-limited diet, use of psychiatric or seizure medications, dosage, developmental history, intellectual disability, or seizures. This indicates that ANRC-EP may be beneficial for a wide range of children and adults with ASD.
A limitation of this study is the retrospective nature of the survey, and that participants who had good benefits were more likely to respond.
Conclusions
This study found that ANRC-EP had significant benefits for a wide range of symptoms, and low adverse effects.
... This could be explained by the sample selected, 80% of children were rated as severe autism while only 20% were rated as risky and moderate ASD. This is different from Fahmy et al. (35) who studied the effect of L-carnitine supplement on the severity of symptoms of ASD, they reported significant improvement in the behavior aspect of autism and decreased severity assessed by CARS. ...
... Aside from the respiratory benefits, carnitine supplementation proved to be effective against multiple diseases: it may be used to prevent and treat mild to severe cardiac disorders [27]; it may reduce insulinresistance in diabetes mellitus [28,29], it may also have neuroprorective effects (especially on neonates and infants) [30] or even reduce autism severity [31]. ...
L-carnitine deficiency is a rare metabolic disorder that results in defective fatty acid oxidation which leads to hypoglycemia, myopathy and severe cardiac dysfunction. It can be presented by an acute respiratory failure and the Carnitine supplementation appears to be effective in correcting the symptoms and improving the lung function. We report a case of a 10 months old infant admitted in the intensive care department for acute respiratory failure; an early intubation was necessary but the infant couldn’t be weaned from the mechanical ventilation and a tracheostomy was performed after three months of failed extubation and weaning attempts. In addition to the persistence of the respiratory distress, recurrent hypoglycemia has been observed and a metablolic screening found an L-Carnitine deficiency. The supplementation allowed a rapid improvement.
... Treatment of mitochondrial dysfunction with mitochondrial-related cofactors and vitamins, including carnitine [85,86], ubiquinol [87] and a "mitochondrial cocktail" containing carnitine, CoEnzyme Q10 and Alpha-Lipoic Acid [88] has been reported to improve some symptoms of ASD. Folate has also been reported to increase ETC Complex I activity in children with ASD and mitochondrial disease and positively modulate the coupling of ETC Complex I and IV and ETC Complex I and Citrate Synthase [89]. ...
The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain; low 5-MTHF in the brain causes cerebral folate deficiency (CFD). CFD has been associated with autism spectrum disorders (ASD) and is treated with d,l-leucovorin (folinic acid). One cause of CFD is an autoantibody that interferes with the function of the FRα. FRα autoantibodies (FRAAs) have been reported in ASD. A systematic review was performed to identify studies reporting FRAAs in association with ASD, or the use of d,l-leucovorin in the treatment of ASD. A meta-analysis examined the prevalence of FRAAs in ASD. The pooled prevalence of ASD in individuals with CFD was 44%, while the pooled prevalence of CFD in ASD was 38% (with a significant variation across studies due to heterogeneity). The etiology of CFD in ASD was attributed to FRAAs in 83% of the cases (with consistency across studies) and mitochondrial dysfunction in 43%. A significant inverse correlation was found between higher FRAA serum titers and lower 5-MTHF CSF concentrations in two studies. The prevalence of FRAA in ASD was 71% without significant variation across studies. Children with ASD were 19.03-fold more likely to be positive for a FRAA compared to typically developing children without an ASD sibling. For individuals with ASD and CFD, meta-analysis also found improvements with d,l-leucovorin in overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%). Twenty-one studies (including four placebo-controlled and three prospective, controlled) treated individuals with ASD using d,l-leucovorin. d,l-Leucovorin was found to significantly improve communication with medium-to-large effect sizes and have a positive effect on core ASD symptoms and associated behaviors (attention and stereotypy) in individual studies with large effect sizes. Significant adverse effects across studies were generally mild but the most common were aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%). Taken together, d,l-leucovorin is associated with improvements in core and associated symptoms of ASD and appears safe and generally well-tolerated, with the strongest evidence coming from the blinded, placebo-controlled studies. Further studies would be helpful to confirm and expand on these findings.
... The results of this study found significant benefits for many nutraceuticals with minimal adverse effects and are consistent with the findings of a number of clinical trials studying nutraceuticals in ASD. For example, double-blind, placebo-controlled studies and/or meta-analyses have reported improvements in children with ASD using L-carnitine [32,33], Coenzyme Q10 (ubiquinone) [34], digestive enzymes [35,36], high dose folinic acid (1-2 mg/kg/day) [23][24][25], MB12 injections [37], melatonin [9,[38][39][40][41][42], a multivitamin/mineral supplement designed specifically for ASD [26,27], NAC [29,[43][44][45], omega 3 fatty acids [46,47], vitamin C [48], vitamin D3 [49,50], and possibly B6/Mg [51,52]. Open-label studies in ASD have also reported benefits for B vitamins [53,54], biotin [55], folic acid [56], an herbal formula [57], glutathione [58], iron [59], vitamin A [60] and zinc [61,62]. ...
Autism spectrum disorder (ASD) often involves a wide range of co-occurring medical conditions (“comorbidities”) and biochemical abnormalities such as oxidative stress and mitochondrial dysfunction. Nutritional supplements (“Nutraceuticals”) are often used to treat both core ASD symptoms and comorbidities, but some have not yet been formally evaluated in ASD. The potential biological mechanisms of nutraceuticals include correction of micronutrient deficiencies due to a poor diet and support for metabolic processes such as redox regulation, mitochondrial dysfunction and melatonin production. This paper reports on the results of the National Survey on Treatment Effectiveness for Autism, focusing on nutraceuticals. The Survey involved 1286 participants from across the United States. Participants rated the overall perceived benefits and adverse effects of each nutraceutical, and also indicated the specific symptoms changed and adverse effects. From these ratings the top-rated nutraceuticals for each of 24 symptoms are listed. Compared to psychiatric and seizure medications rated through the same Survey, on average nutraceuticals had significantly higher ratings of Overall Benefit (1.59 vs. 1.39, p = 0.01) and significantly lower ratings of Overall Adverse Effects (0.1 vs. 0.9, p < 0.001). Folinic acid and vitamin B12 were two of the top-rated treatments. This study suggests that nutraceuticals may have clinical benefits and favorable adverse effect profiles.
... This suggests a difference in the process of carnitine conjugation and may be due to a defect or impairment of the enzymes which control carnitine conjugation, such as carnitine palmitoyltransferase 1 (CPT1). Other studies have also shown that carnitine supplementation is beneficial for children with ASD [35][36][37]. ...
Background
Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.
Methods
Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.
Results
Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules.
Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8–15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.
Conclusions
Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2–5 years after birth.
... Similarly, the results of this study suggest that low levels of maternal carnitine may be correlated with the likelihood of having had a child later diagnosed with ASD. Previous studies have demonstrated that carnitine supplementation is beneficial for children with ASD (38)(39)(40). It is important to note that the results for this pilot study are for maternal levels post-pregnancy, so they are only suggestive of possible nutritional and metabolic differences during pregnancy. ...
Background: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.
Method: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.
Results: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules.
Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.
Conclusions: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.
... 50,97,98 Carnitine is involved in mitochondrial energy production and is relatively deficient in children with autism. 42,99 Some studies have reported improvements in the symptoms with the use of carnitine 100 and carnitine may lower the toxicity of a potential Clostridial metabolite (a derivative of propionic acid) that has been recovered in the urine of some individuals with ASD. 101 Correspondingly, Nrf-2 a known regulator of oxidative stress has been considered as a target for the effective treatment of autism (Fig. 4). ...
