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.
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References
Agarwal AK, Arioglu E, De Almeida S et al (2002) AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 31:21–23
Aguilera-Méndez A, Álvarez-Delgado C, Hernández-Godinez D (2013) Hepatic diseases related to triglyceride metabolism. Mini Rev Med Chem 13:1691–9
Akiyama M (2010) ABCA12 mutations and autosomal recessive congenital ichthyosis: a review of genotype/phenotype correlations and of pathogenetic concepts. Hum Mutat 31:1090–6
Aldahmesh MA, Mohamed JY, Alkuraya HS et al (2011) Recessive mutations in ELOVL4 causes ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet 89:745–750
Aoyama C, Ohtani A, Ishidate K (2002) Expression and characterization of the active molecular forms of choline/ethanolamine kinase-a and -b in mouse tissues, including carbon tetrachloride-induced liver. Biochem J 363:777–784
Baba T, Kashiwagi Y, Arimitsu N et al (2014) Phosphatidic acid (PA)-preferring phospholipase A1 regulates mitochondrial dynamics. J Biol Chem 289:11497–511
Balla T (2013) Phosphoinositides : tiny lipids with giant impact on cell regulation. Physiol Rev 93:1019–1137
Barth PG, Valianpour F, Bowen VM et al (2004) X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update. Am J Med Genet 126A:349–354
Barwick KE, Wright J, Al-Turki S et al (2012) Defective presynaptic choline transport underlies hereditary motor neuropathy. Am J Hum Genet 91:1103–7
Basel-Vanagaite L, Zevit N, Zahav AH et al (2012) Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase1. Am J Hum Genet 90:49–60
Bejaoui K, Wu C, Scheffler (2001) SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet 27:261–262
Below JE, Earl DL, Shively KM et al (2013) Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia. Am J Hum Genet 92:137–43
Brites P, Waterham HR, Ronald JA (2004) Functions and biosynthesis of plasmalogens in health and disease. Biochim Biophys Acta 1636:219–231
Cadieux-Dion M, Turcotte-Gauthier M, Noreau A et al (2014) Expanding the clinical phenotype associated with elovl4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurol 71:470–475
Campeau PM, Lenk GM, Lu JT et al (2013) Yunis-Varón syndrome is caused by mutations in Fig. 4, encoding a phosphoinositide phosphatase. Am J Hum Genet 92:781–91
Carrasco C, Merida I (2007) Diacylglycerol, when simplicity becomes complex. Trends Biochem Sci 32:27–36
Chiarelli LR, Morera SM, Bianchi P et al (2012) Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency. PLoS One 7:e32065
Citterio A, Arnoldi A, Panzeri E (2014) Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis. J Neurol 261(2):373–81
Coleman RA, Lee DP (2004) Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 43:134–176
Cornell RB, Northwood IC (2000) Regulation of CTP: phosphocholine cytidylyltransferase by amphitropism and relocalization. Trends Biochem Sci 25:441–447
Csaki LS, Dwyer JR, Fong LG et al (2013) Lipins, lipinopathies, and the modulation of cellular lipid storage and signalling. Progr Lipid Res 52:305–316
D’Souza K, Epand RM (2014) Enrichment of phosphatidylinositol with specific acyl chains. Biochim Biophys Acta 1838:1501–1508
Dawkins JL, Hulme DJ, Brahmbhatt SB et al (2001) Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet 27:309–312
Di Gregorio E (2014) ELOVL5 mutations cause spinocerebellar ataxia 38. Am J Hum Genet. doi:10.1016/j.ajhg.2014.07.001
Dusi S, Valletta L, Haack TB et al (2014) Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am J Hum Genet 2:11–22
Esposito G, De Falco F, Tinto N et al (2011) Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with Rab geranylgeranyl transferase. Hum Mutat 32:1460–1469
Fahy E, Subramaniam S, Brown HA et al (2005) A comprehensive classification of lipids. J Lipid Res 46:839–861
