Aromatic L-amino Acid Decarboxylase Deficiency Research Articles

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.

PRO50 A Discrete Choice Experiment to Derive Health State Utilities for Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency in France

In the absence of utilities from clinical trials, deriving health utilities for ultra-rare medical conditions such as aromatic L-amino acid decarboxylase (AADC) deficiency poses challenges and requires alternative approaches, e.g. discrete choice experiments (DCE), in order to provide health utilities for cost-effectiveness evaluations of AADC interventions. The study aim was to generate health utilities using a DCE associated with AADC deficiency. The 6 key AADC deficiency attributes (2-6 levels), including mobility, muscle weakness, oculogyric crises (OCG), feeding ability, cognitive impairment and screaming had been identified from published literature, clinician input, parent interviews and expert opinion. Participants from a representative sample of the French general population were presented online with 10 choice sets, including one with reversed levels to evaluate choice consistency. Participants also rated 5 health state vignettes describing AADC deficiency. These were used to elicit utilities using time-trade-off. The utilities for the worst/best health states were used as anchors to convert indirect DCE part-worth utilities to health utilities. A total of 1001 participants completed the DCE (50.9% female, 49.1% male; mean age 45.7 years). Overall, five models were evaluated. Rescaled utilities using the health state utilities as anchors ranged from 0.3891 to 0.5577 (difference of 0.17 utilities), corresponding to the worst (633233) and best (111111) health states. The mean health states utilities were 0.389 for the bedridden state; head control 0.432, sitting unsupported 0.489; standing with assistance 0.526; and walking with assistance 0.558. The disutility moving from “walking with assistance” to “bedridden” was -0.0533; the disutility of “constant screaming” relative to “no screaming” was -0.0248; and, the disutility of daily OCG was -0.0167. Utilities for AADC deficiency were derived through a DCE to allow the usage in an economic model.

PRO51 Caring for an Individual with Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: Analysis of Reported Time for Practical and Emotional Care and Paid/Unpaid Help

Aromatic l-amino acid decarboxylase deficiency (AADCd) is an ultra-rare disorder with an estimated global prevalence of 1:32,000 to 1:148,000. Many individuals are severely delayed in reaching developmental milestones (e.g. walking and talking), and require substantial lifelong care. This study explored the experience of caring for an individual with AADCd. A questionnaire was developed with questions about the individual with AADCd, interactions with healthcare professionals, time spent caring, paid/unpaid help and impact on work. Questionnaires were completed by primary caregivers of individuals with AADCd who had consented to take part in a qualitative interview. Twelve caregivers completed the questionnaire (10 parents, 1 brother, 1 aunt; mean age 44 years). Participants reported seeing a mean of 8 (1-24) clinicians/experts before diagnosis. Mean time from first symptom to seeking medical care was 2.5 months, and from seeking medical care to final diagnosis 16.5 months (total mean 19 months). Caregivers spent an average of 90 hours (56-140h) per week on practical and emotional care for their child, plus a mean of 15 hours (7-33h) per week on administrative tasks such planning activities or travelling to/attending appointments related to their child AADC deficiency. 55% received paid and/or unpaid help with care. Unpaid support was provided mainly by the partner (mean 37 hours (8-93 h) per week); while paid support was provided by a registered nurse or training nursing assistant (mean 27 hours (10-35 h) per week). The latter was paid out of pocket or provided by the national service. 75% of caregivers reported that they stopped working or reduced their working hours. Caregivers spent almost every waking moment caring for the individual with AADCd, requiring most to stop working or reduce their working hours. These findings highlight the importance of considering the caregiver impact when evaluating the burden of disease.

PRO52 A qualitative study on the impact of caring for an individual with aromatic l-amino acid decarboxylase deficiency (AADCd)

