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

Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the SLC6A3 gene. Advances in genomic analysis have revealed an evolving spectrum of SLC6A3-related neurological and neuropsychiatric disorders. Since the initial clinical and genetic characterisation of DTDS in 2009, there have been thirty-one published cases with a variety of protein-truncating variants (nonsense variants, splice-site changes, and deletions) and missense changes. Amino acid substitutions result in mutant proteins with impaired dopamine transporter function due to reduced transporter activity, impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational protein modification with impaired glycosylation. In this review, we provide an overview of the expanding clinical phenotype of DTDS and the precision therapies in development, including pharmacochaperones and gene therapy

Gene Therapy for Dopamine Dyshomeostasis: From Parkinson's to Primary Neurotransmitter Diseases

Neurological disorders encompass a broad range of neurodegenerative and neurodevelopmental diseases that are complex and almost universally without disease modifying treatments. There is, therefore, significant unmet clinical need to develop novel therapeutic strategies for these patients. Viral gene therapies are a promising approach, where gene delivery is achieved through viral vectors such as adeno-associated virus and lentivirus. The clinical efficacy of such gene therapies has already been observed in two neurological disorders of pediatric onset; for spinal muscular atrophy and aromatic L-amino acid decarboxylase (AADC) deficiency, gene therapy has significantly modified the natural history of disease in these life-limiting neurological disorders. Here, we review recent advances in gene therapy, focused on the targeted delivery of dopaminergic genes for Parkinson's disease and the primary neurotransmitter disorders, AADC deficiency and dopamine transporter deficiency syndrome (DTDS). Although recent European Medicines Agency and Medicines and Healthcare products Regulatory Agency approval of Upstaza (eladocagene exuparvovec) signifies an important landmark, numerous challenges remain. Future research will need to focus on defining the optimal therapeutic window for clinical intervention, better understanding of the duration of therapeutic efficacy, and improved brain targeting. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

The Lantern Vol. 36, No. 2, Spring 1970

• On a Plane From Here to There • The Earth • A Cry • Starry-Eyed • Day • Ticking Clocks • Nadir • To---- • Mood • Frost • Island of Life • A Non-Poem • Cooky - Stillborn Like Mother Used to Make • Solar • Come Back • The Hand • Now • Free • Vision of the Action Scene • Potpourri • Confusions of a Stranger • In the Darknesshttps://digitalcommons.ursinus.edu/lantern/1097/thumbnail.jp

The Lantern Vol. 37, No. 1, Fall 1970

• Circumstance • Advice • For What You Do For Me • Blink • Love • Love II • Magic • To Be a Child • A Year Later • A Poem in February • The Crystal Brick Road • Ephemera • Life • Whiskers • Thoughts On Being Sick • A Non-Poem • A Gruk Anthology • Moon • A Thought • Dwarf in an Existential Dawn • Corridors To My Mind • Sadness • The Enzyme Song • Creatures of Sandhttps://digitalcommons.ursinus.edu/lantern/1098/thumbnail.jp

TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus

Background: Advances in molecular genetic technologies have improved our understanding of genetic causes of rare neurological disorders with features of myoclonus. Case Report: A family with two affected siblings, presenting with multifocal polymyoclonus and neurodevelopmental delay, was recruited for whole-exome sequencing following unyielding diagnostic neurometabolic investigations. Compound heterozygous mutations in TBC1D24, a gene previously associated with various epilepsy phenotypes and hearing loss, were identified in both siblings. The mutations included a missense change c.457G>A (p.Glu157Lys), and a novel frameshift mutation c.545del (p.Thr182Serfs*6). Discussion: We propose that TBC1D24-related diseases should be in the differential diagnosis for children with polymyoclonus

<i>TBC1D24</i> Mutations in a Sibship with Multifocal Polymyoclonus

<p><strong>Background:</strong>&nbsp;Advances in molecular genetic technologies have improved our understanding of genetic causes of rare neurological disorders with features of myoclonus.</p><p><strong>Case Report:</strong>&nbsp;A family with two affected siblings, presenting with multifocal polymyoclonus and neurodevelopmental delay, was recruited for whole-exome sequencing following unyielding diagnostic neurometabolic investigations. Compound heterozygous mutations in&nbsp;<em>TBC1D24</em>, a gene previously associated with various epilepsy phenotypes and hearing loss, were identified in both siblings. The mutations included a missense change c.457G&gt;A (p.Glu157Lys), and a novel frameshift mutation c.545del (p.Thr182Serfs*6).</p><p><strong>Discussion:</strong>&nbsp;We propose that&nbsp;<em>TBC1D24-</em>related diseases should be in the differential diagnosis for children with polymyoclonus.</p><p>&nbsp;</p

<i>TBC1D24</i> Mutations in a Sibship with Multifocal Polymyoclonus

<p><strong>Background:</strong>&nbsp;Advances in molecular genetic technologies have improved our understanding of genetic causes of rare neurological disorders with features of myoclonus.</p><p><strong>Case Report:</strong>&nbsp;A family with two affected siblings, presenting with multifocal polymyoclonus and neurodevelopmental delay, was recruited for whole-exome sequencing following unyielding diagnostic neurometabolic investigations. Compound heterozygous mutations in&nbsp;<em>TBC1D24</em>, a gene previously associated with various epilepsy phenotypes and hearing loss, were identified in both siblings. The mutations included a missense change c.457G&gt;A (p.Glu157Lys), and a novel frameshift mutation c.545del (p.Thr182Serfs*6).</p><p><strong>Discussion:</strong>&nbsp;We propose that&nbsp;<em>TBC1D24-</em>related diseases should be in the differential diagnosis for children with polymyoclonus.</p><p>&nbsp;</p