Fatty acid metabolism in neurodevelopmental disorder: a new perspective etc..--actual article this time

[Guest guest]

OK I finally found it but it is the final draft --not the published PDF. which

costs $---so thsi I presume is just as informative

Title

Fatty acid metabolism in neurodevelopmental

disorder: a new perspective on associations between ADHD, dyslexia, dyspraxia

and the autistic spectrum.

Authors:

A J 1,2 and M A Ross3

Affiliations:

1Imperial College School of Medicine, London

2University Lab. of Physiology, Oxford

3Highland Psychiatric Research Foundation

Correspondence

to:

Dr AJ

University Laboratory of Physiology

Parks Road

OxfordOX1 3PT

Tel: 01865 513433

Fax: 01865 438304

e-mail: alex.richardson@...

Acknowledgements

We wish to thank all those who took part in the

workshop, and all of the sponsors. Particular thanks go to the ish

Hospital Endowments Research Trust as the primary sponsor of this event.

Summary

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 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

recognised 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 comorbidity 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

summarised, 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.

Introduction

There is a high degree of overlap between a

range of neurodevelopmental disorders that includes attention-deficit

hyperactivity disorder (ADHD), dyslexia (specific reading difficulties),

dyspraxia

(developmental co-ordination disorder), and the autistic spectrum. Although

these are all neurodevelopmental disorders of childhood, they all persist into

adulthood, causing serious problems not only for those affected, but for

society as a whole.

Between them these conditions may affect as

many as 10% of the population, and although they often go unrecognised, it is

widely acknowledged that the earlier the problems can be identified, the better

are the chances of successful management and remediation. However, a major

problem is that formal diagnoses of ADHD, dyslexia, dyspraxia and autism not

only involve different sets of operational criteria (many of which are

acknowledged to be less than satisfactory), but also tend to involve

specialists from different professional disciplines. Practitioners dealing with

any one of these conditions are often unfamiliar with at least some of the

others, and may therefore be unaware of co-morbidity issues and their

implications.

In research there is even more compartmentalisation,

owing to the very wide range of disciplines involved at this level. There is

thus a clear need for better integration across clinical and research

perspectives, and a compelling case for interdisciplinary approaches to both. A

new perspective is offered here which it is hoped could help towards achieving

this. There is currently little firm agreement regarding the key etiological

factors in any of these conditions, and this situation places serious

limitations on existing methods of both diagnosis and management.

The papers collected together in this special

issue represent the output from a unique workshop on ‘New Approaches to

Neurodevelopmental Disorder’, held in Inverness in September 1999. The

specific purpose was to bring together experts from a

wide range of different disciplines to present and discuss their research and

its relevance to a new paradigm that has the potential to transform our current

understanding of ADHD, dyslexia, dyspraxia and the autistic spectrum. Each of

these disorders is characterised and defined by a different set of core

features that are obviously central to clinical diagnosis, and these will be

outlined very briefly below. However, various associated features are common to

many or all of these conditions, and familial aggregation is also apparent.

Together, these factors could provide important clues to the aetiology of these

complex disorders.

The proposal under consideration at this

workshop was that abnormalities of fatty acid and phospholipid metabolism could

help to account for many of the features that are common not only to these

conditions but also to some other neurodevelopmental and psychiatric disorders

(1). This approach not only represents a new paradigm for research into

dyslexia, dyspraxia, ADHD and the autistic spectrum, but also has implications

that cut across - and could help to unite - almost all of the relevant

disciplines. Moreover, there is already evidence that it could provide new

leads with respect to both the identification and the management of these

conditions.

