Advertisement

Journal of Inherited Metabolic Disease

, Volume 41, Issue 6, pp 1131–1145 | Cite as

Presynaptic disorders: a clinical and pathophysiological approach focused on the synaptic vesicle

  • Elisenda Cortès-Saladelafont
  • Noa Lipstein
  • Àngels García-Cazorla
Original Article

Abstract

The aim of this report is to present a tentative clinical and pathophysiological approach to diseases affecting the neuronal presynaptic terminal, with a major focus on synaptic vesicles (SVs). Diseases are classified depending on which step of the neurobiology of the SV is predominantly affected: (1) biogenesis of vesicle precursors in the neuronal soma; (2) transport along the axon; (3) vesicle cycle at the presynaptic terminal (exocytosis–endocytosis cycle, with the main purpose of neurotransmitter release). Given that SVs have been defined as individual organelles, we highlight the link between the biological processes disturbed by genetic mutations and the clinical presentation of these disorders. The great majority of diseases may present as epileptic encephalopathies, intellectual disability (syndromic or nonsyndromic) with/without autism spectrum disorder (and other neuropsychiatric symptoms), and movement disorders. These symptoms may overlap and present in patients as a combination of clinical signs that results in the spectrum of the synaptopathies. A small number of diseases may also exhibit neuromuscular signs. In general, SV disorders tend to be severe, early encephalopathies that interfere with neurodevelopment. As a consequence, developmental delay and intellectual disability are constant in almost all the defects described. Considering that some of these diseases might mimic other neurometabolic conditions (and in particular treatable disorders), an initial extensive metabolic workup should always be considered. Further knowledge into pathophysiological mechanisms and biomarkers, as well as descriptions of new presynaptic disorders, will probably take place in the near future.

Abbreviations

ASD

Autism spectrum disorder

CSF

Cerebrospinal fluid

HVA

Homovanilic acid

ID

Intellectual disability

MD

Movement disorder

SV

Synaptic vesicle

NT

Neurotransmitter

PD

Parkinson’s disease

Notes

Details of funding

AGC is funded by FIS: PI15/01082 (Instituto de Salud Carlos III: ISCIII and “Fondo Europeo de desarrollo regional” FEDER). NL is grateful for the support and advice of Dr. Nils Brose and is funded by the European Research Council (Brussels, Belgium; ERC-ADG SYNPRIME to Nils Brose).

Compliance with ethical standards

Conflict of interest

E. Cortès-Saladelafont, N. Lipstein and À. García-Cazorla declare that they have no conflict of interest.

A Conflict of Interest Disclosure Form was filled out and submitted.

Informed consent

Not applicable.

Animal rights

Not applicable.

