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Levodopa-responsive aromatic L-amino acid decarboxylase deficiency
Yuh Terng Chang1, Radhakant Sharma, J Lawrence Marsh
1Kimberly H. Courtwright and Joseph W. Summers Institute of Metabolic Disease, Baylor University Medical Center, 3812 Elm Street, Dallas, TX 75226, USA.
Annals of Neurology
|March 3, 2004
Summary
Aromatic L-amino acid decarboxylase deficiency in three siblings responded to levodopa/carbidopa treatment. Genetic analysis revealed a mutation affecting enzyme function, explaining the therapeutic success.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare neurometabolic disorder.
- Patients typically present with severe autonomic dysfunction and movement disorders.
Purpose of the Study:
- To investigate the cause of a clinical phenotype in three siblings.
- To elucidate the mechanism underlying the therapeutic response to levodopa/carbidopa.
Main Methods:
- Empirical treatment with levodopa combined with carbidopa.
- Biochemical assays to identify the enzyme deficiency.
- Molecular genetic analysis including sequencing and mutation identification (c.387 G-->A).
- Enzyme kinetics and structural modeling.
Main Results:
- All three siblings showed an immediate positive response to levodopa/carbidopa.
- Biochemical investigations confirmed aromatic L-amino acid decarboxylase deficiency.
- A homozygous point mutation (c.387 G-->A) in exon 3 was identified.
- Kinetic studies demonstrated reduced substrate binding affinity due to the mutation.
- Structural modeling indicated altered active site configuration.
Conclusions:
- The identified mutation in AADC causes the observed clinical phenotype.
- The mutation's impact on enzyme kinetics and structure explains the effectiveness of levodopa therapy.
- This study highlights the importance of genetic and biochemical investigations in diagnosing and managing AADC deficiency.