Feingold KR (2009) The outer frontier : the importance of lipid metabolism in the skin. J Lip Res 50:S417–S422
Ferdinandusse S, Denis S, Clayton PT et al (2000) Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 24:188–91
Ferguson PJ, Chen S, Tayeh MK et al (2005) Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet 42:551–557
Fischer J, Lefevre C, Morava E et al (2007) The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy. Nat Genet 39:28–30
Fiskerstrand T, Knappskog P, Majewski J et al (2009) A novel Refsum-like disorder that maps to chromosome 20. Neurology 72:20–27
Garwisch K (2012) Tafazzin senses curvatures. Nat Chem Biol 8:811–12
Grall A, Guaguère E, Planchais S et al (2012) PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet 44:140–7
Gregory A, Hayflick SJ (2005) Neurodegeneration with brain iron accumulation. Folia Neuropathol 43:286–296
Gregory A, Westaway SK, Holm IE et al (2008) Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology 71:1402–1409
Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139–50
Hiltunen JK, Autio KJ, Schonauer MS et al (2010) Mitochondrial fatty acid synthesis and respiration. Biochim Biophys Acta 1797:1195–202
Hoover-Fong J, Sobreira N, Jurgens J et al (2014) Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy. Am J Hum Genet 94:105–112
Huber C, Faqeih EA, Bartholdi D et al (2013) Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia. Am J Hum Genet 92:144–9
Ichida F, Tsubata S, Bowles KR et al (2001) Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 103:1256–63
Inoue H, Baba T, Sato S et al (2012) Roles of SAM and DDHD domains in mammalian intracellular phospholipase A1 KIAA0725p. Biochim Biophys Acta 1823:930–9
Israeli S, Khamaysi Z, Fuchs-Telem D et al (2011) A mutation in LIPN, encoding epidermal lipase N, causes a late-onset form of autosomal-recessive congenital ichthyosis. Am J Hum Genet 88:482–7
Jakobsson A, Westerberg R, Jacobsson A (2006) Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog Lipid Res 45:237–249
Jobard F, Lefèvre C, Karaduman A et al (2002) Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. Hum Mol Genet 11:107–13
Joshi M, Eagan J, Desai NK (2014) A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis,and hypertriglyceridemia. Eur J Hum Genet. doi:10.1038/ejhg.8
Kapina V, Sedel F, Truffert A et al (2010) Relapsing rhabdomyolysis due to peroxisomal alpha-methylacyl-coa racemase deficiency. Neurology 75:1300–2
Kennedy EE (1989) Discovery of the pathways for the biosynthesis of phosphatidylcholine. In: Vance DE (ed) Phosphatidylcholine metabolism. CRC Press, Boca Raton, pp 1–9
Kienesberger PC, Oberer M, Lass A, Zechner R (2009) Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions. J Lipid Res 50(Suppl):S63–8
Kolter T (2011) A view on sphingolipids and disease. Chem Phys Lipids 164:590–606
Lamari F, Mochel F, Sedel F, Saudubray JM (2013) Disorders of phospholipids, sphingolipids and fatty acids biosynthesis: toward a new category of inherited metabolic diseases. J Inherit Metab Dis 36(3):411–25
Lefévre C, Audebert S, Jobard F et al (2003) Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet 12:2369–78
Lefèvre C, Bouadjar B, Ferrand V et al (2006) Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3. Hum Mol Genet 15:767–76
Lemaire M, Frémeaux-Bacchi V, Schaefer F (2013) Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 45:531–6
Margot G, Paulick MG, Carolyn R, Bertozz CR (2008) The glycosylphosphatidylinositol anchor: a complex membrane-anchoring structure for proteins. Biochemistry 47:6991–7000
Martin E, Palmic N, Sanquer S et al (2014) CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation. Nature 510:288–292
