Acid Decarboxylase Deficiency Research Articles

Biochemical diagnosis of aromatic-L-amino acid decarboxylase deficiency (AADCD) by assay of AADC activity in plasma using liquid chromatography/tandem mass spectrometry

Aromatic l-amino acid decarboxylase (AADC, EC 4.1.1.28) deficiency is a rare genetic disorder characterized by developmental delay, oculogyric crises, autonomic dysfunction and other problems, caused by biallelic mutations in the DDC gene leading to deficient activity of aromatic l-amino acid decarboxylase, an enzyme involved in the formation of important neurotransmitters, such as dopamine and serotonin. A clinical development program of gene therapy for AADC deficiency is ongoing. An important step for the success of this therapy is the early and precise identification of the affected individuals, but it has been estimated that around 90% of the cases remain undiagnosed. The availability measurement of the AADC activity is mandatory for an accurate biochemical diagnosis. Based on these statements, our objectives were to develop a liquid chromatography tandem mass spectrometry (LC-MS/MS) method suitable for the determination of the AADC activity, and to evaluate its capacity to confirm the deficiency of AADC in potential patients in Brazil. The AADC activities were measured in plasma samples of seven AADC deficient patients and 35 healthy controls, after enzymatic reaction and LC-MS/MS analysis of dopamine, the main reaction product. The results obtained showed clear discrimination between confirmed AADC deficient patients and healthy controls. The method presented here could be incorporated in the IEM laboratories for confirmation of the diagnosis of when a suspicion of AADC deficiency is present due to clinical signs and/or abnormal biomarkers, including when an increased level of 3-O-methyldopa (3-OMD) is found in dried blood spots (DBS) samples from high-risk patients or from newborn screening programs.

Symptoms and impacts of aromatic l-amino acid decarboxylase (AADC) deficiency among individuals with different levels of motor function

BackgroundAromatic l-amino acid decarboxylase (AADC) deficiency is a rare neurological disorder associated with a range of symptoms and functional impairments. The aim of this study was to describe the experience of AADC deficiency across five different motor milestone health states.MethodsQualitative interviews were conducted with caregivers of individuals with AADC deficiency in Italy, Spain, Portugal and the United States. An interview guide was developed with input from clinical experts and caregivers, and explored the symptoms and impacts of AADC deficiency. Interviews were conducted by telephone and were recorded and transcribed. Data were analysed using thematic analysis and the symptoms and impacts were compared across health states.ResultsFourteen caregivers took part, who provided care to 13 individuals with AADC deficiency aged 1–15 years. Six individuals were in the ‘no motor function’ health state, one in the ‘sitting unsupported’ health state, one in the ‘standing/stepping when fully supported’ health state and five in the ‘walking with minimal support’ health state. The results highlight a substantial impact of AADC deficiency, even among those who were able to walk with minimal support. Overall, those with better motor function also had better functional hand use, communication skills, ability to eat and perform other activities independently, and interact with their peers. The burden of caring was high across all health states, but caregivers of individuals in the walking health state were better able to participate in social and leisure activities.ConclusionIndividuals with higher levels of motor function had less severe symptoms and were better able to perform their daily, leisure and social activities. Treatments which improve motor function have the potential to improve other aspects of the lives of individuals with AADC deficiency and their caregivers.

Eliciting health state utilities for Aromatic L-amino Acid Decarboxylase (AADC) deficiency: a UK vignette study