Aromatic l-amino acid decarboxylase deficiency (AADCd) is a rare neurological condition. Individuals with AADCd require 24-hour care and are reliant on their caregivers for all aspects of their daily lives, but little is known about the caregiver experience. This study explored the impact of caring for an individual with AADCd. Qualitative interviews were conducted with caregivers of individuals with AADCd in Italy, Portugal, Spain and the United States. An interview guide was developed with input from clinical experts, and caregivers of individuals with the condition, and included open-ended questions to elicit information on the impact of caring for an individual with AADCd. Interviews were conducted by telephone and were recorded and transcribed. Data were analysed using thematic analysis and saturation was recorded. Twelve interviews were conducted with caregivers of individuals with AADCd aged 1-15 years (including parents and other family members). Caregivers described how their lives were centred around the individual with AADCd, because of their need for constant one-on-one care (e.g. with feeding, washing and dressing) and having to attend regular healthcare appointments. Most caregivers reported having little time to themselves (e.g. for exercise, or even to shower) and this impacted their ability to carry out household tasks, go to work and attend social events. Several participants described how being a caregiver had a substantial impact on their emotional wellbeing, with some reporting depression, anxiety and fear for the future. Impacts on physical health (e.g. back pain and sleep) were also reported. These concepts and relationships were illustrated in a conceptual model on the impact of caring for an individual with AADCd. Caring for an individual with AADCd has a substantial multifaceted impact on the lives of caregivers. These findings highlight the importance of considering the caregiver experience when evaluating the burden of AADCd.

PRO53 Symptoms and impact of aromatic l-amino acid decarboxylase deficiency (AADCd): A qualitative study

Aromatic l-amino acid decarboxylase deficiency (AADCd) is a rare neurological condition, with an estimated global prevalence of 1:32,000 to 1:90,000 live births. AADCd is associated with a range of symptoms and functional issues, but these have not previously been explored qualitatively. This study aimed to understand the symptoms of AADCd and its impact on individuals’ health-related quality of life (HRQoL).

PRO46 Measuring carer utility in rare paediatric disease: a mixed Methods case study in aromatic l-amino acid decarboxylase deficiency (AADCd)

Aromatic l-amino acid decarboxylase deficiency (AADCd) is an rare neurological condition, requiring 24-hour care. The EQ-5D is increasingly being used to evaluate caregiver health-related quality of life (HRQoL), but it is unclear whether it adequately captures the full impact of caring for an individual with AADCd. This study compared caregiver HRQoL as evaluated by the EQ-5D and qualitative interviews.

PRO2 Burden of Aromatic L-Amino Acid Decarboxylase Deficiency (AADC-D) in France with a FOCUS on Patient Symptoms and Motor Milestones Development

AADC-d is an extremely rare autosomal recessive neuro-metabolic disease characterized by a complex syndrome of motor, behavioral, and autonomic symptoms. The aim of this study, part of a global study assessing the burden of AADC-d, was to describe symptoms and developmental motor milestones in French patients.

PRO28 Healthcare Resource Use (HCRU) of Patients with Aromatic L-Amino Acid Decarboxylase Deficiency (AADC-D) in France

AADC-d is an ultra-rare autosomal recessive neurometabolic disorder leading to hypotonia, movement disorders, developmental delay and autonomic symptoms from birth. Given the lack of healthcare resource utilization (HCRU) information, the aim of this study, part of a global burden of disease project, was to generate French data to feed a cost-effectiveness model to support HTA submission.

PR1 Capturing the Health-Related Quality of Life of Children Living with Aadc Deficiency through a Vignette Study: A French Experience

Health-related quality of life (HRQoL) is difficult to measure in rare diseases, especially in pediatric populations, yet capturing HRQoL is critical for evaluating treatment, including the cost-effectiveness of treatments. Given the ultra-rare nature of AADC deficiency (AADC-d) indirect elicitation of HRQoL data through proxy caregiver/parent ratings is not feasible. In these circumstances HRQoL data may be derived through vignette studies using the general public. The study aim was to generate health utilities for AADC-d. The study was completed online by panel participants from a French representative sample. Five health state vignettes, reflecting key milestones in the eladocagene exuparvovec clinical trials and economic model were presented to the participants: bedridden, head control, sitting unsupported, standing with assistance and walking with assistance. Participants have then valued the vignettes through a revealing preferences method (standard gamble and time trade-off). The vignettes had been previously developed with input from parents of AADC-d patients and expert opinions. A total of 1001 participants (51% females; mean age 46 years) completed the study. Utilities increased linearly as the health state improved for both the time trade-off (TTO), and standard gamble (SG). A significant minority had incongruent responses (high utilities for the bedridden compared to walking health states): 27% for TTO and 34% for SG. When these were removed the mean TTO health utilities (n=729) were: 0.3891 (bedridden state), 0.4839 (head control), 0.5271 (sitting unsupported), 0.5293 (standing with assistance) and 0.5577 (walking with assistance). The SG utilities (n=664) ranged from 0.5534 for bedridden to 0.7093 for walking with assistance. Health utilities derived for AADC-d through vignettes are suitable for use as a cost-effectiveness model of an AADC-d treatment.

PRO48 Utilities in a rare disease collected via vignettes in general population samples from the UK and France: comparison of Results

Health state utilities are required to evaluate the cost-effectiveness of an intervention. Vignettes had been developed for aromatic amino acid decarboxylase (AADC) deficiency with input from caregivers, clinicians and other experts, which were then completed online by panel participants from the United Kingdom and France. The objective was to compare the results generated in those two countries.

A Discrete Choice Experiment to Derive Health Utilities for Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency.

PurposeDeriving health utilities for rare medical conditions such as aromatic L-amino acid decarboxylase (AADC) deficiency poses challenges. The rarity of AADC deficiency and the fact that this genetic condition often presents in very young children means that robust utility values cannot be derived from the child or their parent/caregiver. Alternative approaches, eg, discrete choice experiments (DCE), are required in order to provide health utilities. The aim of the study was to generate health utilities for AADC deficiency using a DCE.MethodsThe DCE was completed online by panel participants from a UK representative sample. The DCE comprised 6 AADC deficiency attributes (2–6 levels): mobility, muscle weakness, oculogyric crises, feeding ability, cognitive impairment and screaming. These were identified from published literature, clinician input, parent interviews and expert opinion. Participants were presented with 10 choice sets specified using an orthogonal design, including a repeat task to evaluate choice consistency. Participants were presented with 5 health state vignettes prior to the DCE. These were used to elicit time trade-off (TTO) utilities. Multinomial logit models were estimated for the DCE data. The TTO utilities for the worst/best health states were used as anchors to convert indirect DCE part-worth utilities to health utilities.ResultsA total of 1596 participants completed the DCE. The majority (70.7%) gave consistent responses to the repeated choice task; only 1.7% (27) always chose the same alternative for every choice set. Five models were evaluated. There was one preference reversal (“sitting unaided”/“standing with assistance”) occurring in all models; these two mobility level coefficients were set to be equal in the final model. Rescaled utilities ranged from 0.494 to 0.7279, corresponding to the worst (633233) and best (111111) health states.ConclusionHealth utilities were derived for AADC deficiency through a DCE. These will be used for a cost-effectiveness model of an AADC deficiency treatment.

Blood, urine and cerebrospinal fluid analysis in TH and AADC deficiency and the effect of treatment

BackgroundAromatic L-amino acid decarboxylase (AADC) deficiency and tyrosine hydroxylase (TH) deficiency are rare inherited disorders of monoamine neurotransmitter synthesis which are typically diagnosed using cerebrospinal fluid examination of monoamine neurotransmitter metabolites. Until now, it has not been systematically studied whether analysis of monamine neurotransmitter metabolites in blood or urine has diagnostic value as compared to cerebrospinal fluid examination, or whether monoamine neurotransmitter metabolites in these peripheral body fluids is useful to monitor treatment efficacy. MethodsAssessment, both by literature review and retrospective analysis of our local university hospital database, of monoamine neurotransmitter metabolites in urine, blood and cerebrospinal fluid, and serum prolactin levels, before and during treatment in patients with AADC and TH deficiency. ResultsIn AADC deficiency, 3-O-methyldopa in serum or dried blood spots was reported in 34 patients and found to be (strongly) increased in all, serotonin in serum was decreased in 7/7 patients. Serum prolactin was increased in 34/37 and normal in 3 untreated patients. In urine, dopamine was normal or increased in 21/24 patients, 5-hydroxyindoleacetic acid was decreased in 9/10 patients, and vanillactic acid was increased in 19/20 patients. No significant changes were seen in monoamine neurotransmitter metabolites after medical treatment, except for an increase of homovanillic acid in urine and cerebrospinal fluid after levodopa therapy, sometimes even in absence of a clinical response. After gene therapy, cerebrospinal fluid homovanillic acid increased in most patients (8/12), but 5-hydroxyindoleacetic acid remained unchanged in 9/12 patients.In TH deficiency, serum prolactin was increased in 12/14 and normal in the remaining untreated patients. Urinary dopamine was decreased in 2/8 patients and normal in 6. Homovanillic acid concentrations in cerebrospinal fluid increased upon levodopa treatment, even in the absence of a clear treatment response. ConclusionsThis study confirms that cerebrospinal fluid is the most informative body fluid to measure monoamine neurotransmitter metabolites when AADC or TH deficiency is suspected, and that routine follow-up of cerebrospinal fluid measurements to estimate treatment response is not needed. 3-O-methyldopa in dried blood spots and vanillactic acid in urine are promising peripheral biomarkers for diagnosis of AADC deficiency. However, in many patients with TH or AADC deficiency dopamine in urine is normal or increased thereby not reflecting the metabolic block. The value of serum prolactin for follow-up of AADC and TH deficiency should be further studied.