Autism is a heterogeneous neurodevelopmental and neuropsychiatric disorder with no precise etiology. Deficits in cognitive functions uncover at early stages and are known to have an environmental and genetic basis. Since autism is multifaceted and also linked with other comorbidities associated with various organs, there is a possibility that there may be a fundamental cellular process responsible for this. These reasons place mitochondria at the point of interest as it is involved in multiple cellular processes predominantly involving metabolism. Mitochondria encoded genes were taken into consideration lately because it is inherited maternally, has its own genome and also functions the time of embryo development. Various researches have linked mitochondrial mishaps like oxidative stress, ROS production and mt-DNA copy number variations to autism, Despite dramatic advances in autism research worldwide, the studies focusing on mitochondrial dysfunction in autism is rather minimal, especially in India. India, owing to its rich diversity, may be able to contribute significantly to autism research. It is vital to urge more studies in this domain as it may help to completely understand the basics of the condition apart from a genetic standpoint. This review focuses on the worldwide and Indian scenario of autism research; mitochondrial abnormalities in autism and possible therapeutic approaches to combat it.
... 12 Thus, currently there is no approved medical therapy that targets core ASD symptoms or the pathophysiological processes that underlie ASD. 13 Metabolic Targets for Treating Underlying Pathophysiology in Autism Spectrum Disorder Several compounds which address both underlying pathophysiological abnormalities and core ASD symptoms have been developed. 14 Such compounds that have undergone DBPC trials include L-Carnitine, 15,16 tetrahydrobiopterin (BH 4 ) 17,18 and sulforaphane, 19 but findings from these studies remain preliminary. One of the most promising treatable pathophysiological targets in ASD is abnormalities in folate metabolism, which we will concentrate on in this review. ...
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that currently has no approved medical therapy to address core symptoms or underling pathophysiological processes. Several compounds are under development that address both underlying pathophysiological abnormalities and core ASD symptoms. This article reviews one of these treatments, leucovorin calcium (also known as folinic acid) for treatment of folate pathway abnormalities in children with ASD. Folate is a water-soluble B vitamin that is essential for normal neurodevelopment and abnormalities in the folate and related pathways have been identified in children with ASD. One of these abnormalities involves a partial blockage in the ability of folate to be transported into the brain utilizing the primary transport mechanism, the folate receptor alpha. Autoantibodies which interfere with the function of the folate receptor alpha called folate receptor alpha autoantibodies (FRAAs) have been identified in 58%-76% of children with ASD and independent studies have demonstrated that blood titers of these autoantibodies correlate with folate levels in the cerebrospinal fluid. Most significantly, case-series, open-label, and single and double-blind placebo-controlled studies suggest that leucovorin, a reduced folate that can bypass the blockage at the folate receptor alpha by using the reduced folate carrier, an alternate pathway, can substantially improve particular symptoms in children with ASD, especially those positive for FRAAs. This article reviews the current evidence for treating core and associated symptoms and underlying pathophysiological mechanisms in children with ASD with leucovorin.
... Perhaps the best studied cofactor is L-Carnitine. Two medium sizes (n=30, 30) double-blind placebo controlled (DBPC) studies using L-Carnitine treatment (50mg/kg/day for 3 months and 100mg/kg/day for 6 months) found that scores on the Childhood Autism Rating Scale (CARS) improved with L-Carnitine as compared to placebo 39,40 with one study finding that greater symptomatic improvement was correlated with a greater increase in blood carnitine levels. 40 An small (n=10) 8-week open-label trial of L-Carnitine used particularly high doses (up to 400mg/kg/day in three divided doses, maximum of 6,000mg/day) with only one child transiently stopping treatment and three children remaining on a lower dose (200mg/kg/day) because of odor and loose stools. ...
Several lines of evidence implicate mitochondria in the pathophysiology of autism spectrum disorder (ASD). In this review we outline some of the evidence supporting this notion as well as discuss novel abnormalities in mitochondrial function that appear to be related to ASD as well as treatments which target the mitochondria and have evidence of usefulness in the treatment of ASD. A suspicion of the mitochondria's involvement in ASD can be traced back to 1985 when lactic acidosis was noted in a subset of children with ASD. A large population-based study in 2007 confirmed this notion and found that a subset of children with ASD (∼4%) could be diagnosed with a definite mitochondrial disease. Further studies suggested that children with ASD and mitochondrial disease may have certain characteristics such as fatigability, gastrointestinal disorders, unusual types of neurodevelopmental regression, seizures and motor delay. Further research examining biomarkers of mitochondrial dysfunction and electron transport chain activity suggested that abnormalities of mitochondrial function could affect a much higher number of children with ASD, perhaps up to 80%. Recent research has identified a type of dysfunction of the mitochondrial in which the activity of the electron transport chain is significantly increased. This novel type of mitochondrial dysfunction may be associated with environmental exposures and neurodevelopmental regression. Several treatments that target the mitochondrial appear to have evidence for use in children with ASD, including cofactors such as L-Carnitine, and the ketogenic diet. Although the understanding of the involvement of the mitochondrial in ASD is evolving, the mitochondrial is clearly a novel molecular target which can be helpful in understanding the etiology of ASD and treatments that may improve function of children with ASD.
... Similarly, the results of this study suggest that low levels of maternal carnitine may be correlated with the likelihood of having had a child later diagnosed with ASD. Previous studies have demonstrated that carnitine supplementation is beneficial for children with ASD (32)(33)(34). It is important to note that the results for this pilot study are for maternal levels post-pregnancy, so they are only suggestive of possible nutritional and metabolic differences during pregnancy. ...
Background: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.
Method: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.
Results: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules.
Multivariate analysis with leave one-out cross validation allowed classification of samples as belonging to one of the two groups with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.
Conclusions: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.
... Similarly, the results of this study suggest that low levels of maternal carnitine may be correlated with the likelihood of having had a child later diagnosed with ASD. Previous studies have demonstrated that carnitine supplementation is bene cial for children with ASD (32)(33)(34). It is important to note that the results for this pilot study are for maternal levels post-pregnancy, so they are only suggestive of possible nutritional and metabolic differences during pregnancy. ...
Background: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.
Method: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.
Results: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules. Multivariate analysis with leave one-out cross validation allowed classification of samples as belonging to one of the two groups with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.
Conclusions: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.
... Additionally, a genetic abnormality in carnitine metabolism has been linked to ASD (129) and primary carnitine deficiency was reported to cause ASD in one case report (130). Three clinical trials have reported that carnitine supplementation improves symptoms in ASD (131)(132)(133). Thus, the importance of carnitine is being recognized in ASD and its deficiency is being acknowledged as a potential biomarker of a metabolic subgroup of ASD. ...
Autism spectrum disorder (ASD) affects approximately 2% of children in the United States (US) yet its etiology is unclear and effective treatments are lacking. Therapeutic interventions are most effective if started early in life, yet diagnosis often remains delayed, partly because the diagnosis of ASD is based on identifying abnormal behaviors that may not emerge until the disorder is well established. Biomarkers that identify children at risk during the pre-symptomatic period, assist with early diagnosis, confirm behavioral observations, stratify patients into subgroups, and predict therapeutic response would be a great advance. Here we underwent a systematic review of the literature on ASD to identify promising biomarkers and rated the biomarkers in regards to a Level of Evidence and Grade of Recommendation using the Oxford Centre for Evidence-Based Medicine scale. Biomarkers identified by our review included physiological biomarkers that identify neuroimmune and metabolic abnormalities, neurological biomarkers including abnormalities in brain structure, function and neurophysiology, subtle behavioral biomarkers including atypical development of visual attention, genetic biomarkers and gastrointestinal biomarkers. Biomarkers of ASD may be found prior to birth and after diagnosis and some may predict response to specific treatments. Many promising biomarkers have been developed for ASD. However, many biomarkers are preliminary and need to be validated and their role in the diagnosis and treatment of ASD needs to be defined. It is likely that biomarkers will need to be combined to be effective to identify ASD early and guide treatment.
... The second RCT evaluated the effect of higher dose of carnitine (100 mg/kg/day) or placebo in ASD patients for six months [25]. Significant improvements in autism symptoms based on the childhood autism rating scale (CARS) scores were reported but differently from the Geier et al. [22] study that showed no correlation between carnitine levels at the baseline and changes in CARS scores. ...
