Hereditary Dopamine Transporter Deficiency Syndrome: Challenges in Diagnosis and Treatment

Abstract

Hereditary dopamine transporter deficiency syndrome (DTDS) is a neurotransmitter disorder caused by a defect in the neuronal uptake of dopamine. To date, 20 patients are reported in the literature, and we present 2 additional patients with DTDS harboring novel homozygous gene mutations. Patient A is an 8-month-old male with neonatal-onset hypotonia, who developed orolingual dyskinetic movements and oculogyric crises after 4 months of age, with evolution to status dystonicus episodes. Patient B is a 4-year-old male who also had hypotonia since birth, with additional severe limb contractions and oculogyric crises after the age of 3 months, with a misdiagnosis of epileptic encephalopathy. Both patients had consanguineous parents and similar cerebrospinal fluid (CSF) neurotransmitter profiles with elevated homovanillic acid and increased the ratio of homovanillic acid to 5-hydroxyindoleacetic acid. Diagnostic delay is 4 months, and 3 years 9 months, respectively. Treatment response to levodopa is poor. Early infantile-onset progressive dystonia with oculogyric crises, hypotonia, developmental delay, and CSF neurotransmitter profile led to a diagnosis of DTDS in these two patients. Management of hyperkinetic movement disorder, status dystonicus, and feeding difficulties are challenging. Detailed phenotyping of individual patients along with treatment response should provide insight into dopamine homeostasis.

Behavioral Phenotyping of Dopamine Transporter Knockout Rats: Compulsive Traits, Motor Stereotypies, and Anhedonia

“…Recently, DAT KO mice have been used to model human DAT deficiency syndrome (DTDS), also known as early PD, a rare Parkinsonian-like movement disorder. DTDS’ symptoms can range from dystonic muscle contractions to bradykinesia, postural instability, and hypomimia: these are believed to be caused by an impaired DAT functionality, due to mutations in the SLC6A3 gene ( 27 – 30 ). It should be noted that due to the extreme phenotype of DAT KO mice, which could influence or even impair some behavioral measures, they have been avoided in some recent studies in favor of heterozygous (HET) DAT hypofunctional mice.…”

Dopamine Transporter Deficiency Syndrome (DTDS): Expanding the Clinical Phenotype and Precision Medicine Approaches

“…The detailed clinical characterisation of eleven children with DTDS established the classical features and progression of DTDS over time. Since 2011, there have been thirty-one DTDS patients reported in the literature [8,9,[15][16][17][18][19][20][21][22][23][24], and a further unpublished twenty patients reported to our centre (Kurian personal communication).…”

“…The genetic diagnosis of DTDS can be made through several genetic platforms, including whole-genome/exome analysis, gene panels, and targeted gene sequencing (Figure 1). A number of nonsense variants, splice-site changes, and frameshift deletions have been reported where nonsense-mediated decay or absent/truncated proteins are mechanistic factors in disease [8,9,[15][16][17][18][19][20][21][22][23][24]. To date, twenty missense variants have been reported in DTDS (Table 2), with in vitro modelling undertaken for thirteen variants [8,9,15].…”

A Proposed Diagnostic Algorithm for Inborn Errors of Metabolism Presenting With Movements Disorders

“…Notwithstanding, status dystonicus is a rare and lifethreatening MD emergency. It has been described in the following IEMs: Wilson disease (116), Pantothenate kinaseassociated neurodegeneration (117)(118)(119)(120), aromatic l-amino acid decarboxylase (AADC) deficiency (45) and SLC6A3 dopamine transporter deficiency syndrome (121). Management is adjusted to the characteristics and complications of each patient.…”