The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one third of familial ALS cases of outbred European descent making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

A BS TRACT: Background: Predicting prognosis in Parkinson's disease (PD) has important implications for individual prognostication and clinical trials design and targeting novel treatments. Blood biomarkers could help in this endeavor. Methods: We identified 4 blood biomarkers that might predict prognosis: apolipoprotein A1, C-reactive protein, uric acid and vitamin D. These biomarkers were measured in baseline serum from 624 Parkinson's disease subjects (median disease duration, 1.0 years; interquartile range, 0.5-2.0) from the Oxford Discovery prospective cohort. We compared these biomarkers against PD subtypes derived from clinical features in the baseline cohort using data-driven approaches. We used multilevel models with MDS-UPDRS parts I, II, and III and Montreal Cognitive Assessment as outcomes to test whether the biomarkers predicted subsequent progression in motor and nonmotor domains. We compared the biomarkers against age of PD onset and age at diagnosis. The q value, a false-discovery rate alternative to P values, was calculated as an adjustment for multiple comparisons. Results: Apolipoprotein A1 and C-reactive protein levels differed across our PD subtypes, with severe motor disease phenotype, poor psychological well-being, and poor sleep subtype having reduced apolipoprotein A1 and higher Creactive protein levels. Reduced apolipoprotein A1, higher C-reactive protein, and reduced vitamin D were associated with worse baseline activities of daily living (MDS-UPDRS II). Conclusion: Baseline clinical subtyping identified a proinflammatory biomarker profile significantly associated with a severe motor/nonmotor disease phenotype, lending biological validity to subtyping approaches. No blood biomarker predicted motor or nonmotor prognosis.

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Measurement of oxalate in the blood is essential for monitoring primary hyperoxaluria patients with progressive renal impairment and on dialysis prior to transplantation. As no external quality assurance scheme is available for this analyte, we conducted a sample exchange scheme between six laboratories specifically involved with the investigation of primary hyperoxaluria to compare results. The methodologies compared were gas chromatography/mass spectrometry (GCMS), ion chromatography with mass spectrometry (ICMS), and enzymatic methods using oxalate oxidase and spectrophotometry. Although individual laboratories performed well in terms of reproducibility and linearity, there was poor agreement (absolute values) between centres as illustrated by a longer-term comparison of patient results from two of the participating laboratories. This situation was only partly related to differences in calibration and mainly reflected the lower recoveries seen with the ultrafiltration of samples. These findings lead us to conclude that longitudinal monitoring of primary hyperoxaluria patients with deteriorating kidney function should be performed by a single consistent laboratory and the methodology used should always be defined. In addition, plasma oxalate concentrations reported in registry studies and those associated with the risk of systemic oxalosis in published studies need to be interpreted in light of the methodology used. A reference method and external quality assurance scheme for plasma oxalate analysis would be beneficial.

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