Journal of Inherited Metabolic Disease

, Volume 36, Issue 3, pp 411–425 | Cite as

Disorders of phospholipids, sphingolipids and fatty acids biosynthesis: toward a new category of inherited metabolic diseases

  • F. Lamari
  • F. Mochel
  • F. Sedel
  • J. M. Saudubray
Original Article


We wish to delineate a novel, and rapidly expanding, group of inborn errors of metabolism with neurological/muscular presentations: the defects in phospholipids, sphingolipids and long chain fatty acids biosynthesis. At least 14 disorders have been described so far. Clinical presentations are diverse but can be divided into (1) diseases of the central nervous system; (2) peripheral neuropathies; and (3) muscular/cardiac presentations. (1) Leukodystrophy and/or iron deposits in basal ganglia is a common feature of phospholipase A2 deficiency, fatty acid hydroxylase deficiency, and pantothenate kinase-associated neurodegeneration. Infantile epilepsy has been reported in GM3 synthetase deficiency. Spastic quadriplegia with ichthyosis and intellectual disability are the presenting signs of the elongase 4 deficiency and the Sjogren-Larsson syndrome caused by fatty aldehyde dehydrogenase deficiency. Spastic paraplegia and muscle wasting are also seen in patients with mutations in the neuropathy target esterase gene. (2) Peripheral neuropathy is a prominent feature in PHARC syndrome due to α/β-hydrolase 12 deficiency, and in hereditary sensory autonomic neuropathy type I due to serine palmitoyl-CoA transferase deficiency. (3) Muscular/cardiac presentations include recurrent myoglobinuria in phosphatidate phosphatase 1 (Lipin1) deficiency; cardiomyopathy and multivisceral involvement in Barth syndrome secondary to tafazzin mutations; congenital muscular dystrophy due to choline kinase deficiency, Sengers syndrome due to acylglycerol kinase deficiency and Chanarin Dorfman syndrome due to α/β- hydrolase 5 deficiency. These synthesis defects of complex lipid molecules stand at the frontier between classical inborn errors of metabolism and other genetic diseases involving the metabolism of structural proteins.


Hereditary Spastic Paraplegia Barth Syndrome Congenital Muscular Dystrophy Neuropathy Target Esterase Very Long Chain Fatty Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Conflict of interest