References

  1. Abou Jamra R, Philippe O, Raas-Rothschild A et al (2011) Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet 88:788–795CrossRefGoogle Scholar
  2. Alfieri A, Sorokina O, Adrait A et al (2017) Synaptic Interactome mining reveals p140Cap as a new hub for PSD proteins involved in psychiatric and neurological disorders. Front Mol Neurosci 10:212CrossRefGoogle Scholar
  3. Anikster Y, Haack TB, Vilboux T et al (2017) Biallelic mutations in DNAJC12 cause Hyperphenylalaninemia, dystonia, and intellectual disability. Am J Hum Genet 100:257–266CrossRefGoogle Scholar
  4. Baker K, Gordon SL, Grozeva D et al (2015) Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling. J Clin Invest 125:1670–1678Google Scholar
  5. Bem D, Yoshimura S, Nunes-Bastos R et al (2011) Loss-of-function mutations in RAB18 cause Warburg micro syndrome. Am J Hum Genet 88:499–507CrossRefGoogle Scholar
  6. Bilo L, Peluso S, Antenora A et al (2014) Parkinsonism may be part of the symptom complex of DOOR syndrome. Parkinsonism Relat Disord 20:463–465CrossRefGoogle Scholar
  7. Bonifati V, Rizzu P, van Baren MJ et al (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259CrossRefGoogle Scholar
  8. Cavallin M, Hubert L, Cantagrel V et al (2016) Recurrent KIF5C mutation leading to frontal pachygyria without microcephaly. Neurogenetics 17:79–82CrossRefGoogle Scholar
  9. Chang FC, Westenberger A, Dale RC et al (2016) Phenotypic insights into ADCY5-associated disease. Mov Disord 31:1033–1040CrossRefGoogle Scholar
  10. Cirnaru MD, Marte A, Belluzzi E et al (2014) LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex. Front Mol Neurosci 7:49CrossRefGoogle Scholar
  11. Conroy J, Allen NM, Gorman KM et al (2016) NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy. Clin Genet 89:E1–E3CrossRefGoogle Scholar
  12. Corbett MA, Schwake M, Bahlo M et al (2011) A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia. Am J Hum Genet 88:657–663CrossRefGoogle Scholar
  13. Corradi A, Fadda M, Piton A et al (2014) SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth. Hum Mol Genet 23:90–103CrossRefGoogle Scholar
  14. Cortès-Saladelafont E, Tristán-Noguero A, Artuch R et al (2016) Diseases of the synaptic vesicle: a potential new group of neurometabolic disorders affecting neurotransmission. Semin Pediatr Neurol 23(4):306–320CrossRefGoogle Scholar
  15. Cross-Disorder Group of the Psychiatric Genomics C (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381:1371–1379CrossRefGoogle Scholar
  16. De Rubeis S, He X, Goldberg AP et al (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515:209–215CrossRefGoogle Scholar
  17. Diez H, Cortes-Saladelafont E, Ormazabal A et al (2017) Severe infantile parkinsonism because of a de novo mutation on DLP1 mitochondrial-peroxisomal protein. Mov Disord 32:1108–1110CrossRefGoogle Scholar
  18. Doi H, Yoshida K, Yasuda T et al (2011) Exome sequencing reveals a homozygous SYT14 mutation in adult-onset, autosomal-recessive spinocerebellar ataxia with psychomotor retardation. Am J Hum Genet 89:320–327CrossRefGoogle Scholar
  19. Doummar D, Mignot C, Apartis E et al (2015) A novel homozygous TBC1D24 mutation causing multifocal myoclonus with cerebellar involvement. Mov Disord 30:1431–1432CrossRefGoogle Scholar
  20. Drouet V, Lesage S (2014) Synaptojanin 1 mutation in Parkinson’s disease brings further insight into the neuropathological mechanisms. Biomed Res Int 2014:289728CrossRefGoogle Scholar
  21. Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C (2015) The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain 138:3476–3495CrossRefGoogle Scholar
