Education
-
Oct 1984–
Jul 1989University of Leicester
Medicine · MB ChBUnited Kingdom · Leicester
Publications (156) View all
-
Article: Birth order and the genetics of amyotrophic lateral sclerosis
[show abstract] [hide abstract]
ABSTRACT: The cause of ALS remains largely unknown for the 90% with no known family history, but spontaneous mutation to risk alleles of as yet unidentified genes is possible. It has long been recognized that genetic diseases may be more likely to occur in the last born children of a sibship because increased paternal age is associated with an increased spontaneous point mutation rate in sperm. To test the hypothesis that such a mechanism is responsible for sporadic ALS, we have performed a retrospective analysis of birth order position. We have analyzed sibships of size greater than four using a binomial test for birth position. The 478 pedigrees studied show no birth order effect, suggesting that any genetic contributions to sporadic ALS are more likely to be through deletion in large genes or interactions of common polymorphisms, rather than frequent spontaneous point mutation. This is encouraging for the prospect of finding sporadic ALS susceptibility genes using genome-wide association mapping.Journal of Neurology 04/2012; 255(1):99-102. · 3.47 Impact Factor -
Article: Concordance between site of onset and limb dominance in amyotrophic lateral sclerosis.
[show abstract] [hide abstract]
ABSTRACT: Focality of onset of amyotrophic lateral sclerosis (ALS) is not understood. Attempts to implicate physical exercise in the aetiology of ALS have provided inconsistent results. If physical use of a limb were important in defining the site of onset, then handedness might be expected to influence the side of upper limb-onset disease and footedness likewise in lower limb-onset ALS. ALS patients registered with an internet-based support site were invited to complete an online questionnaire concerning site of onset of symptoms and their dominant hand and foot. A binomial test of proportions was used to investigate the null hypothesis that handedness and footedness do not influence side of onset in upper and lower limb-onset ALS, respectively. 343 ALS patients with limb-onset disease were studied. For upper limb-onset patients, there was concordance for side of onset and handedness (64%; p<0.0006). For lower limb-onset patients, concordance for side of onset and footedness was absent. The frequency of left handedness was commensurate with that found in the general population. These results are potentially consistent with the hypothesis that exercise influences pathogenesis in ALS since routine physical demands on the upper limb are heavily influenced by limb dominance, whereas in the lower limbs the commonest function is standing or locomotion, which uses both legs equally. However, there may also be an inherent cortical vulnerability underlying upper limb-onset laterality, possibly influenced by changes in neuronal connectivity and cortical excitability in relation to handedness and reflected by the "split hand" phenomenon consistently observed in ALS.Journal of neurology, neurosurgery, and psychiatry 08/2011; 82(8):853-4. · 4.87 Impact Factor -
Article: An estimate of amyotrophic lateral sclerosis heritability using twin data.
[show abstract] [hide abstract]
ABSTRACT: Causative gene mutations have been identified in about 2% of those with amyotrophic lateral sclerosis (ALS), often, but not always, when there is a strong family history. There is an assumption that there is a genetic component to all ALS, but genome-wide association studies have yet to produce a robustly replicated result. A definitive estimate of ALS heritability is therefore required to determine whether ongoing efforts to find susceptibility genes are worth while. The authors performed two twin studies, one population- and one clinic-based. The authors used structural equation modelling to perform a meta-analysis of data from these studies and an existing twin study to estimate ALS heritability, and identified 171 twin pairs in which at least one twin had ALS. Five monozygotic twin pairs were concordant-affected, and 44 discordant-affected. No dizygotic twin pairs were concordant-affected, and 122 discordant-affected. The heritability of sporadic ALS was estimated as 0.61 (0.38 to 0.78) with the unshared environmental component 0.39 (0.22 to 0.62). ALS has a high heritability, and efforts to find causative genes should continue.Journal of neurology, neurosurgery, and psychiatry 12/2010; 81(12):1324-6. · 4.87 Impact Factor -
Article: POD09 Using the chick embryo model system to study the neurotoxicity of TDP43.
[show abstract] [hide abstract]
ABSTRACT: We have successfully developed the chick embryo model of ALS. We carried out overexpression of HA and Myc tagged TDP-43WT, TDP-43Q331K and TDP-43M337V constructs (Sreedharan et al, 2008). We also carried out over-expression of pEGFPC1 as a control. TUNEL staining demonstrated that GFP transfection resulted in low levels of apoptotic TUNEL +ve cells. However, embryos electroporated with the WT and MT forms of TDP-43 showed a marked increase. A two-tailed t test of GFP vs HA-TDP-43WT-Myc, GFP vs HA-TDP-43Q331K-Myc and GFP vs HA-TDP-43M337V-Myc gave p-values of 0.1252, 0.0179 and 0.0079 respectively. We also carried out electroporation of N-terminal GFP tagged constructs expressing the same wild-type and mutant genes (GFP-TDP-43WT, GFP-TDP-43Q331K and GFP-TDP-43M337V). TUNEL staining showed a statistically significant increase in the number of apoptotic nuclei in embryos electroporated with TDP-43WT, TDP-43Q331K and TDP-43M337V as compared to those expressing pEGFPC1. A two-tailed t test of GFP vs GFP-TDP-43WT gave a p-value of 0.0337; GFP vs GFP-TDP-43Q331K gave a p-value of 0.0026 and GFP vs GFP-TDP-43M337V gave a p-value of 0.0045. The mutant forms of TDP-43 showed predominantly cytoplasmic localisation as compared to TDP-43WT. Moreover, we observed nuclear aggregates in the sections of embryos electroporated with mutant TDP-43. A two-tailed t-test of GFP-TDP-43WT vs GFP-TDP-43Q331K gave a p-value of 0.012 and that of GFP-TDP-43WT vs GFP-TDP-43M337V gave a p-value of 0.009.Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e44. · 4.87 Impact Factor -
Article: PONM19 The ALS Online Genetics Database.
[show abstract] [hide abstract]
ABSTRACT: The ALS Online Genetics Database (ALSOD) is a central repository of genetic information on amyotrophic lateral sclerosis (ALS). In 1999, when the database was started, the only genetic cause of ALS known was mutation in the SOD1 gene. There have since been rapid advances in our knowledge. We therefore aim to provide a single, continuously updated resource summarising the current state of ALS genetics including automated meta-analysis of published linkage and association studies, deposition of rare genetic variants and documentation of associated core clinical features to generate phenotypic correlations. The requirements of the ALS genetics research community have been collected from the ALSOD feedback page. The web-based application has public pages accessible to all, and secure pages accessible to registered users who are able to access more detailed clinical and statistical information, as well as deposit new data. Integration with existing databases and analysis software means that ALSOD is a powerful resource for exploring existing genetic and phenotypic information in ALS. New tools are in development, and will be made live after initial beta-testing is passed. ALSOD is widely used by the ALS genetics research community. We aim to make it an indispensable tool for ALS research.Journal of neurology, neurosurgery, and psychiatry 11/2010; 81(11):e65. · 4.87 Impact Factor
