MRI Spectrum of Brain Involvement in Sphingosine-1-Phosphate Lyase Insufficiency Syndrome

Abstract

SGPL1 encodes sphingosine-1-phosphate lyase, the final enzyme of sphingolipid metabolism. In 2017, a condition featuring steroid-resistant nephrotic syndrome and/or adrenal insufficiency associated with pathogenic SGPL1 variants was reported. In addition to the main features of the disease, patients often exhibit a range of neurologic deficits. In a handful of cases, brain imaging results were described. However, high-quality imaging results and a systematic analysis of brain MR imaging findings associated with the condition are lacking. In this study, MR images from 4 new patients and additional published case reports were reviewed by a pediatric neuroradiologist. Analysis reveals recurring patterns of features in affected patients, including isolated callosal dysgenesis and prominent involvement of the globus pallidus, thalamus, and dentate nucleus, with progressive atrophy and worsening of brain lesions. MR imaging findings of abnormal deep gray nuclei, microcephaly, or callosal dysgenesis in an infant or young child exhibiting other typical clinical features of sphingosine-1-phosphate lyase insufficiency syndrome should trigger prompt genetic testing for SGPL1 mutations.

FIG 1.

Sphingolipid metabolic pathway. Sphingolipid biosynthesis leads to the formation of ceramide, the main building block of complex sphingolipids. Ceramide is degraded to sphingosine. Sphingosine is phosphorylated by sphingosine kinases, leading to formation of S1P, which has intracellular activities and also serves as a ligand for S1P receptors (S1PR_1–5). S1P can be dephosphorylated by specific and nonspecific lipid phosphatases, regenerating sphingosine. Alternatively, S1P can be irreversibly degraded by sphingosine-1-phosphate lyase (S1P lyase), which controls the sole exit point of sphingolipid metabolism. S1P catabolism by sphingosine-1-phosphate lyase results in formation of hexadecenal and ethanolamine phosphate. CoA indicates coenzyme A.

FIG 2.

SPLIS with mineral deposition and edema. T2-FLAIR axial MR images of a 4-year-old child with SPLIS show involvement of the dentate nuclei (A), cerebral peduncles and tectum (B), and globi pallidi (C). There is surrounding edema. Loss of central signal is attributed to calcium on the basis of the analysis of susceptibility-weighted images in another patient. The findings predominantly involve dopaminergic neurons.

FIG 3.

SPLIS with cerebral and cerebellar cortical lesions. T2-FLAIR axial images of an 8-year-old child with SPLIS show multiple focal hyperintense lesions involving cerebellar and cortical gray matter with some lesions extending into the subcortical white matter (B and C).

FIG 4.

SPLIS at 25 weeks’ gestation. Fetal sonography shows a transverse image of the abdomen (A) with echogenic enlarged adrenal glands with posterior shadowing presumably due to calcification. Fetal whole-body MR imaging (B) shows normal-appearing kidneys and adrenal glands. Mineralization of the adrenal glands is not apparent on this T2-weighted sequence.

FIG 5.

SPLIS appearance and progression of MR imaging findings with age. Sequential MR imaging performed in this infant with SPLIS between 6 weeks and 15 months of age has initially normal findings. At 13 and 15 months of age, there is progressive involvement of the globus pallidus with extensive edema of the caudate, putamen, and thalamus. Diffusivity is increased, and there is a susceptibility effect with a ring of T1- and T2- shortening. The susceptibility-phase images indicate the presence of calcium.

FIG 6.

SPLIS with dysgenesis of the corpus callosum and hypoplasia with an absent rostrum, genu, and splenium. This 2-year-old patient with SPLIS has dysgenesis of the corpus callosum. The sagittal T1- and axial T2-weighted MR images show absence of the rostrum, genu, and splenium (A). The body of the corpus callosum is hypoplastic. Brain volume, gyral complexity, and myelin maturation are grossly normal (B).