A case of an adult with borderline AADC deficiency symptoms is presented here. Genetic analysis revealed that the patient carries two AADC variants (NM_000790.3: c.1040G > A and c.679G > C) in compound heterozygosis, resulting in p.Arg347Gln and p.Glu227Gln amino acid alterations. While p.Arg347Gln is a known pathogenic variant, p.Glu227Gln is unknown. Combining clinical features to bioinformatic and molecular characterization of the AADC protein population of the patient (p.Arg347Gln/p.Arg347Gln homodimer, p.Glu227Gln/p.Glu227Gln homodimer, and p.Glu227Gln/p.Arg347Gln heterodimer), we determined that: i) the p.Arg347Gln/p.Arg347Gln homodimer is inactive since the alteration affects a catalytically essential structural element at the active site, ii) the p.Glu227Gln/p.Glu227Gln homodimer is as active as the wild-type AADC since the alteration occurs at the surface and does not change the chemical nature of the amino acid, and iii) the p.Glu227Gln/p.Arg347Gln heterodimer has a catalytic efficiency 75% that of the wild-type since only one of the two active sites is compromised, thus demonstrating a positive complementation. By this approach, the molecular basis for the mild presentation of the disease is provided, and the experience made can also be useful for personalized therapeutic decisions in other mild AADC deficiency patients. Interestingly, in the last few years, many previously undiagnosed or misdiagnosed patients have been identified as mild cases of AADC deficiency, expanding the phenotype of this neurotransmitter disease.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10958467 | PMC |
http://dx.doi.org/10.1016/j.ymgmr.2024.101071 | DOI Listing |
Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder that results in a lack of the monoamine neurotransmitters dopamine, serotonin, norepinephrine, and epinephrine. Patients present with a wide spectrum of symptoms, including motor and autonomic dysfunction, hypotonia, and developmental delay, often before the age of one. Until recently, treatment options were limited to symptom control, but the recent approval of the first gene therapy for AADC deficiency in Europe and the UK has provided an alternative to treating symptoms for this disease.
View Article and Find Full Text PDFNeurobiol Dis
November 2024
Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan. Electronic address:
The development of the nigrostriatal dopaminergic (DA) pathway in the brain involves many transcriptional and chemotactic molecules, and a deficiency of these molecules can cause nigrostriatal tract defects. However, the role of the end product, dopamine, in nigrostriatal pathway development has not been described. In the present study, we analyzed a mouse model of congenital dopamine and serotonin deficiency, namely, the aromatic l-amino acid decarboxylase (AADC) deficiency (Ddc) mouse model.
View Article and Find Full Text PDFNeurotherapeutics
July 2024
Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address:
Neurotherapeutics
July 2024
Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, United States; Graduate Program in Translational Science, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, United States; NeuroNexus Institute, University of Massachusetts Chan Medical School, United States; Department of Pediatrics, University of Massachusetts Chan Medical School, United States; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, United States. Electronic address:
Adeno-associated virus (AAV) mediated gene therapy is a leading gene delivery platform with potential to transform the landscape of treatment for neurological disorders. While AAV is deemed non-immunogenic compared to other viral vectors, adverse immune reactions have been observed in the clinic, raising concerns. As the central nervous system (CNS) has a tightly regulated immune system, characterized by a degree of tolerance, it has been considered a unique target for AAV gene therapy.
View Article and Find Full Text PDFJ Inherit Metab Dis
August 2024
Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
AADC deficiency is a severe neurometabolic inherited rare disorder due to the absence or decrease of dopamine and serotonin levels, causing deep motor and neurodevelopmental impairments. The disease is often fatal in the first decade of life, and pharmacological treatments (dopamine agonists, pyridoxine, and monoamine oxidase inhibitors as the first-line choices) can only alleviate the symptoms. Gene therapy surgery is now available for severe patients in the European Union and the United Kingdom, and follow-up data witness encouraging improvements.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!