  22. Falace A, Filipello F, La Padula V et al (2010) TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am J Hum Genet 87:365–370CrossRefGoogle Scholar
  23. Fassio A, Patry L, Congia S et al (2011) SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function. Hum Mol Genet 20:2297–2307CrossRefGoogle Scholar
  24. Fernandes AC, Uytterhoeven V, Kuenen S et al (2014) Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration. J Cell Biol 207:453–462CrossRefGoogle Scholar
  25. Fromer M, Pocklington AJ, Kavanagh DH et al (2014) De novo mutations in schizophrenia implicate synaptic networks. Nature 506:179–184CrossRefGoogle Scholar
  26. Fuchs-Telem D, Stewart H, Rapaport D et al (2011) CEDNIK syndrome results from loss-of-function mutations in SNAP29. Br J Dermatol 164:610–616Google Scholar
  27. Gai X, Xie HM, Perin JC et al (2012) Rare structural variation of synapse and neurotransmission genes in autism. Mol Psychiatry 17:402–411CrossRefGoogle Scholar
  28. Garcia CC, Blair HJ, Seager M et al (2004) Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy. J Med Genet 41:183–186CrossRefGoogle Scholar
  29. García-Cazorla A, Saudubray JM (2018) Cellular neurometabolism: a tentative to connect cell biology and metabolism in neurology. J Inher Metab Dis.  https://doi.org/10.1007/s10545-018-0226-8
  30. Gardiner AR, Jaffer F, Dale RC et al (2015) The clinical and genetic heterogeneity of paroxysmal dyskinesias. Brain 138:3567–3580CrossRefGoogle Scholar
  31. Giovedi S, Corradi A, Fassio A, Benfenati F (2014) Involvement of synaptic genes in the pathogenesis of autism spectrum disorders: the case of synapsins. Front Pediatr 2:94Google Scholar
  32. Gonzalez-Jamett AM, Haro-Acuna V, Momboisse F, Caviedes P, Bevilacqua JA, Cardenas AM (2014) Dynamin-2 in nervous system disorders. J Neurochem 128:210–223CrossRefGoogle Scholar
  33. Gupta HV, Vengoechea J, Sahaya K, Virmani T (2015) A splice site mutation in ATP6AP2 causes X-linked intellectual disability, epilepsy, and parkinsonism. Parkinsonism Relat Disord 21:1473–1475CrossRefGoogle Scholar
  34. Herrmann DN, Horvath R, Sowden JE et al (2014) Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-Eaton myasthenic syndrome and nonprogressive motor neuropathy. Am J Hum Genet 95:332–339CrossRefGoogle Scholar
  35. Jamuar SS, Lam AT, Kircher M et al (2014) Somatic mutations in cerebral cortical malformations. N Engl J Med 371:733–743CrossRefGoogle Scholar
  36. Karamohamed S, Golbe LI, Mark MH et al (2005) Absence of previously reported variants in the SCNA (G88C and G209A), NR4A2 (T291D and T245G) and the DJ-1 (T497C) genes in familial Parkinson’s disease from the GenePD study. Mov Disord 20:1188–1191CrossRefGoogle Scholar
  37. Kitada T, Asakawa S, Hattori N et al (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608CrossRefGoogle Scholar
  38. Koutsopoulos OS, Kretz C, Weller CM et al (2013) Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome. Eur J Hum Genet 21:637–642CrossRefGoogle Scholar
  39. Kumar RA, Sudi J, Babatz TD et al (2010) A de novo 1p34.2 microdeletion identifies the synaptic vesicle gene RIMS3 as a novel candidate for autism. J Med Genet 47:81–90CrossRefGoogle Scholar
  40. Lim DS, Kirsch DG, Canman CE et al (1998) ATM binds to beta-adaptin in cytoplasmic vesicles. Proc Natl Acad Sci U S A 95:10146–10151CrossRefGoogle Scholar
  41. Lipstein N, Verhoeven-Duif NM, Michelassi FE et al (2017) Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder. J Clin Invest 127:1005–1018CrossRefGoogle Scholar
  42. Maritzen T, Haucke V (2017) Coupling of exocytosis and endocytosis at the presynaptic active zone. Neurosci ResGoogle Scholar
  43. Milh M, Falace A, Villeneuve N et al (2013) Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Hum Mutat 34:869–872CrossRefGoogle Scholar