  1. Aicardi J, Castelein P (1979) Infantile neuroaxonal dystrophy. Brain 102:727–748PubMedCrossRefGoogle Scholar
  2. Aldahmesh MA, Mohamed JY, Alkuraya HS et al (2011) Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am J Hum Genet 89:745–750PubMedCrossRefGoogle Scholar
  3. Auer-Grumbach M (2008) Hereditary sensory neuropathy type I. Orphanet J Rare Dis 18:3–7Google Scholar
  4. Barth PG, Valianpour F, Bowen VM et al (2004) X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update. Am J Med Genet A 126:349–354CrossRefGoogle Scholar
  5. Bejaoui K, Wu C, Scheffler et al (2001) SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet 27:261–262PubMedCrossRefGoogle Scholar
  6. Bektas M, Payne SG, Liu H, Goparaju S, Milstien S, Spiegel S (2005) A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells. J Cell Biol 169:801–811PubMedCrossRefGoogle Scholar
  7. Berginer VM, Salen G, Shefer S (1984) Long term treatment with CTX with chenodeoxycholic therapy. N Engl J Med 311:1649–1652PubMedCrossRefGoogle Scholar
  8. Bione S, D’Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D (1996) A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet 4:385–389CrossRefGoogle Scholar
  9. Chang PA, Wu YJ (2010) Neuropathy target esterase: an essential enzyme for neural development and axonal maintenance. Int J Biochem Cell Biol 42:573–575PubMedCrossRefGoogle Scholar
  10. Cantagrel V, Lefeber DJ (2011) From glycosylation disorders to dolichol biosynthesis defects:a new class of metabolic diseases. J Inherit Metab Dis 34:859–867PubMedCrossRefGoogle Scholar
  11. Daleke DL (2003) Regulation of transbilayer plasma membrane phospholipid asymmetry. J Lipid Res 44:233–42Google Scholar
  12. Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA (2001) Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet 27:309–312PubMedCrossRefGoogle Scholar
  13. De Konig TJ, Klomp LW, van Oppen AC et al (2004) Prenatal and early post natal treatment in 3-phosphoglycerate deshydrogenase deficiency. Lancet 364:2221–2222CrossRefGoogle Scholar
  14. Dick KJ, Eckhardt M, Paisàn-Ruiz C et al (2010) Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum Mutat 31:E1251–E1260PubMedCrossRefGoogle Scholar
  15. Donkor J, Sariahmetoglu M, Dewald J, Brindley DN, Reue K (2007) Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns. J Biol Chem 282:3450–3457PubMedCrossRefGoogle Scholar
  16. Dorfman ML, Hershko C, Eisenberg S, Sagher F (1974) Ichthyosiform dermatosis with systemic lipidosis. Arch Dermatol 110:261–266PubMedCrossRefGoogle Scholar
  17. Duncan AJ, Bitner-Glindzicz M, Meunier B et al (2009) A non-sense enzymatic mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. Am J Hum Genet 84:558–566PubMedCrossRefGoogle Scholar
  18. Edvardson S, Hama H, Shaag A et al (2008) Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am J Hum Genet 83:643–648PubMedCrossRefGoogle Scholar
  19. Engel LA, Jing Z, O’Brien DE, Sun M, Kotzbauer PT (2010) Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism. PLoS One 5(1–7):e1289Google Scholar
  20. Engelmann B, Wiedmann MKH (2010) Cellular phospholipid uptake: flexible paths to coregulate the functions of intracellular lipids. BBA 1801:609–616PubMedCrossRefGoogle Scholar
  21. 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 42:551–557PubMedCrossRefGoogle Scholar
  22. Fischer J, Lefèvre C, Morava E et al (2007) The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy. Nat Genet 39:28–30PubMedCrossRefGoogle Scholar
  23. Fiskerstrand T, Knappskog P, Majewski J, Wanders JRJ, Boman H, Bindoff LA (2009) A novel Refsum-like disorder that maps to chromosome 20. Neurology 72:20–27PubMedCrossRefGoogle Scholar
  24. Fiskerstrand T, H’mida-Ben Brahim D, Johansson S et al (2010) Mutations in ABHD12 cause the neurodegenerative disease PHARC: an inborn error of endocannabinoid metabolism. Am J Hum Gen 87:410–417CrossRefGoogle Scholar
  25. Garofalo K, Penno A, Schmidt BP et al (2011) Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest 121:4735–4745PubMedCrossRefGoogle Scholar
