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Keith Hyland - One of the best experts on this subject based on the ideXlab platform.
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prevalence of aromatic l Amino Acid Decarboxylase deficiency in at risk populations
Pediatric Neurology, 2020Co-Authors: Keith Hyland, Michael ReottAbstract:Abstract Background Aromatic l -Amino Acid Decarboxylase (AADC) deficiency is an autosomal recessive metabolic disorder that results from disease-causing pathogenic variants of the dopa Decarboxylase (DDC) gene. Loss of dopamine and serotonin production in the brain from infancy prevents achievement of motor developmental milestones. Methods We retrospectively evaluated data obtained from requests to Medical Neurogenetics Laboratories for analyses of neurotransmitter metabolites in the cerebrospinal fluid, AADC enzyme activity in plasma, and/or Sanger sequencing of the DDC gene. Our primary objective was to estimate the prevalence of AADC deficiency in an at-risk population. Results Approximately 20,000 cerebrospinal fluid samples were received with a request for neurotransmitter metabolite analysis in the eight-year study period; 22 samples tested positive for AADC deficiency based on decreased concentrations of 5-hydroxyindoleacetic Acid and homovanillic Acid, and increased 3-O-methyldopa, establishing an estimated prevalence of approximately 0.112%, or 1:900. Of the 81 requests received for plasma AADC enzyme analysis, 25 samples had very low plasma AADC activity consistent with AADC deficiency, resulting in identification of nine additional cases. A total of five additional patients were identified by Sanger sequencing as the primary request leading to the diagnosis of AADC deficiency. Conclusions Overall, these analyses identified 36 new cases of AADC deficiency. Sequencing findings showed substantial diversity with identification of 26 different DDC gene variants; five had not previously been associated with AADC deficiency. The results of the present study align with the emerging literature and understanding of the epidemiology and genetics of AADC deficiency.
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pyridoxal 5 phosphate deficiency causes a loss of aromatic l Amino Acid Decarboxylase in patients and human neuroblastoma cells implications for aromatic l Amino Acid Decarboxylase and vitamin b6 deficiency states
Journal of Neurochemistry, 2010Co-Authors: George F G Allen, Keith Hyland, Peter E Clayton, Viruna Neergheen, Marcus Oppenheim, Julia C Fitzgerald, Emma Footitt, J M Land, Simon J R HealesAbstract:Pyridoxal 5'-phosphate, the active form of vitamin B(6), is an essential cofactor for multiple enzymes, including aromatic l-Amino Acid Decarboxylase that catalyses the final stage in the production of the neurotransmitters dopamine and serotonin. In two patients with inherited disorders of vitamin B(6) metabolism, we observed reductions in plasma aromatic l-Amino Acid Decarboxylase activity. In one patient, this change was related to an increase in K(m) for pyridoxal 5'-phosphate. Furthermore, pyridoxal 5'-phosphate-deficient human SH-SY5Y neuroblastoma cells were found to exhibit reduced levels of aromatic l-Amino Acid Decarboxylase activity and protein but with no alteration in expression. Further reductions in activity and protein were observed with the addition of the vitamin B(6) antagonist 4-deoxypyridoxine, which also reduced aromatic l-Amino Acid Decarboxylase mRNA levels. Neither pyridoxal 5'-phosphate deficiency nor the addition of 4-deoxypyridoxine affected aromatic l-Amino Acid Decarboxylase stability over 8 h with protein synthesis inhibited. Increasing extracellular availability of pyridoxal 5'-phosphate was not found to have any significant effect on intracellular pyridoxal 5'-phosphate concentrations or on aromatic l-Amino Acid Decarboxylase. These findings suggest that maintaining adequate pyridoxal 5'-phosphate availability may be important for optimal treatment of aromatic l-Amino Acid Decarboxylase deficiency and l-dopa-responsive conditions.
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aromatic l Amino Acid Decarboxylase deficiency clinical features treatment and prognosis
Neurology, 2004Co-Authors: Roser Pons, Keith Hyland, B Ford, Claudia A Chiriboga, Peter E Clayton, Veronica J Hinton, Rohit Sharma, Darryl C De VivoAbstract:Background: Deficiency of aromatic l-Amino Acid Decarboxylase (AADC) is associated with severe developmental delay, oculogyric crises (OGC), and autonomic dysfunction. Treatment with dopamine agonists and MAO inhibitors is beneficial, yet long-term prognosis is unclear. Objective: To delineate the clinical and molecular spectrum of AADC deficiency, its management, and long-term follow-up. Results: The authors present six patients with AADC deficiency and review seven cases from the literature. All patients showed reduced catecholamine metabolites and elevation of 3-O-methyldopa in CSF. Residual plasma AADC activity ranged from undetectable to 8% of normal. Mutational spectrum was heterogeneous. All patients presented with hypotonia, hypokinesia, OGC, and signs of autonomic dysfunction since early life. Diurnal fluctuation or improvement of symptoms after sleep were noted in half of the patients. Treatment response was variable. Two groups of patients were detected: Group I (five males) responded to treatment and made developmental progress. Group II (one male, five females) responded poorly to treatment, and often developed drug-induced dyskinesias. Conclusions: The molecular and clinical spectrum of AADC deficiency is heterogeneous. Two groups, one with predominant male sex and favorable response to treatment, and the other with predominant female sex and poor response to treatment, can be discerned.
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levodopa responsive aromatic l Amino Acid Decarboxylase deficiency
Annals of Neurology, 2004Co-Authors: Yuh Terng Chang, Georg F Hoffmann, Keith Hyland, Chad A Brautigam, Radhakant Sharma, Lawrence J Marsh, John Douglas Mcpherson, Joey A Bedell, Andreas KnustAbstract:We report three siblings, who were treated empirically with levodopa combined with carbidopa. There was an immediate therapeutic response. Biochemical investigation surprisingly showed the clinical phenotype to be caused by aromatic L–Amino Acid Decarboxylase deficiency. Molecular characterization showed a homozygous point mutation (c.387 GA) in exon 3. Kinetic studies showed the mutation to decrease the binding affinity for the substrate. This, combined with structural modeling suggesting alteration of active site configuration, provided an explanation for the therapeutic response to levodopa. Ann Neurol 2004
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aromatic l Amino Acid Decarboxylase deficiency overview of clinical features and outcomes
Annals of Neurology, 2003Co-Authors: Kathryn J Swoboda, Philip J Saul, Catherine E Mckenna, Nancy B Speller, Keith HylandAbstract:In this paper, we provide a brief update of diagnostic considerations and biochemical phenotype in L-Amino Acid Decarboxylase deficiency. We review clinical features and outcome data in 11 affected patients, including 7 previously unreported cases. All had onset of the characteristic movement disorder by 6 months of age. The phenomenology of the movement disorder is identical to that previously reported, and includes intermittent oculogyric crises and limb dystonia, generalized athetosis, and impaired voluntary movement in all patients. Autonomic dysfunction is characterized by a significant impairment of sympathetic regulation of heart rate and blood pressure, as documented via detailed studies with spectral analysis techniques in two patients. Functional clinical outcomes as a group remain poor, in spite of a variety of attempted treatment interventions, with marked impairment in motor abilities as well as in speech and communication; however, outcome was quite variable from patient to patient and covered a broad spectrum of neurological disability. Much further work remains to identify and refine the best treatment options for patients with L-Amino Acid Decarboxylase deficiency.
Wuh-liang Hwu - One of the best experts on this subject based on the ideXlab platform.
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a review of aromatic l Amino Acid Decarboxylase aadc deficiency in taiwan
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2019Co-Authors: Ni-chung Lee, Yin-hsiu Chien, Wuh-liang HwuAbstract:Aromatic l-Amino Acid Decarboxylase deficiency (AADCD) is a rare inherited disease prevalent in South East Asia. This disease is due to the founder mutation IVS 6 + 4A > T (c.714 + 4A > T), which accounts for most alleles. Patients with this mutation have severe phenotypes. About 90 % of these patients in South East Asia do not have head control and cannot sit, stand, or speak from birth to the time of observation. In 2012, a gene study to treat these patients with intraputamen injection of adeno-associated virus2-human AADC showed prominent motor improvement and an increased PDMS-2 score 12 months after treatment. In addition, systemic gene therapy in a mouse model of AADCD achieved widespread correction of the Ddc gene. In this article, we review the natural history, clinical course, and treatment effects seen in these clinical and mouse studies. Future studies focusing on noninvasive viral vector delivery or alternative emerging treatments may also benefit patients with AADCD.
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gene therapy improves brain white matter in aromatic l Amino Acid Decarboxylase deficiency
Annals of Neurology, 2019Co-Authors: Chihhsien Tseng, Yin-hsiu Chien, Ni-chung Lee, Yungchin Hsu, Shinnforng Peng, Wenyih Isaac Tseng, Wuh-liang HwuAbstract:Objective Children with aromatic l-Amino Acid Decarboxylase (AADC) deficiency suffer from severe motor dysfunction. Restoration of dopamine levels in the putamen by gene therapy has led to significant improvement in motor function. This study explored brain structure changes in patients. Methods Brain diffusion tensor imaging (DTI) was performed before and 12 months after gene therapy. Whole-brain tract-specific analysis was performed to assess white matter microstructural integrity. Results In the 8 patients (aged 1.67-8.42 years) enrolled in the study, gene therapy did not affect macroscopic structure. DTI before gene therapy revealed lower total mean fractional anisotropy (FA) values in patients than in the age-matched pretreatment controls (p = 0.017; median difference = -0.0136; 95% confidence interval [CI] [-0.0319, -0.0126]). After gene therapy, total mean FA increased (p = 0.012, median difference = 0.0211, 95% CI [0.0094, 0.0456]), and the values in the patients were not different from the age-matched posttreatment controls. Increase in total mean FA after gene therapy in patients was correlated with their increase in motor score (r = 0.846; p = 0.008), but was inversely correlated with their ages at the time of gene therapy (r = -0.754; p = 0.031). Corticospinal tracts, and the thalamic radiation and callosal fibers involving motor function, improved after gene therapy. Interpretation Improvement in the microstructural integrity of white matter tracts is associated with the improvement in motor function following gene therapy. Ann Neurol 2019;85:644-652.
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natural history of aromatic l Amino Acid Decarboxylase deficiency in taiwan
JIMD reports, 2017Co-Authors: Wuh-liang Hwu, Yin-hsiu Chien, Ni-chung LeeAbstract:Objectives: Aromatic l-Amino Acid Decarboxylase (AADC) deficiency is a rare inherited disorder of monoamine neurotransmitter synthesis; this deficiency leads to psychomotor delay, hypotonia, oculogyric crises, dystonia, and extraneurological symptoms. This study aimed to provide further insight into the clinical course of AADC deficiency in Taiwan.
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3-O-methyldopa levels in newborns: Result of newborn screening for aromatic l-Amino-Acid Decarboxylase deficiency.
Molecular genetics and metabolism, 2016Co-Authors: Yin-hsiu Chien, Pin Wen Chen, Ni-chung Lee, Wu-shiun Hsieh, Pao Chin Chiu, Wuh-liang Hwu, Fuu Jen Tsai, Shuan-pei Lin, Shao Yin Chu, Yuh-jyh JongAbstract:Abstract Background The diagnosis of aromatic l-Amino-Acid Decarboxylase (AADC) deficiency is often delayed because a cerebrospinal fluid analysis is required to detect a neurotransmitter deficiency. We here demonstrated that an elevated concentration of l-dopa metabolite 3- O -methyldopa (3-OMD) in dried blood spots could be integrated into newborn screening program to precisely predict AADC deficiency. Methods After obtaining parental consent, an additional spot was punched from newborn filter paper, eluted, cleaned, and analyzed by tandem mass spectrometry. Newborns with a 3-OMD concentration exceeding 500ng/mL were referred for confirmatory testing. Results From September 2013 to December 2015, 127,987 newborns were screened for AADC deficiency. The mean 3-OMD concentration in these newborns was 88.08ng/mL (SD=27.74ng/mL). Four newborns exhibited an elevated 3-OMD concentration (range, 939–3241ng/mL). All four newborns were confirmed to carry two pathologic DDC mutations, indicating an incidence of AADC deficiency of 1:32,000. During the follow-up period, three patients developed typical symptoms of AADC deficiency. Among 16 newborns with mildly elevated 3-OMD levels, six were heterozygous for the DDC IVS6+4A>T mutation. Conclusion Newborn screening of AADC deficiency was achieved with a 100% positive-predictive rate. An association for gestational age could be further elucidated.
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201 neuron specific systemic gene therapy for aromatic l Amino Acid Decarboxylase aadc deficiency
Molecular Therapy, 2015Co-Authors: Ni-chung Lee, Yin-hsiu Chien, Pin Wen Chen, Shinichi Muramatsu, Kaiyuan Tzen, Barry J Byrne, Wuh-liang HwuAbstract:Aromatic L-Amino Acid Decarboxylase (AADC) deficiency is a rare autosomal recessive disease that causes defective synthesis of dopamine and serotonin, and children with AADC deficiency exhibit severe motor, behavioral and autonomic dysfunctions. We have created an IVS6+4A>T knock-in mouse model of AADC (DdcKI mice) and shown that gene therapy at the neonatal stage can rescue the phenotype. In this study, we extended the treatment to systemic therapy on young mice. After intraperitoneal injection of 7-day-old mice with either AAV9-CMV-hAADC (AAV9-AADC) or yfAAV9/3-Syn-I-mAADC (AAVN-AADC), the treated DdcKI mice showed improvements in weight gain, survival, motor function, autonomic function, and behavior, but the effects of AAVN-AADC were superior. The survival of AAVN-AADC treated DdcKI mice (95%) was slightly better than that of the AAV9-AADC treated mice (78%), but this difference was not significant. Brain AADC activity of both AAV9-AADC and AAVN-AADC treated mice was slightly elevated (2.3% and 2.7% of wild-type, respectively). Untreated DdcKI mice had difficulties maintaining body temperature during cold exposure, and both AAV9-AADC- and AAVN-AADC-treated DdcKI mice exhibited body temperature control similar to that of WT mice in cold environments. Moreover, the AAV9-AADC-treated DdcKI mice exhibited slight hyperactivity. Under low magnification, AADC-positive cells were found in the cortex of AAV9-AADC-treated mice. Therefore, mice with a neurotransmitter deficiency can be rescued at a young age using systemic gene therapy, but a neuron-specific vector may be necessary.
Georg F Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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consensus guideline for the diagnosis and treatment of aromatic l Amino Acid Decarboxylase aadc deficiency
Orphanet Journal of Rare Diseases, 2017Co-Authors: Tessa Wassenberg, Marta Moleroluis, Kathrin Jeltsch, Georg F Hoffmann, Birgit Assmann, Nenad Blau, Angeles Garciacazorla, Roser Pons, Rafael Artuch, Toni S PearsonAbstract:Aromatic L-Amino Acid Decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. Onset is early in life, and key clinical symptoms are hypotonia, movement disorders (oculogyric crisis, dystonia, and hypokinesia), developmental delay, and autonomic symptoms. In this consensus guideline, representatives of the International Working Group on Neurotransmitter Related Disorders (iNTD) and patient representatives evaluated all available evidence for diagnosis and treatment of AADCD and made recommendations using SIGN and GRADE methodology. In the face of limited definitive evidence, we constructed practical recommendations on clinical diagnosis, laboratory diagnosis, imaging and electroencephalograpy, medical treatments and non-medical treatments. Furthermore, we identified topics for further research. We believe this guideline will improve the care for AADCD patients around the world whilst promoting general awareness of this rare disease.
