Fatty acid metabolism in neurodevelopmental disorder: a new perspective on associations between attention-deficit/hyperactivity disorder, dyslexia, dyspraxia and the autistic spectrum

There is increasing evidence that abnormalities of fatty acid and membrane phospholipid metabolism play a part in a wide range of neurodevelopmental and psychiatric disorders. This proposal is discussed here in relation to attention-deficit/hyperactivity disorder (ADHD), dyslexia, developmental coordination disorder (dyspraxia) and the autistic spectrum. These are among the most common neurodevelopmental disorders of childhood, with significant implications for society as well as for those directly affected. However, controversy still surrounds both the identification and management of these conditions, and while their aetiology is recognized as being complex and multifactorial, little progress has yet been made in elucidating predisposing factors at the biological level.An overview is provided here of the contents of this Special Issue, which contains a selection of reports from a unique multidisciplinary workshop involving both researchers and clinicians. Its purpose was to explore the possibility that ADHD, dyslexia, dyspraxia and autism fall within a phospholipid spectrum of disorders. This proposal could explain the high degree of co-morbidity between these conditions, their aggregation within families and relation to other psychiatric disorders, and a range of associated features that are already well known at a clinical level. The existing evidence for fatty acid abnormalities in these disorders is summarized, and new approaches are outlined that have the potential to improve both the identification and the management of these and related neurodevelopmental and psychiatric conditions.     

Hair trace element concentrations in autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD)

BackgroundThe existing data demonstrate that alteration of trace element and mineral status in children with neurodevelopmental disorders including ASD and ADHD. However, comparative analysis of the specific patterns of trace element and mineral metabolism in children with ASD and ADHD was not performed. Therefore, the primary objective of the present study was to assess hair trace element and mineral levels in boys with ADHD, ASD, as well as ADHD with ASD.MethodsBoys with ADHD (n = 52), ASD (n = 53), both ADHD and ASD (n = 52), as well as neurotypical controls (n = 52) were examined. Hair analysis was performed using inductively-coupled plasma mass-spectrometry.ResultsThe obtained data demonstrate that hair Co, Mg, Mn, and V levels were significantly reduced in children with ADHD and ASD, and especially in boys with ADHD + ASD. Hair Zn was found to be reduced by 20% (p = 0.009) only in children with ADHD + ASD as compared to healthy controls. Factor analysis demonstrated that ASD was associated with significant alteration of hair Co, Fe, Mg, Mn, and V levels, whereas impaired hair Mg, Mn, and Zn content was also significantly associated with ADHD. In regression models hair Zn and Mg were negatively associated with severity of neurodevelopmental disorders. The revealed similarity of trace element and mineral disturbances in ASD and ADHD may be indicative of certain similar pathogenetic features.ConclusionThe obtained data support the hypothesis that trace elements and minerals, namely Mg, Mn, and Zn, may play a significant role in development of both ADHD and ASD. Improvement of Mg, Mn, and Zn status in children with ASD and ADHD may be considered as a nutritional strategy for improvement of neurodevelopmental disturbances, although clinical trials and experimental studies are highly required to support this hypothesis.     

Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders?

The fatty acid compositions of red blood cell (RBC) phospholipids from a patient with autistic spectrum disorder (ASD) had reduced percentages of highly unsaturated fatty acids (HUFA) compared to control samples. The percentage of HUFA in the RBC from the autistic patient was dramatically reduced (up to 70%) when the sample was stored for 6 weeks at -20 degrees C. However, only minor HUFA reductions were recorded in control samples stored similarly, or when the autistic sample was stored at -80 degrees C. A similar instability in RBC HUFA compositions upon storage at -20 degrees C has been recorded in schizophrenic patients. In a number of other neurodevelopmental conditions, including attention deficit hyperactivity disorder (ADHD) and dyslexia, reduced concentrations of RBC HUFA have been recorded. The extent and nature of these aberrations require further assessment to determine a possible common biochemical origin of neurodevelopmental disorders in general. To facilitate this, a large scale assessment of RBC fatty acid compositions in patients with ASD, and related disorders, should be performed as a matter of urgency. Supplementing cells in culture with the tryptophan metabolite indole acrylic acid (IAA) affected the levels of cellular HUFA and prostaglandin production. Indole acroyl glycine (IAG), a metabolite of IAA excreted in urine, is found in high concentrations in patients with neurodevelopmental disorders including ASD, ADHD, dyslexia, Asperger's syndrome and obsessive compulsive disorder.     

