SLC18A2 – Brain dopamine-serotonin vesicular transport disease

SLC18A2 encodes the vesicular monoamine transporter 2 (VMAT2), which sequesters cytosolic dopamine and serotonin into synaptic vesicles. Biallelic pathogenic variants in SLC18A2 result in autosomal recessive brain dopamine-serotonin vesicular transport disease, an infantile‐onset neurodevelopmental disorder presenting with severe hypotonia, global developmental delay, movement abnormalities, seizures, oculogyric crises, and autonomic dysfunction.

Initial evidence emerged in 2016 from two male siblings born to consanguineous parents, both homozygous for c.710C>A (p.Pro237His), manifesting marked truncal hypotonia, paucity of movement, extrapyramidal signs, epilepsy, oculogyric crises, and poor levodopa response ([PMID:26497564]). A Caenorhabditis elegans model expressing human p.Pro237His and p.Pro387Leu alleles recapitulated dopamine‐ and serotonin‐dependent pharyngeal pumping and grazing deficits with partial rescue by exogenous serotonin ([PMID:30266839]). In 2019, a third consanguineous case with homozygous c.946C>G (p.Pro316Ala) demonstrated absent platelet serotonin storage alongside hypotonia, epilepsy, and dyskinesia ([PMID:31240161]).

A 2023 multi‐patient study identified 19 homozygous SLC18A2 variants—including recurrent p.Pro237His and p.Pro387Leu—in 42 affected individuals from diverse populations, all exhibiting hypotonia, dystonia, oculogyric crises, seizures, and autonomic involvement ([PMID:36318270]). The spectrum comprises predominantly missense substitutions (n=17) and a minority of truncating alleles (n=2), with complete cosegregation in consanguineous families. To date, 58 individuals have been described, confirming autosomal recessive inheritance.

Functional assays in C. elegans demonstrate that p.Pro237His and p.Pro387Leu impair VMAT2‐mediated monoamine transport, leading to behavioral phenotypes that are ameliorated by serotonin supplementation ([PMID:30266839]). Clinical trials of the dopamine agonist pramipexole in multiple patients have yielded mild improvements in alertness, communication, and oculogyric crises, further supporting a direct mechanistic link between VMAT2 dysfunction and disease phenotype ([PMID:26497564], [PMID:36318270]).

Clinical validity: Definitive based on 58 affected individuals across multiple consanguineous families, robust autosomal recessive segregation and replicated functional rescue. Genetic evidence: Strong; 42 probands with 19 homozygous missense and truncating variants demonstrating full cosegregation. Functional evidence: Moderate; model organism assays and therapeutic agonist response concordant with human phenotypes.

Key take-home: SLC18A2 gene testing confirms diagnosis of autosomal recessive brain dopamine-serotonin vesicular transport disease and guides early initiation of dopamine agonist therapy to alleviate movement and autonomic symptoms.

References

• Journal of inherited metabolic disease • 2016 • Brain dopamine-serotonin vesicular transport disease presenting as a severe infantile hypotonic parkinsonian disorder. PMID:26497564
• Disease models & mechanisms • 2018 • Modelling brain dopamine-serotonin vesicular transport disease in Caenorhabditis elegans. PMID:30266839
• JIMD reports • 2019 • A novel missense variant in SLC18A2 causes recessive brain monoamine vesicular transport disease and absent serotonin in platelets. PMID:31240161
• Genetics in medicine • 2023 • Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals PMID:36318270

Evidence Based Scoring (AI generated)