Carnitine is an amino acid derivative, which plays several important roles in human physiology, in the central nervous system, and for mitochondrial metabolism, in particular. Altered carnitine metabolic routes have been associated with a subgroup of patients with autism spectrum disorders (ASD) and could add to the pathophysiology associated with these disorders. We review the current evidence about the clinical effects of carnitine administration in ASD in both non-syndromic forms and ASD associated with genetic disorders. Two randomized clinical trials and one open-label prospective trial suggest that carnitine administration could be useful for treating symptoms in non-syndromic ASD. The effect of carnitine administration in ASD associated with genetic disorders is not conclusive because of a lack of clinical trials and objectives in ASD evaluation, but beneficial effects have also been reported for other comorbid disorders, such as intellectual disability and muscular strength. Side effects observed with a dose of 200 mg/kg/day consisted of gastro-intestinal symptoms and a strong, heavy skin odor. Doses of about 50–100 mg/kg/day are generally well tolerated. Further clinical trials with the identification of the subgroup of ASD patients that would benefit from carnitine administration are warranted.
... Children with ASD, as a group, are deficient in Carnitine (45) with this deficiency potentially related to gastrointestinal symptom (46). Additionally, supplementing with Carnitine has been shown to improve core symptoms of ASD in two double-blind placebo controlled studies (47,48). (2) ASD features and ASD have been reported in patients with propionic acidemia (PA), a severe organic acidemia caused by propionic acid (PPA) accumulation due to propionyl-CoA carboxylase enzyme deficiency (49). ...
Autism spectrum disorder (ASD) is currently diagnosed according to behavioral criteria. Biomarkers that identify children with ASD could lead to more accurate and early diagnosis. ASD is a complex disorder with multifactorial and heterogeneous etiology supporting recognition of biomarkers that identify patient subsets. We investigated an easily testable blood metabolic profile associated with ASD diagnosis using high throughput analyses of samples extracted from dried blood spots (DBS). A targeted panel of 45 ASD analytes including acyl-carnitines and amino acids extracted from DBS was examined in 83 children with ASD (60 males; age 6.06 ± 3.58, range: 2–10 years) and 79 matched, neurotypical (NT) control children (57 males; age 6.8 ± 4.11 years, range 2.5–11 years). Based on their chronological ages, participants were divided in two groups: younger or older than 5 years. Two-sided T-tests were used to identify significant differences in measured metabolite levels between groups. Näive Bayes algorithm trained on the identified metabolites was used to profile children with ASD vs. NT controls. Of the 45 analyzed metabolites, nine (20%) were significantly increased in ASD patients including the amino acid citrulline and acyl-carnitines C2, C4DC/C5OH, C10, C12, C14:2, C16, C16:1, C18:1 (P: < 0.001). Näive Bayes algorithm using acyl-carnitine metabolites which were identified as significantly abnormal showed the highest performances for classifying ASD in children younger than 5 years (n: 42; mean age 3.26 ± 0.89) with 72.3% sensitivity (95% CI: 71.3;73.9), 72.1% specificity (95% CI: 71.2;72.9) and a diagnostic odds ratio 11.25 (95% CI: 9.47;17.7). Re-test analyses as a measure of validity showed an accuracy of 73% in children with ASD aged ≤ 5 years. This easily testable, non-invasive profile in DBS may support recognition of metabolic ASD individuals aged ≤ 5 years and represents a potential complementary tool to improve diagnosis at earlier stages of ASD development.
... Core and associated ASD behaviors have been shown to improve with l-carnitine in two DBPC studies (n = 30, 30) [204,205]. Both studies used the CARS as the primary outcome measure and one study used an additional measures, the modified CGI. ...
Autism spectrum disorder is defined by two core symptoms: a deficit in social communication and the presence of repetitive behaviors and/or restricted interests. Currently, there is no US Food and Drug Administration-approved drug for these core symptoms. This article reviews the biological origins of the social function deficit associated with autism spectrum disorder and the drug therapies with the potential to treat this deficit. A review of the history of autism demonstrates that a deficit in social interaction has been the defining feature of the concept of autism from its conception. Abnormalities identified in early social skill development and an overview of the pathophysiology abnormalities associated with autism spectrum disorder are discussed as are the abnormalities in brain circuits associated with the social function deficit. Previous and ongoing clinical trials examining agents that have the potential to improve social deficits associated with autism spectrum disorder are discussed in detail. This discussion reveals that agents such as oxytocin and propranolol are particularly promising and undergoing active investigation, while other agents such as vasopressin agonists and antagonists are being activity investigated but have limited published evidence at this time. In addition, agents such as bumetanide and manipulation of the enteric microbiome using microbiota transfer therapy appear to have promising effects on core autism spectrum disorder symptoms including social function. Other pertinent issues associated with developing treatments in autism spectrum disorder, such as disease heterogeneity, high placebo response rates, trial design, and the most appropriate way of assessing effects on social skills (outcome measures), are also discussed.
BACKGROUND
Autism spectrum disorder (ASD) presents unique challenges related to feeding and nutritional management. Children with ASD often experience feeding difficulties, including food selectivity, refusal, and gastrointestinal issues. Various interventions have been explored to address these challenges, including dietary modifications, vitamin supplementation, feeding therapy, and behavioral interventions.
AIM
To provide a comprehensive overview of the current evidence on nutritional management in ASD. We examine the effectiveness of dietary interventions, vitamin supplements, feeding therapy, behavioral interventions, and mealtime practices in addressing the feeding challenges and nutritional needs of children with ASD.
METHODS
We systematically searched relevant literature up to June 2024, using databases such as PubMed, PsycINFO, and Scopus. Studies were included if they investigated dietary interventions, nutritional supplements, or behavioral strategies to improve feeding behaviors in children with ASD. We assessed the quality of the studies and synthesized findings on the impact of various interventions on feeding difficulties and nutritional outcomes. Data extraction focused on intervention types, study designs, participant characteristics, outcomes measured, and intervention effectiveness.
RESULTS
The review identified 316 studies that met the inclusion criteria. The evidence indicates that while dietary interventions and nutritional supplements may offer benefits in managing specific symptoms or deficiencies, the effectiveness of these approaches varies. Feeding therapy and behavioral interventions, including gradual exposure and positive reinforcement, promise to improve food acceptance and mealtime behaviors. The findings also highlight the importance of creating supportive mealtime environments tailored to the sensory and behavioral needs of children with ASD.
CONCLUSION
Nutritional management for children with ASD requires a multifaceted approach that includes dietary modifications, supplementation, feeding therapy, and behavioral strategies. The review underscores the need for personalized interventions and further research to refine treatment protocols and improve outcomes. Collaborative efforts among healthcare providers, educators, and families are essential to optimize this population's nutritional health and feeding practices. Enhancing our understanding of intervention sustainability and long-term outcomes is essential for optimizing care and improving the quality of life for children with ASD and their families.
Key Words: Feeding therapy; Behavioral interventions; Mealtime practices; Autism spectrum disorder; Children; High-dose methyl cobalamine
Core Tip: Effective management of feeding challenges in children with autism spectrum disorder (ASD) requires a comprehensive approach integrating feeding therapy and behavioral interventions. Addressing oral motor skills and sensory sensitivities and establishing structured mealtime routines are crucial. Behavioral strategies like gradual exposure, positive reinforcement, and modeling can significantly improve food acceptance and mealtime behaviors. Creating a sensory-friendly environment and involving parents in meal planning are essential. This systematic review highlights the importance of multidisciplinary collaboration and tailored interventions to enhance nutritional intake and overall health outcomes for children with ASD.
Background:
Pharmacological interventions are frequently used for people with autism spectrum disorder (ASD) to manage behaviours of concern, including irritability, aggression, and self-injury. Some pharmacological interventions might help treat some behaviours of concern, but can also have adverse effects (AEs).
Objectives:
To assess the effectiveness and AEs of pharmacological interventions for managing the behaviours of irritability, aggression, and self-injury in ASD.
Search methods:
We searched CENTRAL, MEDLINE, Embase, 11 other databases and two trials registers up to June 2022. We also searched reference lists of relevant studies, and contacted study authors, experts and pharmaceutical companies.