Putative miRNAs for the diagnosis of dyslexia,dyspraxia, and specific language impairment

Disorders of human communication abilities can be classified into speech and language disorders. Speech disorders (e.g., dyspraxia) affect the sound generation and sequencing, while language disorders (e.g., dyslexia and specific language impairment, or SLI) are deficits in the encoding and decoding of language according to its rules (reading, spelling, grammar). The diagnosis of such disorders is often complicated, especially when a patient presents more than one disorder at the same time. The present review focuses on these challenges. We have combined data available from the literature with an in silico approach in an attempt to identify putative miRNAs that may have a key role in dyspraxia, dyslexia and SLI. We suggest the use of new miRNAs, which could have an important impact on the three diseases. Further, we relate those miRNAs to the axon guidance pathway and discuss possible interactions and the role of likely deregulated proteins. In addition, we describe potential differences in expressional deregulation and its role in the improvement of diagnosis. We encourage experimental investigations to test the data obtained in silico.     

Supplementation with flax oil and vitamin C improves the outcome of Attention Deficit Hyperactivity Disorder (ADHD)

Considerable clinical and experimental evidence now supports the idea that deficiencies or imbalances in certain highly unsaturated fatty acids may contribute to a range of common developmental disorders including Attention Deficit Hyperactivity Disorder (ADHD). Few intervention studies with LCPUFA supplementation have reported inconsistent and marginal results. This pilot study evaluates the effect of alpha linolenic acid (ALA)-rich nutritional supplementation in the form of flax oil and antioxidant emulsion on blood fatty acids composition and behavior in children with ADHD. Post-supplementation levels of RBC membrane fatty acids were significantly higher than pretreatment levels as well as the levels in control. There was significant improvement in the symptoms of ADHD reflected by reduction in total hyperactivity scores of ADHD children derived from ADHD rating scale.     

Behavioral,Cognitive, and Motor Preparation Deficits in a Visual Cued Spatial Attention Task in Autism Spectrum Disorder

Abnormalities in motor skills have been regarded as part of the symptomatology characterizing autism spectrum disorder (ASD). It has been estimated that 80 % of subjects with autism display “motor dyspraxia” or clumsiness that are not readily identified in a routine neurological examination. In this study we used behavioral measures, event-related potentials (ERP), and lateralized readiness potential (LRP) to study cognitive and motor preparation deficits contributing to the dyspraxia of autism. A modified Posner cueing task was used to analyze motor preparation abnormalities in children with autism and in typically developing children (N = 30/per group). In this task, subjects engage in preparing motor response based on a visual cue, and then execute a motor movement based on the subsequent imperative stimulus. The experimental conditions, such as the validity of the cue and the spatial location of the target stimuli were manipulated to influence motor response selection, preparation, and execution. Reaction time and accuracy benefited from validly cued targets in both groups, while main effects of target spatial position were more obvious in the autism group. The main ERP findings were prolonged and more negative early frontal potentials in the ASD in incongruent trials in both types of spatial location. The LRP amplitude was larger in incongruent trials and had stronger effect in the children with ASD. These effects were better expressed at the earlier stages of LRP, specifically those related to response selection, and showed difficulties at the cognitive phase of stimulus processing rather that at the motor execution stage. The LRP measures at different stages reflect the chronology of cognitive aspects of movement preparation and are sensitive to manipulations of cue correctness, thus representing very useful biomarker in autism dyspraxia research. Future studies may use more advance and diverse manipulations of movement preparation demands in testing more refined specifics of dyspraxia symptoms to investigate functional connectivity abnormalities underlying motor skills deficits in autism.     

