Early-onset dysphagia and severe neurodevelopmental disorder as early signs in a patient with two novel variants in NARS1: a case report and brief review of the literature.

Aminoacyl-tRNA synthetases (ARSs) aminoacylate tRNA molecules with their cognate amino acid, enabling information transmission and providing substrates for protein biosynthesis. They also take part in nontranslational functions, mediated by the presence of other proteins domains. Mutations in ARS genes have been described as responsive to numerous factors, including neurological, autoimmune, and oncological. Variants of the ARS genes, both in heterozygosity and homozygosity, have been reported to be responsible for different pathological pictures in humankind. We present the case of a patient referred in infancy for failure to thrive and acquired microcephaly (head circumference: -5 SD). During follow-up we highlighted: dysphagia (which became increasingly severe until it became incompatible with oral feeding, with gastrostomy implantation, resulting in resolution of feeding difficulties), strabismus, hypotonia. NCV (Nerve Conduction Velocity) showed four limbs neuropathy, neurophysiological examination performed at 2 years of age mainly sensory and demyelinating. Exome sequencing (ES) was performed, detecting two novel compound heterozygous variants in the NARS1 gene (OMIM *108410): NM_004539:c.[662 A > G]; [1155dup], p.[(Asn221Ser)]; [(Arg386Thrfs*19)], inherited from mother and father respectively. In this article, we would like to focus on the presence of progressive dysphagia and severe neurodevelopmental disorder, associated with two novel variants in the NARS1 gene.

A novel synthesis of two decades of microsatellite studies on European beech reveals decreasing genetic diversity from glacial refugia.

Genetic diversity influences the evolutionary potential of forest trees under changing environmental conditions, thus indirectly the ecosystem services that forests provide. European beech (Fagus sylvatica L.) is a dominant European forest tree species that increasingly suffers from climate change-related die-back. Here, we conducted a systematic literature review of neutral genetic diversity in European beech and created a meta-data set of expected heterozygosity (He) from all past studies providing nuclear microsatellite data. We propose a novel approach, based on population genetic theory and a min-max scaling to make past studies comparable. Using a new microsatellite data set with unprecedented geographic coverage and various re-sampling schemes to mimic common sampling biases, we show the potential and limitations of the scaling approach. The scaled meta-dataset reveals the expected trend of decreasing genetic diversity from glacial refugia across the species range and also supports the hypothesis that different lineages met and admixed north of the European mountain ranges. As a result, we present a map of genetic diversity across the range of European beech which could help to identify seed source populations harboring greater diversity and guide sampling strategies for future genome-wide and functional investigations of genetic variation. Our approach illustrates how to combine information from several nuclear microsatellite data sets to describe patterns of genetic diversity extending beyond the geographic scale or mean number of loci used in each individual study, and thus is a proof-of-concept for synthesizing knowledge from existing studies also in other species. Supplementary Information: The online version contains supplementary material available at 10.1007/s11295-022-01577-4.

In vivo assessment of Lewy body and beta-amyloid copathologies in idiopathic normal pressure hydrocephalus: prevalence and associations with clinical features and surgery outcome.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a clinico-radiological syndrome of elderly individuals likely sustained by different neurodegenerative changes as copathologies. Since iNPH is a potentially reversible condition, assessing neurodegenerative pathologies in vitam through CSF biomarkers and their influence on clinical features and surgical outcome represents crucial steps. METHODS: We measured α-synuclein seeding activity related to Lewy body (LB) pathology by the real-time quaking-induced conversion assay (RT-QuIC) and Alzheimer disease core biomarkers (proteins total-tau, phospho-tau, and amyloid-beta) by immunoassays in the cerebrospinal fluid (CSF) of 293 iNPH patients from two independent cohorts. To compare the prevalence of LB copathology between iNPH participants and a control group representative of the general population, we searched for α-synuclein seeding activity in 89 age-matched individuals who died of Creutzfeldt-Jakob disease (CJD). Finally, in one of the iNPH cohorts, we also measured the CSF levels of neurofilament light chain protein (NfL) and evaluated the association between all CSF biomarkers, baseline clinical features, and surgery outcome at 6 months. RESULTS: Sixty (20.5%) iNPH patients showed α-synuclein seeding activity with no significant difference between cohorts. In contrast, the prevalence observed in CJD was only 6.7% (p = 0.002). Overall, 24.0% of iNPH participants showed an amyloid-positive (A+) status, indicating a brain co-pathology related to Aß deposition. At baseline, in the Italian cohort, α-synuclein RT-QuIC positivity was associated with higher scores on axial and upper limb rigidity (p = 0.003 and p = 0.011, respectively) and lower MMSEc scores (p = 0.003). A+ patients showed lower scores on the MMSEc (p = 0.037) than A- patients. Higher NfL levels were also associated with lower scores on the MMSEc (rho = -0.213; p = 0.021). There were no significant associations between CSF biomarkers and surgical outcome at 6 months (i.e. responders defined by decrease of 1 point on the mRankin scale). CONCLUSIONS: Prevalent LB- and AD-related neurodegenerative pathologies affect a significant proportion of iNPH patients and contribute to cognitive decline (both) and motor impairment (only LB pathology) but do not significantly influence the surgical outcome at 6 months. Their effect on the clinical benefit after surgery over a more extended period remains to be determined.