Dataset Information

Peripheral neuropathy and cognitive impairment associated with a novel monoallelic HARS variant.

ABSTRACT: Background:A 49-year-old male presented with late-onset demyelinating peripheral neuropathy, cerebellar atrophy, and cognitive deficit. Nerve biopsy revealed intra-axonal inclusions suggestive of polyglucosan bodies, raising the suspicion of adult polyglucosan bodies disease (OMIM 263570). Methods and Results:While known genes associated with polyglucosan bodies storage were negative, whole-exome sequencing identified an unreported monoallelic variant, c.397G>T (p.Val133Phe), in the histidyl-tRNA synthetase (HARS) gene. While we did not identify mutations in genes known to be associated with polygucosan body disease, whole-exome sequencing revealed an unreported monoallelic variant, c.397G>T in the histidyl-tRNA synthetase (HARS) gene, encoding a substitution (Val133Phe) in the catalytic domain. Expression of this variant in patient cells resulted in reduced aminoacylation activity in extracts obtained from dermal fibroblasts, without compromising overall protein synthesis. Interpretation:Genetic variants in the genes coding for the different aminoacyl-tRNA synthases are associated with various clinical conditions. To date, a number of HARS variant have been associated with peripheral neuropathy, but not cognitive deficits. Further studies are needed to explore why HARS mutations confer a neuronal-specific phenotype.

SUBMITTER: Royer-Bertrand B

PROVIDER: S-EPMC6562026 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Peripheral neuropathy and cognitive impairment associated with a novel monoallelic <i>HARS</i> variant.

Royer-Bertrand Béryl B Tsouni Pinelopi P Mullen Patrick P Campos Xavier Belinda B Mittaz Crettol Lauréane L Lobrinus Alexander J AJ Ghika Joseph J Baumgartner Matthias R MR Rivolta Carlo C Superti-Furga Andrea A Kuntzer Thierry T Francklyn Christopher C Tran Christel C

Annals of clinical and translational neurology 20190524 6

<h4>Background</h4>A 49-year-old male presented with late-onset demyelinating peripheral neuropathy, cerebellar atrophy, and cognitive deficit. Nerve biopsy revealed intra-axonal inclusions suggestive of polyglucosan bodies, raising the suspicion of adult polyglucosan bodies disease (OMIM 263570).<h4>Methods and results</h4>While known genes associated with polyglucosan bodies storage were negative, whole-exome sequencing identified an unreported monoallelic variant, c.397G>T (p.Val133Phe), in t ...[more]

PMID: 31211171

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Project description:BackgroundTo compare neurocognitive functioning of Type 1 diabetic mellitus (T1DM) and healthy adults, and explore risk factors of cognitive dysfunction of T1DM patients, especially the association between cognitive impairment and diabetic peripheral neuropathy (DPN).MethodsSeventy T1DM (age: 32.17 ± 9.57 yr., duration: 8.99 ± 7.02 yr) patients and 48 healthy volunteers were included. All subjects received evaluation of MMSE and MoCA scales. Cognitive function of T1DM patients was evaluated in different cognitive domains. Risk factors affecting cognitive function were further explored.ResultsThree patients with educational level ≤ 6-year were excluded from final analysis. Scores of both MMSE (28.4 ± 1.7 vs. 29.1 ± 1.0, P = 0.005) and MoCA scales (25.9 ± 2.7 vs.27.1 ± 2.4, P = 0.017) in T1DM group were lower than that in control group. For MMSE scale, scores of orientation (9.60 ± 0.79 vs.9.87 ± 0.39, P < 0.001) and language function (8.56 ± 0.65 vs.8.83 ± 0.38, P < 0.001) in T1DM groups were lower than that in control group. For MoCA scale, scores of attention and concentration (2.30 ± 0.74 vs.2.57 ± 0.58, P < 0.001), visuospatial/executive function (4.32 ± 0.91 vs.4.64 ± 0.63, P < 0.001), memory (2.96 ± 1.50 vs.3.66 ± 1.28, P < 0.001), language function (5.71 ± 0.69 vs.5.87 ± 0.39, P = 0.007), and abstraction (1.55 ± 0.68 vs.1.82 ± 0.42, P < 0.001) were lower in T1DM group than that in control group. Logistic regression showed age, fasting C peptide, educational level and nerve conduction velocity (NCV) were associated with cognitive dysfunction diagnosed by MoCA scores for the patients with type 1 diabetes.ConclusionsT1DM adults had mild to moderate cognitive impairment, mainly presenting as dysfunctions of attention and concentration, visuospatial/executive, language, and abstraction. In addition to age, fasting C peptide level, and educational level, DPN, as a diabetic complication, was identified to be associated with cognitive impairments.

Project description:The incidence of Alzheimer's disease (AD) increases with age and is becoming a significant cause of worldwide morbidity and mortality. However, the metabolic perturbation behind the onset of AD remains unclear. In this study, we performed metabolite profiling in both brain (n = 109) and matching serum samples (n = 566) to identify differentially expressed metabolites and metabolic pathways associated with neuropathology and cognitive performance and to identify individuals at high risk of developing cognitive impairment. The abundances of 6 metabolites, glycolithocholate (GLCA), petroselinic acid, linoleic acid, myristic acid, palmitic acid, palmitoleic acid and the deoxycholate/cholate (DCA/CA) ratio, along with the dysregulation scores of 3 metabolic pathways, primary bile acid biosynthesis, fatty acid biosynthesis, and biosynthesis of unsaturated fatty acids showed significant differences across both brain and serum diagnostic groups (P-value < 0.05). Significant associations were observed between the levels of differential metabolites/pathways and cognitive performance, neurofibrillary tangles, and neuritic plaque burden. Metabolites abundances and personalized metabolic pathways scores were used to derive machine learning models, respectively, that could be used to differentiate cognitively impaired persons from those without cognitive impairment (median area under the receiver operating characteristic curve (AUC) = 0.772 for the metabolite level model; median AUC = 0.731 for the pathway level model). Utilizing these two models on the entire baseline control group, we identified those who experienced cognitive decline in the later years (AUC = 0.804, sensitivity = 0.722, specificity = 0.749 for the metabolite level model; AUC = 0.778, sensitivity = 0.633, specificity = 0.825 for the pathway level model) and demonstrated their pre-AD onset prediction potentials. Our study provides a proof-of-concept that it is possible to discriminate antecedent cognitive impairment in older adults before the onset of overt clinical symptoms using metabolomics. Our findings, if validated in future studies, could enable the earlier detection and intervention of cognitive impairment that may halt its progression.

Dataset Information

Peripheral neuropathy and cognitive impairment associated with a novel monoallelic HARS variant.

Publications

Peripheral neuropathy and cognitive impairment associated with a novel monoallelic <i>HARS</i> variant.

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