Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FDT) are progressive neurodegenerative disorders that, in several cases, overlap in clinical presentation, and genetic and pathological disease mechanisms. About 10–15% of ALS cases and up to 40% of FTD are familial, usually with dominant traits. ALS and FTD, in several cases, share common gene mutations, such as in C9ORF72, TARDBP, SQSTM-1, FUS, VCP, CHCHD10, and TBK-1. Also, several mechanisms are involved in ALS and FTD pathogenesis, such as protein misfolding, oxidative stress, and impaired axonal transport. In addition, neuroinflammation and neuroinflammatory cells, such as astrocytes, oligodendrocytes, microglia, and lymphocytes and, overall, the cellular microenvironment, have been proposed as pivotal players in the pathogenesis the ALS-FTD spectrum disorders. This review overviews the current evidence regarding neuroinflammatory markers in the ALS/FTD continuum, focusing on the neuroinflammatory pathways involved in the genetic cases, moving from post-mortem reports to in vivo biofluid and neuroimaging data. We further discuss the potential link between genetic and autoimmune disorders and potential therapeutic implications.

Context: Mutations in the GHRH receptor (GHRHR) have been detected in the familial type-IB isolated GH deficiency (IGHD-IB) inherited as an autosomal recessive disorder and characterized by a low but detectable serum GH level and good response to substitutive GH therapy. Objective: The aim of our study was the identification of mutations in sporadic patients with a IGHD-IB phenotype. Subjects and Methods: The GHRHR gene was systematically screened by DHPLC in 134 IGHD patients with no family history of the disorder or declared parental consanguinity. Results: We identified a novel variation, Val10Gly, within the signal peptide at the heterozygous state in three patients and in one of 1084 controls (P = 0.004), suggesting that it might contribute to IGHD. The functional analysis showed that the signal peptide is not cleaved from the mutant GHRHR, which in turn is not translocated to the cellular surface, demonstrating that 10Gly drastically affects the receptor correct processing. Because 10Gly was also present in normal-stature relatives of the patients as well as in a control, it is likely that it exerts its effects in the context of other genetic and environmental susceptibility factors. Conclusion: At difference from previous papers reporting GHRHR mutations in familial cases with a clear recessive mode of inheritance, our study was conducted on a large sample of sporadic patients and allowed to discover a novel mechanism of the disease caused by a recurrent dominant mutation in the GHRHR signal peptide associated with incomplete penetrance. A heterozygous Val10Gly mutation in growth hormone releasing hormone receptor signal peptide causes a novel form of isolated growth hormone deficiency.

Background: Alpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson’s disease (PD). A previous study showed that a variant of the alpha-synuclein gene (SNCA), namely the 263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients. Methods: We recruited and genotyped for SNCA Rep1 426 PD patients with age at onset ≥40 years and disease duration ≥4 years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations, and dementia using a multivariate Cox’s proportional hazards regression model. Results: SNCA Rep1 263 carriers showed significantly increased risk of both dementia (HR = 3.03) and visual hallucinations (HR = 2.69) compared to 263 non-carriers. Risk of motor complications did not differ in the two groups. Conclusion: SNCA Rep1 263 allele is associated with a worse cognitive outcome in PD.

Mutations in the 43 kDa transactive-response (TAR)-DNA-binding protein (TARDBP) are associated with 2–5% of familial Amyotrophic Lateral Sclerosis (ALS) cases. TAR DNA-Binding Protein 43 (TDP-43) is an RNA/DNA-binding protein involved in several cellular mechanisms (e.g., transcription, pre-mRNA processing, and splicing). Many ALS-linked TARDBP mutations have been described in the literature, but few phenotypic data on monogenic TARDBP-mutated ALS are available. In this paper, (1) we describe the clinical features of ALS patients carrying mutations in the TARDBP gene evaluated at the Tertiary ALS Center at Maggiore della Carità University Hospital, Novara, Italy, from 2010 to 2020 and (2) present the results of our review of the literature on this topic, analyzing data obtained for 267 patients and highlighting their main clinical and demographic features.

Here, we described the first amyotrophic lateral sclerosis patient presenting the c.881 G > T p.G294V TARDBP mutation in homozygous status. The patient belongs to a large pedigree from Morocco. Except for one older affected brother his parents and remaining 8 sibs are referred to be healthy and do not show any neurological sign or symptom. The lack of evidence of TARDBP deletions of any sizes, together with the presence of several AOH segments, strongly suggests that the homozygosity status of p.G294V in the proband derived from parental consanguinity. A revision of the literature and our cohorts indicates that the p.G294V mutation has been detected in only 15 additional ALS patients in heterozygosity and, except for one additional Moroccan patient, all were of Italian origin. The analysis of microsatellite markers surrounding the TARDBP gene in 8 individuals carrying the p.G294V mutation showed that the haplotypic context of the Moroccan proband is shared with most patients of European origin indicating that they carry the p.G294V mutation inherited from a common ancestor. The analysis of the 15 ALS pedigrees (from literature data and present study), strongly suggests a reduced penetrance of the p.G294V mutation since for 13 of the 15 described p.G294V ALS cases the parents did not show any neurological symptoms. This result has potentially important implications in genetic counseling, since genetic testing of a reduced penetrance mutation on pre-symptomatic individuals proves very difficult to predict the outcome based on the genotype.

Background The T allele of rs9657904 within the CBLB gene was recently found to be significantly associated with multiple sclerosis (MS) in a genome-wide association study in Sardinia. Objective To replicate this association in an independent population with a different genetic background. Methods The rs9657904 variant was typed in a sample of 1435 cases and 1466 controls from the Italian mainland. Results It was found that in this sample also, the common allele T of rs9657904 is significantly positively associated (one-tailed p=7.35×10^-5) and with a comparable effect size with MS (OR=1.31, 95% CI 1.14 to 1.52). Conclusion These data provide further evidence of the association of MS disease with variation within CBLB.