Selection criteria:
We included randomised controlled trials of participants of any age with a clinical diagnosis of ASD, that compared any pharmacological intervention to an alternative drug, standard care, placebo, or wait-list control.
Data collection and analysis:
We used standard Cochrane methods. Primary outcomes were behaviours of concern in ASD, (irritability, aggression and self-injury); and AEs. Secondary outcomes were quality of life, and tolerability and acceptability. Two review authors independently assessed each study for risk of bias, and used GRADE to judge the certainty of the evidence for each outcome.
Main results:
We included 131 studies involving 7014 participants in this review. We identified 26 studies as awaiting classification and 25 as ongoing. Most studies involved children (53 studies involved only children under 13 years), children and adolescents (37 studies), adolescents only (2 studies) children and adults (16 studies), or adults only (23 studies). All included studies compared a pharmacological intervention to a placebo or to another pharmacological intervention. Atypical antipsychotics versus placebo At short-term follow-up (up to 6 months), atypical antipsychotics probably reduce irritability compared to placebo (standardised mean difference (SMD) -0.90, 95% confidence interval (CI) -1.25 to -0.55, 12 studies, 973 participants; moderate-certainty evidence), which may indicate a large effect. However, there was no clear evidence of a difference in aggression between groups (SMD -0.44, 95% CI -0.89 to 0.01; 1 study, 77 participants; very low-certainty evidence). Atypical antipsychotics may also reduce self-injury (SMD -1.43, 95% CI -2.24 to -0.61; 1 study, 30 participants; low-certainty evidence), possibly indicating a large effect. There may be higher rates of neurological AEs (dizziness, fatigue, sedation, somnolence, and tremor) in the intervention group (low-certainty evidence), but there was no clear evidence of an effect on other neurological AEs. Increased appetite may be higher in the intervention group (low-certainty evidence), but we found no clear evidence of an effect on other metabolic AEs. There was no clear evidence of differences between groups in musculoskeletal or psychological AEs. Neurohormones versus placebo At short-term follow-up, neurohormones may have minimal to no clear effect on irritability when compared to placebo (SMD -0.18, 95% CI -0.37 to -0.00; 8 studies; 466 participants; very low-certainty evidence), although the evidence is very uncertain. No data were reported for aggression or self -injury. Neurohormones may reduce the risk of headaches slightly in the intervention group, although the evidence is very uncertain. There was no clear evidence of an effect of neurohormones on any other neurological AEs, nor on any psychological, metabolic, or musculoskeletal AEs (low- and very low-certainty evidence). Attention-deficit hyperactivity disorder (ADHD)-related medications versus placebo At short-term follow-up, ADHD-related medications may reduce irritability slightly (SMD -0.20, 95% CI -0.40 to -0.01; 10 studies, 400 participants; low-certainty evidence), which may indicate a small effect. However, there was no clear evidence that ADHD-related medications have an effect on self-injury (SMD -0.62, 95% CI -1.63 to 0.39; 1 study, 16 participants; very low-certainty evidence). No data were reported for aggression. Rates of neurological AEs (drowsiness, emotional AEs, fatigue, headache, insomnia, and irritability), metabolic AEs (decreased appetite) and psychological AEs (depression) may be higher in the intervention group, although the evidence is very uncertain (very low-certainty evidence). There was no evidence of a difference between groups for any other metabolic, neurological, or psychological AEs (very low-certainty evidence). No data were reported for musculoskeletal AEs. Antidepressants versus placebo At short-term follow-up, there was no clear evidence that antidepressants have an effect on irritability (SMD -0.06, 95% CI -0.30 to 0.18; 3 studies, 267 participants; low-certainty evidence). No data for aggression or self-injury were reported or could be included in the analysis. Rates of metabolic AEs (decreased energy) may be higher in participants receiving antidepressants (very low-certainty evidence), although no other metabolic AEs showed clear evidence of a difference. Rates of neurological AEs (decreased attention) and psychological AEs (impulsive behaviour and stereotypy) may also be higher in the intervention group (very low-certainty evidence) although the evidence is very uncertain. There was no clear evidence of any difference in the other metabolic, neurological, or psychological AEs (very low-certainty evidence), nor between groups in musculoskeletal AEs (very low-certainty evidence). Risk of bias We rated most of the studies across the four comparisons at unclear overall risk of bias due to having multiple domains rated as unclear, very few rated as low across all domains, and most having at least one domain rated as high risk of bias.
Authors' conclusions:
Evidence suggests that atypical antipsychotics probably reduce irritability, ADHD-related medications may reduce irritability slightly, and neurohormones may have little to no effect on irritability in the short term in people with ASD. There was some evidence that atypical antipsychotics may reduce self-injury in the short term, although the evidence is uncertain. There was no clear evidence that antidepressants had an effect on irritability. There was also little to no difference in aggression between atypical antipsychotics and placebo, or self-injury between ADHD-related medications and placebo. However, there was some evidence that atypical antipsychotics may result in a large reduction in self-injury, although the evidence is uncertain. No data were reported (or could be used) for self-injury or aggression for neurohormones versus placebo. Studies reported a wide range of potential AEs. Atypical antipsychotics and ADHD-related medications in particular were associated with an increased risk of metabolic and neurological AEs, although the evidence is uncertain for atypical antipsychotics and very uncertain for ADHD-related medications. The other drug classes had minimal or no associated AEs.
Present study was designed to evaluate the efficacy and safety of l-carnitine as an adjuvant agent to risperidone in the treatment of autism spectrum disorder (ASD)-associated behaviors. In this study, 68 children with confirmed ASD were randomly allocated to receive either l-carnitine (150 mg/day) or matched placebo in addition to risperidone. We utilized the Aberrant Behavior Checklist-Community Edition scale (ABC-C) and a checklist of potential adverse effects to assess changes in behavioral status and safety profile at weeks 0, 5 and 10 of the trial. The primary outcome was defined as a change in the irritability subscale score. Sixty patients with similar baseline characteristics completed the trial period. Although scores of ABC-C subscales significantly decreased in both groups over the trial period, the combination of l-carnitine and risperidone resulted in more reduction on the irritability and hyperactivity subscales compared to the combination of risperidone and placebo (P = 0.033 and P < 0.001, respectively). However, changes in lethargy, stereotypic behavior and inappropriate speech subscales were similar between groups. In conclusion, l-carnitine adjuvant to risperidone could improve irritability and hyperactivity features in children with ASD. Results of this study should be considered preliminary and further clinical trials with larger sample sizes and longer follow-up periods are warranted.
Objectives:
The present research aimed to evaluate the effect of adding l-carnitine to risperidone in treating children and adolescents with autism spectrum disorder (ASD).
Methods:
In this randomized controlled clinical trial study, 50 ASD children and adolescents were divided into 2 groups: those receiving l-carnitine and risperidone (n = 25) and those receiving placebo and risperidone (n = 25). Treatment continued for 8 weeks, and participants were assessed at the beginning of the study, in the fourth and eighth weeks, by the Aberrant Behavior Checklist (ABC).
Results:
l-Carnitine add-on therapy reduced the scores of total ABC and subscales of restlessness, lethargy and social isolation, stereotypic behavior, and inappropriate speech at weeks 4 and 8. There was a significant difference between the 2 groups in the score of total ABC and subscale of lethargy and social isolation.
Conclusions:
According to the present study, adding l-carnitine to risperidone improves ASD symptoms.
Background
There is a multitude of systematic reviews of interventions for children and adolescents with autism spectrum disorder (ASD). However, most reviews seem to be based on research conducted in High-Income Countries (HIC). Thus, summary findings may not directly apply to Lower Middle-Income Countries (LMIC). Therefore, we conducted a Meta-Review analyzing systematic reviews on the effectiveness of interventions for target outcomes in children and adolescents with ASD to find out whether there are differences in effectiveness between HIC and LMIC and which interventions can be considered evidence-based in LMIC.