  44. Miyaji T, Echigo N, Hiasa M, Senoh S, Omote H, Moriyama Y (2008) Identification of a vesicular aspartate transporter. Proc Natl Acad Sci U S A 105:11720–11724CrossRefGoogle Scholar
  45. Mochel F (2018) Lipids and synaptic function. J Inherit Metab Dis.  https://doi.org/10.1007/s10545-018-0204-1
  46. Montecchiani C, Pedace L, Lo Giudice T et al (2016) ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain 139:73–85CrossRefGoogle Scholar
  47. Nakashima M, Kouga T, Lourenco CM et al (2016) De novo DNM1 mutations in two cases of epileptic encephalopathy. Epilepsia 57:e18–e23CrossRefGoogle Scholar
  48. Nguyen HT, Bryois J, Kim A et al (2017) Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders. Genome Med 9:114CrossRefGoogle Scholar
  49. Okamoto N, Miya F, Tsunoda T et al (2014) KIF1A mutation in a patient with progressive neurodegeneration. J Hum Genet 59:639–641CrossRefGoogle Scholar
  50. Olgiati S, Quadri M, Fang M et al (2016) DNAJC6 mutations associated with early-onset Parkinson’s disease. Ann Neurol 79:244–256CrossRefGoogle Scholar
  51. Orlacchio A, Babalini C, Borreca A et al (2010) SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 133:591–598CrossRefGoogle Scholar
  52. Peeraully T, Tan EK (2012) Genetic variants in sporadic Parkinson’s disease: east vs west. Parkinsonism Relat Disord 18(Suppl 1):S63–S65CrossRefGoogle Scholar
  53. Piton A, Michaud JL, Peng H et al (2008) Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Hum Mol Genet 17:3965–3974CrossRefGoogle Scholar
  54. Rafiq MA, Leblond CS, Saqib MA et al (2015) Novel VPS13B mutations in three large Pakistani Cohen syndrome families suggests a Baloch variant with autistic-like features. BMC Med Genet 16:41CrossRefGoogle Scholar
  55. Ramirez A, Heimbach A, Grundemann J et al (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38:1184–1191CrossRefGoogle Scholar
  56. Reid E, Kloos M, Ashley-Koch A et al (2002) A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 71:1189–1194CrossRefGoogle Scholar
  57. Rilstone JJ, Alkhater RA, Minassian BA (2013) Brain dopamine-serotonin vesicular transport disease and its treatment. N Engl J Med 368:543–550CrossRefGoogle Scholar
  58. Rizzoli SO (2014) Synaptic vesicle recycling: steps and principles. EMBO J 33:788–822CrossRefGoogle Scholar
  59. Rohena L, Neidich J, Truitt Cho M et al (2013) Mutation in SNAP25 as a novel genetic cause of epilepsy and intellectual disability. Rare Dis 1:e26314CrossRefGoogle Scholar
  60. Roland BP, Zeccola AM, Larsen SB et al (2016) Structural and genetic studies demonstrate neurologic dysfunction in triosephosphate isomerase deficiency is associated with impaired synaptic vesicle dynamics. PLoS Genet 12:e1005941CrossRefGoogle Scholar
  61. Sarper N, Zengin E, Jakobs C et al (2013) Mild hemolytic anemia, progressive neuromotor retardation and fatal outcome: a disorder of glycolysis, triose- phosphate isomerase deficiency. Turk J Pediatr 55:198–202Google Scholar
  62. Schneider AS, Valentine WN, Hattori M, Heins HL Jr (1965) Hereditary hemolytic anemia with triosephosphate isomerase deficiency. N Engl J Med 272:229–235CrossRefGoogle Scholar
  63. Schubert J, Siekierska A, Langlois M et al (2014) Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet 46:1327–1332CrossRefGoogle Scholar
  64. Scoto M, Rossor AM, Harms MB et al (2015) Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy. Neurology 84:668–679CrossRefGoogle Scholar
  65. Serajee FJ, Huq AM (2015) Homozygous mutation in synaptic vesicle glycoprotein 2A gene results in intractable epilepsy, involuntary movements, microcephaly, and developmental and growth retardation. Pediatr Neurol 52:642–646.e641CrossRefGoogle Scholar
