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.     

Clinical trials of fatty acid treatment in ADHD, dyslexia, dyspraxia and the autistic spectrum

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 ADHD, dyslexia, dyspraxia and autistic spectrum disorders (ASD). Definitive evidence of a causal contribution, however, can only come from intervention studies in the form of randomised, double-blind, placebo-controlled trials. Published studies of this kind are still fairly few in number, and mainly involve the diagnostic categories of ADHD and dyslexia, although other trials involving individuals with dyspraxia or ASD are in progress. The main findings to date from such studies are reviewed and evaluated here with the primary aim of guiding future research, although given that fatty acid supplementation for these conditions is already being adopted in many quarters, it is hoped that some of the information provided may also help to inform clinical practice.     

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.     

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.     

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.     

Schizophrenia and the neurodevelopmental continuum:evidence from genomics

The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention‐deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as “neurodevelopmental disorders”. An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research.     

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.     

Visual function, fatty acids and dyslexia

There is mounting evidence that developmental dyslexia is a neurodevelopmental disorder which involves abnormalities of fatty acid metabolism, particularly with respect to certain long-chain highly unsaturated fatty acids (HUFAs). Psychophysical evidence also strongly suggests that dyslexics may have visual deficits as well as phonological problems. Specifically, these visual deficits appear to be related to the magnocellular pathway, which is specialized for processing fast, rapidly-changing information about the visual scene. It remains unclear how these two aspects of dyslexia - fatty acid processing and visual magnocellular function - could be related. We propose some hypotheses - necessarily speculative, given the paucity of biochemical research in this field to date - which address this question.     

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.     

Developmental comorbidity in attention-deficit/hyperactivity disorder

With the present review, we intend to highlight the importance of considering the age- and development-dependent occurrence of comorbidity in ADHD and to outline distinct trajectories of symptom progression with possible impact on course and outcome of ADHD. The review will focus on introducing the concepts of "developmental epidemiology" and "developmental comorbidity". Psychiatric and non-psychiatric age-dependent comorbidity can be seen in the majority of children, adolescents and adults with ADHD, resulting in a severe impairment of everyday life with considerable functional and psychosocial problems. Concerning the temporal order of occurrence, psychiatric conditions may be present before the appearance of first definite ADHD symptoms ("pre-comorbidity", such as temperament factors, sleep disturbance, autism spectrum disorders and atopic eczema). They may coincide with the time when ADHD symptoms reach a clinically significant level ("simultaneous comorbidity": enuresis, encopresis, developmental dyslexia). The majority of comorbidity, however, appears after the onset of ADHD in the course of disease ("post-comorbidity": tic disorder, depression and suicidality, anxiety disorders, obsessive compulsive disorder, bipolar disorder, conduct and substance use disorders, obesity and personality disorders). The aetio-pathophysiology of ADHD and its comorbid disorders and also the nature of comorbidity itself being highly heterogeneous, we additionally discuss possible models of comorbidity. In the future, longitudinal data on distinct patterns of symptom and comorbidity progression would help to refine disease classification systems, strengthen the power of future genetic studies and finally allow for more specific treatment strategies.     

Diagnosing and treating attention-deficit/hyperactivity disorder in adults

Adult attention deficit/hyperactivity disorder (ADHD) is a valid and impairing psychiatric disorder. In this article, we review the diagnosis of ADHD in adults, focusing on symptom presentation differences between pediatric and adult ADHD as well as the importance of assessing functional impairments. Differentiating ADHD from other clinical disorders is often the most difficult part of making an ADHD diagnosis in adults. Psychiatric comorbidities are also described and discussed as potential impact factors upon not only diagnosing ADHD but also treatment of adult ADHD. Especially in those adults with psychiatric comorbidities, treatments need to be multimodal and include both pharmacotherapy and psychosocial interventions.     

Gap Effect Abnormalities during a Visually Guided Pro-Saccade Task in Children with Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that starts in early childhood and has a comprehensive impact on psychosocial activity and education as well as general health across the lifespan. Despite its prevalence, the current diagnostic criteria for ADHD are debated. Saccadic eye movements are easy to quantify and may be a quantitative biomarker for a wide variety of neurological and psychiatric disorders, including ADHD. The goal of this study was to examine whether children with ADHD exhibit abnormalities during a visually guided pro-saccadic eye-movement and to clarify the neurophysiological mechanisms associated with their behavioral impairments. Thirty-seven children with ADHD (aged 5–11 years) and 88 typically developing (TD) children (aged 5–11 years) were asked to perform a simple saccadic eye-movement task in which step and gap conditions were randomly interleaved. We evaluated the gap effect, which is the difference in the reaction time between the two conditions. Children with ADHD had a significantly longer reaction time than TD children (p < 0.01) and the gap effect was markedly attenuated (p < 0.01). These results suggest that the measurement of saccadic eye movements may provide a novel method for evaluating the behavioral symptoms and clinical features of ADHD, and that the gap effect is a potential biomarker for the diagnosis of ADHD in early childhood.     

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.     

New gene targets related to schizophrenia and other psychiatric disorders: enzymes, binding proteins and transport proteins involved in phospholipid and fatty acid metabolism.

Phospholipids make up about 60% of the brain's dry weight. In spite of this, phospholipid metabolism has received relatively little attention from those seeking genetic factors involved in psychiatric and neurological disorders. However, there is now increasing evidence from many quarters that abnormal phospholipid and related fatty acid metabolism may contribute to illnesses such as schizophrenia, bipolar disorder, depression and attention deficit hyperactivity disorder. To date the possible specific proteins and genes involved have been relatively ill-defined. This paper reviews the main pathways of phospholipid metabolism, emphasizing the roles of phospholipases of the A2 and C series in signal transduction processes. It identifies some likely protein candidates for involvement in psychiatric and neurological disorders. It also reviews the chromosomal locations of regions likely to be involved in these disorders, and relates these to the known locations of genes directly or indirectly involved in phospholipid and fatty acid metabolism.     