Methods
Electronic databases (PsycINFO, PubMed, Cochrane database of systematic reviews) were searched for reviews on interventions for ASD in children and adolescents from January 2011 through December 2021, which included studies not coming from HIC. Systematic reviews with qualitative and quantitative syntheses of findings were included. Two investigators independently assessed studies against predetermined inclusion/exclusion criteria and extracted relevant data including quality and evidence assessments. Evidence for different types of interventions in HIC vs. LMIC was planned to be compared, but none of the reviews assessed potential differences. Therefore, a narrative review of the studies from LMIC was conducted including an assessment of quality and evidence.
Results
Thirty-five reviews fulfilled the inclusion criteria. Eleven considered findings from HIC and LMIC. Sixty-nine percent included studies with various research designs; 63% provided a qualitative synthesis of findings; 77% percent assessed the quality of studies; 43% systematically assessed the level of evidence across studies. No review compared evidence from HIC and LMIC. A review of the studies from LMIC found some promising results, but the evidence was not sufficient due to a small number of studies, sometimes poor quality, and small sample sizes.
Conclusion
Systematic reviews on interventions for children and adolescents with ASD did not look for potential differences in the effectiveness of interventions in HIC and LMIC. Overall, there is very little evidence from LMIC. None of the interventions can be considered evidence-based in LMIC. Hence, additional research and mutually agreed methodological standards are needed to provide a more secure basis for evidence-based treatments in LMIC trying to establish evidence-based practices.
Background: Nutrition is important in autism spectrum disorder (ASD). Because nutritional problems of children with ASD can lead to nutritional deficiencies and this can also directly or indirectly affect symptoms related to autism. We investigated the effect of diet and supplementation treatments on gastrointestinal, behavioral or sleep problems based on the results of literature review.
Methods: We generated four questions based on literature. We carried out title and abstract-based search using the Web of Science database. Of 4580 abstracts were identified, 192 papers were reviewed and 55 papers precisely meeting the inclusion criteria.
Results: The studies examining the effects of vitamins, minerals, probiotics, and other supplements on ASD symptoms had different dosages, different treatment durations, small sample sizes and used different scales for evaluation. The results of the studies of the effectiveness of GFCF and ketogenic diet to reduce gastrointestinal, behavioral and sleeping problems in children and adolescents were contradictory.
Conclusions: It is not possible to suggest the GFCF and/or ketogenic diet, vitamins, minerals and probiotics to individual with ASD based on the available evidence. By planning a sufficient and balanced diet, it should be aimed to prevent nutrient deficiency and to ensure growth in accordance with the age in children with ASD.
Carnitine is an essential metabolite that is absorbed from the diet and synthesized in the kidney, liver, and brain. It ferries fatty acids across the mitochondrial membrane to undergo β-oxidation. Carnitine has been studied as a therapy or protective agent for many neurological diseases and neurotoxicity (e.g., prolonged anesthetic exposure-induced developmental neurotoxicity in preclinical models). Preclinical and clinical data support the notion that carnitine or acetyl carnitine may improve a patient's quality of life through increased mitochondrial respiration, release of neurotransmitters, and global gene expression changes, showing the potential of carnitine beyond its approved use to treat primary and secondary carnitine deficiency. In this review, we summarize the beneficial effects of carnitine or acetyl carnitine on the central nervous system, highlighting protective effects against neurotoxicity-induced damage caused by various chemicals and encouraging a thorough evaluation of carnitine use as a therapy for patients suffering from neurotoxicant exposure.
Background: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.
Method: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.
Results: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules.
Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.
Conclusions: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.
Background: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.
Method: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.
Results: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules.
Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.
Conclusions: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.
Background: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism.
Method: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods.
Results: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules.
Multivariate analysis with leave-one-out cross-validation allowed classification of samples as belonging to one of the two groups of mothers with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules.
Conclusions: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.
Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. We previously explored whether there was an association of ASD with any analyte measured in the first newborn screening blood test. Here we explore the second screen. Our matched case–control study examined data on 3–5 year‐old patients with any ASD diagnosis in the Texas Medicaid system in 2010–2012. Subjects were linked to their 2007–2009 newborn screening blood test data, which included values for 36 analytes or analyte ratios. Data were available for 3,005 cases and 6,212 controls. The most compelling associations were evident for fatty acid oxidation analytes octanoylcarnitine (C8) and octanoylcarnitine/acetylcarnitine (C8/C2). Their adjusted odds ratios comparing 10th versus first analyte deciles were between 1.42 and 1.54 in total births, term births, and males. C8 was consistent with first screen results. Adipylcarnitine (C6DC), an organic acid analyte, showed opposite results in the two screens. Several other analytes exhibiting significant associations in the first screen did not in the second. Our results provide evidence that abnormal newborn blood levels of some carnitines may be associated with risk of later ASD, possibly related to their involvement with mitochondrial function in the developing brain.
CONTEXT
Dietary interventions such as restrictive diets or supplements are common treatments for young people with autism spectrum disorder (ASD). Evidence for the efficacy of these interventions is still controversial.
OBJECTIVE
To assess the efficacy of specific dietary interventions on symptoms, functions, and clinical domains in subjects with ASD by using a meta-analytic approach.
DATA SOURCES
Ovid Medline, PsycINFO, Embase databases.
STUDY SELECTION
We selected placebo-controlled, double-blind, randomized clinical trials assessing the efficacy of dietary interventions in ASD published from database inception through September 2017.
DATA EXTRACTION
Outcome variables were subsumed under 4 clinical domains and 17 symptoms and/or functions groups. Hedges’ adjusted g values were used as estimates of the effect size of each dietary intervention relative to placebo.
RESULTS
In this meta-analysis, we examined 27 double-blind, randomized clinical trials, including 1028 patients with ASD: 542 in the intervention arms and 486 in the placebo arms. Participant-weighted average age was 7.1 years. Participant-weighted average intervention duration was 10.6 weeks. Dietary supplementation (including omega-3, vitamin supplementation, and/or other supplementation), omega-3 supplementation, and vitamin supplementation were more efficacious than the placebo at improving several symptoms, functions, and clinical domains. Effect sizes were small (mean Hedges’ g for significant analyses was 0.31), with low statistical heterogeneity and low risk of publication bias.
LIMITATIONS
Methodologic heterogeneity among the studies in terms of the intervention, clinical measures and outcomes, and sample characteristics.
CONCLUSIONS
This meta-analysis does not support nonspecific dietary interventions as treatment of ASD but suggests a potential role for some specific dietary interventions in the management of some symptoms, functions, and clinical domains in patients with ASD.
The current study examined the relationship between muscle strength, as measured by hand grip strength, and autism severity, as measured by the Childhood Autism Rating Scale (CARS). Thirty-seven (37) children with a diagnosis of autism spectrum disorder (ASD) were evaluated using the CARS and then tested for hand muscle strength using a hand grip dynamometer. Statistical analysis was then conducted to examine the relationship between autism severity and hand muscle strength. The model generated in the present study showed that the CARS score is a significant predictor of Max Hand Muscle Score after adjustment for age, race, gender, year of birth, and a history of prior chelation therapy. Evidence suggests that hand grip strength in children with ASD is related to the severity of the disorder. Further research is needed to determine the extent and consistency of the muscle weakness and possible treatments.
L-carnitine was proposed as a potential treatment for patients diagnosed with an autism spectrum disorder to improve mitochondrial dysfunction, but no prior randomized controlled trials have been conducted.
Thirty subjects diagnosed with an ASD were randomly assigned to receive a standardized regimen (50 mg L-carnitine/kg bodyweight/day) of liquid L-carnitine (n=19) or placebo (n=11) for 3-months. Measures included changes in professionally completed Childhood Autism Rating Scale (CARS), hand muscle testing, and modified clinical global impression (CGI) forms; parent completed Autism Treatment Evaluation Checklist (ATEC), treatment adherence measurement (TAM), frequency and intensity of side effect rating (FISER)/global rating of side effect burden (GRSEB)/patient report of incidence of side effects (PRISE) forms; and lab testing.