ADHD,

dyslexia, dyspraxia, and autistic spectrum disorders:core and associated

features

Attention-deficit

Hyperactivity Disorder (ADHD)

ADHD is one of the most common disorders of

childhood and adolescence, and it is now clear that problems usually persist

into adulthood. However, the validity of the ADHD syndrome is often called into

question, as it involves a rather disparate range of behavioural and learning

problems with no clear discontinuity from normal function. Formal diagnosis

lies in the province of psychiatry, and the current criteria used by the

American Psychiatric Association (2) involve an age-inappropriate level of a

number of symptoms from one or both of two major dimensions, namely inattention

and hyperactivity-impulsivity. These symptoms must also be of early onset,

persistent over time, and must occur across more than one situation. Prevalence

estimates vary from around 2% for the most severe forms of ADHD to 10% or more

when less stringent criteria are used, and the disorder is much more common in

males than females. The most common treatment approach is pharmacological,

involving stimulant medications such as methylphenidate, but their widespread

and increasing use remains a controversial issue. The relative success of these

drugs in managing symptoms does not constitute evidence that dopaminergic

abnormalities are the primary problem in ADHD, and they are ineffective in up

to one third of cases. Further details are given by and Puri (3), who

review and

evaluate the potential role of fatty acids in this condition.

Dyslexia

Developmental dyslexia is sometimes regarded as

synonymous with ‘specific reading difficulties’, i.e. underachievement in

reading in relation to general ability. However, the term properly refers to a

specific neurodevelopmental syndrome with a constitutional basis. Dyslexia

involves much more than just reading difficulties, and any reliable diagnosis

requires additional indicators (4). Core psychological features include

specific weaknesses in working memory, especially for auditory-linguistic

material, and difficulties with direction and sequencing. Early signs typically

include visuo-motor problems and slow or abnormal spoken language development

despite no obvious impairment of general ability. This condition affects around

5% of the population in a severe form, and is more common in males.

The primary domains involved in the

identification and management of dyslexia are psychology and education. There

remains resistance to a ‘medical model’ within these professions (although

this

usually reflects a misunderstanding to the point of caricature of current

biological approaches). The evidence for sensory problems in dyslexia is now

undeniable, but there is still controversy over their significance. In this

issue, Stein(5) discusses the

neurobiology of reading difficulties. He explains how a mild abnormality of the

development of ‘magnocellular’ systems specialised for very rapid neural

processing probably underlies the low-level visual and auditory problems that

are common in dyslexia, and he also outlines how these problems may actually

contribute to difficulties in learning to read. Despite substantial research

into the physiological causes of dyslexia, however, biochemical approaches have

so far been conspicuous by their absence.

Dyspraxia

Dyspraxia or developmental co-ordination

disorder (DCD) is probably the least known and least understood of the

conditions under discussion here. Dyspraxia is primarily defined in terms of

problems with planning and motor co-ordination, while the DCD diagnosis adopted

by the DSM-IV (2) is somewhat broader. Debates over terminology are likely to

continue, and the term dyspraxia is used here for convenience. Attentional,

perceptual and spoken language problems are frequently associated, and there is

a high degree of overlap with ADHD and dyslexia as well as with non-verbal

learning difficulties (6). Other notable features include excitability or

instability of mood, anhedonia and/or hypersensitivity to touch, as well as

minor physical symptoms such as digestive problems, all of which are also

common in autistic spectrum disorders.

Dyspraxia often goes undiagnosed, although

recognition by parents, teachers or GPs of a ‘clumsy child’ syndrome may

lead

to referral to a paediatrician or neurologist. Intervention from

physiotherapists or occupational therapists may be recommended, but management

is more often from within educational and psychological services. The best

estimates of prevalence are around 5% for severe cases, but as with ADHD and

dyslexia, milder forms are more common, and males are disproportionately

affected. Problems persist into adulthood, and there appears to be a high rate

of associated psychiatric disorder (7), usually attributed to the persistent

social difficulties and very low self-esteem associated with dyspraxia.