  66. Shen XM, Selcen D, Brengman J, Engel AG (2014) Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology 83:2247–2255CrossRefGoogle Scholar
  67. Sinajon P, Verbaan D, So J (2016) The expanding phenotypic spectrum of female SLC9A6 mutation carriers: a case series and review of the literature. Hum Genet 135:841–850CrossRefGoogle Scholar
  68. Soykan T, Maritzen T, Haucke V (2016) Modes and mechanisms of synaptic vesicle recycling. Curr Opin Neurobiol 39:17–23CrossRefGoogle Scholar
  69. Sprecher E, Ishida-Yamamoto A, Mizrahi-Koren M et al (2005) A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma. Am J Hum Genet 77:242–251CrossRefGoogle Scholar
  70. Stamberger H, Nikanorova M, Willemsen MH et al (2016) STXBP1 encephalopathy: a neurodevelopmental disorder including epilepsy. Neurology 86:954–962CrossRefGoogle Scholar
  71. Stevanin G, Santorelli FM, Azzedine H et al (2007) Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 39:366–372CrossRefGoogle Scholar
  72. Stockler S, Corvera S, Lambright D et al (2014) Single point mutation in Rabenosyn-5 in a female with intractable seizures and evidence of defective endocytotic trafficking. Orphanet J Rare Dis 9:141CrossRefGoogle Scholar
  73. Straniero L, Guella I, Cilia R et al (2017) DNAJC12 and dopa-responsive nonprogressive parkinsonism. Ann Neurol 82:640–646CrossRefGoogle Scholar
  74. Sudhof TC (2013) Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 80:675–690CrossRefGoogle Scholar
  75. Takamori S, Holt M, Stenius K et al (2006) Molecular anatomy of a trafficking organelle. Cell 127:831–846CrossRefGoogle Scholar
  76. Thomas AC, Williams H, Seto-Salvia N et al (2014) Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome. Am J Hum Genet 95:611–621CrossRefGoogle Scholar
  77. Tristán-Noguero A, García-Cazorla A (2018) Synaptic metabolism: a new approach to inborn errors of neurotransmission. J Inherit Metab Dis.  https://doi.org/10.1007/s10545-018-0235-7
  78. Valente EM, Abou-Sleiman PM, Caputo V et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160CrossRefGoogle Scholar
  79. Verheijen FW, Verbeek E, Aula N et al (1999) A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. Nat Genet 23:462–465CrossRefGoogle Scholar
  80. Verkerk AJ, Schot R, Dumee B et al (2009) Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am J Hum Genet 85:40–52CrossRefGoogle Scholar
  81. Vilarino-Guell C, Rajput A, Milnerwood AJ et al (2014) DNAJC13 mutations in Parkinson disease. Hum Mol Genet 23:1794–1801CrossRefGoogle Scholar
  82. Wilmshurst JM, Wise GA, Pollard JD, Ouvrier RA (2004) Chronic axonal neuropathy with triosephosphate isomerase deficiency. Pediatr Neurol 30:146–148CrossRefGoogle Scholar
  83. Wilson GR, Sim JC, McLean C et al (2014) Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with alpha-synuclein pathology. Am J Hum Genet 95:729–735CrossRefGoogle Scholar
  84. Wojcik SM, Brose N (2007) Regulation of membrane fusion in synaptic excitation-secretion coupling: speed and accuracy matter. Neuron 55:11–24CrossRefGoogle Scholar
  85. Yokoi F, Cheetham CC, Campbell SL, Sweatt JD, Li Y (2013) Presynaptic release deficits in a DYT1 dystonia mouse model. PLoS One 8:e72491CrossRefGoogle Scholar

Copyright information

© SSIEM 2018

Authors and Affiliations

  • Elisenda Cortès-Saladelafont
    • 1
  • Noa Lipstein
    • 2
  • Àngels García-Cazorla
    • 1
  1. 1.Department of Neurology, Neurometabolic Unit and Synaptic Metabolism Laboratory, Institut Pediàtric de Recerca and CIBERER, ISCIIIHospital Sant Joan de DéuEspluguesSpain
  2. 2.Department of Molecular NeurobiologyMax Planck Institute of Experimental MedicineGöttingenGermany

Personalised recommendations