ComorbiditéS associées au trouble déficit de l’attention avec hyperactivité : Données épidémiologiques et implications thérapeutiques

ADHD has become one of the most frequent cause of referrals for children’ behaviour disorders. ADHD is a prevalent psychiatric condition affecting 5% to 9% of school-age children with regards to DSM-IV R diagnostic criteria. In addition, according to the results of different epidemiological studies, patients with ADHD very often experience comorbid conditions in 50% to 90% of the cases. The most frequent comorbidities include externalised disorders, (oppositional defiant disorder, conduct disorders), learning disorders, internalised disorders (anxiety, depression) and tics (chronic motor tics, Tourette’s syndrome). Given their negative impact on the outcome of ADHD in terms of affective and social functioning, and of social and school adaptation, these comorbid conditions should be carefully and systematically searched, even without any actual complaint. Although management of comorbid psychiatric conditions is never simple nor straightforward, therapeutic option should be considered taking into consideration both management of ADHD and specificity of these comorbidities.     

The neurobiology of lipid metabolism in autism spectrum disorders

Autism is a neurodevelopmental disorder characterized by impairments in communication and reciprocal social interaction, coupled with repetitive behavior, which typically manifests by 3 years of age. Multiple genes and early exposure to environmental factors are the etiological determinants of the disorder that contribute to variable expression of autism-related traits. Increasing evidence indicates that altered fatty acid metabolic pathways may affect proper function of the nervous system and contribute to autism spectrum disorders. This review provides an overview of the reported abnormalities associated with the synthesis of membrane fatty acids in individuals with autism as a result of insufficient dietary supplementation or genetic defects. Moreover, we discuss deficits associated with the release of arachidonic acid from the membrane phospholipids and its subsequent metabolism to bioactive prostaglandins via phospholipase A(2)-cyclooxygenase biosynthetic pathway in autism spectrum disorders. The existing evidence for the involvement of lipid neurobiology in the pathology of neurodevelopmental disorders such as autism is compelling and opens up an interesting possibility for further investigation of this metabolic pathway.     

Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes.

Depression and bipolar disorder are two of the commonest illnesses in the developed world. While some patients can be treated effectively with available drugs, many do not respond, especially in the depression related to bipolar disorder. Depression is associated with diabetes, cardiovascular disease, immunological abnormalities, multiple sclerosis, cancer, osteoporosis and ageing: in each case depressed individuals have a worse outcome than non-depressed individuals. In all of these conditions there is now evidence of impaired phospholipid metabolism and impaired fatty acid-related signal transduction processes. Impaired fatty acid and phospholipid metabolism may be a primary cause of depression in many patients and may explain the interactions with other diseases. Several novel gene candidates for involvement in depression and bipolar disorder are proposed.     

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.     

Sleep microstructure is not altered in children with attention-deficit/hyperactivity disorder (ADHD)

The high rate of occurrence of sleep disturbances in children with attention-deficit/hyperactivity disorder (ADHD) prompted the idea that structural and neurotransmitter changes might give rise to specific sleep pattern abnormalities. The aim of this study was to evaluate the microstructure of sleep in children with ADHD who had no polysomnographically diagnosed sleep disorder, had never been treated for ADHD, and were free from any psychiatric comorbidity. Participants were 14 patients with ADHD (12 boys and 2 girls aged 7-12 years, mean age 9.6+/-1.6). ADHD was diagnosed according to DSM-IV criteria (Diagnostic and statistical manual of mental disorders). Psychiatric comorbidities were ruled out by detailed psychiatric examination. The patients underwent two consecutive overnight video-polysomnographic (PSG) recordings, with the sleep microstructure (cyclic alternating pattern - CAP) scoring during the second night. The data were compared with age- and sex-matched controls. Sleep microstructure analysis using CAP revealed no significant differences between the ADHD group and the controls in any of the parameters under study. In conclusions, no ADHD-specific alterations were found in the sleep microstructure.     

Cortisol responses in children and adults with attention deficit hyperactivity disorder (ADHD): a possible marker of inhibition deficits

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disease whose neurobiological background is not completely understood. It has been proposed that deficits of the inhibitory function with an underactive behavioral inhibition system (BIS) may be in the core of ADHD. In this regard, this review summarizes all studies that examine the involvement of cortisol in ADHD. Differences in cortisol responses from different ADHD subtypes, hyperactive/impulsive, inattentive, and combined, are analyzed. In addition, we examine the role of comorbidities as confounding factors in the study of cortisol in ADHD, including comorbid disruptive behavioral disorder (DBD), as well as anxiety and depressive disorders. Because ADHD is a neurodevelopmental condition and approximately half of the children enter adulthood with the disorder, we review cortisol studies in adults and children separately. Two diverse patterns of cortisol have been reported both in children and adults with ADHD. Blunted cortisol responses to stress are associated with comorbid DBD, whereas high cortisol responses are associated to comorbid anxiety disorders. Nevertheless, the inhibitory deficits in ADHD do not appear to be related directly to cortisol deficits in either children or adults. This review increases our understanding of the heterogeneity of ADHD and could help in determining new strategies for the treatment of these patients. Future studies including gender and a more systematic methodology to study the cortisol response are needed.