Autism

Autistic spectrum disorders fall within the

sphere of psychiatry. The core deficits involve social and communication

problems, and autism usually appears in the first two years of life although

the earliest signs can be subtle. Autistic infants appear indifferent or averse

to affection and physical contact, but often show inappropriate attachment to

objects. Speech usually develops slowly and abnormally if at all. There is

often extreme sensitivity to auditory or visual stimulation, yet a lack of

appropriate reactions to sound or genuine danger, and little reaction to pain.

An obsessive desire to prevent environmental change is typical, as are rhythmic

body movements such as rocking or hand‑clapping. Autism is about three to four

times more common in males than females, and prevalence estimates range from 1

to 15 per 10,000 children, depending on the criteria used.

Definitional and diagnostic problems surrounding the

autism syndrome and associated disorders are thoughtfully discussed by Graham

in this volume (8). As with ADHD, the autistic spectrum probably involves

complex and potentially multiple etiologies with a final common pathway with

respect

to symptom expression. Colwyn Trevarthen provides further perspectives on this

(9), highlighting the very complex and multiple interacting factors involved in

the development and emergence of autism.

Many

of the points Trevarthen makes are equally applicable to other

neurodevelopmental disorders. The need to look beyond the cognitive and

behavioural level to consider the actual brain structures and processes

involved - and to do so from a developmental perspective - is particularly

relevant, yet this is easily forgotten in the focus on discrete categories and

labels based primarily on clusters of presenting symptoms. The fact that

sensorimotor, emotional and motivational factors are effectively inseparable

from cognition and behaviour is also self-evident from a biological

perspective. These ‘lower-level’ factors are clearly fundamental during

early

development, when all of these disorders first start to become apparent. We

propose that the study of phospholipid metabolism could help to elucidate the

nature and origins of these and other neurodevelopmental and psychiatric

disorders, as it provides a framework that could bridge many of the gaps in our

current knowledge of the complex relations between brain and behaviour (1).

Comorbidity

issues - a phospholipid spectrum of disorders?.

The clinical overlap between ADHD and dyslexia

is around 30-50% in both directions (10). It seems higher for the inattentive

rather than the hyperactive-impulsive form of ADHD, possibly reflecting a

common dysfunction of parietal mechanisms (11). A similar degree of overlap is

found between dyslexia and dyspraxia, which is interesting in view of the

mounting evidence that cerebellar dysfunction may be a key factor in dyslexia

(12,13). The comorbidity between ADHD and dyspraxia appears to be equally high

(7). Autism - if narrowly defined - is the rarest of these disorders, and would

always be the primary diagnosis. Nonetheless, it is evident that many features

of the autistic spectrum are also characteristic of the other disorders under

consideration here.

Associated features in all of these conditions

include pregnancy and birth complications, minor physical anomalies, and

developmental delay in achieving milestones for motor, visuo-motor and/or

language development. An increased frequency of allergic or auto-immune

disorders in affected individuals and their relatives is another recurring

theme which offers possible clues to shared aspects of biological

predisposition, as discussed by Stein (5). And perhaps the most striking

feature is the clear excess of males affected by each of these conditions, for

which there is as yet no satisfactory explanation. All of these features -

often regarded as peripheral or irrelevant to the central diagnosis - are

potentially explicable in terms of mild abnormalities of fatty acid metabolism,

as noted by and Puri (3).

The importance of certain highly unsaturated

fatty acids (HUFA) for brain development and function is well known (14-18) but

cannot be discussed in any detail here. In this volume, and Puri (3)

provide a very brief

overview, describing the synthesis of HUFA from their essential fatty acid

(EFA) precursors and possible blocks to these conversion processes. and

Horrobin (19) discuss phospholipid metabolism and membrane turnover with

particular reference to the PLA2

cycle. The HUFA necessary for normal brain structure and function are

constantly replaced and recycled, both during the normal turnover and

remodelling of membrane phospholipids and in the cascades triggered by normal

cell signalling processes. The action of PLA2

in removing HUFA from membrane phospholipids creates potentially damaging

interim products including free fatty acids, which are highly susceptible to

oxidation. These have to be recycled in at least two further enzyme steps in

order to complete the full cycle. PLA2

over-activity has been repeatedly implicated in schizophrenia (20) but this is

unlikely to be specific to this condition, as evidenced by the recent finding

of elevated PLA2 in dyslexia,

reported here by MacDonell et al (21). It seems probable that the most damaging

effects of elevated PLA2 activity

will occur only when this is compounded by abnormalities of at least one of the

other enzymes responsible for completing the PLA2

cycle.