Significant improvements were observed in CARS (-2.03, 95% CI=-3.7 to -0.31), CGI (-0.69, 95% CI=-1.1 to -0.06), and ATEC scores. Significant correlations between changes in serum free-carnitine levels and positive clinical changes were observed for hand muscle strength (R2=0.23, P=0.046), cognitive scores (R2=0.27, P=0.019), and CARS scores (R2=0.20, P=0.047). Study subjects were protocol-compliant (average adherence was >85%) and generally well-tolerated the L-carnitine therapy given.
L-carnitine therapy (50 mg/kilogram-bodyweight/day) administered for 3-months significantly improved several clinical measurements of ASD severity, but subsequent studies are recommended.
A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (≈ 0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD.
Classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits. However, in many cases of autism, there is evidence of mitochondrial dysfunction (MtD) without the classic features associated with mitochondrial disease. MtD appears to be more common in autism and presents with less severe signs and symptoms. It is not associated with discernable mitochondrial pathology in muscle biopsy specimens despite objective evidence of lowered mitochondrial functioning. Exposure to environ-mental toxins is the likely etiology for MtD in autism. This dysfunction then contributes to a number of diagnostic symptoms and comorbidities observed in autism including: cognitive impairment, language deficits, abnormal energy metabolism, chronic gastrointestinal problems, abnormalities in fatty acid oxidation, and increased oxidative stress. MtD and oxidative stress may also explain the high male to female ratio found in autism due to increased male vulnerability to these dysfunctions. Biomarkers for mitochondrial dysfunction have been identified, but seem widely under-utilized despite available therapeutic interventions. Nutritional supplementation to decrease oxidative stress along with factors to improve reduced glutathione, as well as hyperbaric oxygen therapy (HBOT) represent supported and rationale approaches. The underlying pathophysiology and autistic symptoms of affected individuals would be expected to either improve or cease worsening once effective treatment for MtD is implemented.
While evidence points to a multigenic etiology of most autism, the pathophysiology of the disorder has yet to be defined and the underlying genes and biochemical pathways they subserve remain unknown. Autism is considered to be influenced by a combination of various genetic, environmental and immunological factors; more recently, evidence has suggested that increased vulnerability to oxidative stress may be involved in the etiology of this multifactorial disorder. Furthermore, recent studies have pointed to a subset of autism associated with the biochemical endophenotype of mitochondrial energy deficiency, identified as a subtle impairment in fat and carbohydrate oxidation. This phenotype is similar, but more subtle than those seen in classic mitochondrial defects. In some cases the beginnings of the genetic underpinnings of these mitochondrial defects are emerging, such as mild mitochondrial dysfunction and secondary carnitine deficiency observed in the subset of autistic patients with an inverted duplication of chromosome 15q11-q13. In addition, rare cases of familial autism associated with sudden infant death syndrome (SIDS) or associated with abnormalities in cellular calcium homeostasis, such as malignant hyperthermia or cardiac arrhythmia, are beginning to emerge. Such special cases suggest that the pathophysiology of autism may comprise pathways that are directly or indirectly involved in mitochondrial energy production and to further probe this connection three new avenues seem worthy of exploration: 1) metabolomic clinical studies provoking controlled aerobic exercise stress to expand the biochemical phenotype, 2) high-throughput expression arrays to directly survey activity of the genes underlying these biochemical pathways and 3) model systems, either based upon neuronal stem cells or model genetic organisms, to discover novel genetic and environmental inputs into these pathways.
Autism is a pervasive developmental disorder. The incidence rate and other related epidemiological characteristics of the Israeli population are not available.
To assess the incidence rate of autism in the Haifa area and to compare family characteristics with previous reports from other countries.
We approached facilities in the Haifa area that are involved with the diagnosis and treatment of autism. The study group comprised children born between 1989 and 1993. Records of the children were scrutinized and 69% of the mothers were interviewed. Live-birth cohorts of the same years were employed for incidence computation.
An incidence rate of 1/1,000 was derived. Male to female ratio was 4.2:1. Pregnancy and perinatal periods were mostly uneventful. A low prevalence of developmental and emotional morbidity was reported for family members.
The epidemiological characteristics found in the Haifa area are similar to those reported from non-Israeli communities. This finding supports an underlying biological mechanism for this disorder. These data can be used for future trend analyses in Israel.
L-Carnitine (L-C) is a naturally occurring quaternary ammonium compound endogenous in all mammalian species and is a vital cofactor for the mitochondrial oxidation of fatty acids. Fatty acids are utilized as an energy substrate in all tissues, and although glucose is the main energetic substrate in adult brain, fatty acids have also been shown to be utilized by brain as an energy substrate. L-C also participates in the control of the mitochondrial acyl-CoA/CoA ratio, peroxisomal oxidation of fatty acids, and the production of ketone bodies. Due to their intrinsic interaction with the bioenergetic processes, they play an important role in diseases associated with metabolic compromise, especially mitochondrial-related disorders. A deficiency of carnitine is known to have major deleterious effects on the CNS. Several syndromes of secondary carnitine deficiency have been described that may result from defects in intermediary metabolism and alterations principally involving mitochondrial oxidative pathways. Mitochondrial superoxide formation resulting from disturbed electron transfer within the respiratory chain may affect the activities of respiratory chain complexes I, II, III, IV, and V and underlie some CNS pathologies. This mitochondrial dysfunction may be ameliorated by L-C and its esters. In addition to its metabolic role, L-C and its esters such as acetyl-L-carnitine (ALC) poses unique neuroprotective, neuromodulatory, and neurotrophic properties which may play an important role in counteracting various disease processes. Neural dysfunction and metabolic imbalances underlie many diseases, and the inclusion of metabolic modifiers may provide an alternative and early intervention approach, which may limit further developmental damage, cognitive loss, and improve long-term therapeutic outcomes. The neurophysiological and neuroprotective actions of L-C and ALC on cellular processes in the central and peripheral nervous system show such effects. Indeed, many studies have shown improvement in processes, such as memory and learning, and are discussed in this review.
A random retrospective chart review was conducted to document serum carnitine levels on 100 children with autism. Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. Values of free and total carnitine (p < 0.001), and pyruvate (p = 0.006) were significantly reduced while ammonia and alanine levels were considerably elevated (p < 0.001) in our autistic subjects. The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant elevations in alanine and ammonia levels, is suggestive of mild mitochondrial dysfunction. It is hypothesized that a mitochondrial defect may be the origin of the carnitine deficiency in these autistic children.
The acylcarnitine profiles obtained from dried blood spots on "Guthrie cards" have been widely used for the diagnosis and follow-up of children suspected of carrying an inherited error of metabolism, but little attention has been paid to potential age-related variations in the reference values. In this study, we evaluated the variations in free carnitine and acylcarnitine concentrations with age, as measured by tandem mass spectrometry.
Filter-paper blood spots were collected from 433 healthy individuals over a period of 17 months. Eight age groups were defined: cord blood, 3-6 days (control group), 15-55 days, 2-18 months, 19-59 months, 5-10 years, 11-17 years, and 18-54 years. Free carnitine and acylcarnitines were measured for each individual. Mean values were calculated for each age group and compared with those for the control group.
Free carnitine was significantly higher in older children than in newborns (P <0.05), but the concentrations of several acylcarnitines tended to be significantly lower in cord blood and in groups of older children than in the control group. Only minor sex-related differences were observed.
Although the risk of underdiagnosis of fatty acid oxidation disorders with the use of newborn values as reference can be considered as small, in some circumstances the use of age-related reference values may have a potential impact on the diagnosis and management of inherited errors of metabolism.
Over the past decade laboratories that test for metabolic disorders have introduced tandem mass spectrometry (MS/MS), which is more sensitive, specific, reliable, and comprehensive than traditional assays, into their newborn-screening programs. MS/MS is rapidly replacing these one-analysis, one-metabolite, one-disease classic screening techniques with a one-analysis, many-metabolites, many-diseases approach that also facilitates the ability to add new disorders to existing newborn-screening panels.
