Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia

Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments

Mendelian adult-onset leukodystrophy genes in Alzheimer´s disease. Critical influence of CSF1R and NOTCH3

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, Cerebral Autosomal Dominant and Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL and CARASIL), Cerebroretinal vasculopathy (CRV), Metachromatic leukodystrophy (MLD), Hereditary diffuse Leukoencephalopathy with spheroids (HDLS), Vanishing white matter disease (VWM) present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer’s disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis 1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10 and TAU), at 5 different developmental stages (Embryo [E15], 2 months, 4 months, 8 months and 18 months), 2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant and single-gene (c-alpha and SKAT tests) based genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (Log2FC>1, adj. p-val<0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ core dense plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H and p.H703Y) in our discovery and validation cohort, composed of 465 AD and MCI Caucasian patients from the UK. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-val = 0.01). Adult onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R and sporadic LOAD, that warrants further investigation

Novel association of Dandy-Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome.

Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy-Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15-related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy-Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy-Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15-related disease

Impact of Genetic and Nongenetic Factors on Body Mass Index and Waist-Hip Ratio Change in HIV-Infected Individuals Initiating Antiretroviral Therapy.

There is limited data on abdominal obesity and the influence of genetics on weight change after antiretroviral therapy (ART) initiation. We assessed body mass index (BMI) and waist hip ration (WHR) change over time in the Swiss HIV Cohort study (SHCS). Mixed-effects models characterizing BMI and WHR change over time in 1090 SHCS participants initiating ART between 2005 and 2015 were developed and used to quantify the influence of demographics, clinical factors, and genetic background. Individuals with CD4 nadir &lt;100 cells/µL gained 6.4 times more BMI than individuals with ≥200, and 2.8 times more WHR than individuals with ≥100 (P &lt; .001) during the first 1.5 and 2.5 years after ART initiation, respectively. The risk of being overweight or obese after 1.5 years increased with CD4 nadir &lt;100 cells/µL compared to 100-199 (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.63-2.74) and ≥200 (OR, 1.69; 95% CI, 1.26-2.32), persisting after 10 years of ART. The risk of abdominal obesity after 2.5 years increased with CD4 nadir &lt;100 compared to ≥100 (OR, 1.35; 95% CI, 1.17-1.54 [in men]; OR, 1.36; 95% CI, 1.18-1.57 [in women]), persisting after 10 years of ART. No significant differences were found across antiretroviral drug classes or genetic scores. The risk of general and abdominal obesity increased with CD4 nadir &lt;100 cells/µL. Based on our results, including the genetic background would not improve obesity predictions in HIV-infected individuals

Clinical and genetic analyses of familial and sporadic frontotemporal dementia patients in Southern Italy

Introduction We investigated the clinical differences between familial and sporadic frontotemporal dementia (FTD), screening for mutations in known FTD genes. Methods We diagnosed 22 affected individuals belonging to eight families and 43 sporadic cases with FTD in Apulia, Southern Italy, in 2 years. Mutations in common causative FTD genes (GRN, MAPT, VCP, and TARDBP) and C9ORF72 expansions were screened. Results Behavioral variant of FTD was the most common clinical subtype (50% and 69% in familial and sporadic cases, respectively). Social conduct impairment/disinhibition, loss of insight, and inflexibility were the most frequent clinical features observed at onset. One new mutation was identified in GRN in family A. Discussion Disease onset in sporadic FTD was more frequently characterized by a clustering of behavioral symptoms with apathy and loss of personal hygiene. Mutations in common causative FTD genes are not a major cause of familial and sporadic FTD in the Southern Italian population

SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families

International audienceBackground: Autosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with high clinical and genetic heterogeneity. In most cases, the cerebellar ataxia is not pure, and complicating clinical features such as pyramidal signs or extraneurological features are found.Objective: To identify the genetic origin of the cerebellar ataxia for 3 consanguineous North African families presenting with ARCA.Methods: Genome-wide high-density SNP genotyping and whole-exome sequencing were performed followed by Sanger sequencing for mutation confirmation.Results: Two variants were identified in SLC25A46. Mutations in this gene have been previously associated with Charcot-Marie-Tooth type 2 and optic atrophy. While the previously reported variant p.Arg340Cys seems to be consistently associated with the same clinical features such as childhood onset, optic atrophy, gait and speech difficulties, and wasting of the lower limbs, the patient with the novel mutation p.Trp160Ser did not present with optic atrophy and his ocular abnormalities were limited to nystagmus and saccadic pursuit.Conclusion: In this study, we report a novel variant (p.Trp160Ser) in SLC25A46 and we broaden the phenotypic spectrum associated with mutations in SLC25A46

Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans

A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans