Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects 1/350 individuals in the United Kingdom. The cause of amyotrophic lateral sclerosis is unknown in the majority of cases. Two-sample Mendelian randomization enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk. We obtained genome-wide association study summary statistics for serum concentrations of 566 metabolites which were population matched with a genome-wide association study of amyotrophic lateral sclerosis. For each metabolite, we performed Mendelian randomization using an inverse variance weighted estimate for significance testing. After stringent Bonferroni multiple testing correction, our unbiased screen revealed three metabolites that were significantly linked to the risk of amyotrophic lateral sclerosis: Estrone-3-sulphate and bradykinin were protective, which is consistent with literature describing a male preponderance of amyotrophic lateral sclerosis and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit the breakdown of bradykinin. Serum isoleucine was positively associated with amyotrophic lateral sclerosis risk. All three metabolites were supported by robust Mendelian randomization measures and sensitivity analyses; estrone-3-sulphate and isoleucine were confirmed in a validation amyotrophic lateral sclerosis genome-wide association study. Estrone-3-sulphate is metabolized to the more active estradiol by the enzyme 17ß-hydroxysteroid dehydrogenase 1; further, Mendelian randomization demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17ß-hydroxysteroid dehydrogenase 1, modify risk for amyotrophic lateral sclerosis. Finally, in a zebrafish model of C9ORF72-amyotrophic lateral sclerosis, we present evidence that estradiol is neuroprotective. Isoleucine is metabolized via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction that consumes vitamin B12. Multivariable Mendelian randomization revealed that the toxic effect of isoleucine is dependent on the depletion of vitamin B12; consistent with this, rare variants which reduce the function of MMUT are protective against amyotrophic lateral sclerosis. We propose that amyotrophic lateral sclerosis patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12.

A review of Mendelian randomization in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a relatively common and rapidly progressive neurodegenerative disease that, in the majority of cases, is thought to be determined by a complex gene-environment interaction. Exponential growth in the number of performed genome-wide association studies combined with the advent of Mendelian randomization is opening significant new opportunities to identify environmental exposures that increase or decrease the risk of amyotrophic lateral sclerosis. Each of these discoveries has the potential to shape new therapeutic interventions. However, to do so, rigorous methodological standards must be applied in the performance of Mendelian randomization. We have reviewed Mendelian randomization studies performed in amyotrophic lateral sclerosis to date. We identified 20 Mendelian randomization studies, including evaluation of physical exercise, adiposity, cognitive performance, immune function, blood lipids, sleep behaviours, educational attainment, alcohol consumption, smoking and type 2 diabetes mellitus. We have evaluated each study using gold standard methodology supported by the Mendelian randomization literature and the STROBE-Mendelian randomization checklist. Where discrepancies exist between Mendelian randomization studies, we suggest the underlying reasons. A number of studies conclude that there is a causal link between blood lipids and risk of amyotrophic lateral sclerosis; replication across different datasets and even different populations adds confidence. For other putative risk factors, such as smoking and immune function, Mendelian randomization studies have provided cause for doubt. We highlight the use of positive control analyses in choosing exposure single nucleotide polymorphisms (SNPs) to make up the Mendelian randomization instrument, use of SNP clumping to avoid false positive results due to SNPs in linkage and the importance of multiple testing correction. We discuss the implications of survival bias for study of late age of onset diseases such as amyotrophic lateral sclerosis and make recommendations to mitigate this potentially important confounder. For Mendelian randomization to be useful to the amyotrophic lateral sclerosis field, high methodological standards must be applied to ensure reproducibility. Mendelian randomization is already an impactful tool, but poor-quality studies will lead to incorrect interpretations by a field that includes non-statisticians, wasted resources and missed opportunities.

Cerebrotendinous Xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare but treatable neurometabolic disorder of lipid storage and bile acid synthesis. Whilst CTX is said to present with the classic triad of juvenile onset cataracts, tendon xanthomata and progressive ataxia, the diversity of presentation can be such that the diagnosis may be substantially delayed resulting in permanent neurological disability. METHODS: A retrospective review of the clinical characteristics and imaging findings of 4 patients with CTX presenting to the Sheffield Ataxia Centre over a period of 25 years. RESULTS: Although CTX-related symptoms were present from childhood, the median age at diagnosis was 39 years. Only 1 of the 4 cases had tendon xanthomata, only 2 cases had juvenile onset cataracts and 3 had progressive ataxia with one patient presenting with spastic paraparesis. Serum cholestanol was elevated in all 4 patients, proving to be a reliable diagnostic tool. In addition, cholestanol was raised in the CSF of 2 patients who underwent lumbar puncture. Despite treatment with chenodeoxycholic acid (CDCA) and normalization of serum cholestanol, CSF cholestanol remained high in one patient, necessitating increase in the dose of CDCA. Further adjustments to the dose of CDCA in the patient with raised CSF cholestanol resulted in slowing of progression. Two of the patients who have had the disease for the longest continued to progress, one subsequently dying from pneumonia. CONCLUSION: A high index of suspicion for CTX, even in the absence of the classical triad is essential in reaching such diagnosis. The earlier the diagnosis and treatment, the better the outcome.