Spontaneously regressing brain lesions in Smith–Lemli–Opitz syndrome

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation. However, the individuals' clinical and neurological course remained stable, and the lesions regressed after several years. These lesions have similarities to spongiotic changes observed in individuals with neurofibromatosis type 1 (NF1). Notably, impaired activity of small GTPases is present in both SLOS and NF1, perhaps giving mechanistic insight into the formation of these lesions.

Temporal changes in the brain lipidome during neurodevelopment of Smith–Lemli–Opitz syndrome mice

“…13 Although myelination defects have not been observed in the limited studies of SLOS patients, 59 the MRI characteristics of SLOS patients are similar to those of other disorders with myelination defects 60 and white matter lesions have been previously reported in SLOS patient brains. 60…”

“…Furthermore, as major components of myelin, the reduced levels in SMs and cholesterol may affect myelination in SLOS. 13 Although myelination defects have not been observed in the limited studies of SLOS patients, 59 the MRI characteristics of SLOS patients are similar to those of other disorders with myelination defects 60 and white matter lesions have been previously reported in SLOS patient brains. 60 The decreases in the levels of PEs and increases in the levels of lyso-PEs and FFAs suggest upregulation of the phospholipase A 2 (PLA 2 ) activity.…”

“…13 Although myelination defects have not been observed in the limited studies of SLOS patients, 59 the MRI characteristics of SLOS patients are similar to those of other disorders with myelination defects 60 and white matter lesions have been previously reported in SLOS patient brains. 60 The decreases in the levels of PEs and increases in the levels of lyso-PEs and FFAs suggest upregulation of the phospholipase A 2 (PLA 2 ) activity. The activities of PLA 2 , releasing FFAs and lysophospholipids, are known to play important roles in neurotransmission, learning and memory, and neuroinflammation.…”

Chronic oligodendrocyte injury in central nervous system pathologies

“…For instance, the cholesterol biosynthesis pathway is downregulated in MS and in astrocytes in the poorly remyelinating model EAE 119 , and single nuclei sequencing of chronic active MS lesions indicate altered lipid storage/response genes in microglia and astrocytes 47 . Decreased cholesterol levels observed in Smith-Lemli-Optiz Syndrome (SLOS) due to 7-dehydrocholesterol reductase (DHCR7) dysfunction are associated with abnormal developmental myelination 120 , 121 . Conversely, cholesterol accumulation can lead to hypomyelination and decompacted myelin as observed in some leukodystrophies.…”

Temporal gene expression changes and affected pathways in neurodevelopment of a mouse model of Smith-Lemli-Opitz syndrome

“…Clinically, the disorder manifests a wide variety of phenotypes, including multiple congenital malformations (structural abnormalities and functional defects across several organ systems), developmental delay, and cognitive impairment [9]. Specifically in the CNS, anatomical abnormalities have been observed in SLOS patients, ranging from microcephaly to enlarged ventricles and hypoplasia of the corpus callosum, and in the most severe cases, holoprosencephaly [6,[10][11][12].…”