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Background The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored. Objective To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared with neurologically healthy normal controls (NC) and Alzheimer9s disease (AD) as dementia controls. Design Case control. Setting Academic medical centres. Participants 129 svPPA, 39 PGRN, 186 NC and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN and NC cohorts underwent serum analysis for tumour necrosis factor α (TNF-α) levels. Outcome measures χ 2 Comparison of autoimmune prevalence and follow-up logistic regression. Results There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared with NC. Conclusions svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared with NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 aggregation.

Introduction Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease. Results We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance. Conclusions TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0190-6) contains supplementary material, which is available to authorized users.

Genetics studies have revealed a genetic contribution to susceptibility for common or sporadic forms of neurodegenerative disease such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supra-nuclear palsy (PSP, a syndrome characterized by oculomotor and gait abnormalities). In AD, early genetic mapping approaches have identified rare variants in genes such as APP, PSEN1, and PSEN2that cause familial, early-onset forms.1 APOE was also pinpointed as a late-onset AD susceptibility gene.2 Genome-wide association studies3–5 (GWAS) targeted toward common variants in primarily European populations have identified many variants associated with AD, most clearly near APOE but also consistently near ABCA7, BIN1, CLU, CR1, PICALM, SORL1, and other genes. Next-generation sequencing approaches have also found rare variants with strong effect in the MAPT and TREM2 genes.6,7 In FTD, the most frequently observed mutations in familial cases occur in C9ORF72, GRN, MAPT, TARDBP, and other genes.8 In sporadic cases, a haplotype variant on the long arm of chromosome 17 has been repeatedly associated with PSP.9–11 In addition, GWAS have been performed for sporadic cases of FTD, identifying associated single-nucleotide polymorphisms (SNPs) near TMEM106B12 and BTNL2/HLA-DRA/HLA-DRB5 and RAB38/CTSC,13 as well as for PSP, identifying associated SNPs near MAPT, EIF2AK3, STX6, and MOBP.11 Despite progress in understanding the genetics of neurodegenerative diseases, known genetic risk factors cannot explain a large portion of the heritability of these diseases. For example, in AD, all common variants (including known and unknown risk variants) have been predicted to account for less than 25% of disease variance,14 and known high-penetrance rare variants account for few cases, collectively totaling only a fraction of the estimated 58% to 79% heritability of AD.15 Some of this missing heritability may be due to a blind spot in conventional genetic studies to date. A moderately rare variant with moderate effect size would be too uncommon to be tagged by a standard genotyping array and have too small of an effect to be detected by linkage or genome sequencing in practical sample sizes. The exome array bridges this gap by genotyping at low cost more than 200 000 coding variants identified through sequencing studies (Figure 1). This approach has been applied to phenotypes such as insulin homeostasis,16 bronchopulmonary dysplasia,17 and heart disease.18,19 For AD, Chung et al20 recently reported an exome array study in Korean participants that found an association with APOE, APOC1, and TOMM40 variants (near the APOE locus) but did not identify novel genetic variants. Herein, we report findings from the application of the exome array to the multiancestral Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease (GIFT) Study cohort to determine the contribution of low-frequency coding variants to susceptibility to sporadic AD, PSP, and FTD. Figure 1 Comparison of the Exome Array and Related Genotyping and Sequencing Technologies

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.