During the past few years experts have authored many valuable articles describing various approaches to newborn metabolic screening by MS/MS. We attempted to document key developments in the introduction and validation of MS/MS screening for metabolic disorders. Our approach used the perspective of the metabolite and which diseases may be present from its detection rather than a more traditional approach of describing a disease and noting which metabolites are increased when it is present.
This review cites important historical developments in the introduction and validation of MS/MS screening for metabolic disorders. It also offers a basic technical understanding of MS/MS as it is applied to multianalyte metabolic screening and explains why MS/MS is well suited for analysis of amino acids and acylcarnitines in dried filter-paper blood specimens. It also describes amino acids and acylcarnitines as they are detected and measured by MS/MS and their significance to the identification of specific amino acid, fatty acid, and organic acid disorders.
Multianalyte technologies such as MS/MS are suitable for newborn screening and other mass screening programs because they improve the detection of many diseases in the current screening panel while enabling expansion to disorders that are now recognized as important and need to be identified in pediatric medicine.
The accumulation of carnitine was measured in cerebral cortex neurons isolated from adult rat brain. This process was found to be lowered by 40% after preincubation with ouabain and with SH-group reagents (N-ethylmaleimide and mersalyl). The initial velocity of carnitine transport was found to be inhibited by 4-aminobutyrate (GABA) in a competitive way (Ki = 20.9 ± 2.4 mm). However, of various inhibitors of GABA transporters, only nipecotic acid and very high concentrations of 1-[2-([(diphenylmethylene)amino]oxy)ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NO-711) acid decreased carnitine accumulation while betaine, taurine and β-alanine had no effect. The GABA transporters expressed in Xenopus laevis oocytes did not transport carnitine. Moreover, carnitine was not observed to diminish the accumulation of GABA in cerebral cortex neurons, which further excluded a possible involvement of the GABA transporter GAT1 in the process of carnitine accumulation, despite the expression of this protein in the cells under study. The absence of carnitine transporter OCTN2 in rat cerebral cortex neurons (K. A. Nałecz, D. Dymna, J. E. Mroczkowska, A. Broër, S. Broër, M. J. Nałecz and R. Cecchelli, unpublished results), together with the insensitivity of carnitine accumulation towards betaines, implies that a novel transporting protein is present in these cells.
This study investigated the childhood autism rating scale (CARS) as a tool for ASD diagnoses for 2-year-old (n = 376) and 4-year-old (n = 230) children referred for possible autism. The cut-off score to distinguish autistic disorder from PDD-NOS was 32 in the 2-year-old sample (consistent with Lord in J Child Psychol Psychiatry Allied Discipl, 36, 1365-1382, 1995), and 30 in the 4-year-old sample, with good sensitivity and specificity at both ages. The cut-off score to distinguish ASD from non-ASD at both ages was 25.5, with good sensitivity and specificity. Results confirm the utility of the CARS in distinguishing autistic disorder from PDD-NOS, and distinguishing ASD from other developmental disorders and typical development and suggest that an ASD cutoff around 25, which is in common clinical use, is valid.
Autism is a neurological disorder that manifests as noticeable behavioral and developmental abnormalities predominantly in males between the ages of 2 and 10. Although the genetics, biochemistry and neuropathology of this disease have been extensively studied, underlying causal factors to this disease have remained elusive. Using a longitudinal trial design in which three plasma samples were collected from 15 autistic and 12 non-autistic age-matched controls over the course of 1 year, universal and unambiguous alterations in lipid metabolism were observed. Biomarkers of fatty acid elongation and desaturation (poly-unsaturated long chain fatty acids (PUFA) and/or saturated very long chain fatty acids (VLCFA)-containing ethanolamine phospholipids) were statistically elevated in all autistic subjects. In all 8 of the affected/non-affected sibling pairs, the affected sibling had higher levels of these biomarkers than the unaffected sibling. Exposure of neurons, astrocytes and hepatocytes in vitro to elevated extracellular glutamate levels resulted in lipid biomarker changes indistinguishable from those observed in autistic subjects. Glutamate stress also resulted in in vitro decreased levels of reduced glutathione (GSH), methionine and cysteine, in a similar way to the decreases we observed in autism plasma. Impaired mitochondrial fatty acid oxidation, elevated plasma VLCFAs, and glutamate toxicity as putative causal factors in the biochemistry, neuropathology, and gender bias in autism are discussed.
We report the application of tandem mass spectrometry to prospective newborn screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. MCAD deficiency is diagnosed from dried blood spots on filter paper cards from newborns on the basis of the increase of medium chain length acylcarnitines identified by isotope dilution mass spectrometry methods. A robust and accurate semiautomated method for the analysis of medium chain length acylcarnitines as their butyl esters was developed and validated. Quantitative data from the analyses of 113 randomly collected filter paper blood spots from healthy newborns showed low concentrations of medium chain length acylcarnitines such as octanoylcarnitine. The maximum concentration of octanoylcarnitine was 0.22 mumol/L, with the majority being at or below the detection limit. In all 16 blood spots from newborns with confirmed MCAD deficiency, octanoylcarnitine was highly increased [median 8.4 mumol/L (range 3.1-28.3 mumol/L)], allowing easy detection. The concentration of octanoylcarnitine was significantly higher in these 16 newborns (< 3 days of age) than in 16 older patients (ages 8 days to 7 years) with MCAD deficiency (median 1.57 mumol/L, range 0.33-4.4). The combined experience of prospective newborn screening in Pennsylvania and North Carolina has shown a disease frequency for MCAD deficiency of 1 in 17,706. No false-positive and no known false-negative results have been found. A validated method now exists for prospective newborn screening for MCAD deficiency.
The objective of this study was to assess age- and sex-related differences of serum carnitine in a Japanese population.
Fasting blood samples were obtained from 296 Japanese males and 258 females 0 to 65 years of age. Serum free carnitine and acylcarnitine levels were determined by a fluorometric method using carnitine dehydrogenase. Of these, serum samples from 20 males 10 to 20 years of age and 23 females 40 to 60 years of age were assayed for testosterone and estradiol, respectively. Fasting blood samples and 24-hour urine samples were also obtained from 20 males and 23 females 0 to 50 years of age for the assessment of renal carnitine reabsorption.
Serum free carnitine increased with age in children of both sexes, reaching adult value between 15 to 20 years of age in males and between 2 to 10 years of age in females. The mean free carnitine in males (50.3 +/- 7.5 mumol/L) was significantly higher than that in female (41.2 +/- 7.5 mumol/L) between 15-50 years of age (p < 0.05). Serum acylcarnitine remained constant (14.7 +/- 3.3 mumol/L) in each subject of various ages in both sexes. A significant negative correlation was observed between serum free carnitine and estradiol in females (r = -0.55, p < 0.01), but was not observed between serum free carnitine and testosterone in males (r = 0.015). The percent renal reabsorption of free carnitine showed no age-related and sex-related differences.
Serum free carnitine level is related to age and sex, while serum acylcarnitine level remains constant. Our findings suggest that estrogen decreases serum free carnitine and causes sex-related differences.
Autism is a developmental disorder characterized by disturbance in language, perception and socialization. A variety of biochemical, anatomical and neuroradiographical studies imply a disturbance of brain energy metabolism in autistic patients. The underlying etiology of a disturbed bioenergetic metabolism in autism is unknown. A likely etiological possibility may involve mitochondrial dysfunction with concomitant defects in neuronal oxidative phosphorylation within the central nervous system. This hypothesis is supported by a frequent association of lactic acidosis and carnitine deficiency in autistic patients. Mitochondria are vulnerable to a wide array of endogenous and exogenous factors which appear to be linked by excessive nitric oxide production. Strategies to augment mitochondrial function, either by decreasing production of endogenous toxic metabolites, reducing nitric oxide production, or stimulating mitochondrial enzyme activity may be beneficial in the treatment of autism.
