High throughput newborn screening for aromatic ʟ‐amino‐acid decarboxylase deficiency by analysis of concentrations of 3‐<i>O</i>‐methyldopa from dried blood spots

Brennenstuhl, Heiko; Kohlmüller, Dirk; Gramer, Gwendolyn; Garbade, Sven F.; Syrbe, Steffen; Feyh, Patrik; Kölker, Stefan; Okun, Jürgen G.; Hoffmann, Georg F.; Opladen, Thomas

doi:10.1002/jimd.12208

Cited by 29 publications

(21 citation statements)

References 24 publications

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“…9 Newborn screening using 3-OMD concentration in dried blood spots has also been developed. [10][11][12] Currently approved treatment options are limited to attempts to increase monoamine neurotransmitter production; decrease their catabolism through the inhibition of monoamine oxidase (MAO); or address symptomatic concerns such as nasal congestion, difficulties with sleep, and irritability. 1,3 These therapies provide variable results and do not treat the underlying cause of disease, which is related to the insufficiency or absence of AADC activity.…”

Section: Introductionmentioning

confidence: 99%

Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency

et al. 2022

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Aromatic L-amino acid decarboxylase deficiency results in decreased neurotransmitter levels and severe motor dysfunction. Twenty-six patients without head control received bilateral intraputaminal infusions of a recombinant adenoassociated virus type 2 vector containing the human aromatic L-amino acid decarboxylase gene (eladocagene exuparvovec) and have completed 1-year evaluations. Rapid improvements in motor and cognitive function occurred within 12 months after gene therapy and were sustained during follow-up for >5 years. An increase in dopamine production was demonstrated by positron emission tomography and neurotransmitter analysis. Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. Although improvements were observed in all treated participants, younger age was associated with greater improvement. There were no treatment-associated brain injuries, and most adverse events were related to underlying disease. Post-surgery complications such as cerebrospinal fluid leakage were managed with standard of care. Most patients experienced mild to moderate dyskinesia that resolved in a few months. These observations suggest that eladocagene exuparvovec treatment for aromatic L-amino acid decarboxylase deficiency provides durable and meaningful benefits with a favorable safety profile.

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Section: Introductionmentioning

confidence: 99%

Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency

et al. 2022

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“…9 Gene therapy for this disorder is under investigation using two different stereotactic neurosurgical approaches to deliver gene vector either to the putamen 5,10,11 or the midbrain (ClinicalTrials.gov Identifier: NCT02852213). In the context of new methods for early diagnosis already implemented in some newborn screening programs 12 and these prospective novel therapeutic opportunities, an improved knowledge of the natural history of the disease, modified by available medical treatments, is critical.…”

Section: Introductionmentioning

confidence: 99%

AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients

Pearson

Gilbert

Opladen

et al. 2020

J of Inher Metab Disea

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Aromatic l‐amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurodevelopmental disorder characterized by impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin, leading to a complex syndrome of motor, behavioral, and autonomic symptoms. This retrospective study assessed the symptoms and developmental outcome of a large international cohort of patients with AADCD via physician and/or caregiver responses to a detailed, standardized questionnaire. Sixty‐three patients (60% female; ages 6 months‐36 years, median 7 years; 58 living) from 23 individual countries participated. Common symptoms at onset (median age 3 months, range 0‐12 months) were hypotonia, developmental delay, and/or oculogyric crises. Oculogyric crises were present in 97% of patients aged 2 to 12 years, occurred in the majority of patients in all age groups, and tended to be most severe during early childhood. Prominent non‐motor symptoms were sleep disturbance, irritable mood, and feeding difficulties. The majority of subjects (70%) had profound motor impairment characterized by absent head control and minimal voluntary movement, while 17% had mild motor impairment and were able to walk independently. Dopamine agonists were the medications most likely to produce some symptomatic benefit, but were associated with dose‐limiting side effects (dyskinesia, insomnia, irritability, vomiting) that led to discontinuation 25% of the time. The age distribution of our cohort (70% of subjects under age 13 years) and the observation of a greater proportion of patients with a more severe disease phenotype in the younger compared to the older patients, both suggest a significant mortality risk during childhood for patients with severe disease.

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“…These metabolites are not only highly elevated in CSF, but also in blood and urine, a finding we could confirm here in a relatively large group of patients. The work that is done to develop newborn screening for AADC deficiency measuring 3-OMD in DBS [ 16 , 27 , 28 ] is therefore interesting and promising to decrease the long diagnostic delay that is often present in this disorder [ 3 ]. However, some caution regarding these accumulating metabolites is warranted.…”

Section: Discussionmentioning

confidence: 99%

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

Wassenberg

Geurtz

Monnens

et al. 2021

Molecular Genetics and Metabolism Reports

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Background Aromatic 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. Methods Assessment, 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. Results In 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. Conclusions This 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.

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High throughput newborn screening for aromatic ʟ‐amino‐acid decarboxylase deficiency by analysis of concentrations of 3‐O‐methyldopa from dried blood spots

Cited by 29 publications

References 24 publications

Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency

Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency

AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients

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

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