Gene therapy for neurotransmitter disorders, specifically focusing on Aromatic L-Amino Acid Decarboxylase (AADC) deficiency and GTP Cyclohydrolase I (GTPCH) deficiency in paediatric populations.
Historical Context and Discovery
- Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency
- First described in 1990 by Hyland and Clayton.
- Initial report involved infantile twins presenting with severe hypotonia and oculogyric crises.
- AADC deficiency is an ultra-rare autosomal recessive disorder.
- Caused by biallelic mutations in the dopa decarboxylase gene (DDC).
- Identified as a congenital neurotransmitter disorder with profound dopamine and serotonin deficiencies.
Pathophysiology and Genetic Underpinnings
- Initially described by Segawa in 1971 as "hereditary progressive dystonia with marked diurnal fluctuation."
- Now commonly known as Segawa’s disease or autosomal dominant GTPCH deficiency (DYT5a).
- Characterized by childhood-onset dystonia with marked responsiveness to L-Dopa.
- A rarer autosomal recessive form was later identified, associated with severe neurological impairment from infancy.
- The recessive form often includes hyperphenylalaninemia detectable on newborn screening, due to tetrahydrobiopterin (BH4) deficiency affecting phenylalanine metabolism.
- These discoveries underscored GTPCH’s critical role in monoamine neurotransmitter synthesis, influencing therapeutic strategies used today.
Clinical Presentation in Children
- AADC Deficiency
- Caused by mutations in the DDC gene located on chromosome 7.
- Leads to deficiency of the enzyme aromatic L-amino acid decarboxylase (AADC).
- AADC converts L-DOPA to dopamine and 5-hydroxytryptophan (5-HTP) to serotonin.
- Deficient AADC activity results in markedly reduced dopamine, serotonin, norepinephrine, and epinephrine.
- Accumulation of precursor substances: L-DOPA and 5-HTP.
- Typical cerebrospinal fluid (CSF) biochemical profile:
- Low dopamine metabolite: Homovanillic acid (HVA)
- Low serotonin metabolite: 5-hydroxyindoleacetic acid (5-HIAA)
- Elevated precursors: L-DOPA and 5-HTP
Challenges in Conventional Treatment
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