PurposeThe aim of this study was to generate health state utilities for aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic, lifelong neurogenerative condition predominantly manifesting in young infants.MethodsParticipants were presented with health state vignettes. These had been previously developed based on published literature, clinician input, interviews with parents of AADC deficiency patients and expert opinion. A total of 5 health state vignettes were presented: bedridden, head control, sitting unsupported, standing with assistance and walking with assistance. Health state utilities (HSU) were elicited using time-trade off (TTO; 10-year time horizon) and the standard gamble (SG). The vignettes were completed online by panel participants drawn from a representative sample of the United Kingdom residential population.ResultsA total of 1598 participants completed the vignettes. Around 21% had incongruent responses (higher utilities for the bedridden compared to walking health states). Incongruent responses were associated with shorter task completion times, gender and parental status. These responses were removed from the analysis. Health state utilities (HSU) increased correspondingly as health states improved for both the TTO and SG. The mean HSU (standard deviation) for the TTO task were: bedridden state 0.49 (0.34); head control 0.54 (0.33), sitting unsupported 0.63 (0.31); standing with assistance 0.68 (0.31); and walking with assistance 0.73 (0.31). For the SG, mean health state utilities were: 0.56 (0.28), 0.57 (0.27), 0.67 (0.24), 0.70 (0.24), and 0.75 (0.25), respectively.ConclusionHealth state utilities were derived for AADC deficiency through a vignette study. These will be used for a cost-effectiveness model of an AADC deficiency treatment.

Approaches for diagnosis and treatment in neurotransmitter disorders of childhood.

Neurotransmitter disorders are a group of neurometabolic syndromes caused by disturbances of neurotransmitter metabolism. The primary aim of this retrospective study is to present patients with disturbances of monoamine neurotransmitter metabolism. Cerebrospinal fluid (CSF) neurotransmitter measurements and genetic analysis were performed on five patients. Five patients who had various movement disorders and motor and cognitive disabilities were included. Four patients were diagnosed with sepiapterin reductase (SR) deficiency, and one was diagnosed with aromatic L-amino acid decarboxylase (AADC) deficiency. Different treatment responses appeared in patients with SR and AADC deficiency. The responses to drug treatment ranged from good to weak in our patients. The diagnosis process is challenging in patients with SR and AADC deficiency, which present similar clinical features to other neurological and metabolic diseases. Investigations of neurotransmitters in CSF and analysis of related genes are essential to differentiate disturbances of monoamine neurotransmitter metabolism from other neurometabolic diseases. For patients with monoamine neurotransmitter disorders, drugs that target these disturbances should be combined as necessary to produce the appropriate response.

The impact of caring for an individual with aromatic l-amino acid decarboxylase (AADC) deficiency: a qualitative study and the development of a conceptual model

Background Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare neurological condition, associated with a wide range of symptoms and functional issues, such as profound motor impairment and learning disability. Most individuals with AADC deficiency are completely dependent on their caregivers. This study explored the impact of caring for an individual with AADC deficiency. Methods Qualitative interviews were conducted with caregivers of individuals with AADC deficiency in Italy, Portugal, Spain and the United States. An interview guide was developed with input from clinical experts and caregivers and included questions on the impact of caring for an individual with AADC deficiency. Interviews were conducted by telephone/videoconference and were recorded and transcribed. Data were analysed using thematic analysis. Results Fourteen caregivers took part who provided care to 13 individuals with AADC deficiency aged 1–15 years. Caregivers reported that their lives centred around the individual with AADC deficiency, due to their need for 24-hour care and regular healthcare appointments. They reported both proximal impacts (impact on time, planning, physical health and emotional wellbeing), and distal impacts (impact on social/leisure activities, relationships, work and finances). These concepts and relationships were illustrated in a conceptual model. Conclusions This is the first qualitative study to report on the experience of caring for an individual with AADC deficiency. Caregivers reported that caring had a substantial multifaceted impact on their lives. These findings highlight the importance of considering the caregiver experience when evaluating the burden of AADC deficiency.

Symptoms and impact of aromatic l-amino acid decarboxylase (AADC) deficiency: a qualitative study and the development of a patient-centred conceptual model

Background Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare neurological condition, with an estimated global prevalence of 1:32,000 to 1:90,000 live births. AADC deficiency is associated with a range of symptoms and functional impairments, but these have not previously been explored qualitatively. This study aimed to understand the symptoms of AADC deficiency and its impact on individuals’ health-related quality of life. Methods Qualitative interviews were conducted with caregivers of individuals with AADC deficiency in Italy, Spain, Portugal and the United States. An interview guide was developed with input from clinical experts and caregivers, and explored the symptoms and impacts of AADC deficiency. Interviews were conducted by telephone and were recorded and transcribed. Data were analysed using thematic analysis and saturation was recorded. Results Fourteen caregivers took part, who provided care to 13 individuals with AADC deficiency aged 1–15 years. All individuals had impaired motor function, which was attributed to low muscle tone and muscle weakness. The level of motor function varied considerably, ranging from no motor function (no head control) to being able to take a few steps without support. Other impairments included cognitive impairment, communication difficulties, movement disorders (e.g. oculogyric crises), gastrointestinal symptoms, eating difficulties, fatigue and sleep disruption. Most individuals were completely dependent on their caregivers for all aspects of their lives. This limited function had a negative impact on their ability to socialise with their peers and on their emotional wellbeing. These concepts and relationships are illustrated in a conceptual model, and moderating factors (e.g. physiotherapy and medication) are discussed. Conclusion This is the first qualitative study to report on the experience of living with AADC deficiency. Caregivers report individuals with AADC deficiency experience a wide range of symptoms and functional impairments, which have a substantial impact on their health-related quality of life.

Aromatic L-amino Acid Decarboxylase (AADC) deficiency: results from an Italian modified Delphi consensus

BackgroundAromatic L-amino acid decarboxylase (AADC) deficiency is a rare and underdiagnosed neurometabolic disorder resulting in a complex neurological and non-neurological phenotype, posing diagnostic challenges resulting in diagnostic delay. Due to the low number of patients, gathering high-quality scientific evidence on diagnosis and treatment is difficult. Additionally, based on the estimated prevalence, the number of undiagnosed patients is likely to be high.MethodsItalian experts in AADC deficiency formed a steering committee to engage clinicians in a modified Delphi consensus to promote discussion, and support research, dissemination and awareness on this disorder. Five experts in the field elaborated six main topics, each subdivided into 4 statements and invited 13 clinicians to give their anonymous feedback.Results100% of the statements were answered and a consensus was reached at the first round. This enabled the steering committee to acknowledge high rates of agreement between experts on clinical presentation, phenotypes, diagnostic work-up and treatment strategies. A research gap was identified in the lack of standardized cognitive and motor outcome data. The need for setting up an Italian working group and a patients’ association, together with the dissemination of knowledge inside and outside scientific societies in multiple medical disciplines were recognized as critical lines of intervention.ConclusionsThe panel expressed consensus with high rates of agreement on a series of statements paving the way to disseminate clear messages concerning disease presentation, diagnosis and treatment and strategic interventions to disseminate knowledge at different levels. Future lines of research were also identified.

Gene therapy improves brain white matter in aromatic l-amino acid decarboxylase deficiency.

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. 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. 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. 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.

Acceleration of rare disease therapeutic development: a case study of AGIL-AADC

Rare-disease drug development is both scientifically and commercially challenging. This case study highlights Agilis Biotherapeutics (Agilis), a small private biotechnology company that has developed the most clinically advanced adeno-associated virus (AAV) gene therapy for the brain. In an international collaboration led by Agilis with National Taiwan University (NTU) Hospital and the Therapeutics for Rare and Neglected Diseases (TRND) program of the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health, Agilis' gene therapy for aromatic l-amino acid decarboxylase deficiency (AADC), AGIL-AADC, was granted biologics license application (BLA)-ready status by the FDA in 2018, only 18 months after being licensed from NTU by Agilis. Here, we highlight the factors that enabled this remarkable pace of successful drug development for an ultra-rare disease.

An Inhibited Dopamine Synthesizing Cell Model of AADC Deficiency

Introduction: Aromatic L-amino acid decarboxylase deficiency (AADC) is a rare autosomal recessive pediatric neurotransmitter disease. To date it remains poorly understood mainly due to an absence of a disease model. The dopaminergic neuroblastoma cell SH-SY5Y was chosen to develop our AADC deficiency model. These cells are not native dopamine synthesizers. Objective: To develop a dopamine-producing cellular model of AADC deficiency using SH-SY5Y neuroblastoma cells. Methods: Dopamine pathway proteins were identified with Western Blotting. Dopaminergic differentiation was attempted using all-trans retinoic acid (ATRA) with dopamine detection via HPLC-ECD post alumina extraction. Treatment with L-DOPA provided SH-SY5Y with excess precursor. RT-PCR was used to determine the expression of markers of mature neurons. Results: Western Blot screening identified AADC, dopamine β-hydroxylase and tyrosine hyrdoxylase proteins, indicative of a dopaminergic pathway. ATRA was unsuccessful in producing dopamine from the cells. L-DOPA treatment however, generated dopamine first visible as a HPLC-ECD peak 30 minutes post-incubation. Prior to this, SH-SY5Y dopamine synthesis from L-DOPA has never been documented. This de novo synthesis is then inhibited using benserazide to form our AADC deficiency cell model. RT-PCR showed that SH-SY5Y cells express markers of mature neurons in its ‘native’ state and is not affected by L-DOPA and benserazide treatment. This cell model will potentially benefit many areas of AADC deficiency research. Conclusion: SH-SY5Y cells produced HPLC-ECD measureable amounts of dopamine with the addition of L-DOPA. Our model of AADC deficiency is generated by quelling the dopamine production with Benserazide.

Successful Pregnancy in a Patient with L-Amino Acid Decarboxylase Deficiency: Therapeutic Management and Clinical Outcome.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited disorder of biogenic amine metabolism presenting with developmental delay, hypokinetic movement disorders, hypotonia, and autonomic dysfunctions.1 We report on the successful pregnancy in a previously reported 26-year-old AADC patient with a mild phenotype (Table 1).2 Since the diagnosis at the age of 22, treatment with rotigotine, pyridoxine, and escitalopram resulted in a remarkable improvement of fluctuating muscular weakness, oculogyric crises, palpebral ptosis, balance, and gait.2 After, as consequence of behavioral disinhibition and reduced control of sexual impulses, rotigotine was replaced by a prolonged release formulation of pramipexole (up to 0.78 mg/day once a day). Selegine was added to improve diurnal fluctuation of motor symptoms (up to 7.5 mg/day after a very slow dose increasing). While MAO-inhibitors and SSRIs association is contraindicated in common neuropsychiatric disorders due to the risk of serotonin intoxication syndrome, their synergic effect may be exploited to magnify the residual enzymatic activity in the defect of serotonin synthesis, such as AADC deficiency. Compound heterozygous for the mutations p.Tyr37Thrfs*5 (c.105delC) and p.Phe237Ser (c.710 T>C) The pregnancy of our patient occurred naturally at the age of 26. Escitalopram was suspended to prevent the risk of low birth weight.3 Doses of pramipexole and selegiline could be decreased (Table 1) without obvious neurological worsening. No oculogyric crises or myoclonic jerks were observed, and limb rigidity, fatigability, and muscular weakness were well controlled. UPDRS-part III score did not change with respect the prepregnancy status (Table 1). Blood pressure remained below the normal range for the age. At the 31st week of gestation preeclampsia occurred. At the 38th week of gestation, a cesarean delivery (cardiac deceleration at cardiotocography) resulted in the birth of a vital (Apgar score 91 and 105) low birth weight (2.440 grams) and small (for gestational age) male newborn. The infant presented with transient tachypnea and hypoglycemia in the first day after birth. His growth was regular after the early introduction of artificial nursing. No significant health problems were observed in the following months. Pregnancy was previously reported in inherited neurotransmitter disorders with a less severe phenotype than AADC deficiency (35 women with autosomal dominant guanosine triphosphate cyclohydrolase 1 deficiency, one with dihydropterine reductase deficiency, and one with 6-pyrovoyl-tetrahydrobiopterin synthase deficiency).4, 5 The defect of monoaminergic neurotransmitters in AADC deficiency potentially impairs embryo-maternal interactions at preimplantation stages of early embryogenesis, which could be prevented by the treatment with drugs acting on dopaminergic axis.6 Efficacy and safety profile of pramipexole and selegiline during pregnancy and lactation are reported, in 24 and three women affected by Parkinson disease or restless legs syndrome, respectively.5, 7 Pramipexole was associated with spontaneous abortion in 3 cases (co-exposition with isotretinoin in one case) while selegiline was associated with a ventral septal defect in a twin newborn (co-exposition with L-DOPA/carbidopa and entacapone).5 The present case shows that in AADC deficiency: (a) fertility may be not impaired, (b) the course of pregnancy can be successfully managed in patients with mild phenotypes, and (c) low dosages of pramipexole and selegiline may have a good efficacy and safety profile during pregnancy. 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. M.M.: 1A, 1B, 1C, 3A, 3B F.M.: 1B, 1C, 3A L.P.: 1A, 1B, 1C, 3A S.F.: 1A, 1B, 1C, 3A C.C.: 1C, 3B Cl.C.: 1C, 3B G.M.: 1A, 1B, 1C, 3B V.L.: 1A, 1B, 1C, 3A, 3B Ethical Compliance Statement: We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work and that they have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Informed written consent was obtained from the patient for the publication of her clinical data. Funding Sources and Conflicts of Interest: None of the authors have anything to declare. Financial Disclosures for previous 12 months: None of the authors have anything to declare.

Microstructural changes of brain in patients with aromatic L-amino acid decarboxylase deficiency.

Aromatic L-amino acid decarboxylase (AADC) deficiency is an uncommon inherited neurometabolic disease. The clinical presentations and MR findings in children with AADC deficiency were investigated. Total 12 children (6 boys, 6 girls), aged from 9 to 50 months (mean, 23 ±13 months), with AADC deficiency, were enrolled for analysis. Of 12 patients enrolled, clinical presentations included global developmental delay with generalized hypotonia in 12 (100%), dystonia in 12 (100%), oculogyric crisis in 12 (100%), and excessive sweating in 8 (67%). Sleep problem was also found in 4 (33%). Of 15 MR examinations, the major changes included 6 (40%) with diffusely prominent bilateral frontal sulci, 10 (67%) with prominent frontal horns, and 12 (80%) with hypomyelination. In AADC patients, the frontal horn was significantly widened (P < 0.01), and the volume of caudate nucleus was also significantly smaller than that of controls (P = 0.02). The ratios of thickness of the splenium to that of the genu of corpus callosum were also significantly increased (P < 0.01). There was also significant decrease of fiber density indices in major white matter fiber tracts. Using Tract-Based Spatial Statistics approach, we also revealed significant change in major fiber tracts related to language function and motor function. In conclusion, the present study indicated that AADC deficiency may have significant impact on brain development, especially the frontal lobe and fiber tracts related to language function and motor function. Long-term follow-up of brain MRI in patients with AADC deficiency may clarify the possible effect of AADC deficiency on brain development. Hum Brain Mapp 38:1532-1540, 2017. © 2016 Wiley Periodicals, Inc.

Preimplantation and prenatal genetic diagnosis of aromatic L-amino acid decarboxylase deficiency with an amplification refractory mutation system-quantitative polymerase chain reaction

Objectives To develop a diagnostic platform for preimplantation genetic diagnosis (PGD) and prenatal genetic diagnosis (PND) to prevent births of aromatic L-amino acid decarboxylase deficiency (AADC) patients. Materials and Methods Five Taiwanese families carrying AADC were enrolled. A novel technique, amplification refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR), was developed for both of PGD and PND. For PGD, blastomere biopsies of day-3 cleavage-stage embryos were subjected to ARMS-qPCR. Villi, cultured amniocytes, or both were used to confirm the PGD result; this approach could also be used as the sole method for PND after in vivo conception). Results Unaffected live births were achieved in four of the five families, except one with ongoing PGD. The ARMS-qPCR correctly classified blastomeres (from day-3 cleavage-stage embryos) as affected (homozygous mutant), carrier (heterozygous for mutant and wild-type alleles), or normal (homozygous wild-type) within 1 working day. Conclusions To our knowledge, this is the first report of successful PGD of AADC. The molecular technique we devised (ARMS-qPCR) was applicable for PGD as well as PND of AADC. Furthermore, it has great potential for similar applications in other monogenic disorders.

