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REVEAL-CP: Selective Screening of Pediatric Patients for Aromatic L-Amino Acid Decarboxylase Deficiency with a
Eugen-Matthias Strehle1,2, Roberta Battini3,4, Vasantha Gowda5
1Northumbria Healthcare NHS Foundation Trust, Newcastle upon Tyne, UK.
Insights
Aromatic L-amino acid decarboxylase deficiency (AADCd) can be screened using 3-O-methyldopa (3-OMD) blood levels. Children with movement disorders should be tested for AADCd if newborn screening is unavailable.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Cerebral palsy-like signs and symptoms can indicate rare metabolic disorders.
- Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare neurometabolic disorder.
- 3-O-methyldopa (3-OMD) is a biomarker for AADCd.
Purpose of the Study:
- To screen children with cerebral palsy-like symptoms for elevated 3-OMD levels.
- To identify the molecular basis of aromatic L-amino acid decarboxylase (AADC) gene defects.
Main Methods:
- Prospective, multicenter study involving 166 pediatric patients.
- 3-OMD levels measured from Guthrie cards using liquid chromatography/mass spectrometry.
- Cerebrospinal fluid analysis and DDC gene sequencing performed for elevated 3-OMD.
Main Results:
- One patient diagnosed with AADCd due to a homozygous pathogenic DDC variant (p.Ser250Phe).
- The identified Ser250Phe AADC enzyme variant showed destabilization via in-silico modeling.
- Cerebral palsy was diagnosed in 39.8% of the enrolled patients.
Conclusions:
- Guthrie card 3-OMD testing is a viable screening method for AADCd.
- Investigating AADCd in children with movement disorders is crucial when newborn screening is absent.
Abstract:
Background: The main objective of this prospective, multicenter study (REVEAL-CP) was to test children with cerebral palsy-like signs and symptoms for raised 3-O-methyldopa (3-OMD) blood levels, a biomarker for aromatic L-amino acid decarboxylase deficiency (AADCd). A secondary objective was to characterize the molecular basis for the defective aromatic L-amino acid decarboxylase (AADC) gene product. Methods: Patients were identified in pediatric secondary and tertiary care hospitals through database searches and personal communication. 3-OMD concentrations from Guthrie card tests were determined using liquid chromatography/mass spectrometry. If 3-OMD was raised, cerebrospinal fluid analysis and dopa decarboxylase (DDC) gene sequencing were performed. An in-silico mutagenesis analysis was carried out to model altered AADC enzymes. Results: In total, 166 patients were enrolled in this study. The median age was 8 years. Sixty-six patients (39.8%) had a diagnosis of cerebral palsy, with the most common type being "mixed" (n = 42; 25.3%). One patient (0.6%), an 11-month-old boy from Italy, was diagnosed with AADCd caused by a homozygous, pathogenic DDC variant (c.749C>T; p.Ser250Phe). Three-dimensional modeling of the Ser250Phe AADC enzyme variant revealed its destabilization. Conclusions: A Guthrie card test for 3-OMD is a recognized screening technique for AADCd. If universal newborn screening for this metabolic disease is not available, children with signs and symptoms of a movement disorder should be investigated for AADCd.
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