As and Horrobin (19) make clear, PLA2 and many other phospholipid

enzymes are good

candidates for contributing to the genetic predisposition to neurodevelopmental

disorders, because they are strongly expressed during brain growth and

development. However, gene-environment interactions are clearly crucial at

every stage, and phospholipid metabolism is also at the interface of these,

depending as heavily as it does on the dietary intake of fatty acids.

The importance of an adequate dietary supply of

HUFA in early development has already been the subject of much research (22).

This issue is covered here in the paper by Willatts & Forsyth (23). They

have carried out very careful studies of the effects of HUFA supplementation on

the cognitive development of infants, and as well as reporting their recent

findings they highlight some of the difficulties involved in distinguishing

cognitive from sensorimotor abnormalities. In a theoretical paper, and

(24) discuss some of the ways in which fatty acid abnormalities

could plausibly account for the visual magnocellular deficits that have been

well documented in dyslexia, and which may well play some role in related

conditions.

It is clear that ADHD, dyslexia, dyspraxia and

autism are all complex neurodevelopmental syndromes with a biological basis.

Moreover, they not only show a high degree of clinical overlap but often

cluster together in families, suggesting common elements at the level of

genetic predisposition. In fact, a family history of other neurodevelopmental

or psychiatric disorders is one of the most striking features of all of these

conditions. Familial associations in ADHD include depression, bipolar disorder,

substance abuse and antisocial personality disorders (25,26) while dyslexia

appears to show some degree of familial association with the schizophrenia

spectrum, in which phospholipid abnormalities have already been well-documented

(27). Of particular interest is the substantial co-morbidity between ADHD and

disorders of mood. Recent evidence suggests that as many as one third of

children who currently receive an ADHD diagnosis may actually be suffering from

early onset bipolar disorder (28), although this can rarely be diagnosed in

children owing to the current reliance on criteria for the adult form of this

disorder. This kind of misdiagnosis could be extremely significant, because

omega-3 fatty acids have already shown considerable promise in the treatment of

bipolar disorder (29), while stimulant medications are likely to exacerbate

this condition.

Epidemiology

and genetics of neurodevelopmental disorders

In the first paper in this collection, n

Little (30) describes the epidemiology of a wider range of developmental

disorders, including those involving neural tube defects such as spina bifida

where nutritional factors during pregnancy are believed to play a critical

role. There is currently little reliable epidemiological data concerning

neurodevelopmental disorders such as dyslexia, dyspraxia, ADHD and autistic

spectrum disorders, at least partly owing to problems of awareness, accurate

identification and diagnosis. His paper clarifies the difficulties involved in

epidemiological research and the potentially serious methodological confounds.

It is clear that further work in this area is required, but equally clear that

an interdisciplinary approach is not only desirable, but necessary.

The

genetics of specific language impairment (SLI)

and dyslexia are discussed in two papers by Nasir and colleagues (31) and

Francks and colleagues (32) respectively. These common neurodevelopmental

conditions present particular problems to molecular geneticists seeking to

identify the actual genes underlying disorder, although advances in methodology

are starting to improve the prospects (33, 34). Very rare conditions that are

transmitted in an autosomal dominant manner, such as Huntington’s Disease,

present a much simpler task; and in this case the gene responsible has already

been identified. In disorders such as schizophrenia, with a lifetime population

risk of around 1%, at least a few - and probably many - different genes are

likely to be involved. Heritability for schizophrenia is around 50%, but

despite extensive study, no reliable linkage has yet been established, and the

best strategies will probably involve narrowing the search by first identifying

candidate genes.

