Mutations in the SPTLC1 gene are a cause of amyotrophic lateral sclerosis that may be amenable to serine supplementation

Johnson, J. O.; Chia, R.; Kumaran, R.; Alahmady, N.; Miller, D. E.; Abramzon, Y.; Faghri, F.; Renton, A. E.; Topp, S. D.; Pliner, H. A.; Gibbs, J. R.; Ding, J.; Smith, N.; Landeck, N.; Nalls, M. A.; Cookson, M. R.; Pletnikova, O.; Troncoso, J.; Scholz, S. W.; Sabir, M. S.; Ahmed, S.; Dalgard, C. L.; Troakes, C.; Jones, A. R.; Shatunov, A.; Iacoangeli, A.; Al Khleifat, A.; Ticozzi, N.; Silani, V.; Gellera, C.; Blair, I. P.; Dobson-Stone, C.; Kwok, J. B.; England, B. K.; Bonkowski, E. S.; The International ALS Genomics Consortium,; The ITALSGEN Consortium,; The FALS Sequencing Consortium,

doi:10.1101/770339

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bioRxiv · 10.1101/770339

Mutations in the SPTLC1 gene are a cause of amyotrophic lateral sclerosis that may be amenable to serine supplementation

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Abstract

Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of childhood motor disorder with a heterogeneous clinical presentation. The underlying causes of this condition are poorly understood, hindering the development of effective therapies. In a whole-exome sequencing trio-family study of three unrelated juvenile patients diagnosed with ALS and failure to thrive, we identified de-novo mutations in SPTLC1 (p.Ala20Ser in two patients and p.Ser331Tyr) not present in their healthy parents or siblings. SPTLC1 encodes a subunit of the serine palmitoyltransferase complex, a key enzyme in sphingolipid biosynthesis. Mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A, with a characteristic increase in plasma levels of neurotoxic deoxymethyl-sphinganine. We found an increase of this metabolite in one of our patients carrying the p.Ala20Ser mutation. Treatment of one of the patients with high dose, oral L-serine led to an increase in body weight, suggesting that serine supplementation may be beneficial among patients carrying mutations in this gene.

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Johnson, J. O., Chia, R., Kumaran, R., Alahmady, N., Miller, D. E., Abramzon, Y., Faghri, F., Renton, A. E., Topp, S. D., Pliner, H. A., Gibbs, J. R., Ding, J., Smith, N., Landeck, N., Nalls, M. A., Cookson, M. R., Pletnikova, O., Troncoso, J., Scholz, S. W., Sabir, M. S., Ahmed, S., Dalgard, C. L., Troakes, C., Jones, A. R., Shatunov, A., Iacoangeli, A., Al Khleifat, A., Ticozzi, N., Silani, V., Gellera, C., Blair, I. P., Dobson-Stone, C., Kwok, J. B., England, B. K., Bonkowski, E. S., The International ALS Genomics Consortium,, The ITALSGEN Consortium,, The FALS Sequencing Consortium,. 2019-09-19. Mutations in the SPTLC1 gene are a cause of amyotrophic lateral sclerosis that may be amenable to serine supplementation. https://doi.org/10.1101/770339

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