Volumetric growth rate of incidental asymptomatic meningiomas: a single-center prospective cohort study.

BACKGROUND: Decision about treatment of incidentally found intracranial meningiomas is controversial and conditioned by the growth potential of these tumors. We aimed to evaluate the growth rate of a cohort of incidentally found asymptomatic meningiomas and to analyze their natural course and the need for eventual treatment. METHODS: A total of 193 patients harboring intracranial meningiomas (85 with 109 incidental and 108 with 112 symptomatic) were included between 2015 and 2019. In the prospective cohort of incidental meningiomas, we measured size at diagnosis, volumetric growth rate (by segmentation software), appearance of symptoms, and need for surgery or radiotherapy. Progression-free survival and risk factors for growth were assessed with Kaplan-Meier survival and Cox regression analyses. RESULTS: Among incidental meningiomas, 94/109 (86.2%) remained untreated during a median follow-up of 49.3 months. Tumor growth was observed in 91 (83.5%) and > 15% growth in 40 (36.7%). Neurological symptoms developed in 1 patient (1.2%). Volume increased an average of 0.51 cm3/year (95% CI, 0.20-0.82). Nine patients were operated (9.2%) and 4 underwent radiotherapy (4.7%). Treatment-related complication rates of incidental and symptomatic meningiomas were 0% and 35.4%, respectively. Persistent neurological defects occurred in 46 (40.7%) of symptomatic versus 2 (2.3%) of incidental meningiomas. Among covariates, only brain edema resulted in an increased risk of significant tumor growth in the female subgroup (Cox regression HR 2.96, 95% CI 1.02-8.61, p = 0.046). Size at diagnosis was significantly greater in the symptomatic meningioma group (37.33 cm3 versus 4.74 cm3, p < 0.001). CONCLUSIONS: Overall, 86% of incidentally found meningiomas remained untreated over the first 4 years of follow-up. The majority grew within the 20% range, yet very few developed symptoms. Treatment-related morbidity was absent in the incidental meningioma group.

Exome-wide rare variant analysis in familial essential tremor.

INTRODUCTION: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing. METHODS: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes. RESULTS: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders. CONCLUSIONS: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.

Vancomycin powder for the prevention of surgical site infection in posterior elective spinal surgery. / Polvo de vancomicina tópico para la prevención de infección de herida quirúrgica en cirugía electiva de columna por vía posterior.

OBJECTIVE: To assess the effectiveness and safety of vancomycin powder as surgical site infection (SSI) prophylaxis in posterior bilateral elective spinal surgery. MATERIALS AND METHODS: Single-center quasi-experimental pre and postintervention comparative cohort study. The post-intervention group received standard intravenous antibiotic prophylaxis plus 1g of vancomycin powder into the surgical field before wound closure, and the pre-intervention group only the intravenous prophylaxis. RESULTS: 150 patients were included in each group. Twelve SSI (7 superficial and 5 deep) occurred in the post-intervention group and 16 SSI (7 superficial and 9 deep) in the pre-intervention group. The risk of deep SSI decreased from 6.0% to 3.3% (OR 0,54, 95%CI 0.17-1.65, p=0.411) with vancomycin powder. The percentage of deep SSI due to gram negative-positive germs were 80%-20% and 33%-67% for the post- and pre-intervention groups, respectively (p=0.265). No local or systemic adverse effects occurred attributable to vancomycin powder. CONCLUSION: In posterior elective spinal surgery, prophylaxis with vancomycin powder did not result in a significantly reduced incidence of superficial and deep SSI. There was a trend towards a higher incidence of deep SSI caused by gram negative microorganisms among those treated with vancomycin.

Cauda equina syndrome due to disk herniation: Long-term functional prognosis.

OBJECTIVE: Cauda equina syndrome (CES) caused by lumbar disk extrusion is classically considered an indication of urgent surgery. CES can be subdivided into CESI (incomplete CES) and CESR (complete CES with urinary retention and incontinence). This paper evaluates the long-term functional outcome of a CES cohort operated on due to disk herniation. METHODS: Single-center retrospective observational study. CES patients due to disk herniation that underwent surgery between 2000 and 2016 were included in the study. Demographic data, time intervals to diagnosis and surgery, preoperative neurologic status and outcome at the end of follow up were recorded. RESULTS: Twenty-two patients were included (median age 44 years). Eight patients were CESR and 14 CESI. Median time from symptom onset to diagnosis was 78h (range, 12-720h), and from diagnosis to surgery 24h (range, 5-120h). Median follow up was 75 months (range, 20-195 months). At the end of follow up, in the CESR group (median time from diagnosis to surgery, 23h) only pain significantly improved after surgery (p=0.007). In the CESI group (median time from diagnosis to surgery 23h) low back pain, sciatica and urinary sphincter function significantly improved (p<0.001). There were no significant differences between early (<48h) operation (n=4) and late (n=18) in terms of sphincter recovery (Fisher's Exact Test, p=0.076). CONCLUSION: Pain associated to CES improved both in the CESI and CESR groups. However, urinary sphincter impairment significantly improved only in the CESI group. No significant differences were found regarding long-term functional outcome between early and late surgery.

Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48).

OBJECTIVE: To describe a new spinocerebellar ataxia (SCA48) characterized by early cerebellar cognitive-affective syndrome (CCAS) and late-onset SCA. METHODS: This is a descriptive study of a family that has been followed for more than a decade with periodic neurologic and neuropsychological examinations, MRI, brain SPECT perfusion, and genetic analysis. Whole exome sequencing was performed in 3 affected and 1 unaffected family member and subsequently validated by linkage analysis of chromosome 16p13.3. RESULTS: Six patients fully developed cognitive-affective and complete motor cerebellar syndrome associated with vermian and hemispheric cerebellar atrophy, suggesting a continuum from a dysexecutive syndrome slowly evolving to a complete and severe CCAS with late truncal ataxia. Three presymptomatic patients showed focal cerebellar atrophy in the vermian, paravermian, and the medial part of cerebellar lobes VI and VII, suggesting that cerebellar atrophy preceded the ataxia, and that the neurodegeneration begins in cerebellar areas related to cognition and emotion, spreading later to the whole cerebellum. Among the candidate variants, only the frameshift heterozygous c.823_824delCT STUB1 (p.L275Dfs*16) pathogenic variant cosegregated with the disease. The p.L275Dfs*16 heterozygous STUB1 pathogenic variant leads to neurodegeneration and atrophy in cognition- and emotion-related cerebellar areas and reinforces the importance of STUB1 in maintaining cognitive cerebellar function. CONCLUSIONS: We report a heterozygous STUB1 pathogenic genetic variant causing dominant cerebellar ataxia. Since recessive mutations in STUB1 gene have been previously associated with SCAR16, these findings suggest a previously undescribed SCA locus (SCA48; MIM# 618093).

Pooled-DNA target sequencing of Parkinson genes reveals novel phenotypic associations in Spanish population.

Eighteen loci and several susceptibility genes have been related to Parkinson's disease (PD). However, most studies focus on single genes in small PD series. Our aim was to establish the genetic background of a large Spanish PD sample. Pooled-DNA target sequencing of 7 major PD genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, GBA, and MAPT) was performed in 562 PD cases. Forty-four variants were found among 114 individuals (20.28%, p<0.05). Among these variants, 30 were found in Mendelian genes (68.18%) and 14 in PD susceptibility genes (31.82%). Seven novel variants were identified. Interestingly, most variants were found in PARK2 and PINK1 genes, whereas SNCA and DJ-1 variants were rare. Validated variants were also genotyped in Spanish healthy controls (n = 597). Carriers of heterozygous PARK2 variants presented earlier disease onset and showed dementia more frequently. PD subjects carrying 2 variants at different genes (1.42%) had an earlier age of onset and a predominantly akinetic-rigid PD phenotype (55.6%, p < 0.05), suggesting that the accumulation of genetic risk variants could modify PD phenotype.

Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease.

Background: The prevalence of dementia in Parkinson disease (PD) increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established. Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients. Methods: We analyzed the coding regions of the amyloid-beta precursor protein (APP), Presenilin 1 and 2 (PSEN1, PSEN2), and Granulin (GRN) genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES) data by single variant and gene base (SKAT-O and burden tests) analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status. Results: Known AD pathogenic mutations in the PSEN1 (p.A79V) and PSEN2 (p.V148I) genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients (p = 2.0 × 10-4), independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site. Conclusions: Pathogenic mutations in the Alzheimer disease-causing genes (PSEN1 and PSEN2) are found in sporadic PD patients. PD patients with cognitive decline carry rare variants in dementia-causing genes. Variants in genes causing Mendelian neurodegenerative diseases exhibit pleiotropic effects.

Target-enriched sequencing of chromosome 17q21.31 in sporadic tauopathies reveals no candidate variants.

The main genetic risk factors for progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are located at chromosome 17q21.31. The identification of risk H1 subhaplotypes suggests that disease-specific variants can be identified by resequencing the 17q21.31 region (1.4 Mb) in carriers of risk H1 subhaplotypes. We hypothesized that PSP/CBD H1 subhaplotype carriers could have undergone a mutational event absent among unaffected carriers leading to the disease risk. We performed this strategy in definite PSP subjects, definite CBD subjects, and healthy controls and tried to replicate the findings in a larger PSP/CBD case-control series. In the resequencing process, 40 candidate variants were identified, but an association between PSP and rs76970862 was replicated only using an unadjusted model. Gene expression association analysis of this variant suggested no potential functional effect. Although our results failed to identify disease-associated variants, it is still possible that the risk of PSP/CBD at chromosome 17 is driven by rare variants, even in PSP/CBD H1 cases or variants located outside the capture regions.

