The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients

Abstract The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a G4C2-repeat expansion in C9orf72. However, the lower limit for pathological repeats has not been established and expansions with different sizes could have different pathological consequences. One of the implicated disease mechanisms is haploinsufficiency. Previously, we identified expansion-specific hypermethylation at the 5′ CpG-island near the G4C2-repeat, but only in a fraction of carriers (up to 36 %). Here, we tested the hypothesis that the G4C2-repeat itself could be the main site of methylation. To evaluate (G4C2) n -methylation, we developed a novel assay, which was validated by an independent methylation-sensitive restriction enzyme assay. Notably, both assays are qualitative but not quantitative. Blood DNA was available for 270 unrelated individuals, including 71 expansion carriers. In addition, we investigated blood DNA from family members of 16 probands, and 38 DNA samples from multiple tissues of 10 expansion carriers. Finally, we tested DNA from different tissues of an ALS patient carrying a somatically unstable 90-repeat. We demonstrated that the G4C2-expansion is generally methylated in unrelated carriers of alleles>50 repeats (97 %), while small (
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Insoluble protein inclusions accumulate in somatic cells in amyotrophic lateral sclerosis. The most common gene mutations associated with this pathology areSOD1 andC9orf72. Protein aggregates can be removed from cells by autophagy. We studied the relationship between the presence of genetic abnormalities in theSOD1 andC9orf72 genes and changes in autophagy in lymphomonocytes in amyotrophic lateral sclerosis. The study included 85 patients with amyotrophic lateral sclerosis and 15 healthy volunteers. Genetic analysis for the presence of mutations in theSOD1 andC9orf72 genes and detection of autophagy marker LC3 in lymphomon...
Source: Bulletin of Experimental Biology and Medicine - Category: Biology Source Type: research
The Pharmacogenomics Journal, Published online: 17 October 2019; doi:10.1038/s41397-019-0111-3Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?
Source: The Pharmacogenomics Journal - Category: Drugs & Pharmacology Authors: Source Type: research
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Source: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration - Category: Neurology Authors: Source Type: research
Authors: Ono Y, Yoshikura N, Takekoshi A, Ohe N, Hayashi H, Yamada M, Hayashi Y, Kimura A, Shimohata T Abstract A 57-year-old woman with amyotrophic lateral sclerosis (ALS) receiving mechanical ventilation developed intractable right temporal headache. She was diagnosed with brain abscess secondary to chronic suppurative otitis media. In this case, the otitis media was caused by nasopharyngeal reflux associated with eustachian tube muscle weakness and a supine position. In addition, ALS patients under mechanical ventilation have a limited ability to convey their pain. Their complaints are often overlooked because m...
Source: Internal Medicine - Category: Internal Medicine Tags: Intern Med Source Type: research
Last month, House Speaker Nancy Pelosi unveiled aradical drug pricing plan, H.R. 3, that could jeopardize the development of innovative treatments for some of the most challenging diseases and leave U.S. patients behind. For example,researchers are focused every day on finding new treatments and cures for amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig ’s Disease), but Pelosi’s plan could threaten future treatments for ALS by imposing government-set prices on critical medicines, creating increased uncertainty and eroding incentives for investment into risky research and development (R&D).
Source: The Catalyst - Category: Pharmaceuticals Authors: Tags: Research and Development ALS Source Type: news
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Source: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration - Category: Neurology Authors: Source Type: research
Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disease affecting only males characterized by progressive muscular atrophy and weakness in bulbar and limb muscles. The present study aimed to evaluate the features of velopharyngeal dysfunction (VPD) in SBMA subjects by an acoustic analysis of speech. Twenty-three genetically confirmed patients with SBMA were enrolled and assessed their speech by measuring the nasalance score with a Nasometer II. The nasalance scores of the SBMA group was higher than that of healthy controls (p  = .035) and significantly correlated with the total score of the revi...
Source: Journal of the Neurological Sciences - Category: Neurology Authors: Source Type: research
This study assessed the bioequivalence between 40‐mg BHV‐0223 and standard 50‐mg oral riluzole tablets, and the food effect on BHV‐0223 pharmacokinetics in healthy volunteers. Overall, 133 healthy subjects received BHV‐0223 and riluzole tablets under fasted conditions. Geometric mean ratios for the area under the plasma concentration–time curve (AUC) from time zero to time of last nonzero concentration (AUC0 ‐t) (89.9%; confidence interval [CI], 87.3% –92.5%), AUC from time zero to infinity (AUC0 ‐∞) (89.8%; CI, 87.3% –92.4%), and maximum observed concentration (112.7%; CI, 105.5%&ndas...
Source: Clinical Pharmacology in Drug Development - Category: Drugs & Pharmacology Authors: Tags: Original Manuscript Source Type: research
Conclusions This study demonstrates that cerebral degeneration in ALS is more pronounced in the motor than prefrontal cortex, that multicenter MRS studies are feasible, and that motor tNAA/Ino shows promise as a potential biomarker.
Source: Neurology Clinical Practice - Category: Neurology Authors: Tags: MRI, MRS, Amyotrophic lateral sclerosis Research Source Type: research
This study assessed the bioequivalence between 40‐mg BHV‐0223 and standard 50‐mg oral riluzole tablets, and the food effect on BHV‐0223 pharmacokinetics in healthy volunteers. Overall, 133 healthy subjects received BHV‐0223 and riluzole tablets under fasted conditions. Geometric mean ratios for the area under the plasma concentration–time curve (AUC) from time zero to time of last nonzero concentration (AUC0 ‐t) (89.9%; confidence interval [CI], 87.3% –92.5%), AUC from time zero to infinity (AUC0 ‐∞) (89.8%; CI, 87.3% –92.4%), and maximum observed concentration (112.7%; CI, 105.5%&ndas...
Source: Clinical Pharmacology in Drug Development - Category: Drugs & Pharmacology Authors: Tags: Original Manuscript Source Type: research
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