Mayr JA, Zimmermann FA, Fauth C (2011) Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation. Am J Hum Genet 89:792–797
Mayr JA, Haack TB, Graf E et al (2012) Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. Am J Hum Genet 90:314–320
Merolli A, Santin M (2009) Role of phosphatidyl-serine in bone repair and its technological exploitation. Molecules 22:5367–81
Merrill AH Jr, Sandhoff K (2002) Sphingolipids: Metabolism and cell signaling. In: Vance DE, Vance JE (eds) New comprehensive biochemistry: biochemistry of lipids, lipoproteins, and membranes. Elsevier Science, New York, pp 373–407
Michot C, Hubert L, Brivet M et al (2010) LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood. Hum Mutat 31:E1564–E1573
Michot C, Huber L, Pomero NB et al (2012) Study of LPIN1, LPIN 2, and LPIN3 in rhabdomyolysis and execcise induced-myalgia. J Inherit Metab Dis 35:1119–1128
Mir H, Raza SI, Touseef M (2014) A novel recessive mutation in the gene ELOVL4 causes a neuro-ichthyotic disorder with variable expressivity. BMC Med Genet 15:25, 26
Mitsuhashi S, Ohkuma A, Talim B et al (2011) A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. Am J Hum Genet 10:845–851
Molday RS, Zhong M, Quazi F (2009) The role of the photoreceptor ABC transporter ABCA4 in lipid transport and stargradt macular degeneration. Biochim Biophys Acta 1791:573–583
Morel E, Chamoun Z, Lasiecka ZM (2013) Phosphatidylinositol-3 phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system. Nat Commun 4:2250
Muhammad E, Reish O, Ohno Y et al (2013) Congenital myopathy is caused by mutation of HACD1. Hum Mol Genet 22:5229–36
Mühlhausen C, Salomons GS, Lukacs Z et al(2014) Combined D2-/L2-hydroxyglutaric aciduria (SLC25A1 deficiency): clinical course and effects of citrate treatment. J Inherit Metab Dis Apr 1. [Epub ahead of print]
Munnich A, Saudubray JM, Coude FX et al (1980) Fatty acid-responsive alopecia in multiple carboxylase deficiency. Lancet 17:1080–1081
Murakami Y, Tawamie H, Maeda Y et al (2014) Null mutation in PGAP1 impairing GPI-anchor maturation in patients with intellectual disability and encephalopathy. PLoS Genet 10(5): e1004320. doi:10.1371
Nishiguchi KM, Avila-Fernandez A, van Huet RA et al (2014) Exome sequencing extends the phenotypic spectrum for abhd12 mutations: from syndromic to nonsyndromic retinal degeneration. Ophthalmology 31. pii: S0161-6420(14)00138-9
Nota B, Struys EA, Pop A et al (2013) Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria. Am J Hum Genet 92:627–31
Oikawa T, Kuroda Y, Matsuo K (2013) Regulation of osteoclasts by membrane-derived lipid mediators. Cell Mol Life Sci 70:3341–53
Oji V, Tadini G, Akiyama M et al (2010) Revised nomenclature and classification of inherited ichthyoses: results of the first ichthyosis consensus conference in Sorèze 2009. J Am Acad Dermatol 63:607–41
Ombrello MJ, Remmers EF, Sun G et al (2012) Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. New Eng J Med 366:330–338
Paisán-Ruiz C, Guevara R, Federoff M et al (2010) Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. Mov Dis- ord 25:1791–1800
Platt FM (2014) Sphingolipid lysosomal storage disorders. Nature 510:68–75
Quehenberger O, Armando AM, Brown AH et al (2010) Lipidomics reveals a remarkable diversity of lipids in human plasma. J Lipid Res 51:3299–3305
Rainier S, Bui M, Mark E et al (2008) Neuropathy target esterase gene mutations cause motor neuron disease. Am J Hum Genet 82:780–785
Reilich P, Horvath R, Krause S et al (2011) The phenotypic spectrum of neutral lipid storage myopathy due to mutations in the PNPLA2 gene. J Neurol 258:1987–97
Resh MD (2012) Targeting protein lipidation in disease. Trends Mol Med 18:206–14
Riezman H (2007) The long and short of fatty acids. Cell 130:587–588
