Background: Loss of function mutations in SGPL1 are associated with
Sphingosine-1-phosphate lyase insufficiency syndrome, comprising
steroid resistant nephrotic syndrome, and
primary adrenal insufficiency (PAI) in the majority of cases. SGPL1 encodes
sphingosine-1-phosphate lyase (SGPL1) which is a major modulator of
sphingolipid signaling. Case Presentation: A Pakistani male infant presented at 5 months of age with
failure to thrive,
nephrotic syndrome,
primary adrenal insufficiency,
hypothyroidism, and
hypogonadism. Other systemic manifestations included persistent
lymphopenia,
ichthyosis, and motor developmental delay. Aged 9 months, he progressed rapidly into end stage oligo-anuric
renal failure and subsequently died. Sanger sequencing of the entire coding region of SGPL1 revealed the novel association of a rare homozygous mutation (chr10:72619152, c.511A>G, p.N171D; MAF-1.701e-05) with the condition.
Protein expression of the p.N171D mutant was markedly reduced compared to SGPL1 wild type when overexpressed in an SGPL1 knockout cell line, and associated with a severe clinical phenotype. Conclusions: The case further highlights the emerging phenotype of patients with loss-of-function SGPL1 mutations. Whilst
nephrotic syndrome is a recognized feature of other disorders of
sphingolipid metabolism,
sphingosine-1-phosphate lyase insufficiency syndrome is unique amongst the
sphingolipidoses in presenting with multiple endocrinopathies. Given the multi-systemic and progressive nature of this form of PAI/
nephrotic syndrome, a genetic diagnosis is crucial for optimal management and appropriate screening for comorbidities in these patients.