[Role of surgery in spontaneous spondylodiscitis: Experience in 83 consecutive patients]. / Papel de la cirugía en el tratamiento de las espondilodiscitis espontáneas: experiencia en 83 casos consecutivos.

OBJECTIVE: To describe and discuss the role of surgery in the management of spontaneous spondylodiscitis. PATIENTS AND METHODS: Retrospective review on the outcome and complications of a cohort of patients undergoing surgery for spontaneous (non-postoperative) spondylodiscitis of any spinal level or aetiology. RESULTS: From 1995 to 2014, 83 patients (45% females, median age 66) with spondylodiscitis were treated. Microbiological confirmation was obtained in 67.4%. Forty-four percent of patients presented with neurological defect. The most common affected level was thoracic (54.2%). The most frequent isolations were Mycobacterium tuberculosis (229%), Staphylococcus aureus (20.5%) and MRSA (7.2%). Eighty-one patients underwent surgery: simple laminectomy and/or biopsy (22.2%), debridement and posterior fixation (43.2%) and debridement and anterior fixation (34.5%). Improvement of pain or neurological defect was achieved in 86.7% of the patients; 7 patients stabilized and 2 worsened. Complications occurred in 35 patients, mainly pleural effusion (9), anaemia (7) and need for re-debridement (7). Median postoperative stay was 14days. After a median follow up of 8.5 months, 46 patients were considered completely cured, 10 presented sequelae, 22 patients were lost and 5 patients died. No readmissions occurred because of the infectious episode. CONCLUSIONS: Although prolonged and specific antibiotic therapy remains the mainstay of treatment in spontaneous spondylodiscitis, surgery provides samples for microbiological confirmation and histopathologic study, allows debridement of the infectious foci and stabilizes the spine. In our experience, the use of internal metallic fixation material accelerates recovery and does not predispose to chronic infection.

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease.

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.

Delta-amino-levulinic acid dehydratase gene and essential tremor.

BACKGROUND: Several reports found a relationship between increased serum lead levels and the risk for essential tremor (ET), especially in carriers of the minor allele of the single nucleotide polymorphism (SNP) rs1800435 in the aminolevulinate dehydratase (ALAD) gene, which is involved in the synthesis of haem groups. Our group reported decreased risk for ET in carriers of the minor alleles of the rs2071746 and rs1051308 SNPs in the haem-oxygenases 1 and 2 (HMOX1 and HMOX2), respectively, involved in haem metabolism. We analysed whether ALAD rs1800435 alone and their interactions with the four common SNPs in the HMOX1 and HMOX2 genes are associated with the risk for ET. MATERIALS AND METHODS: We analysed the genotype and allele variants frequencies of ALAD rs1800435 in 202 patients with familial ET and 218 healthy controls using a TaqMan method. We also analysed the role of the interaction between ALAD rs1800435 and the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363 and HMOX2 rs1051308 with the risk of developing ET. RESULTS: The frequencies of genotype and allelic variants of ALAD rs1800435 did not differ significantly between patients with ET and controls, and were not influenced by gender. Subjects carrying the ALAD rs1800435CC genotype (wild-type) and the HMOX2 rs1051308GG genotype or the HMOX2 rs1051308G allele had significantly decreased risk for ET. CONCLUSIONS: These results suggest that the ALAD rs1800435 SNP is not related with the risk for ET, but its interaction with the HMOX2 rs1051308 SNP could be weakly associated with the risk for this disease.

Thr105Ile (rs11558538) polymorphism in the histamine-1-methyl-transferase (HNMT) gene and risk for restless legs syndrome.

A recent meta-analysis suggests an association between the rs11558538 single nucleotide polymorphism in the histamine-N-methyl-transferase (HNMT) gene and the risk for Parkinson's disease. Based on the possible relationship between PD and restless legs syndrome (RLS), we tried to establish whether rs11558538 SNP is associated with the risk for RLS. We studied the genotype and allelic variant frequencies of HNMT rs11558538 SNP 205 RLS patients and 410 healthy controls using a TaqMan assay. The frequencies of the HNMT rs11558538 genotypes allelic variants were similar between RLS patients and controls, and were not influenced by gender, family history of RLS, or RLS severity. RLS patients carrying the genotype rs11558538TT had an earlier age at onset, but this finding was based on three subjects only. These results suggest a lack of major association between HNMT rs11558538 SNP and the risk for RLS.

Genome-wide association study in essential tremor identifies three new loci.

We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.

A family study of DRD3 rs6280, SLC1A2 rs3794087 and MAPT rs1052553 variants in essential tremor.

