An overview of inborn errors of complex lipid biosynthesis and remodelling

Abstract

In a review published in 2012, we delineated 14 inborn errors of metabolism (IEM) related to defects in biosynthesis of complex lipids, particularly phospholipids and sphingolipids (Lamari et al 2013). Given the numerous roles played by these molecules in membrane integrity, cell structure and function, this group of diseases is rapidly expanding as predicted. Almost 40 new diseases related to genetic defects in enzymes involved in the biosynthesis and remodelling of phospholipids, sphingolipids and complex fatty acids are now reported. While the clinical phenotype associated with these defects is currently difficult to outline, with only a few patients identified to date, it appears that all organs and systems may be affected - central and peripheral nervous system, eye, muscle, skin, bone, liver, immune system, etc. This chapter presents an introductive overview of this new group of IEM. More broadly, this special issue provides an update on other IEM involving complex lipids, namely dolichol and isoprenoids, glycolipids and congenital disorders of glycosylation, very long chain fatty acids and plasmalogens. Likewise, more than 100 IEM may actually lead to primary or secondary defects of complex lipids synthesis and remodelling. Because of the implication of several cellular compartments, this new group of disorders affecting the synthesis and remodelling of complex molecules challenges our current classification of IEM still largely based on cellular organelles--i.e. mitochondrial, lysosomal, peroxisomal disorders. While most of these new disorders have been identified by next generation sequencing, we wish to emphasize the promising role of lipidomics in deciphering their pathophysiology and identifying therapeutic targets.

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

“…Some exemplary clusters of shared or interacting pathways underlying ASS diseases are: Phospholipid metabolism , including the genes PNPLA6 , 12,40,41 PLA2G6, DDHD1 (SPG 28), DDHD2 (SPG54 42 ), CYP2U1 (SPG49), and ABHD12 43 (for further overview, see references 40 and 44 ). Sphingolipid metabolism , including the genes FA2H , 15 GBA2 , 33,45 GALC, HEXA, ASA, PSAP , and GLB1 . Autophagy-lysosomal activity , including the genes SPG15 , SPG11 , 46,47 ATP13A2 (SPG78), 48,49 NPC1 , and NPC2 disease. 50-55 …”

“…Phospholipid metabolism , including the genes PNPLA6 , 12,40,41 PLA2G6, DDHD1 (SPG 28), DDHD2 (SPG54 42 ), CYP2U1 (SPG49), and ABHD12 43 (for further overview, see references 40 and 44 ).…”

LPIN1 deficiency with severe recurrent rhabdomyolysis and persistent elevation of creatine kinase levels due to chromosome 2 maternal isodisomy

“…Lipin-1 has phosphatidic acid phosphatase (PAP1) activity [12], converting phosphatidic acid (PA) to diacylglycerol (DAG). DAGs are substrates for the synthesis of triacylglycerols, phosphatidylcholine and phosphatidylethanolamine [13], [14], [15] and in mouse cells with severe lipin-1 deficiency, incubation with DAGs enhances autophagy and survival [16]. Lipin-1 is also a co-activator of PPARγ and PPARα, factors that control the transcription of genes of fatty acid oxidation [11], [17], [18], [19].…”

Outline of metabolic diseases in adult neurology

“…Besides the existing blood biomarkers cited above that are progressively changing our approach to clinical diagnoses of spastic paraplegia or atypical psychiatric symptoms for example, it is likely that additional biomarkers will be identified in the soon future thanks to the development of lipidomic approaches. This may be especially true for the field of inherited spastic paraplegia as several recently identified genes are involved in the remodeling of phospholipids -SPG54 (DDHD1), SPG28 (DDHD2), SPG39 (NTE), SPG56 (CYP2U1) -and the biosynthesis of sphingolipids -SPG35 (FA2H), SPG46 (GBA2), SPG26 (B4GALNT1) -opening the way to a novel class of IEM [1,18]. These rare diseases also shed light on mechanisms involved in common neurological diseases or symptoms such as, for spasticity, the importance of the maintenance of lipid membrane homeostasis.…”

“…The current classification of IEM based on cellular organelles -i.e. mitochondrial, lysosomal, peroxisomal disorders -is also challenged by the delineation of a new group of disorders affecting the synthesis and remodeling of complex lipids that involve several cellular compartments [1]. Furthermore, it becomes difficult to distinguish neurometabolic diseases among other neurogenetic entities.…”