This cross-sectional cohort study provides the first large-scale data on disease manifestation, progression, and modifying factors, with relevance for counseling of HSP families and planning of future cross-sectional and natural history studies. Later age of onset, specific complicating features, and the SPG11 genotype are strongly associated with more severe disease. Future interventional studies will require stratification for modifiers of disease progression identified in this study. Prospective longitudinal studies will verify progression rates calculated in this baseline analysis.

We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7–24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

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This retrospective series explores temozolomide monotherapy in elderly patients with primary CNS lymphoma (PCNSL) and severe comorbidities. In 17 patients (62-90 years old), complete response rate was 47%, median progression-free survival was five months and median overall survival was 21 months. Five of 17 patients (29.4%) had prolonged responses for at least 12 months and survived for more than 24 months. Three of these patients had a methylated O 6 -methylguanine-DNA methyltransferase (MGMT) promoter while the MGMT status was not assessable in the remaining two patients. Temozolomide monotherapy appears to be effective in a subgroup of elderly PCNSL patients and deserves further evaluation.

word count: 239 Character count for the title: 88 Number of references: 32 Number of tables: 3 Number of figures: 4 Search terms: cerebellar ataxia, hereditary spastic paraplegia, SPG7, paraplegin, Ala510Val variant Study fundingThe study received funding from the "Agence Nationale de la Recherche" (SPATAX-QUEST, to GS), the "Connaitre les Syndromes Cérébelleux" association (to GS), Verum foundation (to AD and GS), and SPATAX Hospital Abstract Objective: We took advantage of a large multinational recruitment to delineate genotypephenotype correlations in a large, trans-European multicenter cohort of SPG7 patients. Methods:We analyzed clinical and genetic data from 241 SPG7 patients, integrating neurological follow-up data. One case was examined neuropathologically.Results: SPG7 patients had a mean age of 35.5±14.3 years (n=233) at onset and presented with either spasticity (n=89), ataxia (n=74), or both (n=45). At the first visit, patients with a longer disease duration (>20 years, n=62) showed more cerebellar dysarthria (p<0.05), deep sensory loss (p<0.01), muscle wasting (p<0.01), ophthalmoplegia (p<0.05), sphincter dysfunction (p<0.05) than those with a shorter duration (<10 years, n=93). Progression, measured by SARA evaluations, showed a mean annual increase of 1.0±1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n=65) presented significantly more often with pyramidal signs (p<0.05), diminished visual acuity due to optic atrophy (p<0.0001), and deep sensory loss (p<0.0001) than those with at least one missense variant (n=176). Patients with at least one Ala510Val variant (58%) were older (37.6±13.7 vs 32.8±14.6, p<0.05) and showed ataxia at onset (p<0.05). Neuropathological examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons.Conclusions: This is the largest SPG7 cohort study to date, and shows a spasticitypredominant phenotype of LOF variants and more frequent cerebellar ataxia and later onset in patients carrying at least one Ala510Val variant. Word 239/250 6 Abbreviations AD: autosomal dominant AR: autosomal recessive LOF: loss of function MBP-SF: myelin basic protein serum factor MLPA: multiplex ligation-dependent probe amplification PolyQ: polyglutamine SARA: Scale for the Assessment and Rating of AtaxiaSCA: spinocerebellar ataxia SPRS: Spastic Paraplegia Rating Scale XL: X-linked Cerebellar ataxia, % (n) 66% (87/132) 58% (56/97) 0.2 Cerebellar dysarthria, % (n) 36% (51/131) 36% (35/93) 0.7 Brisk reflexes, % (n) 76% (96/126) 92% (80/87) 0.003 Babinski sign, % (n) 71% (89/125) 77% (66/86) 0.4 Pyramidal syndrome, % (n) 86% (116/134) 97% (93/96) 0.01 Pes cavus, % (n) 17% (22/129) 30% (28/92) 0.02 Parkinsonism, % (n) 4% (5/131) 5% (5/94) 0.74

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