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Introduction: Hereditary spastic paraplegia (HSP) associated with SPAST mutations (SPG4) is the most frequent form of autosomal dominant HSP accounting approximately for 40% of reported cases. The phenotype associated with HSP due to mutation in the spastin gene (SPG4) tends to be pure HSP with slowly progress- ing spasticity of the legs and hyper- reflexia. Onset is mostly in the third to fifth decade but ample variability has been reported with congenital as well as late onset cases. Methods: We searched an ample series of families harboring SPAST mutation (over 100 patients) for SPG4 patients with in- fantile or congenital onset. We iden- tified 12 patients with onset rang- ing from 0 to 5 years. We reviewed past information, and assessed their clinical condition by means of clini- cal examination and SPRS scale for HSP evaluation. Results: While clini- cal characteristics of infantile-onset SPG4 is apparently similar to more common adult-onset form, the pro- gression of the disease was found to be significantly slower. Conclusions: Age of onset seems to be correlated with a significantly slower and more “benign” course of HSP as compared to classical adult-onset form. This result is clearly relevant for prognos- tic considerations as well as genetic counseling and could even reflect a different pathogenetic mechanism of SPAST mutations during fetal development and early infancy.

BACKGROUND: The most common spinocerebellar ataxias (SCA)--SCA1, SCA2, SCA3, and SCA6--are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset. METHODS: We combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log-normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age. RESULTS: For SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (-0.105±0.005 and -0.056±0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: -0.049±0.002 and -0.090±0.009, respectively; normal: +0.013±0.005 and -0.029±0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age. CONCLUSIONS: These estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies. CLINICALTRIALSGOV, NUMBER: NCT01037777 and NCT00136630 for the French patients. peerReviewed

Summary Background Spinocerebellar ataxias (SCAs) are autosomal, dominantly inherited, fully penetrant neurodegenerative diseases. Our aim was to study the preclinical stage of the most common SCAs: SCA1, SCA2, SCA3, and SCA6. Methods Between Sept 13, 2008, and Dec 1, 2011, offspring or siblings of patients with SCA1, SCA2, SCA3, or SCA6 were enrolled into a prospective, longitudinal observational study at 14 European centres. To be eligible for inclusion in our study, individuals had to have no ataxia and be aged 18–50 years if directly related to individuals with SCA1, SCA2, or SCA3, or 35–70 years if directly related to individuals with SCA6. We did anonymous genetic testing to identify mutation carriers. We assessed participants with clinical scales, questionnaires, and performance-based coordination tests. In eight of the 14 centres, participants underwent MRI. We analysed relations between outcome variables and time from onset (defined as the difference between present age and estimated age at ataxia onset). This study is registered with ClinicalTrials.gov, number NCT01037777. Findings 276 participants met inclusion criteria and agreed to participate, of whom 12 (4%) were excluded from final analysis because DNA samples were missing or genotyping failed. Estimated time from onset was −9 years (IQR −13 to −6) in 50 carriers of the SCA1 mutation, −12 years (–15 to −9) in 31 SCA2 mutation carriers, −8 years (–11 to −6) in 26 SCA3 mutation carriers, and −18 years (–22 to −16) in 16 SCA6 mutation carriers. Compared with non-carriers of each mutation, SCA1 mutation carriers had higher median scores on the scale for the assessment and rating of ataxia (SARA; 0·5 [IQR 0–1·0] vs 0 [0–0]; p=0·0052), as did SCA2 mutation carriers (0·5 [0–2·0] vs 0 [0–0·5]; p=0·0037). SCA2 mutation carriers had lower SCA functional index scores than did non-carriers (–0·43 [–0·91 to −0·07] vs 0·09 [–0·30 to 0·56]; p=0·0007). SCA2 mutation carriers had worse composite cerebellar functional scores than did their non-carrier counterparts (0·915 [0·861–0·959] vs 0·849 [0·764–0·886]; p=0·0039). All other differences between carriers and non-carriers were non-significant. In SCA1 and SCA2 mutation carriers, SARA scores were increased in participants who were closer to the estimated age at onset (SCA1: r =0·36, p=0·0112; SCA2: r =0·50, p=0·0038). 83 individuals (30%) underwent MRI. Voxel-based morphometry showed grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and normalised brainstem volume was lower in SCA2 mutation carriers (median 0·015, range 0·012–0·016) than in non-carriers (0·019, 0·017–0·021; p=0·0107). Interpretation Preclinical SCA1 and SCA2 mutation carriers seem to have mild coordination deficits and abnormalities in the brain that are more common in carriers who are closer to the estimated onset of ataxia. Individuals in this early disease stage could be targeted in future preventive trials. Funding ERA-Net E-Rare and Polish Ministry of Science and Higher Education.

3,7-endo-Disubstituted 2,5-diazabicyclo[2.2.1]heptanes were obtained by iodo-cyclization ofN,N′-di[(S)-1-phenylethyl]-(E,E)-4,5-diamino-1,8-diphenyl-1,7-octadiene and substitutedN,N′-di[(S)-1-phenylethyl]-1,2-diamino-4-alkenes. Removal of only oneN-substituent of the bridged piperazines was achieved by reduction with ammonium formate and Pd/C. Unexpected cleavage of the skeleton of vinyl-substituted bridged piperazines was observed using hydrogen, leading to substituted 3-aminopyrrolidines.