Childhood Onset Amyotrophic Lateral Sclerosis Associated with SPTLC2 Gain-of-Function Pathogenic Variants: Clinical, Genetic, and Biochemical Insights
Rotem Orbach1, Safoora Syeda1, Payam Mohassel1, Maike Dohrn2, Museer A. Lone3, Sandra Donkervoort1, A. Reghan Foley1, Danique Beijer2, Elif Bayraktar4, Piraye Oflazer4, Pinki Munot5, Aubrey Rose6, Michael Lyons6, Raymond Louie6, Kenneth Gable7, Marcondes C. Franca8, Juan E. Galarza-Brito9, Matthias Eckenweiler10, Alexander Asamoah11, Anirban Majumdar12, Perry Shieh13, Anke Schumann10, Sita D. Gupta7, Arpita Lakhotia14, Kelly Jackson14, Kathrine R. Chao15, Thomas Winder16, Francesco Catapano5, Lucy Feng5, Janbernd Kirschner10, Sitong Chen2, Matt Danzi2, Matthis Synofzik17, Francesco Muntoni5, A. Nazli Başak4, Teresa M. Dunn7, Thorsten Hornemann3, Stephan Zuchner2, Carsten Bonnemann1
1NNDCS, NINDS/NIH, 2University of Miami, 3Institute of Clinical Chemistry, University of Zurich, 4School of Medicine, Koç University, 5UCL Institute of Child Health, 6Greenwood Genetic Center, 7Uniformed Services University of Health Sciences, 8University of Campinas, 9Hospital Pablo Arturo Suarez, 10University of Freiburg, 11University of Louisville, 12Bristol Children's Hospital, 13University of California Los Angeles, 14University of Louisville/Norton Children Medical Group, 15Broad Institute of MIT and Harvard, 16Invitae Corp., 17Hertie-Institute for Clinical Brain Research
Objective:

To characterize the clinical, genetic, and biochemical profiles of eight unrelated patients with juvenile-onset ALS with de-novo recurrent variants in SPTLC2.

Background:

Amyotrophic lateral sclerosis (ALS) is an etiologically heterogeneous, severe, progressive motor neuron disease characterized by the degeneration of upper and lower motor neurons. A childhood onset monogenic form of ALS caused by unrestrained sphingolipid synthesis by serine palmitoyltransferase (SPT) secondary to variants in serine palmitoyltransferase long chain base subunit 1 (SPTLC1) gene has been recently established.

Design/Methods:

Patients were identified using our collaborative network. Clinical examination of the patients along with ancillary and genetic testing, followed by biochemical investigations of patients’ plasma, fibroblasts and/or transfected HEK cells were performed.

Results:

The cohort consists of six patients carrying a dominantly acting variant c.778G>A [p.Glu260Lys] and two patients carrying a dominantly acting variant, c.203T>G [p.Met68Arg], de-novo in all eight. All patients presented with early-childhood onset progressive weakness, with signs and symptoms of upper and lower motor neuron degeneration and without a component of sensory neuropathy. Three patients had progressive academic difficulties, and the most severely affected patient (neonatal onset, died at age 7 years of respiratory failure) was also diagnosed with an autism spectrum disorder. In silico mapping based on the cryo-EM structure of SPT shows that the SPTLC2 E260 residue and the M68 residue interact with the SPT negative regulatory subunit ORMDL3. Biochemical investigations in patients’ plasma, fibroblasts or transfected HEK cells showed excess canonical sphingolipid biosynthesis, similar to SPTLC1-associated ALS.

Conclusions:

SPTLC2 is the second SPT-associated gene that underlies monogenic, childhood-onset ALS and further establishes alterations of sphingolipid metabolism in motor neuron disease pathogenesis. Understanding the common pathogenesis of these two SPT related forms paves the way for targeted therapeutic approaches to dampen SPT overactivity. Of note, serine supplementation should be avoided as it would exacerbate the excess sphingolipid synthesis. 

10.1212/WNL.0000000000205651