Potential diagnostic aids for abnormal fatty acid metabolism in a range of neurodevelopmental disorders

Disorders of neurodevelopment include attention deficit hyperactivity disorder, dyspraxia, dyslexia and autism. There is considerable co-morbidity of these disorders and their identification often presents difficulties to those making a diagnosis. This is especially difficult when a multidisciplinary approach is not adopted. All of these disorders have been reported as associated with fatty acid abnormalities ranging from genetic abnormalities in the enzymes involved in phospholipid metabolism to symptoms reportedly improved following dietary supplementation with long chain fatty acids. If definitive disorders of lipid metabolism could be defined then the diagnosis and subsequent management of neurodevelopmental disorders might be transformed. In the identification of those disorders of development which involve lipid metabolism, there are now several tests, measures of lipid metabolism, which could be useful.     

Project DyAdd: Fatty acids and cognition in adults with dyslexia, ADHD, or both

Both attention deficit hyperactivity disorder (ADHD) and dyslexia are suggested to co-occur with altered fatty acid (FA) metabolism, but it is unknown how FAs are associated with the cognitive domains that characterize these disorders. In the project DyAdd, we investigated the associations between FAs in serum phospholipids and phonological processing, reading, spelling, arithmetic, executive functions, and attention. Healthy controls (n=36), adults with ADHD (n=26), dyslexia (n=36), or both (n=9) were included in the study. FAs included saturated, monounsaturated, total polyunsaturated, n-3, and n-6 FAs, together with n-6/n-3, AA/EPA, and LA/ALA ratios. When all the study subjects were included in the analyses, especially polyunsaturated FAs (PUFAs) were positively associated with cognition, but reading was least associated with FAs. These associations were modulated by gender, intelligence, n-3 PUFA intake, and group. Accordingly, within the ADHD group, only few associations emerged with PUFAs, n-6 PUFAs, and cognitive domains, whereas in the dyslexia group the more prevalent associations appeared with PUFAs and n-3 PUFAs.     

Role of neurotrophic factors in attention deficit hyperactivity disorder

Neurotrophins (NTs), a family of proteins including nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4, are essential for neural growth, survival, and differentiation, and are therefore crucial for brain development. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by problems of inattention and/or hyperactivity-impulsivity. ADHD is one of the most common childhood onset psychiatric disorders. Studies have suggested that both genetic and environmental factors influence the development of the disorder, although the precise causes of ADHD have not yet been identified. In this review, we assess the role of NTs in the pathophysiology of ADHD. Preclinical evidence indicates that BDNF knockout mice are hyperactive, and an ADHD rodent model exhibited decreased cerebral BDNF levels. Several lines of evidence from clinical studies, including blood level and genetic studies, have suggested that NTs are involved in the pathogenesis of ADHD and in the mechanism of biological treatments for ADHD. Future directions for research are proposed, such as using blood NTs as ADHD biomarkers, optimizing NT genetic studies in ADHD, considering NTs as a link between ADHD and other comorbid mental disorders, and investigating methods for optimally modulating NT signaling to discover novel therapeutics for treating ADHD.     

The potential role of fatty acids in attention-deficit/hyperactivity disorder

As currently defined, attention-deficit/hyperactivity disorder (ADHD) encompasses a broad constellation of behavioural and learning problems and its definition and diagnosis remain controversial. The aetiology of ADHD is acknowledged to be both complex and multifactorial. The proposal considered here is that at least some features of ADHD may reflect an underlying abnormality of fatty acid metabolism. Clinical and biochemical evidence is discussed which suggests that a functional deficiency of certain long-chain polyunsaturated fatty acids could contribute to many of the features associated with this condition. The implications in terms of fatty acid treatment proposals are also discussed; such a form of treatment is relatively safe compared to existing pharmacological interventions, although further studies are still needed in order to evaluate its potential efficacy in the management of ADHD symptoms.     

