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-CazorlaEmail author
Original Article


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.



Autism spectrum disorder


Cerebrospinal fluid


Homovanilic acid


Intellectual disability


Movement disorder


Synaptic vesicle




Parkinson’s disease


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.


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Copyright information

© SSIEM 2018

Authors and Affiliations

  • Elisenda Cortès-Saladelafont
    • 1
  • Noa Lipstein
    • 2
  • Àngels García-Cazorla
    • 1
    Email author
  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

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