With

even more common conditions such as ADHD, dyslexia, SLI and dyspraxia, the genes

involved are likely to be not only many, but widely

distributed in the general population. Even in autism, where the severest forms

of disorder are rare and show very high heritability, the genetic picture

appears complicated (34). In all these disorders, the mode of inheritance still

remains unknown. Other problems include genetic

heterogeneity (the condition may arise from any of several different

‘genotypes’), incomplete penetrance (individuals with the genotype may fail

to develop the condition or

‘phenotype’) and phenocopy (individuals without the genotype may show

problems that resemble the

phenotype). Accurate definition of the phenotype is a major problem for

research, and better diagnostic procedures are sorely needed, especially if

these could be linked to biological markers of predisposition.

Nonetheless,

recent advances in both genotyping technology and quantitative statistical

methods have now made it possible to investigate the genetic correlates of

quantitative traits using large samples of sibling pairs. In the study of

neurodevelopmental disorder these strategies clearly offer much more promise

than conventional methods requiring arbitrary categorical classifications of

affected versus non-affected individuals. As Francks and colleagues report here

(32), a site on chromosome 6p has now been implicated by several independent

studies of dyslexia, making this a robust finding. Work underway now includes

screening the entire genome for further linkages, and the next steps will

involve narrowing down those regions enough to begin physical mapping or

candidate gene studies.

Horrobin and (35) recently reviewed the

evidence for candidate genes in a range of psychiatric disorders, showing where

proposed sites of linkage for these conditions coincide with those for genes

known to be important in phospholipid and fatty acid metabolism. Molecular

genetics is of course a very rapidly expanding field of knowledge, so a

valuable update of this work is provided in this volume (19). These authors

highlight many interesting correspondences, including the fact that the same

region of chromosome 6 now firmly associated with dyslexia has also been

implicated in ADHD, autism and schizophrenia. Moreover, genes encoding several

enzymes important in phospholipid metabolism have also been linked to the same

region, including a lyso-phospholipid coenzyme-A acyl transferase (36). This

family of enzymes is important in completing the PLA2

cycle, making this a good potential candidate for investigation in relation to

these disorders. However, there are many other plausible candidates, and

supportive evidence would be needed from basic biochemical studies prior to any

such investigations.

Current evidence for

abnormalities of fatty acid metabolism in ADHD, dyslexia, dyspraxia and the

autistic spectrum

ADHD

Deficiency

in certain HUFA as a factor in ADHD was first proposed almost twenty years ago

(37). Supporting evidence from blood biochemical and other studies has been

accumulating since then, as reviewed by and Puri in this issue (3).

Findings are broadly in line with the original

proposal that ADHD involves difficulties in the synthesis of HUFA, rather than

a lack of their EFA precursors, although other mechanisms may well be

operating. Given the heterogeneity of ADHD it seems probable that fatty acid

abnormalities would affect only a subset of individuals receiving this

diagnosis. However, biochemical studies have shown that even in a combined

sample of ADHD boys and controls, omega-3 deficiencies were associated with

behavioural and learning problems as well as with some aspects of general

health, notably allergic conditions (38). The fact that these relationships

held irrespective of clinical diagnosis suggests that a dimensional perspective

may well be more appropriate than a reliance on categorical classifications of

disorder.

Dyslexia

In

dyslexia, the proposal of fatty acid abnormalities is more recent, and followed

from reports that certain visual deficits in dyslexic adults could be corrected

via treatment with omega-3 fatty acids (39). Brain imaging using 31-phosphorus

magnetic resonance spectroscopy further indicates some kind of lipid

abnormality in dyslexia (40). Important new supporting

evidencehas come from the recent

finding of elevated levels of a PLA2 enzyme in dyslexia,as discussed by

MacDonell et al in this volume

(21),

consistent with an abnormally high rate of removal of HUFA from the sn-2

position of membrane phospholipids.