Increased levels of cytosolic phospholipase A2 in dyslexics

Research findings are increasingly reporting evidence of physiological abnormalities in dyslexia and sites for dyslexia have been identified on three chromosomes. It has been suggested that genetic inheritance may cause phospholipid abnormalities in dyslexia somewhat similar to those found in schizophrenia. A key enzyme in phospholipid metabolism, Type IV, or cytosolic, phospholipase A2 (cPLA2), releases arachidonic acid (AA), a 20-carbon fatty acid, which is the major source of production of prostaglandins and leukotrienes. An entirely new assay, which for the first time has enabled determination of the amount of the enzyme rather than its activity, was used to measure cPLA2 in dyslexic-type adults and controls and the two groups were found to differ significantly, the dyslexic-types having more of the enzyme. A report elsewhere of schizophrenics having even greater amounts of the enzyme suggests that dyslexia may be on a continuum with schizophrenia, as may be other neurodevelopmental disorders - which have also been described as phospholipid spectrum disorders.     

Association study of the nicotinic acetylcholine receptor alpha4 subunit gene, CHRNA4, in attention-deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric condition with a strong genetic component. Evidence from pharmacological, clinical and animal studies has suggested that the nicotinic system could be involved in the disorder. Previous studies have implicated the nicotinic acetylcholine receptor α4 subunit gene, CHRNA4 , in ADHD. Particularly, a polymorphism in the exon 2–intron 2 junction of CHRNA4 has been associated with severe inattention defined by latent class analysis. In the current study, we used the transmission disequilibrium test (TDT) to investigate four polymorphisms encompassing this region of CHRNA4 for association with ADHD in a sample of 264 nuclear families from Toronto. No significant evidence of biased transmission was observed for any of the marker alleles for ADHD defined as a categorical trait (all subtypes included), although one haplotype showed marginal evidence of under-transmission. No association was found with the ADHD predominantly inattentive subtype or with symptom dimension scores of inattention. On the contrary, nominally significant evidence of association of individual markers was obtained for the ADHD combined subtype and with teacher-rated hyperactivity–impulsivity scores, with the same haplotype being under-transmitted. Based on our results and others, CHRNA4 may be involved in ADHD; however, its role in ADHD symptomatology remains to be clarified.     

A systematic review of circadian function,chronotype and chronotherapy in attention deficit hyperactivity disorder

Reports of sleep disturbances in attention deficit hyperactivity disorder (ADHD) are common in both children and adults; however, the aetiology of such disturbances is poorly understood. One potentially important mechanism which may be implicated in disrupted sleep in ADHD is the circadian clock, a known key regulator of the sleep/wake cycle. In this systematic review, we analyse the evidence for circadian rhythm changes associated with ADHD, as well as assessing evidence for therapeutic approaches involving the circadian clock in ADHD. We identify 62 relevant studies involving a total of 4462 ADHD patients. We find consistent evidence indicating that ADHD is associated with more eveningness/later chronotype and with phase delay of circadian phase markers such as dim light melatonin onset and delayed sleep onset. We find that there is evidence that melatonin treatment may be efficacious in addressing ADHD-related sleep problems, although there are few studies to date addressing other chronotherapeutic approaches in ADHD. There are only a small number of genetic association studies which report linkages between polymorphisms in circadian clock genes and ADHD symptoms. In conclusion, we find that there is consistent evidence for circadian rhythm disruption in ADHD and that such disruption may present a therapeutic target that future ADHD research might concentrate explicitly on.     

