Does genetic anticipation occur in familial Alexander disease?

Alexander Disease (AxD) is a rare leukodystrophy caused by missense mutations of glial fibrillary acidic protein (GFAP). Primarily seen in infants and juveniles, it can present in adulthood. We report a family with inherited AxD in which the mother presented with symptoms many years after her daughter. We reviewed the age of onset in all published cases of familial AxD and found that 32 of 34 instances of parent–offspring pairs demonstrated an earlier age of onset in offspring compared to the parent. We suggest that genetic anticipation occurs in familial AxD and speculate that genetic mosaicism could explain this phenomenon

A central resource for accurate allele frequency estimation from pooled DNA genotyped on DNA microarrays

Analysing pooled DNA on microarrays is an efficient way to genotype hundreds of individuals for thousands of markers for genome-wide association. Although direct comparison of case and control fluorescence scores is possible, correction for differential hybridization of alleles is important, particularly for rare single nucleotide polymorphisms. Such correction relies on heterozygous fluorescence scores and requires the genotyping of hundreds of individuals to obtain sufficient estimates of the correction factor, completely negating any benefit gained by pooling samples. We explore the effect of differential hybridization on test statistics and provide a solution to this problem in the form of a central resource for the accumulation of heterozygous fluorescence scores, allowing accurate allele frequency estimation at no extra cost

Infection of the Central Nervous System, Sepsis and Amyotrophic Lateral Sclerosis

Severe infections may lead to chronic inflammation in the central nervous system (CNS) which may in turn play a role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). The relentless progression and invasive supportive treatments of ALS may on the other hand induce severe infections among ALS patients.The present study included 4,004 ALS patients identified from the Swedish Patient Register during 1991-2007 and 20,020 age and sex matched general population controls. Conditional logistic regression was used to estimate the odds ratios (ORs) of ALS given a previous hospitalization for CNS infection or sepsis. Cox models were used to estimate the hazard ratios (HRs) of hospitalization for CNS infection or sepsis after ALS diagnosis. Overall, previous CNS infection (OR: 1.3, 95% confidence interval [CI]: 0.8, 2.4) or sepsis (OR: 1.2, 95% CI: 0.9, 1.6) was not associated with ALS risk. However, compared to ALS free individuals, ALS cases were more likely to be hospitalized for sepsis after diagnosis (HR: 2.6, 95% CI: 1.9, 3.5). We did not observe a higher risk of CNS infection after ALS diagnosis.Our results suggest that acute and severe infections unlikely contribute to the development of ALS; however, ALS patients are at a higher risk of sepsis after diagnosis, compared to ALS free individuals

Improving the measurement properties of the amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R): deriving a valid measurement total for the calculation of change

Background The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score is a widely used measure of functional status in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS), but recent evidence has raised doubts about its validity. The objective was to examine the measurement properties of the ALSFRS-R, aiming to produce valid measurement from all 12 scale items. Method Longitudinal ALSFRS-R data were collected between 2013-2020 from 1120 people with ALS recruited from 35 centers, together with other scales in the Trajectories of Outcomes in Neurological Conditions-ALS (TONiC-ALS) study. The ALSFRS-R was analyzed by confirmatory factor analysis (CFA), Rasch Analysis (RA) and Mokken scaling. Results No definite factor structure of the ALSFRS-R was confirmed by CFA. RA revealed the raw score total to be invalid even at the ordinal level because of multidimensionality; valid interval level subscale measures could be found for the Bulbar, Fine-Motor and Gross-Motor domains but the Respiratory domain was only valid at an ordinal level. All four domains resolved into a single valid, interval level measure by using a bifactor RA. The smallest detectable difference was 10.4% of the range of the interval scale. Conclusion A total ALSFRS-R ordinal raw score can lead to inferential bias in clinical trial results due to its non-linear nature. On the interval level transformation, more than 5 points difference is required before a statistically significant detectable difference can be observed. Transformation to interval level data should be mandatory in clinical trials

The risk to relatives of patients with sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons with a median survival of 2 years. Most patients have no family history of amyotrophic lateral sclerosis, but current understanding of such diseases suggests there should be an increased risk to relatives. Furthermore, it is a common question to be asked by patients and relatives in clinic. We therefore set out to determine the risk of amyotrophic lateral sclerosis to first degree relatives of patients with sporadic amyotrophic lateral sclerosis attending a specialist clinic. Case records of patients with sporadic amyotrophic lateral sclerosis seen at a tertiary referral centre over a 16-year period were reviewed, and pedigree structures extracted. All individuals who had originally presented with sporadic amyotrophic lateral sclerosis, but who subsequently had an affected first degree relative, were identified. Calculations were age-adjusted using clinic population demographics. Probands (n = 1502), full siblings (n = 1622) and full offspring (n = 1545) were identified. Eight of the siblings and 18 offspring had developed amyotrophic lateral sclerosis. The unadjusted risk of amyotrophic lateral sclerosis over the observation period was 0.5% for siblings and 1.0% for offspring. Age information was available for 476 siblings and 824 offspring. For this subset, the crude incidence of amyotrophic lateral sclerosis was 0.11% per year (0.05–0.21%) in siblings and 0.11% per year (0.06–0.19%) in offspring, and the clinic age-adjusted incidence rate was 0.12% per year (0.04–0.21%) in siblings. By age 85, siblings were found to have an 8-fold increased risk of amyotrophic lateral sclerosis, in comparison to the background population. In practice, this means the risk of remaining unaffected by age 85 dropped from 99.7% to 97.6%. Relatives of people with sporadic amyotrophic lateral sclerosis have a small but definite increased risk of being affected

Epitaxial growth of Bi₁₂GeO₂₀ thin film optical waveguides using excimer laser ablation

Thin-film optical waveguides of the photorefractive optical material bismuth germanium oxide (Bi12GeO20) have been epitaxially grown onto heated zirconia substrates by excimer laser ablative sputtering. The epitaxial nature and stoichiometry of the films were verified using x-ray diffraction analysis. Waveguide modes were observed for effective refractive indices in close agreement with theoretical predictions

Measuring quality of life in ALS/MND: validation of the WHOQOL-BREF

Objectives: The World Health Organization Quality of Life-BREF Scale (WHOQOL-BREF) is a generic QOL measure with four domains covering Physical, Psychological, Social and Environment. Providing the opportunity to contrast QoL with other conditions, or with population norms, the current study had three aims: 1) can the established domains of the WHOQOL-BREF be validated within a large ALS/MND population; 2) can a total score be validated and 3) can they provide interval level measurement? / Methods: Data were obtained from the Trajectories of Outcomes in Neurological Conditions study. Internal construct validity was determined by fit of the data to the Rasch measurement model. / Results: 636 participants with ALS/MND were included. All domains, except the Social domain, showed satisfactory fit to the Rasch model. All were unidimensional, and showed no Differential Item Functioning by age, gender, or onset type. Finally, a total score was validated from a bi-factor perspective. / Conclusions: The WHOQOL-BREF is valid for use in populations with ALS/MND and can be analyzed to yield interval level measurement: It offers a range of domains that reflect QOL, which can be used for parametric analysis and for comparison with other conditions or general populations, two advantages for its inclusion as a trial outcome measure and for observational studies

A pilot randomised controlled trial of the feasibility of using body scan and isometric exercises for reducing urge to smoke in a smoking cessation clinic

BACKGROUND: The main cause of relapse in smokers attempting to quit is inability to resist urges to smoke. Pharmacotherapy ameliorates but does not entirely prevent urges to smoke when abstinent, so other methods to resist urges to smoke might be helpful. Exercise is effective, but aerobic exercise is often impractical when urges strike. Two techniques, body scan and isometric exercise, have been shown to reduce urge intensity and nicotine withdrawal symptoms in temporarily abstinent smokers. It is unclear whether they would be used or effective in typical smokers attempting to quit. METHODS: In a pilot trial set in a UK smoking cessation clinic, 20 smokers were randomised to receive emails containing.mp3 files and.pdf illustrations of the instructions for doing the body scan and isometric exercises. Twenty smokers received no other intervention, although all 40 were receiving weekly behavioural support and nicotine replacement therapy. Carbon monoxide confirmed abstinence, nicotine withdrawal symptoms, urges to smoke, and use of the techniques to resist urges were recorded weekly for four weeks after quit day. RESULTS: 60-80% of quitters reported using the isometric exercises each week and 40-70% reported using the body scan to deal with urges. On average, these techniques were rated as 'slightly helpful' for controlling the urges. There were no large or significant differences in withdrawal symptoms or urge intensity between the two groups. The risk ratio and 95% confidence interval for exercises compared with controls for prolonged confirmed abstinence at four weeks was 0.82 (0.44-1.53). 81% of quitters intended to continue using isometric exercises and 25% body scan, while 81% and 50% respectively would recommend using these techniques to others trying to stop. CONCLUSION: Isometric exercises, and to a lesser extent body scan, were popular and perceived as somewhat helpful by quitters. The trial showed that these techniques were used and a larger trial could now be developed to examine the influence of the methods on reducing urges to smoke and increasing abstinence