Abstract
Two male siblings from a consanguineous union presented in early infancy with marked truncal hypotonia, a general paucity of movement, extrapyramidal signs and cognitive delay. By mid-childhood they had made little developmental progress and remained severely hypotonic and bradykinetic. They developed epilepsy and had problems with autonomic dysfunction and oculogyric crises. They had a number of orthopaedic problems secondary to their hypotonia. Cerebrospinal fluid (CSF) neurotransmitters were initially normal, apart from mildly elevated 5-hydroxyindolacetic acid, and the children did not respond favourably to a trial of levodopa-carbidopa. The youngest died from respiratory complications at 10 years of age. Repeat CSF neurotransmitters in the older sibling at eight years of age showed slightly low homovanillic acid and 5-hydroxyindoleacetic acid levels. Whole-exome sequencing revealed a novel mutation homozygous in both children in the monoamine transporter gene SLC18A2 (p.Pro237His), resulting in brain dopamine-serotonin vesicular transport disease. This is the second family to be described with a mutation in this gene. Treatment with the dopamine agonist pramipexole in the surviving child resulted in mild improvements in alertness, communication, and eye movements. This case supports the identification of the causal mutation in the original case, expands the clinical phenotype of brain dopamine-serotonin vesicular transport disease and confirms that pramipexole treatment may lead to symptomatic improvement in affected individuals.
Similar content being viewed by others
References
Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U (2011) Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab 104(Supplement):S2–S9
Christiansen L, Tan Q, Iachina M et al (2007) Candidate gene polymorphisms in the serotonergic pathway: influence on depression symptomatology in an elderly population. Biol Psychiatry 61:223–230
Cordes FS, Bright JN, Sansom MSP (2002) Proline-induced distortions of transmembrane helices. J Mol Biol 323:951–960
Eiden LE, Weihe E (2011) VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Ann N Y Acad Sci 1216:86–98
Exome Aggregation Consortium (ExAC) (2014) Cambridge MA (URL: http://exac.broadinstitute.org). December 2014
Frank S (2010) Tetrabenazine: the first approved drug for the treatment of chorea in US patients with Huntington disease. Neuropsychiatr Dis Treat 6:657–665
Kurian MA, Gissen P, Smith M, Heales S Jr, Clayton PT (2011) The monoamine neurotransmitter disorders: an expanding range of neurological syndromes. Lancet Neurol 10:721–733
Marecos C, Ng J, Kurian MA (2014) What is new for monoamine neurotransmitter disorders? J Inherit Metab Dis 37:619–626
Ng J, Heales SJR, Kurian MA (2014) Clinical features and pharmacotherapy of childhood monoamine neurotransmitter disorders. Pediatr Drugs 16:275–291
Partridge AW, Therien AG, Deber CM (2004) Missense mutations in transmembrane domains of proteins: phenotypic propensity of polar residues for human disease. Proteins 54:648–656
Rilstone JJ, Alkhater RA, Minassian BA (2013) Brain dopamine–serotonin vesicular transport disease and its treatment. N Engl J Med 368:543–550
Rodan LH, Gibson KM, Pearl PL (2015) Clinical use of CSF neurotransmitters. Pediatr Neurol 53:277–286
Simons CJ, van Winkel R (2013) Intermediate phenotype analysis of patients, unaffected siblings, and healthy controls identifies VMAT2 as a candidate gene for psychotic disorder and neurocognition. Schizophr Bull 39:848–856
Solovieff N, Roberts AL, Ratanatharathorn A et al (2014) Genetic association analysis of 300 genes identifies a risk haplotype in SLC18A2 for post-traumatic stress disorder in two independent samples. Neuropsychopharmacol 39:1872–1879
Takahashi N, Miner LL, Sora I et al (1997) VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc Natl Acad Sci 94:9938–9943
Walker M (1977) Makaton system of communication. Spec Educ Forw Trends 4:11
Acknowledgments
We would like to thank the Centre for Genomics, Proteomics and Metabolomics at The University of Auckland for Sanger sequencing services, and the New Zealand eScience Infrastructure for high-performance computing support.
Funding
JCJ is supported by a Rutherford Discovery Fellowship from Government funding, administered by the Royal Society of New Zealand, SPR is supported by Curekids NZ and KL is supported by the Minds for Minds Charitable Trust. The research was funded by the Neurological Foundation of New Zealand and the Oakley Mental Health Research Foundation.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
None.
Informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
Additional information
Communicated by: Nenad Blau
Rights and permissions
About this article
Cite this article
Jacobsen, J.C., Wilson, C., Cunningham, V. et al. Brain dopamine-serotonin vesicular transport disease presenting as a severe infantile hypotonic parkinsonian disorder. J Inherit Metab Dis 39, 305–308 (2016). https://doi.org/10.1007/s10545-015-9897-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-015-9897-6