# New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1  
[PERSON]  
1 Department of Paeediatric Neurology, Center for Neuromuscular Disorders in Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Clinic Essen, University of Duisburg,Essen, 45122 Essen, Germany; [EMAIL_ADDRESS] (A.G.);  
[EMAIL_ADDRESS] (U.S.-S.); [EMAIL_ADDRESS] (A.R.)  
2 Institute of Human Genetics, Medical Faculty, RWTH Aachen University, 52062 Aachen, Germany;  
[EMAIL_ADDRESS]  
3 Leibniz-Institut fur Analytische Wissenschaften\(-\)I  
complex [1]. The composition of the serine palmitosyltransferase (SPT) complex determines the substrate preference: the SPTLC1-SPTLC2-SPT small subunit A (SPTSSA) complex indicates a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC3-SPTSSA isozyme uses both, C14-CoA and C16-CoA are substrates with a slight preference for C14-Coenzyme (CoA) [1]. The complex is localized to the endoplasmic reticulum (ER) [2] and expressed at various abundances across the neuromuscular axis and within cultured fibroblasts and blood cells (Supplementary Figure S1).  
Notably, dominant variants are causative for an axonal form of hereditary sensory and autonomic neuropathy (HSA1A: MIM#162400) with onset in the second or third decades of life. Initial symptoms are loss of pain, touch, heat, and cold sensation over the feet, followed by distal muscle wasting and weakness [3; 4]. Loss of pain sensation may lead to chronic skin ulcers and distal amputations [3; 4]. Smaller studies indicated the efficacy of L-serine for SPTLC1-related HSAN [5]. Whereas manifestation of the HSA1A phenotype was linked to a loss of SPTLC1 function based on the pathogenic variants, recently dominant variants were linked to childhood onset of amyotrophic lateral sclerosis based on a pathological gain of SPTLC1 function. These variants disrupt the normal homeostatic SPT regulation, resulting in unregulated activity and elevated levels of canonical SPT products. Pathophysiologically, this is in contrast with pathogenicity of HSA1A-associated SPTLC1 variants. In our patient, a shift of SPT amino acid usage from serine to alanine resulting in elevated levels of deoxysphingolipids was already described, in addition to a detailed description of the pathogenicity [6]. However, the vulnerability of motor neurons is in line with the ubiquitous expression of the protein including the proven expression of SPTLC1 in motor neurons of healthy spinal cord [7].  
It was postulated that phenotypes associated with dominant variants in SPTLC1 may represent a continuum between sensory neuropathy and ALS, complicated by additional symptoms such as cognitive impairment and retina pathology. Future (post-mortem) studies that determine the central nervous system pathology (e.g., TDP43 and tau protein deposition) underlying the motor neuron deficits and the cognitive impairment may resolve the nature of the overlap with other neurodegenerative diseases [7]. By performing unbiased proteomic profiling on immortalized lymphoblastoid cells derived from an SPTLC1-patient with juvenile-onset of ALS without brain abnormalities and normal cognitive function, we identified a set of proteins which might contribute to manifestation of certain symptoms of SPTLC1-pathology upon an individual expression level. The results of our proteomic studies demonstrate that the alanine to serine amino acid substitution at position 20 leads to a 50% decrease of SPTLC1 protein level. Microscopic investigations on the quadriceps muscle derived from our patient revealed a neurogenic atrophy characterized by fiber-type grouping and accompanied by unspecific subsarcolemmal enrichment of mitochondria and unravelled presence of mild inflammation. Latter findings were confirmed by the results of comprehensive quantitative transcript studies.