Blood platelet research in autism spectrum disorders: In search of biomarkers.

Autism spectrum disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder that is caused by gene-environment interactions. To improve its diagnosis and treatment, numerous efforts have been undertaken to identify reliable biomarkers for autism. None of them have delivered the holy grail that represents a reproducible, quantifiable, and sensitive biomarker. Though blood platelets are mainly known to prevent bleeding, they also play pivotal roles in cancer, inflammation, and neurological disorders. Platelets could serve as a peripheral biomarker or cellular model for autism as they share common biological and molecular characteristics with neurons. In particular, platelet-dense granules contain neurotransmitters such as serotonin and gamma-aminobutyric acid. Molecular players controlling granule formation and secretion are similarly regulated in platelets and neurons. The major platelet integrin receptor αIIbß3 has recently been linked to ASD as a regulator of serotonin transport. Though many studies revealed associations between platelet markers and ASD, there is an important knowledge gap in linking these markers with autism and explaining the altered platelet phenotypes detected in autism patients. The present review enumerates studies of different biomarkers detected in ASD using platelets and highlights the future needs to bring this research to the next level and advance our understanding of this complex disorder.

A novel missense variant in SLC18A2 causes recessive brain monoamine vesicular transport disease and absent serotonin in platelets.

BACKGROUND: Brain monoamine vesicular transport disease is an infantile onset neurodevelopmental disorder caused by variants in SLC18A2, which codes for the vesicular monoamine transporter 2 (VMAT2) protein, involved in the transport of monoamines into synaptic vesicles and of serotonin into platelet dense granules. CASE PRESENTATION: The presented case is of a child, born of healthy consanguineous parents, who exhibited hypotonia, mental disability, epilepsy, uncontrolled movements, and gastrointestinal problems. A trial treatment with L-DOPA proved unsuccessful and the exact neurological involvement could not be discerned due to normal metabolic and brain magnetic resonance imaging results.Platelet studies and whole genome sequencing were performed. At age 4, the child's platelets showed a mild aggregation and adenosine triphosphate secretion defect that could be explained by dysmorphic dense granules observed by electron microscopy. Interestingly, the dense granules were almost completely depleted of serotonin. A novel homozygous p.P316A missense variant in VMAT2 was detected in the patient and the consanguineous parents were found to be heterozygous for this variant. Although the presence of VMAT2 on platelet dense granules has been demonstrated before, this is the first report of defective platelet dense granule function related to absent serotonin storage in a patient with VMAT2 deficiency but without obvious clinical bleeding problems. CONCLUSIONS: This study illustrates the homology between serotonin metabolism in brain and platelets, suggesting that these blood cells can be model cells for some pathways relevant for neurological diseases. The literature on VMAT2 deficiency is reviewed.