A perilous path: the inborn errors of sphingolipid metabolism

Abstract

The sphingolipid (SL) metabolic pathway generates structurally diverse lipids that have roles as membrane constituents and as bioactive signaling molecules. The influence of the SL metabolic pathway in biology is pervasive; it exists in all mammalian cells and has roles in many cellular and physiological pathways. Human genetic diseases have long been recognized to be caused by mutations in the pathway, but until recently these mutational defects were only known to affect lysosomal SL degradation. Now, with a nearly complete delineation of the genes constituting the SL metabolic pathway, a growing number of additional genetic disorders caused by mutations in genes within other sectors of the pathway (de novo ceramide synthesis, glycosphingolipid synthesis, and nonlysosomal SL degradation) have been recognized. Although these inborn disorders of SL metabolism are clinically heterogeneous, some common pathogenic mechanisms, derived from the unique properties and functions of the SLs, underlie several of the diseases. These mechanisms include overaccumulation of toxic or bioactive lipids and the disruption of specific critical cellular and physiological processes. Many of these diseases also have commonalities in physiological systems affected, such as the nervous system and skin. While inborn disorders of SL metabolism are rare, gene variants in the pathway have been linked to increased susceptibility to Parkinson's disease and childhood asthma, implying that the SL metabolic pathway may have a role in these disorders. A more complete understanding of the inborn errors of SL metabolism promises new insights into the convergence of their pathogenesis with those of common human diseases.

Keywords: bioactive lipids; ceramides; gangliosides; genetics; glycosphingolipids; metabolic disease; rare disease; sphingolipids; storage diseases.

Graphical abstract

Fig. 1.

Disorders resulting from mutational defects in the SL synthesis pathway for ceramide and GSLs and the nonlysosomal SL degradation pathway. Sectors correspond to (A) de novo ceramide synthesis, (B) GSL synthesis, and (C) nonlysosomal SL degradation. Oligosaccharide structures are illustrated by colored symbols. The designations, o-Series, a-Series, b-Series and c-Series, refer to specific subgroups of GSLs and gangliosides (1, 24). Substrate names are presented in gray rounded boxes, genes are presented in green text, and disorders are presented in red boxed arrows. An asterisk identifies a disease predisposition associated with a gene variant. ¹ Progressive symmetric erythrokeratoderma. ² Autosomal recessive congenital ichthyosis.

Fig. 2.

Mechanisms of pathogenesis of inborn errors of SL metabolism. A: Overaccumulation of toxic lipids. In HNAS1, mutations in either the SPTLC1 or SPTLC2 subunit of SPT increase utilization of alanine or glycine at the expense of serine for the increased production of deoxysphingosine. The deoxysphingosine can only proceed to deoxyceramide formation and cannot move farther down the pathway for complex sphingolipid synthesis or through the canonical degradation sphingolipid pathway. Accumulation of toxic deoxy-SLs result. SS: small subunit of SPT, SPTSSA. B: Overaccumulation of bioactive lipids. Mutations in S1P lyase cause nephrotic syndrome type 14 and block the only exit for sphingolipid substrate out of the SL metabolic pathway. As a consequence, S1P accumulates and some S1P is converted to sphingosine and ceramide, increasing levels of S1P, sphingosine, and ceramide. Each of these SLs is bioactive: excess S1P activates S1P receptors and sphingosine and ceramide trigger pathways causing apoptosis. In patients with SGPL1 deficiency, these SL alterations may contribute to the multisystemic manifestations in the disease (Table 1). The elevated circulating and tissue S1P levels may alter S1P receptor signaling to impair lymphocyte trafficking and cause immunodeficiency. Elevated levels of pro-apoptotic sphingosine and ceramide may contribute to neurologic symptoms. C: Disruption of a critical physiologic process. Establishment of the epidermal permeability barrier, which is essential for life, is critically dependent on the synthesis and metabolism of SLs. 3-Ketosphinganine reductase (KDSR) forms dihydrosphingosine and ceramide synthase 3 (CERS3), which is highly abundant in the epidermis, produces ceramide with very-long chain ω -hydroxy fatty acids, which are then acylated with linoleic acid to form acyl-ceramide. Glucosylation of acyl-ceramide by glucosylceramide transferase (UGCG) is believed to be required for the intracellular transport of lipids as lamellar bodies for secretion into the extracellular space at the stratum corneum. The secreted acyl-GlcCeramide is processed by glucocerebrosidase (GBA1) for proper formation of lipid lamellae and protein-bound ceramide in the stratum corneum to produce an intact permeability barrier. Biallelic mutations in each of the KDSR, CERS3, UGCG, or GBA1 genes cause forms of epidermal permeability barrier abnormalities. D: Disruption of a critical cellular process. Lysosomal sphingolipid accumulation in Sandhoff (HEXB) and Gaucher (GBA1) diseases blocks autophagy, which is a critical self-degradative process for the removal of damaged organelles and aggregated proteins. An autophagy defect results in the cellular accumulation of damaged organelles and aggregated proteins and inflammation, which can lead to cellular dysfunction and apoptosis. Heterozygous mutations in GBA1 increase the risk of Parkinson’s disease by possibly causing lysosome/autophagy dysfunction (47). Oligosaccharide structures are illustrated by colored symbols. Substrate names are presented in gray rounded boxes, genes are presented in green text, and disorders are presented in boxed red arrows. An asterisk identifies a disease predisposition associated with a gene variant. ¹ Progressive symmetric erythrokeratoderma. ² Autosomal recessive congenital ichthyosis.

Fig. 3.

Disorders resulting from mutational defects in the lysosomal SL degradation pathway. Oligosaccharide structures are illustrated by colored symbols. Substrate names are presented in gray rounded boxes, genes are presented in green text, and disorders are presented in boxed red arrows. An asterisk identifies a disease predisposition associated with a gene variant.