  26. Ghosh AK, Ramakrishnan G, Chandramohan C, Rajasekharan R (2008) CGI-58, the causative gene for Chanarin-Dorfman syndrome, mediates acylation of lysophosphatidic acid. J Biol Chem 283:24525–33Google Scholar
  27. Grall A, Guaguère E, Planchais S et al (2012) PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet 15:140–147CrossRefGoogle Scholar
  28. Gregory A, Hayflick SJ (2005) Neurodegeneration with brain iron accumulation. Folia Neuropathol 43:286–296PubMedGoogle Scholar
  29. Gregory A, Polster BJ, Hayflick SJ (2009) Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 46:73–80Google Scholar
  30. Hart CE, Race V, Achouri Y et al (2007) Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am J Hum Genet 80:931–7Google Scholar
  31. Hayflick SJ, Westaway SK, Levinson B et al (2003) Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 348:33–40PubMedCrossRefGoogle Scholar
  32. Houtkooper RH, Turkenburg M, Poll-The BT (2009a) The enigmatic role of tafazzin in cardiolipin metabolism. Biochem Biophys Acta 1788:2003–2014PubMedCrossRefGoogle Scholar
  33. Houtkooper RH, Rodenburg RJ, Thiels C et al (2009b) Cardiolipin and monolysocardiolipin analysis in fibroblasts, lymphocytes, and tissues using high performance liquid chromatography–mass spectrometry as a diagnostic test for Barth syndrome. Anal Biochem 387:230–237PubMedCrossRefGoogle Scholar
  34. Huck JHJ, Verhoeven NM, Struys EA et al (2004) Ribose 5 phosphate isomerase deficiency:new inborn error in the pentose phosphate pathway associated with a slowly progressive leukoencephalopathy. Am J Hum Genet 74:745–751PubMedCrossRefGoogle Scholar
  35. Huppke P, Brendel C, Kalscheuer V et al (2012) Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin. Am J Hum Genet 13:61–68CrossRefGoogle Scholar
  36. Ichida F, Tsubata S, Bowles KR et al (2001) Novel gene mutation in patients with left ventricular noncompaction or Barth syndrome. Circulation 103:1256–1263PubMedCrossRefGoogle Scholar
  37. 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 88:482–487PubMedCrossRefGoogle Scholar
  38. Jaaken J (2011) Congenital disorders of glycosylation (CDG): it’s (nearly) all in their regulation and roles in metabolism. J Inherit Metab Dis 34:853–858CrossRefGoogle Scholar
  39. Jakobsson A, Westerberg R, Jacobsson A (2006) Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog Lipid Res 45:237–249PubMedCrossRefGoogle Scholar
  40. Johnston J, Kelley RI, Feigenbaum A et al (1997) Mutation characterization and genotype-phenotype correlation in Barth syndrome. Am J Hum Genet 5:1053–1058CrossRefGoogle Scholar
  41. Johnson MA, Kuo YM, Westaway SK et al (2004) Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration. Ann N Y Acad Sci 1012:282–298PubMedCrossRefGoogle Scholar
  42. Kelley RI, Cheatham JP, Clark BJ et al (1991) X linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria. J Pediatr 119:738–747PubMedCrossRefGoogle Scholar
  43. Khateeb S, Flusser H, Ofir R et al (2006) PLA2G6 mutation underlies infantile neuroaxonal dystrophy. Am J Hum Genet 79:942–948PubMedCrossRefGoogle Scholar
  44. Kolter T (2011) A view on sphingolipids and diseases. Chem Phys Lipids 164:590–606PubMedCrossRefGoogle Scholar
  45. Konrad PN, McCarthy DJ, Mauer AM et al (1973) Erythrocyte and leukocyte phosphoglycerate kinase deficiency with neurologic disease. J Pediatr 82:456PubMedCrossRefGoogle Scholar
  46. Kruer MC, Paisán-Ruiz C, Boddaert N et al (2010) Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 68:611–618PubMedCrossRefGoogle Scholar
  47. Kulik W, van Lenthe H, Stet FS, Houtkooper RH (2008) Bloodspot assay using HPLC-tandem mass spectrometry for detection of Barth syndrome. Clin Chem 54:371–378PubMedCrossRefGoogle Scholar
  48. Lefèvre C, Jobard F, Caux F et al (2001) Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome. Am J Hum Genet 69:1002–1012PubMedCrossRefGoogle Scholar