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does the aromatic l Amino Acid Decarboxylase contribute to thyronamine biosynthesis
Molecular and Cellular Endocrinology, 2012Co-Authors: Carolin S Hoefig, Georg F Hoffmann, Kostja Renko, Susanne Piehl, Thomas S Scanlan, Mariarita Bertoldi, Thomas Opladen, Jeannette Klein, Oliver Blankenstein, Ulrich SchweizerAbstract:Thyronamines (TAM), recently described endogenous signaling molecules, exert metabolic and pharmacological actions partly opposing those of the thyromimetic hormone T(3). TAM biosynthesis from thyroid hormone (TH) precursors requires decarboxylation of the L-alanine side chain and several deiodination steps to convert e.g. L-thyroxine (T(4)) into the most potent 3-T(1)AM. Aromatic L-Amino Acid Decarboxylase (AADC) was proposed to mediate TAM biosynthesis via decarboxylation of TH. This hypothesis was tested by incubating recombinant human AADC, which actively catalyzes dopamine production from DOPA, with several TH. Under all reaction conditions tested, AADC failed to catalyze TH decarboxylation, thus challenging the initial hypothesis. These in vitro observations are supported by detection of 3-T(1)AM in plasma of patients with AADC-deficiency at levels (46 ± 18 nM, n=4) similar to those of healthy controls. Therefore, we propose that the enzymatic decarboxylation needed to form TAM from TH is catalyzed by another unique, perhaps TH-specific, Decarboxylase.
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aromatic l Amino Acid Decarboxylase deficiency clinical features drug therapy and follow up
Journal of Inherited Metabolic Disease, 2009Co-Authors: C Manegold, Georg F Hoffmann, Andreas Knust, I Degen, H Ikonomidou, M W Laas, M Pritsch, Ekkehard Wilichowski, Friederike HorsterAbstract:Background Aromatic l-Amino Acid Decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded.
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aromatic l Amino Acid Decarboxylase deficiency clinical features drug therapy and follow up
Journal of Inherited Metabolic Disease, 2009Co-Authors: C Manegold, Georg F Hoffmann, Andreas Knust, I Degen, H Ikonomidou, M W Laas, M Pritsch, Ekkehard Wilichowski, Friederike HorsterAbstract:Aromatic l-Amino Acid Decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded. To gain more insight into this rare disorder we collected clinical and laboratory data of nine German patients. All patients were clinically examined by one investigator, and their responses to different drug regimes were evaluated by the patients’ charts. Symptoms were obvious from early infancy. Later, main neurological features were truncal muscular hypotonia, hypokinesia, oculogyric crises and rigor. Three patients had single seizures. All patients presented distinct extraneurological symptoms, such as hypersalivation, hyperhidrosis, nasal congestion, sleep disturbances and hypoglycaemia. In CSF all patients revealed the pattern typical of AADC with decreased concentrations of homovanillic and 5-hydroxyindoleacetic Acid and elevated concentration of 3-ortho-methyldopa. Diagnosis was confirmed by measurement of AADC activity in plasma in all patients. Drug regimes consisted of vitamin B6, dopamine agonists, MAO inhibitors and anticholinergics in different combinations. No patient achieved a complete recovery from neurological symptoms, but partial improvement of mobility and mood could be achieved in some. AADC deficiency is a severe neurometabolic disorder, characterized by muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Medical treatment is challenging, but a systematic trial of the different drugs is worthwhile.
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levodopa responsive aromatic l Amino Acid Decarboxylase deficiency
Annals of Neurology, 2004Co-Authors: Yuh Terng Chang, Georg F Hoffmann, Keith Hyland, Chad A Brautigam, Radhakant Sharma, Lawrence J Marsh, John Douglas Mcpherson, Joey A Bedell, Andreas KnustAbstract:We report three siblings, who were treated empirically with levodopa combined with carbidopa. There was an immediate therapeutic response. Biochemical investigation surprisingly showed the clinical phenotype to be caused by aromatic L–Amino Acid Decarboxylase deficiency. Molecular characterization showed a homozygous point mutation (c.387 GA) in exon 3. Kinetic studies showed the mutation to decrease the binding affinity for the substrate. This, combined with structural modeling suggesting alteration of active site configuration, provided an explanation for the therapeutic response to levodopa. Ann Neurol 2004
Andreas Knust - One of the best experts on this subject based on the ideXlab platform.