Appropriateness of array‐CGH in the ADHD clinics: A comparative study

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorder with a worldwide prevalence of about 5%. The disorder is characterized by inattentive, hyperactive and impulsive behavior and is often comorbid with other neuropsychiatric conditions. Array comparative genomic hybridization (array‐CGH) testing has been proved to be useful to detect chromosomal aberrations in several neuropsychiatric conditions including autism spectrum disorders (ASD) and intellectual disability (ID). The usefulness of array‐CGH in the ADHD clinics is still debated and no conclusive evidence has been reached to date. We performed array‐CGH in 98 children and adolescents divided in two similarly sized groups according to the clinical diagnosis: (a) one group diagnosed with ADHD as primary diagnosis; (b) the other group in which ADHD was co‐morbid with ASD and/or ID. We detected pathogenetic and likely pathogenetic copy number variants (CNVs) in 12% subjects in which ADHD was co‐morbid with autism and/or intellectual disability and in 8.5% subjects diagnosed with ADHD as primary diagnosis. Detection of CNVs of unknown clinical significance was similar in the two groups being 27% and 32%, respectively. Benign and likely benign CNVs accounted for 61% and 59.5% in the first and second group, respectively. Differences in the diagnostic yield were not statistically significant between the two groups (P > .05). Our data strongly suggest that array‐CGH (a) is a valuable diagnostic tool to detect clinically significant CNVs in individuals with ADHD even in the absence of comorbidity with ASD and/or ID and (b) should be implemented routinely in the ADHD clinics.     

Autistic disorder and phospholipids: A review

Dysregulated phospholipid metabolism has been proposed as an underlying biological component of neurodevelopmental disorders such as autistic disorder (AD) and attention-deficit/hyperactivity disorder (ADHD). This review provides an overview of fatty acid and phospholipid metabolism and evidence for phospholipid dysregulation with reference to the membrane hypothesis of schizophrenia. While there is evidence that phospholipid metabolism is at least impaired in individuals with AD, it has not been established whether phospholipid metabolism is implicated in causal, mechanistic or epiphenomenological models. More research is needed to ascertain whether breastfeeding, and specifically, the administration of colostrum or an adequate substitute can play a preventative role by supplying the neonate with essential fatty acids (EFAs) at a critical juncture in their development. Regarding treatment, further clinical trials of EFA supplementation are essential to determine the efficacy of EFAs in reducing AD symptomatology and whether supplementation can serve as a cost-effective and readily available intervention.     

Project DyAdd: Fatty acids in adult dyslexia, ADHD, and their comorbid combination

In project DyAdd, we compared the fatty acid (FA) profiles of serum phospholipids in adults with attention deficit hyperactivity disorder (ADHD) (n=26), dyslexia (n=36), their comorbid combination (n=9), and healthy controls (n=36). FA proportions were analyzed in a 2×2 design with Bonferroni corrected post hoc comparisons. A questionnaire was used to assess dietary fat quality and use of supplements. Results showed that ADHD and dyslexia were not associated with total saturated FAs, monounsaturated FAs, or n-3 polyunsaturated FAs (PUFAs). However, those with ADHD had elevated proportions of total n-6 PUFAs (including γ-linolenic and adrenic acids) as compared to those without ADHD. Dyslexia was related to a higher proportion of monounsaturated nervonic acid and a higher ratio of n-6/n-3 PUFAs. Among females none of the associations were significant. However in males, all the original associations observed in all subjects remained and ADHD was associated with elevated nervonic acid and n-6/n-3 PUFA ratio like dyslexia. Controlling for poorly diagnosed reading difficulties, education, dietary fat quality, or use of FA supplements did not generally remove the originally observed associations.     

The Strengths and Difficulties Questionnaire as a Predictor of Parent-Reported Diagnosis of Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder

The Strengths and Difficulties Questionnaire (SDQ) is widely used as an international standardised instrument measuring child behaviour. The primary aim of our study was to examine whether behavioral symptoms measured by SDQ were elevated among children with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) relative to the rest of the population, and to examine the predictive value of the SDQ for outcome of parent-reported clinical diagnosis of ASD/ADHD. A secondary aim was to examine the extent of overlap in symptoms between children diagnosed with these two disorders, as measured by the SDQ subscales. A cross-sectional secondary analysis of data from the Millennium Birth Cohort (n = 19,519), was conducted. Data were weighted to be representative of the UK population as a whole. ADHD or ASD identified by a medical doctor or health professional were reported by parents in 2008 and this was the case definition of diagnosis; (ADHD n = 173, ASD n = 209, excluding twins and triplets). Study children''s ages ranged from 6.3–8.2 years; (mean 7.2 years). Logistic regression was used to examine the association between the parent-reported clinical diagnosis of ASD/ADHD and teacher and parent-reported SDQ subscales. All SDQ subscales were strongly associated with both ASD and ADHD. There was substantial co-occurrence of behavioral difficulties between children diagnosed with ASD and those diagnosed with ADHD. After adjustment for other subscales, the final model for ADHD, contained hyperactivity/inattention and impact symptoms only and had a sensitivity of 91% and specificity of 90%; (AUC) = 0.94 (95% CI, 0.90–0.97). The final model for ASD was composed of all subscales except the ‘peer problems’ scales, indicating of the complexity of behavioural difficulties that may accompany ASD. A threshold of 0.03 produced model sensitivity and specificity of 79% and 93% respectively; AUC = 0.90 (95% CI, 0.86–0.95). The results support changes to DSM-5 removing exclusivity clauses.     

Disentangling weak coherence and executive dysfunction: planning drawing in autism and attention-deficit/hyperactivity disorder

A tendency to focus on details at the expense of configural information, 'weak coherence', has been proposed as a cognitive style in autism. In the present study we tested whether weak coherence might be the result of executive dysfunction, by testing clinical groups known to show deficits on tests of executive control. Boys with autism spectrum disorders (ASD) were compared with age- and intelligence quotient (IQ)-matched boys with attention-deficit/hyperactivity disorder (ADHD), and typically developing (TD) boys, on a drawing task requiring planning for the inclusion of a new element. Weak coherence was measured through analysis of drawing style. In line with the predictions made, the ASD group was more detail-focused in their drawings than were either ADHD or TD boys. The ASD and ADHD groups both showed planning impairments, which were more severe in the former group. Poor planning did not, however, predict detail-focus, and scores on the two aspects of the task were unrelated in the clinical groups. These findings indicate that weak coherence may indeed be a cognitive style specific to autism and unrelated to cognitive deficits in frontal functions.     

注意缺陷多动障碍共患阅读障碍：认知-脑-基因的多维度研究进展

注意缺陷多动障碍（Attention-Deficit/Hyperactivity Disorder, ADHD）和发展性阅读障碍（Developmental Dyslexia, DD）是两种常见的神经发育性障碍,二者共患的比率高达25%～48%。本文拟从认知-脑-基因等多个维度对ADHD共患DD的研究进展进行综述。ADHD和DD共患的共同认知损害可能是加工速度缺陷,其作为内表型能够很好的帮助解释遗传因素如何通过影响认知功能进而导致出现ADHD共患DD的临床表型。而国内对ADHD共患DD的研究较少,已有的多项研究仅关注ADHD伴学习障碍,但缺乏标准的DD临床诊断标准。本文指出了统一诊断标准、结合多学科研究以及未来个体化训练的必要性。     

ADHD and autism: differential diagnosis or overlapping traits? A selective review

According to DSM-IV TR and ICD-10, a diagnosis of autism or Asperger Syndrome precludes a diagnosis of attention-deficit/hyperactivity disorder (ADHD). However, despite the different conceptualization, population-based twin studies reported symptom overlap, and a recent epidemiologically based study reported a high rate of ADHD in autism and autism spectrum disorders (ASD). In the planned revision of the DSM-IV TR, dsm5 (www.dsm5.org), the diagnoses of autistic disorder and ADHD will not be mutually exclusive any longer. This provides the basis of more differentiated studies on overlap and distinction between both disorders. This review presents data on comorbidity rates and symptom overlap and discusses common and disorder-specific risk factors, including recent proteomic studies. Neuropsychological findings in the areas of attention, reward processing, and social cognition are then compared between both disorders, as these cognitive abilities show overlapping as well as specific impairment for one of both disorders. In addition, selective brain imaging findings are reported. Therapeutic options are summarized, and new approaches are discussed. The review concludes with a prospectus on open questions for research and clinical practice.