[tri-med] FYI - Part 1 of an editorial on speech disorders

I am forwarding this article or URL for your information (FYI) as I believe
it may be of interest and is from a reliable source. As always, check the
information with your own doctor or health care professional before starting
or changing any treatments.

PART 1 of 2
Brain, Vol. 125, No. 3, 449-451, March 2002
© 2002 Oxford University Press
Editorial

Towards the elucidation of the genetic and brain bases of
developmental speech and language disorders

Jenny Harasty1 and John R. Hodges2

1 Prince of Wales Medical Research Institute and Faculty of Medicine,
University of New South Wales, Randwick, Australia 2 MRC Cognition
and Brain Sciences Unit and University Neurology Unit, Addenbrooke's
Hospital, Cambridge, UKS

Two papers in this issue of Brain by Watkins and colleagues (Watkins
et al., 2002a, b) provide fascinating and important new data about
the core behavioural features and neural basis of an inherited form
of speech and language disorder. This work is particularly relevant
in the light of recent discoveries about the genetic basis of the
same developmental disorder.

Individuals affected by developmental speech and language disorders
have major difficulties acquiring expressive and/or receptive
language despite adequate intelligence and opportunity, and in the
absence of any profound sensory or neurological impairment (Bishop et
al., 1995 ). Although twin studies consistently show a significant
genetic component, the majority of families show a complex pattern of
inheritance. The present studies concern the unique three-generation
pedigree, the KE family, in whom a severe speech and language
disorder is transmitted as an autosomal-dominant monogenetic trait.
Speech in affected individuals is effortful, distorted and often
unintelligible with word order and other grammatical errors. Previous
work on the KE family had mapped the locus responsible (SPCH1) to
7q31 (Fisher et al., 1998). Further studies by the same research
group have now identified a point mutation in affected family
members, which alters an invariant amino acid residue in the
DNA-binding domain in a forkhead/winged helix transcription factor,
encoded by the FOXP2 gene (Lai et al., 2001). The case for a causal
association is further strengthened by the finding of a translocation
break in the same gene in another unrelated individual who has a very
similar speech and language disorder (Lai et al., 2001). Many members
of the forkhead/winged helix protein family are known to be
regulators of embryogenesis and mutations of the FOX genes have been
implicated in a range of other human developmental disorders. Lai et
al. (2001) propose that an insufficient dosage of critical forkhead
transcription factors during embryogenesis, leads to maldevelopment
of brain speech and language regions of the brain.

Developing a full understanding of neural basis and associated
cognitive/linguistic deficits in the KE family is clearly important
particularly with the hope of future gene based therapies.

In their first paper, Watkins et al. (2002a) describe the results of
detailed volumetric measurements, using the automated technique of
voxel-based morphometry (VBM) supplemented by targeted manual
volumetry, in affected and unaffected members of the KE family, and a
group of age-matched controls. In contrast to simple visual
inspection of MRIs, the sophisticated methods employed by the authors
demonstrated clear abnormalities in the affected family members that
were not present in behaviourally normal members of the family. The
direction of the difference was not, however, a simple matter of
reduced cortical volumes, as some regions were larger than normal;
while the caudate nucleus and inferior frontal gyrus were found to be
reduced in size bilaterally, the left frontal opercular region (pars
triangularis and anterior insular cortex) and the putamen bilaterally
had a greater volume of grey matter. It is tempting to simplify the
finding of studies using
volumetric analyses to a 'big is better' paradigm. We have been
guilty of adopting this approach ourselves (Harasty et al., 1997,
2001; Galton et al., 2001), although this assumption is probably more
valid in acquired degenerative brain disorders. Recent data have
shown that in some instances, such as stuttering, bigger is certainly
worse. For instance, Foundas et al. (2001) showed that stutterers
have an increase in cortical volume in two main speech areas. Ongoing
work in one of our laboratories (J. A. Harasty et al., unpublished
observations) has replicated this finding in stutterers but has
found, in addition, that white matter tracts underlying the
abnormally large cortical regions are reduced, suggesting that
corticocortical connections have failed to develop normally. Similar
findings have been reported in some areas of the brain of dyslexic
individuals but often involving the right hemisphere and implicating,
therefore, a defect in the development of normal brain asymmetry
(Galaburda et al., 1985).


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