In

one early case report, fatty acid deficiency in a dyslexic child was confirmed

by biochemical testing, and benefits from fatty acid treatment were noted (41).

This child showed the same clinical signs that were first reported in ADHD such

as dry, dull skin and hair, and soft, brittle nails. Moreover, their

disappearance following nutritional intervention to correct the fatty acid

deficiency was followed by reported improvements in schoolwork. s et al

(1995) created a simple scale to assess these signs, and demonstrated that

scores were indeed related to blood biochemical measures of HUFA deficiency,

particularly of n-3 fatty acids (42). In this volume , and

colleagues report

recent studies confirming that scores on this scale also relate to dyslexia in

both adults (43) and children (44), although in each case some interesting sex

differences are apparent.

Dyspraxia

Of

the conditions under consideration here, dyspraxia has probably been the least

studied in relation to fatty acid metabolism. However, the high co-morbidity of

dyspraxia with both ADHD and dyslexia has not yet been factored out in studies

of fatty acid metabolism in these conditions. It is quite possible that

dyspraxic features may help to identify relevant subgroups within dyslexia or

ADHD, and this is currently under investigation. Meanwhile, in the study

reported here by et al (43), self-reported motor problems were among the

features associated with clinical signs of fatty acid deficiency in dyslexic

adults.

There

is already evidence that HUFA deficiencies relate to movement disorders both in

the general population (45) and in psychiatric patients treated with

neuroleptics (46). In dyspraxic children, both anecdotal reports and open

studies of treatment with LC-PUFAs further suggest that fatty acid

abnormalities in this condition deserve serious investigation (47,48).

Autistic spectrum disorders

In relation to autistic spectrum disorders (ASD) there is again plenty of

suggestive evidence

that abnormalities of fatty acid metabolism may play a role (49) but very

little in the way of formal study. One previous report has suggested an

impairment

of peroxisomal function to account for an apparent accumulation of very long

chain fatty acids in some autistic individuals (50).

In

this volume, Bell and colleagues (51) report a single case study of an

individual with ASD that revealed reduced HUFA concentrations in

red blood cell membranes. In addition, they found evidence of an instability of

membrane HUFA that has also been observed in schizophrenia. The mechanisms

underlying this are not yet known, but it is consistent with the abnormal

elevation

of PLA2 found in schizophrenia

(20,52) and more recently in dyslexia (21). Excessive oxidative stress could

also be involved, as discussed below, and these two possibilities are by no

means mutually exclusive (53). Intriguingly, Bell and colleagues also studied

two

individuals with Asperger’s syndrome, a milder form of ASD,

and found that red cell membrane HUFA concentrations in these subjects showed

instead a remarkable stability relative to control samples, consistent with

earlier speculations that phospholipase

activity may be reduced in this condition (49). They also report evidence that

abnormalities of tryptophan metabolism linked to ASD and related disorders have

implications for HUFA metabolism. Clearly this is an

area that deserves further study, and a biochemical approach of this kind has

obvious potential in helping to clarify some of the heterogeneity in ASD.

Interpretation of the

evidence

In

attempting to interpret the current evidence for fatty acid abnormalities in

these neurodevelopmental disorders, it is clear that many issues still remain

to be resolved. Fatty acid and phospholipid metabolism is exquisitely complex

and can be influenced by many factors, both constitutional and environmental.

Any single biochemical measure is open to a range of interpretations, and until

further evidence is available – ideally from a range of measure used

concurrently in the same subjects – very few firm conclusions can be drawn.

Having said this, the available evidence does suggest that fatty acid

abnormalities

are probably implicated to at least some extent in all of these conditions.

