Brain dopamine‐serotonin vesicular transport disease presenting as a severe infantile hypotonic parkinsonian disorder

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.

Genetic investigation of 93 families with microphthalmia or posterior microphthalmos

“…This mutation has previously been reported in another Saudi family who presented with global developmental delay, abnormal movement, hypotonia, and ataxia amongst other phenotypes but not microphthalmia . While the possibility of dual molecular diagnosis should be entertained, we note that only 3 patients have been reported with mutations in SLC18A2 making it possible that the phenotypic expression has not been fully elucidated yet . An unexpected discovery was made in patient 11DG0558, who presented with hypoplastic columella, flat nasal bridge and micropenis and colobomatous microphthalmia, in whom we found a splice site mutation in DSC3 (NM_001941.4:c.2236‐2A>G).…”

“…An elegant series of experiments conducted by Rilstone et al showed that Pro387Leu results in severe, but not complete, loss of function . With only 3 cases reported to date, it will be interesting to see the varying phenotypes that are associated with the gene as additional mutations are discovered …”

“…45 With only 3 cases reported to date, it will be interesting to see the varying phenotypes that are associated with the gene as additional mutations are discovered. [45][46][47] In conclusion, next generation sequencing in the form of multigene panels and WES enabled molecular diagnosis for the majority of patients. Our study demonstrates the importance of studying a large collection of families with microphthalmia as we show the complexity of the disease due to the presence of different modes of inheritance, incomplete penetrance, gonadal mosaicism, phenotypic variability and expansion of the phenotypic spectrum for a number of genes.…”

Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child

“…A defect in the glucose transporter Glut1 leads to microcephaly and seizures (Seidner et al 1998), a defect in the citrate transporter leads to an epileptic encephalopathy in the first days of life (Thevenon et al 2014), a defect in the thiamine transporter leads to encephalopathy and developmental delays (Kono et al . 2009), a defect in the dopamine-serotonin transporter leads to neonatal hypotonia and bradykinesis (Jacobsen et al 2016), and a defect in the manganese and zinc transporter affects brain growth and function, as well as bone mineralization (Boycott et al 2015). That the affected child in our study was found to have normal blood levels of biotin and pantothenic acid is not unexpected since the child was fed via a Broviac appliance.…”

DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously

“…In 2016, Jacobsen et al reported that exome sequencing on infant twins with developmental delay, hypotonia and oculogyric crises (prolonged upward deviation of the eyes), revealed a SLC18A2 mutation, the mutation in these infants was p. pro237his. The twins also benefitted from treatment with a dopamine receptor agonist.…”