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Johnson V.E.,University of Pennsylvania | Stewart W.,Laboratory Medicine Building
Nature Reviews Neurology | Year: 2015

Traumatic brain injury (TBI) is increasingly recognized as a risk factor for dementia. New data provide further support for this association and demonstrate the influence of age at injury and injury severity on dementia risk after TBI, revealing that even mild TBI increases dementia risk in those aged ?65 years.


Stewart W.,Laboratory Medicine Building | McNamara P.H.,St Jamess Hospital | Lawlor B.,St Jamess Hospital | Hutchinson S.,St Jamess Hospital | Farrell M.,Dr.
QJM | Year: 2016

The association between exposure to head injury and increased risk of neurodegenerative disease, specifically chronic traumatic encephalopathy (CTE), is widely recognized. Historically, this was largely considered a phenomenon restricted to boxers, with more recent case series identifying further 'high risk' individuals, such as former American footballers, or military personnel. However, in all cases thus far reported, it is clear that it is the exposure to head injury which is associated with increased dementia risk, and not the circumstances or environment of exposure. As such, there is considerable potential for under-recognition of CTE in patients presenting with neurodegenerative disease, particularly where head injury exposure might have been historical and through sport. This article reviews current understanding of CTE and, via an illustrative case in rugby union, highlights the value of a detailed history on head injury and also draws attention to imaging studies in assessing patients with neurodegenerative disease. © The Author 2015.


Nikkel S.M.,University of Ottawa | Dauber A.,Boston Childrens Hospital | De Munnik S.,Radboud University Nijmegen | Connolly M.,Manton Center for Orphan Disease Research at Childrens Hospital | And 63 more authors.
Orphanet Journal of Rare Diseases | Year: 2013

Background: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results. Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. Conclusions: This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols. © 2013 Nikkel et al.; licensee BioMed Central Ltd.


Kashevarova A.A.,Institute of Medical Genetics | Nazarenko L.P.,Siberian State Medical University | Schultz-Pedersen S.,Private Pediatric Clinics Bornelaegen Aarhus | Skryabin N.A.,Tomsk State University | And 10 more authors.
Molecular Cytogenetics | Year: 2014

Background: Detection of submicroscopic chromosomal alterations in patients with a idiopathic intellectual disability (ID) allows significant improvement in delineation of the regions of the genome that are associated with brain development and function. However, these chromosomal regions usually contain several protein-coding genes and regulatory elements, complicating the understanding of genotype-phenotype correlations. We report two siblings with ID and an unrelated patient with atypical autism who had 3p26.3 microdeletions and one intellectually disabled patient with a 3p26.3 microduplication encompassing only the CNTN6 gene. Results: Two 295.1-kb microdeletions and one 766.1-kb microduplication of 3p26.3 involving a single gene, CNTN6, were identified with an Agilent 60K array. Another 271.9-kb microdeletion of 3p26.3 was detected using an Affymetrix CytoScan HD chromosome microarray platform. The CHL1 and CNTN4 genes, although adjacent to the CNTN6 gene, were not affected in either of these patients. Conclusions: The protein encoded by CNTN6 is a member of the immunoglobulin superfamily and functions as a cell adhesion molecule that is involved in the formation of axon connections in the developing nervous system. Our results indicate that CNTN6 may be a candidate gene for ID. © 2014 Kashevarova et al.


McGowan R.,Laboratory Medicine Building | Tydeman G.,Victoria Hospital | Shapiro D.,Royal Infirmary | Craig T.,Laboratory Genetics | And 7 more authors.
Fertility and Sterility | Year: 2015

Objective: To clinically and genetically investigate women with müllerian disorders, including Mayer-Rokitanksy-Kuster-Hauser (MRKH) syndrome. Design: Two-year prospective clinical and laboratory study. Setting: Not applicable. Patient(s): Thirty-five women over 16 years of age with a müllerian disorder, including MRKH. Intervention(s): Women were recruited from specialist gynecology clinics or identified from the Scottish Disorders of Sex Development Register (www.sdsd.scot.nhs.uk/index.html). Associated abnormalities were detected by clinical examination, imaging studies, and biochemical analyses. Chromosomal microduplications and microdeletions were detected by array comparative genomic hybridization (CGH) and validated by fluorescence in situ hydridization. Main Outcome Measure(s): Identification of associated congenital and biochemical abnormalities and identification of regions of genomic imbalance using array CGH. Result(s): Associated congenital anomalies were common, present in 25/35 (71%) of affected women, particularly renal and skeletal abnormalities, which were present in 15/35 (43%) and 17/35 (49%) women, respectively. Using array CGH, novel or recurrent regions of genomic imbalance were identified in 4/11 (36%) women with MRKH and in 5/24 (21%) women with other müllerian abnormalities. Conclusion(s): Additional congenital abnormalities and regions of genomic imbalance are common in women with müllerian disorders, including MRKH. Recurrent microdeletions and microduplications associated with MRKH implicate specific possibly causative genes. The investigation of women with müllerian disorders should be thorough, and array CGH should be considered, given the potential highly significant familial implications of a chromosomal abnormality.

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