Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1 -KO cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global KO of Spns1 caused embryonic lethality between E12.5 and E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC), and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1 -KO mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1 -KO mice affected liver functions and altered the PI3K/AKT signaling pathway. Furthermore, we identified 3 human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.

Tuberous sclerosis complex is an autosomal dominant disorder that often causes refractory seizures. The presence of multiple lesions makes it difficult to identify a single lesion responsible for the epilepsy. Our purpose is to assess the single-voxel proton spectroscopic findings of the tubers in 11 children with tuberous sclerosis complex. Prior to age 4 years, all of the patients had presented with epileptic seizures and multiple bilateral tubers in magnetic resonance images. Single-voxel proton spectroscopy was performed from the tubers especially showing epileptogenic activity using both the long and short echo time and in 14 controls. The results were analyzed using the Mann-Whitney U-test. Compared with the control group, the spectroscopic findings of tubers were characterized by decreased N-acetylaspartate to creatine ratios (1.43 ± 0.33; P < .001) in both the long and short echo time spectra, increased choline to creatine ratios (0.91 ± 0.082; P < .05), and myo-inositol to creatine ratios (0.97 ± 0.19; P < .01) in the short echo time spectra. A lactate peak was detected in the regions corresponding to an epileptic focus on electroencephalography in six patients. Single-voxel proton spectroscopy could be a useful noninvasive method to evaluate epileptogenic tubers. ( J Child Neurol 2005;20:517—522).

Leukoencephalopathies with cystic changes in the white matter on magnetic resonance imaging are aetiologically heterogeneous neurological disorders seen in children. A group of leukoencephalopathies characterised by white matter lesions progressing to multifocal cystic degeneration has been reported in various disorders, including mitochondrial enzyme deficiencies, leukodystrophies, and infectious processes. We report two patients with leukoencephalopathy showing progressive cystic changes on serial MRI, and magnetic resonance spectroscopy resembling progressive cavitating leukoencephalopathy.

Background: Neurodegeneration with brain iron accumulation (NBIA) comprises a genetically and clinically heterogeneous group of rare neurological disorders characterized particularly by iron accumulation in the basal ganglia. To date, 15 genes have been associated with NBIA. Among them, WDR45 , linked to beta‐propeller protein‐associated neurodegeneration (BPAN), represents the only X‐linked dominant subtype of NBIA. Herein, clinical, electrophysiological, and neuroimaging evaluations were used to broaden the understanding of BPAN in a newly reported case series. Methods: This study included 10 individuals with BPAN, categorized into three age groups. WDR45 variant data retrieved from next‐generation sequencing or Sanger sequencing were reviewed and reassessed. Comprehensive clinical evaluations including magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG‐PET), and video electroencephalographic monitoring were conducted. Results: The clinical manifestations were highly heterogeneous, with cognitive impairment being a consistent finding among the patients, with variable severity. The associated WDR45 variants are likely to exert loss‐of‐function effects. Electroencephalogram (EEG) abnormalities included age‐dependent background slowing and epileptiform discharges. MRI indicated a characteristic pattern, while two patients lacked these typical findings. FDG‐PET imaging demonstrated hypometabolism extending beyond cerebral structures, with predominant cerebellar and pontine involvement in pediatric patients and frontoparietal hypometabolism in adults. Conclusions: This study contributes further to our understanding of the heterogeneous clinical spectrum of BPAN. Genotype–phenotype correlation in BPAN remains unclear due to the absence of sufficiently large cohorts in the literature, including the present study. Nevertheless, even within this small sample, the phenotypic heterogeneity observed among individuals harboring the same genotype highlights the biological complexity of the disease. Neuroimaging findings may reflect progressive and widespread neurological involvement in an age‐dependent pattern, whereas EEG data suggest that epilepsy severity tends to decrease after adolescence.