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

Abstract

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.

Keywords: epilepsy; platelet dense granules; serotonin; vesicular monoamine transporter 2; whole genome sequencing.

Figure 1

Pedigree with genetic data and platelet morphology studies. A, Pedigree showing the index patient and consanguineous parents. Sanger sequencing shows heterozygosity for the c.946C

Figure 2

Platelet dense granule studies. A, Western blot of total platelet lysates showing protein expression of dense granule markers VMAT2, CD63, and Lamp2 and loading control Integrin β3. The two patient samples are from two blood samples that were taken at separate occasions. B, Quantification of the blots using band density measurement, corrected to the loading control Integrin β3 and normalized to one of the control samples set to 1. The bars represent the mean ± SD obtained from duplicate experiments followed by unpaired t test showing no significant differences. C, Graph showing 5‐HT levels measured in total platelet lysate using Enzyme‐linked immunosorbent assay (ELISA) and performed in duplicate for each sample. The two patient samples are from two blood samples that were taken at different occasions (grey vs black dots). Data represent the mean ± SD. ***P < 0.001 as determined by one‐way ANOVA. C1, C2, and C3 are three unrelated healthy controls; F, father; M, mother