BACKGROUND/OBJECTIVE: Despite many data suggesting a role of genetic factors in the risk for essential tremor (ET), the responsible genes have not been identified. We analyzed in ET Spanish families three single nucleotide polymorphisms (SNPs): DRD3 rs6280, SLC1A2 rs3794087, and MAPT rs1052553) previously related to an increased risk for developing the disease. METHODS: We recruited 45 subjects with ET and 13 subjects without tremor belonging to 11 families who were evaluated because of familial tremor. Diagnosis of probable or definite ET was done according to TRIG criteria. Genotyping of the 3 SNPs was done using TaqMan-based qPCR assays. Data were compared with those of healthy controls of our laboratory. Family-based association testing for disease traits was performed as well. RESULTS: rs6280 and rs3794087 genotype and allelic frequencies did not differ significantly between subjects with ET and healthy controls. However, rs1052553AA genotype and the allele rs1052553A allele were significantly more frequent among ET patients. rs1052553A allele was non-significantly overrepresented in ET patients compared with controls when considering only the more severely affected member of each ET family. Family-based association test for disease traits showed lack of association between ET and the three SNPs studied. CONCLUSIONS: Our results showed a lack of association between rs6280 and rs3794087 with the risk for ET, though a marginal increased risk for ET was observed among the rs1052553A allele carriers, which was not confirmed with a family-based association study.

Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). OBJECTIVE: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. METHODS: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender. RESULTS: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. CONCLUSIONS: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern.

Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.

BACKGROUND: Most sequencing studies in Parkinson's disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases. To date, there is no systematic study that sequences the most common PD causing genes with Mendelian inheritance [α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1) and DJ-1 (Daisuke-Junko-1)] and susceptibility genes [glucocerebrosidase beta acid (GBA) and microtubule-associated protein tau (MAPT)] identified through genome-wide association studies (GWAS) in a European-American case-control sample (n=815). RESULTS: Disease-causing variants in the SNCA, LRRK2 and PARK2 genes were found in 2% of PD patients. The LRRK2, p.G2019S mutation was found in 0.6 % of sporadic PD and 4.8 % of familial PD cases. Gene-based analysis suggests that additional variants in the LRRK2 gene also contribute to PD risk. The SNCA duplication was found in 0.8 % of familial PD patients. Novel variants were found in 0.8% of PD cases and 0.6 % of controls. Heterozygous Gaucher disease-causing mutations in the GBA gene were found in 7.1 % of PD patients. Here, we established that the GBA variant (p.T408M) is associated with PD risk and age at onset. Additionally, gene-based and single-variant analyses demostrated that GBA gene variants (p.L483P, p.R83C, p.N409S, p.H294Q and p.E365K) increase PD risk. CONCLUSIONS: Our data suggest that the impact of additional untested coding variants in the GBA and LRRK2 genes is higher than previously estimated. Our data also provide compelling evidence of the existence of additional untested variants in the primary Mendelian and PD GWAS genes that contribute to the genetic etiology of sporadic PD.

A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease.

The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD.

Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Multiple Sclerosis.

Several neurochemical, neuropathological, and experimental data suggest a possible role of oxidative stress in the ethiopathogenesis of multiple sclerosis(MS). Heme-oxygenases(HMOX) are an important defensive mechanism against oxidative stress, and HMOX1 is overexpressed in the brain and spinal cord of MS patients and in experimental autoimmune encephalomyelitis(EAE). We analyzed whether common polymorphisms affecting the HMOX1 and HMOX2 genes are related with the risk to develop MS. We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations(CNVs) of these genes in 292 subjects MS and 533 healthy controls, using TaqMan assays. The frequencies of HMOX2 rs1051308AA genotype and HMOX2 rs1051308A and HMOX1 rs2071746A alleles were higher in MS patients than in controls, although only that of the SNP HMOX2 rs1051308 in men remained as significant after correction for multiple comparisons. None of the studied polymorphisms was related to the age at disease onset or with the MS phenotype. The present study suggests a weak association between HMOX2 rs1051308 polymorphism and the risk to develop MS in Spanish Caucasian men and a trend towards association between the HMOX1 rs2071746A and MS risk.

MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium.

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.

Assessing the role of TUBA4A gene in frontotemporal degeneration.

The tubulin alpha 4a (TUBA4A) gene has been recently associated with amyotrophic lateral sclerosis. Interestingly, some of the mutation carriers were also diagnosed with frontotemporal degeneration (FTD) or mild cognitive impairment. With the aim to investigate the role of TUBA4A in FTD, we screened TUBA4A in a series of 814 FTD patients from Spain. Our data did not disclose any nonsense or missense variant in the cohort, thus suggesting that TUBA4A mutations are not associated with FTD.