Remarkable motor recovery after riboflavin therapy in adult-onset Brown-Vialetto-Van Laere syndrome.

The clinical diagnosis of Brown-Vialetto-Van Laere syndrome in this woman with rapidly progressive pontobulbar palsy led to empirical high-dose oral riboflavin (1200 mg/day) therapy. This resulted in a dramatic improvement in her motor function from being anarthric, dysphagic, tetraparetic and in ventilatory failure to living independently with mild dysarthria and distal limb weakness. DNA sequencing of the SLC52A3 gene found compound heterozygous C-terminus mutations, V413A1/D461Y, consistent with recent reports of mutations within the riboflavin transporter genes (SLC52A2 and SLC52A3) in this condition. Early diagnosis and empirical riboflavin therapy can lead to major motor recovery in this condition, that can be sustained with long-term maintenance therapy.

The sex ratio in amyotrophic lateral sclerosis: A population based study.

Replicable risk factors for ALS include increasing age, family history and being male. The male: female ratio has been reported as being between 1 and 3. We tested the hypothesis that the sex ratio changes with age in a population register covering the south-east of England. The sex ratio before and after the age of 51 years was compared using a Z-test for proportions. Kendall's tau was used to assess the relationship between age group and sex ratio using incidence and prevalence data. Publicly available data from Italian and Irish population registers were compared with results. There was a significant difference in the proportion of females with ALS between those in the younger group (30.11%) and those in the older group (43.66%) (p = 0.013). The adjusted male: female ratio dropped from 2.5 in the younger group to 1.4 in the older group using prevalence data (Kendall's tau = -0.73, p = 0.039). Similar ratios were found in the Italian but not the Irish registry. We concluded that sex ratios in ALS may change with age. Over-representation of younger patients in clinic registers may explain the variation in sex ratios between studies. Menopause may also play a role.

The rise and fall of fasciculations in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a median survival of 3 years from symptom onset. Accessible and reliable biomarkers of motor neuron decline are urgently needed to quicken the pace of drug discovery. Fasciculations represent an early pathophysiological hallmark of amyotrophic lateral sclerosis and can be reliably detected by high-density surface electromyography. We set out to quantify fasciculation potentials prospectively over 14 months, seeking comparisons with established markers of disease progression. Twenty patients with amyotrophic lateral sclerosis and five patients with benign fasciculation syndrome underwent up to seven assessments each. At each assessment, we performed the amyotrophic lateral sclerosis-functional rating scale, sum power score, slow vital capacity, 30-min high-density surface electromyography recordings from biceps and gastrocnemius and the motor unit number index. We employed the Surface Potential Quantification Engine, which is an automated analytical tool to detect and characterize fasciculations. Linear mixed-effect models were employed to account for the pseudoreplication of serial measurements. The amyotrophic lateral sclerosis-functional rating scale declined by 0.65 points per month (P < 0.0001), 35% slower than average. A total of 526 recordings were analysed. Compared with benign fasciculation syndrome, biceps fasciculation frequency in amyotrophic lateral sclerosis was 10 times greater in strong muscles and 40 times greater in weak muscles. This was coupled with a decline in fasciculation frequency among weak muscles of -7.6/min per month (P = 0.003), demonstrating the rise and fall of fasciculation frequency in biceps muscles. Gastrocnemius behaved differently, whereby strong muscles in amyotrophic lateral sclerosis had fasciculation frequencies five times greater than patients with benign fasciculation syndrome while weak muscles were increased by only 1.5 times. Gastrocnemius demonstrated a significant decline in fasciculation frequency in strong muscles (2.4/min per month, P < 0.0001), which levelled off in weak muscles. Fasciculation amplitude, an easily quantifiable surrogate of the reinnervation process, was highest in the biceps muscles that transitioned from strong to weak during the study. Pooled analysis of >900 000 fasciculations revealed inter-fasciculation intervals <100 ms in the biceps of patients with amyotrophic lateral sclerosis, particularly in strong muscles, consistent with the occurrence of doublets. We hereby present the most comprehensive longitudinal quantification of fasciculation parameters in amyotrophic lateral sclerosis, proposing a unifying model of the interactions between motor unit loss, muscle power and fasciculation frequency. The latter showed promise as a disease biomarker with linear rates of decline in strong gastrocnemius and weak biceps muscles, reflecting the motor unit loss that drives clinical progression.

UK case control study of smoking and risk of amyotrophic lateral sclerosis.

Introduction: Susceptibility to amyotrophic lateral sclerosis (ALS) is associated with smoking in some studies, but it is not clear which aspect of smoking behavior is related. Using detailed records of lifetime smoking we investigated the relationship between smoking and ALS in a UK population. Methods: In this retrospective case-control study, smoking status was collected using environmental questionnaires from people diagnosed with ALS between 2008 and 2013 and from age, sex and geographically matched controls. Categorical measures of smoking behavior were: smoking at the time of survey and smoking initiation; continuous measures were intensity (cigarettes per day), duration (years from starting to stopping or time of survey), cigarette pack years, and comprehensive smoking index (CSI), a measure of lifetime smoking. We used logistic regression to assess the risk of ALS with different combinations of smoking variables adjusted for age at survey, gender, level of education, smoking status and alcohol initiation, selecting the best model using the Akaike Information Criterion. Results: There were 388 records with full smoking history. The best-fitting model used CSI and smoking status at the time of survey. We found a weak association between current smoking and risk of ALS, OR 3.63 (95% CI 1.02-13.9) p value 0.05. Increase in CSI score did not increase risk of ALS: OR 0.81 (95% CI 0.58-1.11) p value 0.2.Conclusion: There is weak evidence of a positive effect of current smoking on the risk of ALS which does not show dose-dependence with higher levels of lifetime smoking and maybe a false positive result.

Homozygosity analysis in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. Six-hundred and twenty ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2 Mb were identified, and 3568 rare segments remained after filtering 'common' segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, P=0.05). Two-thousand and seventeen ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (P=1 × 10(-5)), a greater proportion of cases harboured homozygosity (P=2 × 10(-5)), a longer average length of segment (P=1 × 10(-5)), a longer total genome coverage (P=1 × 10(-5)), and a higher rate of these segments overlapped with RefSeq gene regions (P=1 × 10(-5)), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9-4.8 Mb, and chromosome 5 in the 65 Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS, which are not identified as common variants in GWAS.

No association of DPP6 with amyotrophic lateral sclerosis in an Italian population.

We have attempted to replicate a recently reported association of polymorphism rs10260404, in the Dipeptidyl-peptidase 6 gene (DPP6), with susceptibility to amyotrophic lateral sclerosis (ALS) in a large independent Italian cohort of 904 cases and 1036 controls. Minor allele frequency was 0.38 in cases and 0.39 in controls and no evidence of association with ALS was observed (P=0.638). Our negative results agree with those recently reported in additional Polish and Italian cohorts.

Comparison of two percutaneous radiological gastrostomy tubes in the nutritional management of ALS patients.

Patient care and minimizing complications post gastrostomy have to date received little attention in ALS patients. We compare the complications associated with pigtail and mushroom type percutaneous radiological gastrostomy tubes in this patient group. Patients requiring PRG received either Wills-Oglesby or the skin level Entristar. Retrospective review of the clinical notes was performed capturing demographic data, peristomal infection, tube displacement, tube failure, nutritional status, site of disease onset, and survival. Thirty-five patients (Group 1) had the Wills-Oglesby tube of which 14 (40%) tubes required replacement. The Entristar tube was inserted in 29 patients (Group 2) where 8 (28%) required replacement (NS). The incidence of infection was significantly lower with the Entristar tube, (p<0.001). The mean time to tube removal in Group 2 was 223 days (SD 147; range 71-494 days) due to 'buried bumper syndrome'. We conclude that the Entristar skin level gastrostomy tube is associated with a reduction in peristomal infection, tube failure and blockage compared with the Wills-Oglesby tube.