An Unusual Case of Feeding Intolerance in a 7 Month Old Female

Purpose: Background: Aromatic L-amino acid decarboxylase deficiency (AADC) is an inborn error in neurotransmitter metabolism caused by mutations in the dopa decarboxylase (aromatic L-amino acid decarboxylase) gene, which leads to combined serotonin and catecholamine deficiency. Symptoms include severe developmental delay, hypotonia, muscle stiffness, athetosis, lethargy, feeding intolerance, sleep disturbances, oculogyric crises, extreme irritability, pain, muscle spasms, and uncontrolled movements. Patient: A 7 month old Caucasian female with a history of hypotonia and developmental motor delay presented with excessive irritability and feeding intolerance. Clinical Course: She was well until 3-4 months of age, when she became inconsolable, had non-bilious, non-bloody emesis, and irritability with feeds. Symptoms worsened over the last 3 months. She had decreased activity, poor eye tracking, and hypotonia. Initial workup showed normal gastric emptying scan, MBS revealing frank aspiration, and pH probe showed copious reflux, so a Nissen fundoplication with gastric feeding tube was placed. Lorazepam and phenobarbital did not have a perceived effect. Additional workup included an EEG, head CT scan, head MRI, karyotype, serum lactate level, serum ammonia level, and plasma amino acids which were all within normal limits except for a low cysteine level. Urine organic acids showed minimal dicarboxylic acids and acetylcarnitine profile showed a mildly elevated C4OH due to diet or a ketotic state. Magnetic resonance spectroscopy (MRS) was notable for nonspecific lactate spikes. Because of suspicion of a possible mitochondrial or neurotransmitter disorder, a lumbar puncture was performed. Neurotransmitter analysis and plasma enzymology confirmed the diagnosis of AADC. Pyridoxal-5-phosphate (coenzyme B6) and ropinirole (a dopamine agonist) were added, in addition to hyoscyamine, pantoprazole, and sucralfate. Two months after diagnosis, she has been tolerating feeds with less irritability. Conclusion: Children with feeding disorder, developmental delay and hypotonia should have a work-up for inborn errors of metabolism. Initial laboratory workup should include CBC, electrolytes, LFTs, urine organic acids, blood amino acids and acylcarnitine profile, total and free carnitine levels, as well as an MRI and MRS.

AROMATIC L-AMINO ACID DECARBOXYLASE DEFICIENCY (AADC) –3 UNUSUAL CASE REPORTS

Objectives: To describe the clinical and biochemical findings in 3 unrelated patients of Mediterranean origin suffering from aromatic L-amino acid decarboxylase (AADC) deficiency. No detectable mutation in the 5'-UTR and CSD of the AADC gene was found in one male patient. Methods: We describe 3 unrelated children (2F, 1M) who presented with severe developmental delay, hypotonia, hypokinesia, oculogyric crises, autonomic dysfunction and diurnal fluctuation. In 2 patients recurrent episodes of profuse sweating were the prominent autonomic symptoms. Results: All patients had marked reduction of HVA and 5HIAA level in CSF. The AADC activity was severely decreased in all patients, but no mutation was identified in the AADC gene CDS in the male patient. Molecular genetic analysis results of the 2 female patients are pending. None responded to treatment regimens including MAO inhibitors, dopamine agonists, melatonin and Vitamin B6. Conclusion: The clinical and biochemical findings of these 3 patients are similar to previously described data, but the poor response to treatment without gender preferences is unique. Moreover, the lack of detectable mutation in the AADC gene in the one investigated patient suggests a heterogeneous molecular background in AADC deficiency. Further genetic investigation in the 3 patients and their extended families is underway.

Synthesis of deuterium‐labeled 3‐O‐methyldopa and 4‐O‐methyldopa

AbstractConcise methods for the synthesis of 4‐hydroxy‐3‐[2H3]‐methoxyphenylalanine (3‐O‐[2H3]‐methydopa) and 3‐hydroxy‐4‐[2H3]‐methoxyphenylalanine (4‐O‐[2H3]‐methydopa) are described. The 3‐O‐[2H3]‐methydopa is a valuable internal standard for the tandem MS quantification of 3‐O‐methyldopa, a metabolite of value in the diagnosis of aromatic l‐amino acid decarboxylase (AADC) deficiency. Copyright © 2003 John Wiley &amp; Sons, Ltd.

Pathobiochemical implications of hyperdopaminuria in patients with aromatic L-amino acid decarboxylase deficiency.

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.