Rett syndrome is a severe neurodevelopmental disorder of unknown etiology, occurring almost exclusively in female patients. The etiology and functional significance of plasma carnitine deficiency seen in some patients with Rett syndrome is unknown. To investigate whether L-carnitine might be of benefit in Rett syndrome, a randomized, placebo-controlled, double-blind crossover trial of L-carnitine has been completed in 35 subjects. Eight-week treatment phases were completed for both a placebo and L-carnitine. Outcome was measured by parents/caregivers and at medical follow-up using three established tools: the Rett Syndrome Motor Behavioral Assessment, the Hand Apraxia Scale, and the Patient Well-Being Index. Analysis comparing change between baseline and week 8 of treatment for L-carnitine and the placebo showed that both parents/caregivers and medical follow-up detected improvements in the subjects' well-being. In addition, medical review showed an improvement on the Hand Apraxia Scale for a higher proportion of girls on L-carnitine. Identification of predictors of clinical improvement has been limited by the power of the study. These findings suggest that L-carnitine is of benefit in some patients with Rett syndrome. While L-carnitine did not lead to major functional changes in ability, the type of changes reported could still have a substantial impact on the girls and their families. Information is still needed, however, to determine if only subgroups of girls with the disorder are responsive to L-carnitine and the appropriate duration of therapy.
++Electrospray-tandem mass spectrometry represents a powerful method for detection of inborn errors of fatty acid metabolism. In the present study, it was used to examine neonatal carnitine metabolism, which reflects fatty acid metabolism. In 70 healthy neonates, blood samples were taken from the umbilical cord and by heel-stick puncture in full-term neonates on postnatal d 5. Cord blood specimens were also obtained from 15 preterm and 10 small-for-gestational-age infants. Acylcarnitine concentrations were measured in dried blood spots by electrospray tandem mass spectrometry. Compared with cord blood, the levels of nearly all acylcarnitine species were significantly higher on the postnatal d 5, whereas free carnitine remained unchanged. Total acylcarnitine/free carnitine-ratio increased, whereas the free carnitine/total carnitine-ratio (0.54 +/- 0.05; p < 0.01) further decreased. A reduced availability of free carnitine in the early neonatal period may affect fatty acid oxidation and thus be of potential pathophysiological relevance under conditions with higher energy demands, e.g. in sepsis. Cord blood concentrations of free carnitine, total carnitine, and total acylcarnitines were strongly related to birth weight (p < 0.01). Lower umbilical artery pH, i.e. mild hypoxia, caused accumulation of mainly long-chain acylcarnitines. This implicates that long-chain acylcarnitines could serve as a parameter of perinatal asphyxia.
Treatment strategies in Rett syndrome so far have been essentially symptomatic and supportive. In order to establish the medium-term effects of L-carnitine, an open label trial was performed in a cohort of 21 Rett syndrome females, with a control group of 62 Rett syndrome females of a similar age, for a 6-month period. Compared with the Rett syndrome controls, treatment with L-carnitine led to significant improvements in sleep efficiency (P=0.027), especially in the subjects with a baseline sleep efficiency less than 90%, energy level (P<0.005) and communication skills (P=0.004). There was no significant difference in the subject's level of physical activity, hand function or in the quality of life of the subject's parents. In addition, before and after comparisons of the treatment group showed improvements in expressive speech (P=0.011). Treatment with L-carnitine seems to be of significant benefit in a subgroup of girls with Rett syndrome. In these girls, small but discernible improvements may be of considerable importance to their parents and carers.
To determine safety and the efficacy of carnitine treatment in children with attention-deficit hyperactivity disorder (ADHD). The ADHD behavior was observed by parents completing the Child Behavior Checklist (CBCL) and by teachers completing the Conners teacher-rating score, in a randomized, double-blind, placebo-controlled double-crossover trial. In 13/24 boys receiving carnitine, home behavior improved as assessed with the CBCL total score (P < 0.02). In 13/24 boys, school behavior improved as assessed with the Conners teacher-rating score (P < 0.05). Before treatment, the CBCL total and sub-scores were significantly different from those of normal Dutch boys (P < 0.0001). Responders showed a significant improvement of the CBCL total scores compared to baseline (P < 0.0001). In the majority of boys no side effects were seen. At baseline and after carnitine treatment, responders showed higher levels of plasma-free carnitine (P < 0.03) and acetylcarnitine (P < 0.05). Compared to baseline, the carnitine treatment caused in the responsive patients a decrease of 20-65% (8-48 points) as assessed by the CBCL total problem rating scale. Treatment with carnitine significantly decreased the attention problems and aggressive behavior in boys with ADHD.
Autism has been becoming the focus of attention as its apparently increasing prevalence is better appreciated. According to some estimates, the frequency of children with autistic spectrum disorder (ASD) can be as high as 1 in 150. The diagnosis can be made as early as 2 years of age, and autistic patients often have a normal life span. Thus, in terms of the number of "patient years," ASD represents a market that is as large as that of the biggest neurological indication, Alzheimer's disease. Despite the clear unmet medical need, no effective treatment is available. This may be because the mechanism of ASD is not understood. The aim of the present paper is to review recent advances in autism research and to discuss some of the most stressing problems mainly from a preclinical research standpoint. We hope to draw attention to the need to study this devastating disease that places an enormous burden on the society in general and the relatives and caregivers of autistic patients in particular.
Autism spectrum disorder (ASD) is a spectrum of behavioral anomalies characterized by impaired social interaction and communication, often accompanied by repetitive and stereotyped behavior. The condition manifests within the first 3 years of life and persists into adulthood. There are numerous hypotheses regarding the etiology and pathology of ASD, including a suggested role for immune dysfunction. However, to date, the evidence for involvement of the immune system in autism has been inconclusive. While immune system abnormalities have been reported in children with autistic disorder, there is little consensus regarding the nature of these differences which include both enhanced autoimmunity and reduced immune function. In this review, we discuss current findings with respect to immune function and the spectrum of autoimmune phenomena described in children with ASD.
L-carnitine plays an important regulatory role in the mitochondrial transport of long-chain free fatty acids. In this study, the antioxidant activity of L-carnitine was investigated as in vitro. The antioxidant properties of the L-carnitine were evaluated by using different antioxidant assays such as 1, 1-diphenyl-2-picryl-hydrazyl free radical (DPPH.) scavenging, total antioxidant activity, reducing power, superoxide anion radical scavenging, hydrogen peroxide scavenging and metal chelating activities. Total antioxidant activity was measured according to ferric thiocyanate method. alpha-tocopherol and trolox, a water-soluble analogue of tocopherol, were used as the reference antioxidant compounds. At the concentrations of 15, 30 and 45 microg/mL, l-carnitine showed 94.6%, 95.4% and 97.1% inhibition on lipid peroxidation of linoleic acid emulsion, respectively. On the other hand, 45 microg/mL of standard antioxidant such as alpha-tocopherol and trolox indicated an inhibition of 88.8% and 86.2% on peroxidation of linoleic acid emulsion, respectively. In addition, L-carnitine had an effective DPPH. scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, total reducing power and metal chelating on ferrous ions activities. Also, those various antioxidant activities were compared to alpha-tocopherol and trolox as references antioxidants.
Pervasive developmental disorders and childhood psychosis Nelson textbook of pediatrics
- R Dalton
- M A Forman
- N W Boris
Dalton, R., Forman, M. A., & Boris, N. W. (2004). Pervasive developmental disorders and childhood psychosis Nelson textbook of pediatrics, (17th ed.). Philadelphia:
WB Saunders. (pp. 93-94).
National study of autism in Saudi Arabia King Abdulaziz City for Science and Technology Efficacy of carnitine in the treatment of children with attention-deficit hyperactivity disorder
- A Talat
- L J Van Oudheusden
- H R Scholte
Talat, A. (2008). National study of autism in Saudi Arabia King Abdulaziz City for Science and Technology. Van Oudheusden, L. J., & Scholte, H. R. (2002). Efficacy of carnitine in the treatment of children with attention-deficit hyperactivity disorder. Prostaglandins, Leukotrienes and Essential Fatty Acids, 67(1), 33–38.
National study of autism in Saudi Arabia King Abdulaziz City for Science and Technology
- A Talat
Talat, A. (2008). National study of autism in Saudi Arabia King Abdulaziz City for Science and Technology.