A novel mutation in sphingosine-1-phosphate lyase causing congenital brain malformation

Abstract

Introduction

Recently recessive mutations in sphingosine-1-phosphate lyase (SGPL1) have been published as a cause of syndromic congenital nephrotic syndrome with adrenal insufficiency. We have identified a case with fetal hydrops and brain malformations due to a mutation in SGPL1.

Case report

We report a patient presenting with severe fetal hydrops, congenital nephrotic syndrome and adrenal calcifications. MRI imaging showed generalized cortical atrophy with simplified gyral pattern and hypoplastic temporal lobes as well as cerebellar hypoplasia and hyperintensity in the pons. The boy deceased at 6 weeks of age. Via whole exome sequencing, we identified a novel homozygous frameshift mutation c.1233delC (p.Phe411Leufs^∗56) in SGPL1.

Conclusion

In our patient, we describe a novel mutation in sphingosine-1-phosphate lyase (SGPL1) leading to severe brain malformation. Neurodevelopmental phenotypes have been reported earlier, but not described in detail. To this end, we present a review on all published SGPL1-mutations and genotype-phenotype correlations focusing on neurodevelopmental outcomes. We hypothesized on the severe neurological phenotypes, which might be due to disruption of neuronal autophagy. Mutations in SGPL1 shall be considered in the differential diagnosis of fetal hydrops as well as congenital brain malformations and neuropathies.

Introduction

Sphingosine-1-phosphate lyase (SGPL1) is a ubiquitously expressed enzyme involved in the degradation of the regulatory sphingolipid sphingosine-1-phosphate (S1P). Recently SGPL1 mutations have been published to cause a syndromic form of a congenital nephrotic syndrome associated with adrenal insufficiency and/or calcification, ichthyosis, immunodeficiency and a wide range of pathological neurological features (Fig. 1, Supplementary Tables 1, 2) [1], [2], [3]. Here we present a novel mutation in SGPL1 causing microcephaly, neuronal migration defects, and cerebellar hypoplasia additionally to the classical features of fetal hydrops. We have elaborated on the neurological spectrum and provide a review of SGPL1 related phenotypes.