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 PARTICIPANTSIn 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 MEASURESDe novo variants present only in the index case and not in unaffected family members. RESULTSTrio 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.

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In the recent years we have witnessed an increasing interest in studying cardiac control in amyotrophic lateral sclerosis (ALS) patients. The variability of the overall duration of cardiac electrical activity comprising depolarization and repolarization periods, namely the QT interval, could provide information about the cardiac control of ALS patients complementary to that derived from the variability of heart period (HP). In this study we evaluate first the HP and QT variabilities in 10 ALS patients at rest in supine position (REST) and during 75° head-up tilt (TILT). The QT interval was approximated as RTapex and RTend intervals, representing the temporal distance between R-wave peak and T-wave apex and end, respectively. HP was taken as the time distance between two consecutive R-wave peaks. Time and frequency domain markers were computed over HP, RTa and RTe beat-to-beat series. The RTa-HP and RTe-HP squared coherence was calculated as well. We found that time and frequency domain indexes derived from QT variability changed during TILT in the direction expected for a healthy population. Frequency domain HP variability markers showed a blunted response to TILT. RTa-HP and RTe-HP squared coherence did not vary during TILT. QT variability and QT-HP coupling markers in ALS patients showed an apparently normal response to TILT not fully mirrored by HP variability indexes.