Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal α-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorder

Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3–5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed

Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics

Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. Expression of arginine-rich DPRs in cells induced spontaneous stress granule assembly that required both eIF2α phosphorylation and G3BP. Together with recent reports showing that DPRs affect nucleocytoplasmic transport, our results point to an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD

Silicon in foods: content and bioavailability

The silicon content of various foodstuffs marketed in Belgium was measured by a validated graphite furnace absorption spectrometric method. Dietary intake has been identified as the major source of silicon. However, data on its bioavailability remain scarce and insufficient. In vitro methods can provide an indication of bioavailability in case of lacking in vivo data. Bioavailability of silicon from different foodstuffs was estimated using an in vitro continuous flow gastroduodenal simulation method. The major food sources of silicon were unrefined grains, cereal products and root vegetables. The availabilities of silicon from, meat, milk and beers were high, whereas low availability was observed for seafood and cereal products. Plotting the availability data versus the total elemental silicon content of the foods revealed an exponential inverse relationship. The inverse relationship between silicon content and silicon availability was found in all foods, with the exception of various silicon containing drinks. Nevertheless, food categories classified as major silicon sources in the diet still appear to provide the highest absolute amounts of available silicon per 100 g of food including breakfast cereals, bread and baking products, and beers

Silicon in foods: content and bioavailability

The silicon content of various foodstuffs marketed in Belgium was measured by a validated graphite furnace absorption spectrometric method. Dietary intake has been identified as the major source of silicon. However, data on its bioavailability remain scarce and insufficient. In vitro methods can provide an indication of bioavailability in case of lacking in vivo data. Bioavailability of silicon from different foodstuffs was estimated using an in vitro continuous flow gastroduodenal simulation method. The major food sources of silicon were unrefined grains, cereal products and root vegetables. The availabilities of silicon from, meat, milk and beers were high, whereas low availability was observed for seafood and cereal products. Plotting the availability data versus the total elemental silicon content of the foods revealed an exponential inverse relationship. The inverse relationship between silicon content and silicon availability was found in all foods, with the exception of various silicon containing drinks. Nevertheless, food categories classified as major silicon sources in the diet still appear to provide the highest absolute amounts of available silicon per 100 g of food including breakfast cereals, bread and baking products, and beers

Whole-genome sequencing reveals a coding non-pathogenic variant tagging a non-coding pathogenic hexanucleotide repeat expansion in C9orf72 as cause of amyotrophic lateral sclerosis

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has a familial cause in 10% of patients. Despite significant advances in the genetics of the disease, many families remain unexplained. We performed whole-genome sequencing in five family members from a pedigree with autosomal-dominant classical ALS. A family-based elimination approach was used to identify novel coding variants segregating with the disease. This list of variants was effectively shortened by genotyping these variants in 2 additional unaffected family members and 1500 unrelated population-specific controls. A novel rare coding variant in SPAG8 on chromosome 9p13.3 segregated with the disease and was not observed in controls. Mutations in SPAG8 were not encountered in 34 other unexplained ALS pedigrees, including 1 with linkage to chromosome 9p13.2–23.3. The shared haplotype containing the SPAG8 variant in this small pedigree was 22.7 Mb and overlapped with the core 9p21 linkage locus for ALS and frontotemporal dementia. Based on differences in coverage depth of known variable tandem repeat regions between affected and non-affected family members, the shared haplotype was found to contain an expanded hexanucleotide (GGGGCC)n repeat in C9orf72 in the affected members. Our results demonstrate that rare coding variants identified by whole-genome sequencing can tag a shared haplotype containing a non-coding pathogenic mutation and that changes in coverage depth can be used to reveal tandem repeat expansions. It also confirms (GGGGCC)n repeat expansions in C9orf72 as a cause of familial ALS

Absorption of silicon from artesian aquifer water and its impact on bone health in postmenopausal women: a 12 week pilot study

<p>Abstract</p> <p>Background</p> <p>Decreased bone mineral density and osteoporosis in postmenopausal women represents a growing source of physical limitations and financial concerns in our aging population. While appropriate medical treatments such as bisphosphonate drugs and hormone replacement therapy exist, they are associated with serious side effects such as osteonecrosis of the jaw or increased cardiovascular risk. In addition to calcium and vitamin D supplementation, previous studies have demonstrated a beneficial effect of dietary silicon on bone health. This study evaluated the absorption of silicon from bottled artesian aquifer water and its effect on markers of bone metabolism.</p> <p>Methods</p> <p>Seventeen postmenopausal women with low bone mass, but without osteopenia or osteoporosis as determined by dual x-ray absorptiometry (DEXA) were randomized to drink one liter daily of either purified water of low-silicon content (PW) or silicon-rich artesian aquifer water (SW) (86 mg/L silica) for 12 weeks. Urinary silicon and serum markers of bone metabolism were measured at baseline and after 12 weeks and analyzed with two-sided t-tests with p < 0.05 defined as significant.</p> <p>Results</p> <p>The urinary silicon level increased significantly from 0.016 ± 0.010 mg/mg creatinine at baseline to 0.037 ± 0.014 mg/mg creatinine at week 12 in the SW group (p = 0.003), but there was no change for the PW group (0.010 ± 0.004 mg/mg creatinine at baseline vs. 0.009 ± 0.006 mg/mg creatinine at week 12, p = 0.679). The urinary silicon for the SW group was significantly higher in the silicon-rich water group compared to the purified water group (p < 0.01). NTx, a urinary marker of bone resorption did not change during the study and was not affected by the silicon water supplementation. No significant change was observed in the serum markers of bone formation compared to baseline measurements for either group.</p> <p>Conclusions</p> <p>These findings indicate that bottled water from artesian aquifers is a safe and effective way of providing easily absorbed dietary silicon to the body. Although the silicon did not affect bone turnover markers in the short-term, the mineral's potential as an alternative prevention or treatment to drug therapy for osteoporosis warrants further longer-term investigation in the future.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: NCT01067508</p