  49. Leoni V, Strittmatter L, Zorzi G et al (2012) Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations. Mol Genet Metab 105:463–471PubMedCrossRefGoogle Scholar
  50. Lichtman AH, Blankman JL, Cravatt BF (2010) Endocannabinoid overload. Mol Pharmacol 78:993–995PubMedCrossRefGoogle Scholar
  51. Mangat J, Lunnon-Wood T, Rees P, Elliott M, Burch M (2007) Successful cardiac transplantation in Barth syndrome single-centre experience of four patients. Pediatr Transplant 11:327–331PubMedCrossRefGoogle Scholar
  52. Mayatepek E, Flock B (1998) Leukotriene C4 synthesis deficiency: a new inborn error of metabolism linked to a fatal developmental syndrome. Lancet 352:1514–1517PubMedCrossRefGoogle Scholar
  53. Maydan G, Noyman I, Har-Zahav A et al (2011) Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN. J Med Genet 48:383–389PubMedCrossRefGoogle Scholar
  54. Mayr JA, Haack TB, Graf E et al (2012) Lack of the mitochondrial protein acylglycerol kinase causes sengers syndrome. Am J Hum Genet 90:314–320PubMedCrossRefGoogle Scholar
  55. Méneret A, Wiame E, Marelli C, et al (2012) A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy. Arch Neurol. Mar 5. [Epub ahead of print]Google Scholar
  56. 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–E1573PubMedCrossRefGoogle Scholar
  57. Michot C, Hubert L, Romero NB, et al (2012) Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia. J Inherit Metab Dis. Apr 6. [Epub ahead of print]Google Scholar
  58. 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(88):845–851CrossRefGoogle Scholar
  59. Morgan NV, Westaway SK, Morton JE et al (2006) PLA2G6, encoding a phospholipase A(2), is mutated in neurodegenerative disorders with high brain iron. Nat Genet 38:752–754PubMedCrossRefGoogle Scholar
  60. Nardocci N, Zorzi G, Farina L et al (1999) Infantile neuroaxonal dystrophy: clinical spectrum and diagnostic criteria. Neurology 52:1472–1478PubMedCrossRefGoogle Scholar
  61. Nishino I, Kobayashi O, Goto Y et al (1998) A new congenital muscular dystrophy with mitochondrial structural abnormalities. Muscle Nerve 21:40–47PubMedCrossRefGoogle Scholar
  62. Oberer M, Boeszoermenyi A, Nagy HM, Zechner R (2011) Recent insights into the structure and function of comparative gene identification-58. Curr Opin Lipidol 22:149–158PubMedCrossRefGoogle Scholar
  63. Ombrello MJ, Remmers EF, Sun G et al (2012) Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med 366:330–338PubMedCrossRefGoogle Scholar
  64. Osman C, Voelker DR, Langer T (2011) Making heads or tails of phospholipids in mitochondria. J Cell Biol 10:7–16CrossRefGoogle Scholar
  65. 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 Disord 25:1791–1800PubMedCrossRefGoogle Scholar
  66. Pellecchia MT, Valente EM, Cif L et al (2005) The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration. Neurology 64:1810–1812PubMedCrossRefGoogle Scholar
  67. Penno A, Reilly MM, Houlden H et al (2010) Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem 285:11178–11187PubMedCrossRefGoogle Scholar
  68. Phillis JW, Horrocks LA, Farooqui AA (2006) Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Rev 52:201–243PubMedCrossRefGoogle Scholar
  69. Poll-The BT, Aicardi J, Girot R, Rosa R (1985) Neurological findings in Triose phosphate isomerase deficiency. Ann Neurol 35:439–443CrossRefGoogle Scholar
  70. Quehenberger O, Armando AM, Brown AH et al (2010) Lipidomics reveals a remarkable diversity of lipids in human plasma. J Lipid Res 51:3299–3305PubMedCrossRefGoogle Scholar
  71. Quehenberger O, Dennis EA (2011) The human plasma lipidome. N Engl J Med 365:1812–1823PubMedCrossRefGoogle Scholar
  72. Rainier S, Bui M, Mark E, Thomas D et al (2008) Neuropathy target esterase gene mutations cause motor neuron disease. Am J Hum Genet 82:780–785PubMedCrossRefGoogle Scholar
  73. Riezman H (2007) The long and short of fatty acid synthesis. Cell 130:587–588PubMedCrossRefGoogle Scholar
  74. Rizzo WB, Carney G, Lin Z (1999) The molecular basis of Sjogren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene. Am. J. Hum. Genet. 65:1547–1560Google Scholar
