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Fragile X Associated Disorders
Although fragile X syndrome results from changes to a single gene, there is now widespread agreement that the condition has a broad spectrum of involvement that impacts those who carry the gene and those who have fragile X syndrome.
Fragile X Syndrome: Fragile X syndrome was first described in 1943 by Martin and Bell (originally labelled the "Martin-Bell" syndrome) and is the world's most common hereditary cause of developmental delay in males. Although still lacking consensus, recent estimates indicate a frequency of approximately 1 per 2,500. The condition is caused by the silencing of a single gene on the long arm of the X chromosome. The gene, named the Fragile X Mental Retardation Gene-1 (FMR1), was identified in 1991 and is "turned off" in affected individuals. When this happens, a specific protein (FMRP) is not produced resulting in a unique constellation of strengths and weaknesses that characterise fragile X children and adults across their lifespan. These can include:
- behaviour problems including anxiety, shyness, mood disorders, depression
- severe inattentive behaviours and hyperactivity similar to ADHD
- intellectual disability and language delay
- cognitive impairments in working memory
- distractibility and lack of inhibitory control
- autism-like characteristics leading to a diagnosis of autism spectrum disorder in approximately 40% of children
- good visual memory for faces and meaningful material
Useful reading: Cornish, Scerif, & Karmiloff-Smith 2007, download pdf (204kb); Cornish, Turk, & Hagerman 2008, download pdf (148kb).
Fragile X Carriers: Recent estimates indicate that carriers of the fragile x syndrome (those individuals with a small change in the gene) are more common in the general population (approximately 1 in 250 females and 1 in 800 males) than those who are fully affected and so the frequency of the problems associated with being a carrier are more common than the problems associated with the full mutation-fragile x syndrome. In recent years a newly diagnosed neurodegenarative disorder has been discovered by Dr Randi Hagerman and her colleagues at the MIND Institute at UC Davis in the USA and is known as Fragile X Tremor and Ataxia Syndrome (FXTAS). FXTAS does not occur in fully affected individuals and rarely in female carriers.
The Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)
When grandfathers of children with fragile X were evaluated, a consistent neurological disorder was discovered in a subgroup of these men that included both intention tremor and ataxia. Further research prompted by this discovery has revealed a range of other symptoms that include:
- psychiatric features including agitation, dysinhibition and anxiety
- neuropathy in the lower extremities (Berry-Kravis et al., 2007)
- cognitive deficits - notably executive function and memory deficits (e.g. Grigsby et al., 2006)
Useful reading: Cornish, Li et al. 2008, download pdf (244kb); Hay, 2008, download pdf (88kb); Cornish, Kogan et al. 2009, download pdf (224kb); Cornish, Turk, & Hagerman 2008, download pdf (148kb); Cornish, Manly et al. 2005.
Interview: What is Fragile X?
Project: FXS
Project: FXS Premutation
Autism
Autism is a complex neurodevelopmental disorder that has intrigued clinicians and researchers for decades. It was originally described by Kanner in 1943 and is characterized by "a triad of impairment" that includes severe disruption in communication/language skills, impaired reciprocal social interactions and restricted/repetitive patterns of behaviour, interests and routines. However, it is perhaps the clinical heterogeneity of this disorder that makes capturing the causal mechanism of autism so elusive. For example, there appear to be two causal pathways resulting in autistic behaviour:
- The first has been labeled "idiopathic" in which autism presents independent of any other disorder. Idiopathic autism is found in familial clusters as identified by twin and family studies.
- The second is referred to as "syndromic autism" and occurs as part of a broader genetic phenotype such as fragile x syndrome or 22q11 DS.
The idiopathic pathway has received considerable research interest, with a number of exciting discoveries that have begun to isolate putative susceptibility genes for autism. The second syndromic pathway has received less focus, but is an emerging area that is likely to generate considerable interest in the next few years. What remains unknown is the extent to which different autism pathways, presumably resulting from different etiologies, converge or diverge across development.
Project: Attention Kids!
Project: ARC Sleep Study
Williams Syndrome
Williams syndrome, also known as William-Beuren syndrome, was initally identified independently by Williams and Beuren in 1961. Until quite recently, it was assumed to be a rare disorder (1 in 15,000-20,000), but one recent estimate indicates the frequency at approximately 1 in 7,500. The disorder is not usually hereditary and results from the deletion of approximately 25-30 genes on the long arm of chromosome 7.
