Mutations in the SPTLC1 gene are a cause of juvenile amyotrophic lateral sclerosis that may be amenable to serine supplementation
By
J. O. Johnson,
R. Chia,
D. E. Miller,
R Li,
Y. Abramzon,
R. Kumaran,
N. Alahmady,
Faraz Faghri,
A. E. Renton,
S. D. Topp,
H. A. Pliner,
J. R. Gibbs,
Jinhui Ding,
N. Smith,
N. Landeck,
M A Nalls,
M. R. Cookson,
O. Pletnikova,
J. Troncoso,
S. W. Scholz,
M. S. Sabir,
S Ahmed,
C. L. Dalgard,
C. Troakes,
A. R. Jones,
A Shatunov,
Alfredo Iacoangeli,
A Al Khleifat,
N. Ticozzi,
V. Silani,
C. Gellera,
I. P. Blair,
C Dobson-Stone,
J. B. Kwok,
B. K. England,
E. S. Bonkowski,
The International ALS Genomics Consortium,
The ITALSGEN Consortium,
The FALS Sequencing Consortium,
The American Genome Center,
P. J. Tienari,
D. J. Stone,
K. E. Morrison,
P. J. Shaw,
A Al-Chalabi,
R. H. Brown,
M. Brunetti,
A. Calvo,
G. Mora,
H. Al-Saif,
M. Gotkine,
F. Leigh,
I. J. Chang,
S. J. Perlman,
I. Glass,
C. E. Shaw,
J. E. Landers,
Adriano Chiò,
T. O. Crawford,
B. N. Smith,
B. J. Traynor
Posted 19 Sep 2019
bioRxiv DOI: 10.1101/770339
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. ### Competing Interest Statement PJT and BJT hold the US, Canadian and European patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion in C9orf72. ACh serves on scientific advisory boards for Biogen Idec, Cytokinetics, Italfarmaco, and Neuraltus. AA-C reports consultancies for Biogen Idec, Cytokinetics Inc, OrionPharma, Chronos Therapeutics, and Mitsubishi-Tanabe Pharma. The other authors report no conflicts of interest.
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