Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Janel O Johnson, Ruth Chia, Danny E Miller, Nicola Ticozzi, Vincenzo Silani, Cinzia Gellera, Gabriele Mora, Nicola Ticozzi, Cinzia Tiloca, Claudia Colombrita, Viviana Pensato, Barbara Castellotti, Giacomo P Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina CeredaFranco Taroni, Cinzia Gellera, Antonia Ratti, Vincenzo Silani, Francesco Landi, Gabriele Mora, Ilaria Bartolomei, Enrica Bersano, Corrado Cabona, Claudia Caponnetto, Paola Carrera, Eleonora Dalla Bella, Massimo Filippi, Serena Lattante, Giuseppe Lauria, Rocco Liguori, Paola Mandich, Ilaria Martinelli, Gabriele Mora, Paola Origone, Angelo Quattrini, Claudia Ricci, Nilo Riva, Mario Sabatelli, Fabrizio Salvi, Riccardo Sideri, Rossella Spataro, Veria Vacchiano, Paolo Volanti, Marcella Zollino

Research output: Contribution to journalArticlepeer-review


Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

Original languageEnglish
Pages (from-to) 1236-48
Number of pages13
JournalJAMA Neurology
Volume 78
Issue number10
Publication statusE-pub ahead of print - Aug 30 2021


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