Rizzo WB (2014) Fatty aldehyde and fatty alcohol metabolism: review and importance for epidermal structure and function. Biochim Biophys Acta 1841:377–389
Salaun C, Greaves J, Chamberlain LH (2010) The intracellular dynamic of protein palmitoylation. J Cell Biol 191:1229–38
Sarig O, Goldsher D, Nousbeck J et al (2013) Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1. Am J Med Genet A 161:2204–15
Schuurs-Hoeijmakers JH, Vulto-van Silfhout AT, Vissers LE et al (2013) Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing. J Med Genet 50:802–11
Shaheen R, Rahbeeni Z, Alhashem A et al (2014) Neu-laxova syndrome, an inborn error of serine metabolism. is caused by mutations in PHGDH. Am J Hum Genet 94:898–904
Soreze Y, Boutron A, Habarou F et al (2013) Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. Orphanet J Rare Dis 8:192
Sousa SB, Jenkins D, Chanudet E et al (2014) Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. Nature Genet 46:70–77
Sparrow JR, Wu Y, Zhou J (2010) Phospholipids meets all-trans-retinal : the making of RPE bisretinoids. J Lipid Res 51:247–261
Synofzik M, Gonzalez MA, Lourenco CM et al (2014) PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain 137:69–77
Tesson C, Nawara M, Salih MA et al (2012) Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet 91:1051–64
Thompson SA, Calvin J, Hogg S et al (2008) Relapsing encephalopathy in a patient with alpha-methylacyl-CoA racemase deficiency. J Neurol Neurosurg Psychiatry 79:448–50
van der Crabben SN, Verhoeven-Duif NM, Brilstra EH et al (2013) An update on serine deficiency disorders. J Inher Metab Dis 36:613–619
Vance DE, (2002) Phospholipid biosynthesis in eukaryotes, in Biochemistry of Lipids, Lipoproteins and Membranes Vance D.E. and. Vance J.E (Eds.) (4th Edn)
Vance JE, Tasseva G (2013) Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells. Biochim Biophys Acta 1831:543–554
Verhoeven NM, Jakobs C (2001) Human metabolism of phytanic acid and pristanic acid. Prog Lip Res 40:453–456
Wallner S, Scmitz G (2011) Plasmalogens the neglected regulatory and scavenging lipid species. Chem Phys Lipids 164:573–589
Wanders RJ, Komen J, Ferdinandusse S (2011) Phytanic acid metabolism in health and disease. Biochim Biophys Acta 1811:498–507
Willemsen MA, Ijlst L, Steijlen PM et al (2001) Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjogren-Larsson syndrome. Brain 124:1426–1437
Wortmann SB, Vaz FM, Gardeitchik T et al (2012) Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet 44:797–802
Xu C, Zheng Z, Fang L et al (2013) Phosphatidylserine enhances osteogenic differentiation in human mesenchymal stem cells via ERK signal pathways. Mater Sci Eng C Mater Biol Appl 33:1783–8
Yamamoto GL, Wagner ARB, Almeida TF et al (2014) Mutations in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy. Am J Hum Genet 94:113–119
Yoshino H, Tomiyama H, Tachibana N et al (2010) Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism. Neurology 75:1356–1361
Zeharia A, Shaag A, Houtkooper RH (2009) Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood. Am J Hum Genet 83:489–494, 2008. Note: Erratum: Am J Hum Genet 84: 95 only, 2009
Zhang K, Kniazeva M, Han M et al (2001) A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 27:89–93
Zhou B, Westaway SK, Levinson B et al (2001) A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 28:345–349
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Communicated by: Matthias Baumgartner
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Lamari, F., Mochel, F. & Saudubray, JM. An overview of inborn errors of complex lipid biosynthesis and remodelling. J Inherit Metab Dis 38, 3–18 (2015). https://doi.org/10.1007/s10545-014-9764-x
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DOI: https://doi.org/10.1007/s10545-014-9764-x