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aromatic l Amino Acid Decarboxylase deficiency clinical features drug therapy and follow up
Journal of Inherited Metabolic Disease, 2009Co-Authors: C Manegold, Georg F Hoffmann, Andreas Knust, I Degen, H Ikonomidou, M W Laas, M Pritsch, Ekkehard Wilichowski, Friederike HorsterAbstract:Aromatic l-Amino Acid Decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded. To gain more insight into this rare disorder we collected clinical and laboratory data of nine German patients. All patients were clinically examined by one investigator, and their responses to different drug regimes were evaluated by the patients’ charts. Symptoms were obvious from early infancy. Later, main neurological features were truncal muscular hypotonia, hypokinesia, oculogyric crises and rigor. Three patients had single seizures. All patients presented distinct extraneurological symptoms, such as hypersalivation, hyperhidrosis, nasal congestion, sleep disturbances and hypoglycaemia. In CSF all patients revealed the pattern typical of AADC with decreased concentrations of homovanillic and 5-hydroxyindoleacetic Acid and elevated concentration of 3-ortho-methyldopa. Diagnosis was confirmed by measurement of AADC activity in plasma in all patients. Drug regimes consisted of vitamin B6, dopamine agonists, MAO inhibitors and anticholinergics in different combinations. No patient achieved a complete recovery from neurological symptoms, but partial improvement of mobility and mood could be achieved in some. AADC deficiency is a severe neurometabolic disorder, characterized by muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Medical treatment is challenging, but a systematic trial of the different drugs is worthwhile.
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aromatic l Amino Acid Decarboxylase deficiency clinical features drug therapy and follow up
Journal of Inherited Metabolic Disease, 2009Co-Authors: C Manegold, Georg F Hoffmann, Andreas Knust, I Degen, H Ikonomidou, M W Laas, M Pritsch, Ekkehard Wilichowski, Friederike HorsterAbstract:Background Aromatic l-Amino Acid Decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded.
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levodopa responsive aromatic l Amino Acid Decarboxylase deficiency
Annals of Neurology, 2004Co-Authors: Yuh Terng Chang, Georg F Hoffmann, Keith Hyland, Chad A Brautigam, Radhakant Sharma, Lawrence J Marsh, John Douglas Mcpherson, Joey A Bedell, Andreas KnustAbstract:We report three siblings, who were treated empirically with levodopa combined with carbidopa. There was an immediate therapeutic response. Biochemical investigation surprisingly showed the clinical phenotype to be caused by aromatic L–Amino Acid Decarboxylase deficiency. Molecular characterization showed a homozygous point mutation (c.387 GA) in exon 3. Kinetic studies showed the mutation to decrease the binding affinity for the substrate. This, combined with structural modeling suggesting alteration of active site configuration, provided an explanation for the therapeutic response to levodopa. Ann Neurol 2004
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the influence of l dopa on methylation capacity in aromatic l Amino Acid Decarboxylase deficiency biochemical findings in two patients
Journal of Inherited Metabolic Disease, 2000Co-Authors: Chad A Brautigam, Keith Hyland, Radhakant Sharma, Ron A Wevers, Andreas Knust, Georg F HoffmannAbstract:Aromatic L-Amino Acid Decarboxylase (AADC, EC 4.1.1.28), a vitamin B 6 -requiring enzyme, converts L-dopa into dopamine (DA), and 5-hydroxytryptophan (5-HTP) into serotonin (Figure 1). The enzyme is ubiquitous in nature, occurring in high levels in the cytoplasm of most tissues including liver, stomach, kidney and brain. Lack of AADC leads to a combined deficiency of the neurotransmitters DA, norepinephrine (NE), epinephrine (E) and serotonin. The major biochemical hallmarks of AADC deficiency are increases of L-dopa, 3-O-methyldopa (3-OMD) and 5-HTP in urine, plasma and cerebrospinal fluid (CSF), together with decreased CSF concentrations of homovanillic Acid (HVA), 5-hydroxyindoleacetic Acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) (Abeling et al 2000; Hyland et al 1992a) (Figure 1). L-Dopa and 5-HTP are the substrates for the enzyme and 3-OMD accumulates after the catechol O-methyltransferase-catalysed methylation of L-dopa in a reaction that uses S-adenosylmethionine (SAM) as a methyl donor. In the periphery, 3-OMD is converted into vanillyllactic Acid (VLA) and excreted in the urine (Hyland et al 1992a).
