Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (HSAN1) due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS–expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.

Gaucher disease (GD) is an autosomal recessive inherited lysosomal storage disease that often presents in early childhood and is associated with damage to multiple organ systems. Many challenges associated with GD diagnosis and management arise from the considerable heterogeneity of disease presentations and natural history. Phenotypic classification has traditionally been based on the absence (in type 1 GD) or presence (in types 2 and 3 GD) of neurological involvement of varying severity. However, patient management and prediction of prognosis may be best served by a dynamic, evolving definition of individual phenotype rather than by a rigid system of classification. Patients may experience considerable delays in diagnosis, which can potentially be reduced by effective screening programs; however, program implementation can involve ethical and practical challenges. Variation in the clinical course of GD and an uncertain prognosis also complicate decisions concerning treatment initiation, with differing stakeholder perspectives around efficacy and acceptable cost/benefit ratio. We review the challenges faced by physicians in the diagnosis and management of GD in pediatric patients. We also consider future directions and goals, including acceleration of accurate diagnosis, improvements in the understanding of disease heterogeneity (natural history, response to treatment, and prognosis), the need for new treatments to address unmet needs for all forms of GD, and refinement of the tools for monitoring disease progression and treatment efficacy, such as specific biomarkers.

Gaucher disease (GD) is a lysosomal storage disorder (LSD) characterized by glycosphingolipid accumulation. Age of symptomonset and disease progression varies across types of disease. Newborn screening (NBS) for Gaucher disease facilitates early identification of affected individuals and enables pre-symptomatic monitoring with the goal of starting therapies early and improving clinical outcomes. This multi-center study involved New Jersey NBS referral centers. Data regarding initial NBS results, confirmatory testing, diagnosis, and treatment were collected. For patients on therapy, monitoring biomarkers and exam findings are available as of the last clinical evaluation. Between July 2019 and December 2023, 438,515 newborns were screened, with 60 screen-positive cases. Of those positive screens, 19 cases with positive screens did not undergo confirmatory testing due to parental refusal, loss to follow-up, or death; 23 cases were false positives; 14 newborns were diagnosed with GD type I; 2 newborns were diagnosed with suspected type I GD; 2 newborns were diagnosed with GD type II; and 1 case is still pending. Three type I GD patients started enzyme replacement therapy, with the youngest starting at 28 months of age. Post-treatment data are available for these individuals. One type II case was referred to experimental gene therapy, and one was started on ERT. Our results demonstrate that NBS for GD is a valuable public health tool that can facilitate early diagnosis and intervention.