Improved Motor Function in Children With Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency Treated With Eladocagene Exuparvovec (PTC-AADC): Interim Findings From a Phase 1/2 Study (2057)

Improved Motor Function in Children With Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency Treated With Eladocagene Exuparvovec (PTC-AADC): Interim Findings From a Phase 1/2 Study (2057)

Improved Motor Function in Children With Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency Treated With Eladocagene Exuparvovec (PTC-AADC): Compassionate Use Study (2387)

Improved Motor Function in Children With Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency Treated With Eladocagene Exuparvovec (PTC-AADC): Compassionate Use Study (2387)

SAFETY AND IMPROVED EFFICACY OUTCOMES IN CHILDREN WITH AADC DEFICIENCY TREATED WITH ELADOCAGENE EXUPARVOVEC GENE THERAPY: RESULTS FROM THREE CLINICAL TRIALS

Background Aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder of neurotransmitter synthesis, is characterized by motor developmental deficits and clinical features associated with the autonomic nervous system, including dyskinesia, oculogyric crisis, and feeding/swallowing problems. Objective To evaluate clinical outcomes in children with AADC deficiency treated with eladocagene exuparvovec, a recombinant adeno-associated virus vector containing the human cDNA encoding the AADC enzyme. Methods In 3 open-label clinical studies, children with AADC deficiency who had no full head control and no ability to sit, stand, or walk received eladocagene exuparvovec as bilateral, intraputaminal, stereotactic infusions during a single operative session (total dose, 1.8 × 1011 vg). Body weight, oculogyric crisis episodes, and adverse events (AEs) were recorded. Results In the 3 studies, patients aged 21 months to 8.5 years (N=26) received eladocagene exuparvovec, constituting the safety population. In the intent-to-treat population (N=21), mean body weight at baseline was 12.0 kg (median 10.5 kg) and increased to 15.2 kg (median 13.2 kg) at 12 months posttreatment. Frequency of oculogyric crises was improved at 12 months posttreatment. Dyskinesia was recorded as an AE in 23 patients in the safety population; most events were mild or moderate, occurred within 3 months after eladocagene exuparvovec treatment, generally responded to standard pharmacotherapy, and resolved in all patients by 10 months. Conclusions In children with AADC deficiency who received eladocagene exuparvovec gene therapy, body weight increased and oculogyric crises and dyskinesia improved.

Aromatic Amino Acid Decarboxylase Deficiency: The Added Value of Biochemistry.

Aromatic amino acid decarboxylase (AADC) deficiency is a rare, autosomal recessive neurometabolic disorder caused by mutations in the DDC gene, leading to a deficit of AADC, a pyridoxal 5′-phosphate requiring enzyme that catalyzes the decarboxylation of L-Dopa and L-5-hydroxytryptophan in dopamine and serotonin, respectively. Although clinical and genetic studies have given the major contribution to the diagnosis and therapy of AADC deficiency, biochemical investigations have also helped the comprehension of this disorder at a molecular level. Here, we reported the steps leading to the elucidation of the functional and structural features of the enzyme that were useful to identify the different molecular defects caused by the mutations, either in homozygosis or in heterozygosis, associated with AADC deficiency. By revisiting the biochemical data available on the characterization of the pathogenic variants in the purified recombinant form, and interpreting them on the basis of the structure-function relationship of AADC, it was possible: (i) to define the enzymatic phenotype of patients harboring pathogenic mutations and at the same time to propose specific therapeutic managements, and (ii) to identify residues and/or regions of the enzyme relevant for catalysis and/or folding of AADC.