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pathobiochemical implications of hyperdopaminuria in patients with aromatic l Amino Acid Decarboxylase deficiency
Journal of Inherited Metabolic Disease, 2000Co-Authors: N G G M Abeling, Georg F Hoffmann, Agata Fiumara, Chad A Brautigam, J Jaeken, Ron A Wevers, Andreas Knust, P G Barth, A H Van GennipAbstract:Aromatic L-Amino Acid Decarboxylase (AADC, EC 4.1.1.28) catalyses the conversion of 5-hydroxytryptophan to serotonin in serotonergic neurons and of dopa to dopamine in catecholaminergic neurons and adrenal medullary cells. The enzyme thus plays a key role in the synthesis of both groups of neurotransmitter biogenic amines. AADC is found in both neuronal (monoaminergic neurons in the CNS, adrenal medulla) and nonneuronal cells (liver, intestine, kidney), which distribution is ascribed to tissue-specific expression of the AADC gene as a result of alternative promoter usage and differential splicing (Jahng et al 1996). The first human case of AADC deficiency was described (Hyland and Clayton 1990; Hyland et al 1992) in 1990, and since then several new patients have been identified (Abeling et al 1998; Fiumara et al 1998; Hyland et al 1998; Korenke et al 1997; Maller et al 1997). Mutations in the human AADC gene have been described in six patients, but expression studies to prove their association with altered enzyme activity are still in progress (Chang et al 1998). The condition is considered to be a neurotransmitter defect leading to a combined deficiency of the catecholamines and serotonin. The clinical presentation comprises developmental delay, hypotonia and an extrapyramidal movement disorder with oculogyric crises. Temperature instability, sweating and hypersalivation are also observed. Most patients present in the first years of life. The diagnosis is based on abnormal metabolite patterns in CSF, plasma and urine and on greatly reduced activity of AADC in plasma. Recently (Abeling et al 1998) a new case of AADC deficiency in a 2-year-old Dutch girl was published, with mild clinical presentation and unexpected biochemical findings, i.e. a urinary metabolite pattern partly consistent with AADC deficiency, but also with elements that could not easily be explained from the defect. The most prominent finding was hyperdopaminuria. In addition, elevated urinary concentrations of dopamine metabolites were found. This prompted us to perform further investigations in this and other AADC-deficient patients in search of an explanation for this finding.
Friederike Horster - One of the best experts on this subject based on the ideXlab platform.
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aromatic l Amino Acid Decarboxylase deficiency clinical features drug therapy and follow up
Journal of Inherited Metabolic Disease, 2009Co-Authors: C Manegold, Georg F Hoffmann, Andreas Knust, I Degen, H Ikonomidou, M W Laas, M Pritsch, Ekkehard Wilichowski, Friederike HorsterAbstract:Background Aromatic l-Amino Acid Decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded.
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aromatic l Amino Acid Decarboxylase deficiency clinical features drug therapy and follow up
Journal of Inherited Metabolic Disease, 2009Co-Authors: C Manegold, Georg F Hoffmann, Andreas Knust, I Degen, H Ikonomidou, M W Laas, M Pritsch, Ekkehard Wilichowski, Friederike HorsterAbstract:Aromatic l-Amino Acid Decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded. To gain more insight into this rare disorder we collected clinical and laboratory data of nine German patients. All patients were clinically examined by one investigator, and their responses to different drug regimes were evaluated by the patients’ charts. Symptoms were obvious from early infancy. Later, main neurological features were truncal muscular hypotonia, hypokinesia, oculogyric crises and rigor. Three patients had single seizures. All patients presented distinct extraneurological symptoms, such as hypersalivation, hyperhidrosis, nasal congestion, sleep disturbances and hypoglycaemia. In CSF all patients revealed the pattern typical of AADC with decreased concentrations of homovanillic and 5-hydroxyindoleacetic Acid and elevated concentration of 3-ortho-methyldopa. Diagnosis was confirmed by measurement of AADC activity in plasma in all patients. Drug regimes consisted of vitamin B6, dopamine agonists, MAO inhibitors and anticholinergics in different combinations. No patient achieved a complete recovery from neurological symptoms, but partial improvement of mobility and mood could be achieved in some. AADC deficiency is a severe neurometabolic disorder, characterized by muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Medical treatment is challenging, but a systematic trial of the different drugs is worthwhile.