Inteleectual impairment, although variable in severity, is a core characteristic of almost all children with Williams syndrome, but perhaps the most salient is their distinctive behavioural and cognitive profile that can include:
- obsessive behaviour and high degrees of anxiety
- extreme friendliness and sociability, with an excessive display of empathy
- hyperactivity, distractibility, inattention and lack of persistence
- impaired visual-spatial working memory
- relative strength in perceptual attention skills
- relative strength in face processing skills
- relative strength in language production
In our research, we have compared the attention profile of toddlers and children with Williams syndrome and fragile X syndrome across their respective trajectories to establish when in development skills converge and diverge from each other and typically developing peers
Useful reading: Scerif, Cornish et al. 2004, download pdf (252kb); Cornish, Scerif & Karmiloff-Smith 2007, download pdf (204kb).
Project: WS Motor Study
Attention Deficit/Hyperactivity Disorder
Attention Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood psychiatric disorders and is characterized by a triad of clinical features: inattention, impulsivity, and hyperactivity. Consequently, children with ADHD are at a greater risk for low academic achievement, substance abuse and anti-social behaviour/delinquency in adolescence. Impairments in attentional control may lie at the core of this condition and these are likely to interact with working memory difficulties across development. The search for susceptibility genes (e.g. DAT1, DRD4, COMT, SNAP-25) that might contribute tot he ADHD phenotype has been the subject of intense investigation and it is now widely accepted that several genes may be implicated in ADHD.
In this research, we have been looking at the association between dopamine transporter gene (DAT1) and ADHD symptoms and response inhibition in a general population of schoolchildren.
Useful reading: Cornish, Manly et al. 2005, download pdf (370kb); Cornish, Wilding, & Hollis 2008.
Future Directions
A core research interest of this newly established lab is fragile X syndrome (CORNISH, TURK & HAGERMAN 2008 and http://www.fragilex.org.au), the world’s most common hereditary cause of developmental delay. Arguing that fragile X should be viewed as “continuum” of clinical involvement we explore genetic-brain-neurocognitive pathways in both carriers of the condition (premutation status) and those with fragile X syndrome (full mutation status).
Below are some examples of research projects that we invite potential students and fellows to be involved in.
- Identifying ADHD and autism phenotypes in genetic disorders such as fragile X syndrome and their early developmental trajectories
Within this topic, we are focusing on the frequently observed heterogeneity within fragile X. Specifically exploring how early markers of autism and/or ADHD symptoms in this condition may help to identify the different pathways of cognitive and social outcomes that represent the fragile X phenotype. Beginning this exploration as early as possible after diagnosis will produce the greatest benefits in terms of development and timing of appropriate clinical and educational interventions. Furthermore by exploring the relation between so called “attention” genes and ADHD profiles we aim to elucidate the contribution of other genetic variations to the fragile X phenotype.
- Identifying early cognitive and motor “signatures” in different neurodegenerative disorders including fragile-X tremor ataxia syndrome (FXTAS)
Within this topic, we are focusing on identifying early cognitive and motor predictors of later decline across different neurodegenerative conditions with an emphasis on a newly diagnosed tremor/ataxia disorder known as Fragile X Tremor Ataxia Syndrome (FXTAS). Our previous work has shown that male carriers of fragile X possibly follow two developmental pathways – a carrier related trajectory present throughout life and possibly related to mild reductions of the fragile X mental retardation protein (FMRP). This pathway results in a subtle yet measurable Fragile X “signature” including attention problems. A second pathway – a FXTAS- related trajectory that increases in severity with age and is most likely related to the toxic mRNA effect that can cause cell death and brain atrophy over time, and eventually the full clinical picture of FXTAS. HAY, 2008 download pdf (88kb); CORNISH, LI, KOGAN ET AL 2008 download pdf (244kb); CORNISH, KOGAN, LI ET AL. 2009 download pdf (220kb); CORNISH, MANLY ET AL 2005; KOGAN, TURK, HAGERMAN & CORNISH 2008, download pdf (372kb)
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