Evaluation of 3-O-methyldopa as a biomarker for aromatic L-amino acid decarboxylase deficiency in 7 Brazilian cases

Aromatic L-amino acid decarboxylase (AADCD) deficiency is an autosomal recessive neurometabolic disorder, caused by biallelic mutations in the DDC gene, that impairs the synthesis or metabolism of neurotransmitters leading to severe motor dysfunction. The main clinical signs are oculogyric crisis, hypotonia, hypokinesia, and dystonia. The biochemical diagnosis can be performed in cerebrospinal fluid by neurotransmitter analysis, which requires an invasive lumbar puncture, and the sample needs to be shipped frozen to a reference laboratory, usually across a country border. Measurement of AADC activity in plasma is also possible, but available in a few labs globally. 3-O-methyldopa (3-OMD) is a catabolic product of L-dopa and it is elevated in patients with AADC deficiency. The quantification of 3-OMD can be performed in dried blood spots (DBS), a sample that could be shipped at room temperature. 3-OMD levels of AADCD patients and controls were quantified in DBS by liquid chromatography tandem mass spectrometry. DBS samples from 7 Brazilian patients previously diagnosed with AADCD were used to validate the 3-OMD quantification as a screening procedure for this condition. All AADCD patients had at least a four-fold increase of 3-OMD. Thus, 3-OMD seems to be a reliable marker for AADCD, with potential use also in the newborn screening of this disease.

Detection of 3-O-methyldopa in dried blood spots for neonatal diagnosis of aromatic L-amino-acid decarboxylase deficiency: The northeastern Italian experience

ObjectiveAromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited autosomal recessive disorder of biogenic amine metabolism. Diagnosis requires analysis of neurotransmitter metabolites in cerebrospinal fluid, AADC enzyme activity analysis, or molecular analysis of the DDC gene. 3-O-methyldopa (3-OMD) is a key screening biomarker for AADC deficiency. MethodsWe describe a rapid method for 3-OMD determination in dried blood spots (DBS) using flow-injection analysis tandem mass spectrometry with NeoBase™ 2 reagents and 13C6-tyrosine as an internal standard, which are routinely used in high-throughput newborn screening. We assessed variability using quality control samples over a range of 3-OMD concentrations. ResultsWithin-day and between-day precision determined with quality control samples demonstrated coefficients of variation <15%. 3-OMD concentrations in 1000 healthy newborns revealed a mean of 1.33 μmol/L (SD ± 0.56, range 0.61–3.05 μmol/L), 100 non-AADC control subjects (age 7 days – 1 year) showed a mean of 1.19 μmol/L (SD ± 0.35–2.00 μmol/L), and 81 patients receiving oral L-Dopa had a mean 3-OMD concentration of 14.90 μmol/L (SD ± 14.18, range 0.4–80.3 μmol/L). A patient with confirmed AADC was retrospectively analyzed and correctly identified (3-OMD 10.51 μmol/L). In April 2020, we started a pilot project for identifying AADC deficiency in DBSs routinely submitted to the expanded newborn screening program. 3-OMD concentrations were measured in 21,867 samples; no patients with AADC deficiency were identified. One newborn had a high 3-OMD concentration due to maternal L-Dopa treatment. DiscussionWe demonstrated a rapid new method to identify AADC deficiency using reagents and equipment already widely used in newborn screening programs. Although our study is limited, introduction of our method in expanded neonatal screening is feasible and could facilitate deployment of screening, allowing for early diagnosis that is important for effective treatment.

Atypical Presentation of Aromatic L-Amino Acid Decarboxylase Deficiency with Developmental Epileptic Encephalopathy

AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive metabolic disorder resulting from disease-causing pathogenic variants of the dopa decarboxylase (DDC) gene. The neurological features of AADC deficiency include early-onset hypotonia, oculogyric crises, ptosis, dystonia, hypokinesia, impaired development, and autonomic dysfunction. In this article, we reported a patient with genetically confirmed AADC deficiency presenting with developmental epileptic encephalopathy (DEE). Our patient was a boy with severe intractable epileptic spasms and DEE. The patient was evaluated for cognitive and neurologic impairment. Exome sequencing revealed a homozygous mutation (NM_000790.4:c.121C &gt; A; p.Leu41Met) in the DDC gene. This case expands the clinical spectrum of AADC deficiency and strengthens the association between dopa decarboxylase deficiency and epilepsy. Additional studies are warranted to clarify the mechanisms linking dopa decarboxylase dysfunction to DEE.

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.