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Heterozygous SPTLC1 p.Leu39del is a major cause of slow-progressing juvenile ALS
  1. Claire Guissart1,2,
  2. Elisa De la Cruz3,
  3. Olivier Flabeau4,
  4. Aude-Marie Grapperon5,
  5. Giovanni Corazza5,
  6. Lucie Junilhon1,
  7. Jean-Charles Delmas1,
  8. Stéphanie Millecamps6,
  9. Anne Polge1,
  10. Maria del Mar Amador7,
  11. Francois Salachas7,
  12. Julie Rochat8,
  13. Cyril Goizet9,
  14. Raul Juntas Morales3,
  15. Serge Lumbroso1,2,
  16. Pascal Philibert1,
  17. David Cheillan8,10,
  18. Kevin Mouzat1,2
  1. 1 Laboratoire de Biochimie et Biologie Moléculaire, CHU Nimes, Univ Montpellier, Nîmes, France
  2. 2 The Neuroscience Institute of Montpellier, INM, INSERM, Montpellier, France
  3. 3 Department of Neurology, Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier, France
  4. 4 Centre de Compétence des Maladies Neuromusculaires de Bayonne, Centre Hospitalier de la Cote Basque, Bayonne, France
  5. 5 Reference Center for Neuromuscular Diseases and ALS, Timone University Hospital, Marseille, France
  6. 6 Sorbonne Université, Institut du Cerveau - Paris Brain Institute, ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France
  7. 7 Centre référent SLA, Département de Neurologie, APHP, Hôpital Pitié-Salpêtrière, Paris, France
  8. 8 Service de Biochimie et Biologie Moléculaire, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France
  9. 9 Rare Diseases Laboratory: Genetics and Metabolism (MRGM), INSERM U1211, Bordeaux University, Bordeaux, France
  10. 10 Laboratoire CarMeN - Cardiovasculaire Métabolisme diabétologie et Nutrition, Inserm U1060, INRAE UMR1397, Université Claude Bernard Lyon 1, Pierre-Bénite, France
  1. Correspondence to Dr Claire Guissart, Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes, Nîmes, France; claire.guissart{at}inserm.fr

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Introduction

Juvenile amyotrophic lateral sclerosis (JALS) is a rare and severe motor neuron disease defined by an onset before the age of 25 with currently no available therapy. Only a few genes have been linked to JALS such as ALS2, FUS, SETX, SPG11, SIGMAR1, and more recently SPTLC1. This gene encodes one of the subunits of serine palmitoyltransferase (SPT), which is the first enzyme for de novo sphingolipid biosynthesis.1 Initially, SPTLC1 was a known cause of hereditary sensory and autonomic neuropathy, type 1A.2 In 2021, Johnson et al 3 and Mohassel et al 4 extended the phenotype associated with this gene by reporting several mutations of SPTLC1 in patients with JALS.

Methods

We performed molecular analysis of 1130 patients with ALS, with 50 of them meeting the criteria for juvenile ALS. Plasma lipid profile of patients with SPTLC1 mutation were analysed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and tandem mass spectrometry (MS/MS).

Results

We identified a total of five individuals harbouring the heterozygous already known pathogenic SPTLC1 (NM_006415.4): c.115_117del, p.(Leu39del) variant (figure 1). Analysis of the single-nucleotide polymorphisms (SNPs) surrounding the mutation allowed us to confidently exclude the possibility of a founder effect (online supplemental material 1).

Supplemental material

[jnnp-2023-331753supp001.pdf]
Figure 1

Identification of SPTLC1 p.Leu39del mutation in four non-related families. (A) Pedigree showing segregation of the disease with p.Leu39del mutation. (B) Deficit of intrinsic hand muscles and wrist extensors with atrophy and tongue muscle wasting in patient 3B. (C) Plasma lipid profile of patients with SPTLC1 p.Leu39del mutation. CER, ceramide; SM, sphingomyelin; N, normal range; high CER or SM levels are shown in red and low levels in light blue. (D) In silico modelling of missense SPTLC1 variants. Homology model of the human SPT heterodimer wild-type (on the left) and with Leu39del (on the right) …

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Footnotes

  • Contributors Conceptualisation: CGu. Methodology: CGu. Three-dimensional modelling: J-CD and PP. Formal analysis: CGu, DC, JR, KM, LJ and SM. Investigation: OF, CGo, A-MG; RJM, EDLC, FS and MdMA. Writing—original draft preparation: GC. Writing—review and editing: GC, DC, EDLC, FS, KM, OF and SM. All authors have read and agreed to the published version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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