With

respect to mechanisms, a constitutional inefficiency in the conversion of EFA

to HUFA has been proposed as a factor not only in ADHD (37,42) but also in

dyslexia and dyspraxia (47,48). However, other kinds of abnormalities are

equally plausible. The recent finding of elevated PLA2

in dyslexia (21) makes that case clear, and a similar abnormality could help to

explain the apparent instability of HUFA in autism (51). Other enzymes involved

in membrane phospholipid synthesis and breakdown are discussed elsewhere in

this volume (19), and it is obvious that much work remains to be done to

elucidate precise patterns of abnormality that may underlie different symptoms

or conditions.

Oxidative

stress is another possible interpretation of the biochemical findings of low

levels of HUFA in neurodevelopmental disorder, and this proposal is discussed

in this volume by n Ross (53). Increased PLA2

activity could well be related to oxidative stress, and many studies of

schizophrenia have indicated a pathology involving free radicals (54). There

could certainly be parallels with this in other neurodevelopmental disorders,

and this possibility clearly requires further investigation.

Implications for Diagnosis

and Management

ADHD,

dyslexia, dyspraxia and autism are all complex, multifactorial syndromes, but

currently definition and diagnosis is based on their phenomenology - and from a

limited perspective in each case. These issues are spelt out clearly by in

this volume with respect to

the autistic spectrum (6), but the same problems apply equally to ADHD,

dyslexia and dyspraxia, and they seriously hinder accurate identification and

effective management.

All

of these conditions clearly have a biological basis with a strong genetic

component, so we would argue that it makes sense to focus further research

efforts on discovering more about this level. In this, phospholipid metabolism

looks like an extremely promising paradigm. This approach has already led to

the development of new tests for the identification of certain fatty acid

abnormalities, and with further validation these could potentially become

important diagnostic tools. ine Ward’s paper in this volume (55) outlines

some promising new measures that have already been used to assess the fatty

acid abnormalities associated with schizophrenia. The niacin skin patch test,

assessing abnormalities in the prostaglandin pathway, may provide an index of

deficiency in certain HUFA, particularly arachidonic acid. A simple breath test

has also been developed which measures alkanes, the end products of lipid

peroxidation (56). Lipid peroxidation caused by oxidative stress could prove to

be an important factor in neurodevelopmental disorders, as suggested by Ross in

this volume (53). Both of these tests are non-invasive and would therefore be

highly acceptable for use with children.

Another major attraction of

this approach is the possibility that it raises of new, safe treatments for

these disorders, particularly given the limitations of current methods of

management. Benefits following treatment with omega-3 fatty acids have already

been shown in the management of both schizophrenia (57-62) and mood disorder

(29), both of which show some comorbidity with the neurodevelopmental disorders

under discussion here. It is still too early to evaluate the potential of fatty

acid treatments in these conditions, but there is sufficient rationale and

preliminary evidence to warrant large-scale randomised controlled trials. A few

small studies of ADHD have already yielded some positive results as well as

some equivocal or negative findings, but further trials are indicated and these

need to be carefully designed and hypothesis-driven (3). In dyslexia, no

results from controlled trials are yet available, but several large-scale

studies of this kind involving both dyslexic children and adults are

approaching completion (62). Similar work is needed in relation to dyspraxia

and the autistic spectrum.

Conclusion

At present, controversies

over aetiology, diagnosis and management pervade both research and clinical

practice with respect to ADHD, dyslexia, dyspraxia and the autistic spectrum.

It is probably fair to say that the only point on which there is almost

unanimous agreement is the need for better methods of early identification and

management. The challenge is therefore to develop a better understanding of the

nature and interaction of the genetic and environmental influences that produce

the overlapping cognitive and behavioural profiles associated with these

relatively common neurodevelopmental conditions. Given the extraordinary

complexity of the inter-relationships between brain and behaviour, this is no

easy task. However, at a biochemical level, we suggest that the study of fatty

acid and phospholipid metabolism appears to have a great deal to offer.

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