  75. Rotthier A, Auer-Grumbach M, Janssens K et al (2010) Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet 87:513–522PubMedCrossRefGoogle Scholar
  76. Sanders RJ, Ofman R, Dekker C et al (2009) Enzymatic diagnosis of Sjogren-Larsson syndrome using electrospray ionization mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci 877:451–455CrossRefGoogle Scholar
  77. Sengers RCA, ter Haar BGA, Trijbels JMF et al (1975) Congenital cataract and mitochondrial myopathy of skeletal and heart muscle associated with lactic acidosis after exercise. J Pediatr 86:873–880PubMedCrossRefGoogle Scholar
  78. Sergouniotis PI, Davidson AE, Mackay DS et al (2011) Biallelic mutations in PLA2G5, encoding group V phospholipase A2 cause benign Fleck retina. Am J Hum Gen 89:782–791CrossRefGoogle Scholar
  79. Sher RB, Aoyama C, Huebsch KA et al (2006) A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis. J Biol Chem 281:4938–4948PubMedCrossRefGoogle Scholar
  80. Schmidt MR, Birkebaek GI, Sunde L (2004) Barth syndrome without 3-methylglutaconic aciduria. Acta Paediatr 93:419–421PubMedCrossRefGoogle Scholar
  81. Shneider S (2010) Three faces of the same gene: FA2H links neurodegenration with brain iron accumulation, leucodystrophies and hereditary spastic paraplegias. Ann Neurol 68:575–576CrossRefGoogle Scholar
  82. Simpson MA, Cross H, Proukakis C et al (2004) Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss of function mutation of GM3 synthase. Nat Genet 36:1225–1229PubMedCrossRefGoogle Scholar
  83. Steward CG, Newbury-Ecob RA, Hastings R et al (2010) Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth. Prenat Diagn 30:970–976PubMedCrossRefGoogle Scholar
  84. Willemsen MA, Ijlst L, Steijlen PM et al (2001a) Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjogren-Larsson syndrome. Brain 124:1426–1437PubMedCrossRefGoogle Scholar
  85. Willemsen MA, Rotteveel JJ, de Jong JG et al (2001b) Defective metabolism of leukotriene B4 in the Sjogren-Larsson syndrome. J Neurol Sci 183:61–67PubMedCrossRefGoogle Scholar
  86. Willemsen MA, Lutt MA, Steijlen PM et al (2001c) Clinical and biochemical effects of zileuton in patients with the Sjogren-Larsson syndrome. Eur J Pediatr 160:711–717PubMedGoogle Scholar
  87. Wortmann S, Rodenburg RJT, Huizing M et al (2006) Association of 3-methylglutaconic aciduria with sensori-neural deafness, encephalopathy, and Leigh-like syndrome (MEGDEL association) in four patients with a disorder of the oxidative phosphorylation. Mol Genet Metab 88:47–52PubMedCrossRefGoogle Scholar
  88. Xu YH, Barnes S, Sun Y, Grabowski GA (2010) Multi-system disorders of glycosphingolipid and ganglioside metabolism. J Lipid Res 51:1643–1675PubMedCrossRefGoogle Scholar
  89. Yoshino H, Tomiyama H, Tachibana N et al (2010) Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism. Neurology 75:1356–1361PubMedCrossRefGoogle Scholar
  90. Zeharia A, Shaag A, Houtkooper RH et al (2008) Mutations in LPIN1 causes recurrent acute myoglobinuria in childhood. Am J Hum Genet 83:489–494PubMedCrossRefGoogle Scholar
  91. 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 27:89–93PubMedGoogle Scholar
  92. Zhou B, Westaway SK, Levinson B et al (2001) A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 28:345–349PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2012

Authors and Affiliations

  • F. Lamari
    • 1
    • 2
  • F. Mochel
    • 1
    • 3
    • 4
  • F. Sedel
    • 1
    • 5
  • J. M. Saudubray
    • 1
    • 6
  1. 1.Neurometabolic Unit, Pitié-Salpêtrière HospitalAP-HP & University Pierre and Marie CurieParisFrance
  2. 2.Department of Metabolic BiochemistryPitié-Salpêtrière Hospital, AP-HPParisFrance
  3. 3.INSERM UMR S975, Brain and Spine InstituteHospital Pitié-SalpêtrièreParisFrance
  4. 4.Department of GeneticPitié-Salpêtrière Hospital, AP-HPParisFrance
  5. 5.Department of NeurologyPitié-Salpêtrière Hospital, AP-HPParisFrance
  6. 6.ParisFrance

Personalised recommendations