Identification of Potential Clusters of Signs and Symptoms to Prioritize Patients' Eligibility for AADCd Screening by 3-OMD Testing: An Italian Delphi Consensus

Overview

Journal Behav Neurol

Publisher Wiley

Specialty Psychiatry

Date 2024 Sep 16

PMID 39280026

Authors

Carlotta Spagnoli

Roberta Battini

Filippo Manti

Duccio Maria Cordelli

Andrea Pession

Melissa Bellini

Andrea Bordugo

Gaetano Cantalupo

Antonella Riva

Pasquale Striano

Marco Spada

Francesco Porta

Carlo Fusco

Affiliations

Soon will be listed here.

Abstract

Introduction: AADCd is an ultrarare, underdiagnosed neurometabolic disorder for which a screening test (3-OMD dosing on dried blood spot (DBS)) and targeted gene therapy (authorized in the EU and the UK) are available. Therefore, it is mandatory to raise awareness of presenting symptoms and signs among practitioners. Delivering scientifically sound information to promote screening of patients with the correct cluster of symptoms and signs would be critical.

Materials And Methods: In light of the lack of sound evidence on this issue, expert opinion level of evidence was elicited with the Delphi method. Fourteen steering committee members invited a panel of 29 Italian experts to express their opinions on a series of crucial but controversial topics related to using 3-OMD DBS as a screening method in AADCd. Clusters of symptoms and signs were divided into typical or atypical, depending on age groups. Inclusion in newborn screening programs and the usefulness of a clinical score were investigated. A five-point Likert scale was used to rate the level of priority attributed to each statement.

Results: The following statements reached the highest priority: testing pediatric patients with hypotonia, developmental delay, movement disorders, and oculogyric crises; inclusion of 3-OMD dosing on DBS in neonatal screening programs; development of a clinical score to support patients' selection for 3-OMD screening; among atypical phenotypes based on clinical characteristics of Italian patients: testing patients with intellectual disability and parkinsonism-dystonia. . Clusters of symptoms and signs can be used to prioritize testing with 3-OMD DBS. A clinical score was rated as highly relevant for the patient's selection. The inclusion of 3-OMD dosing in newborn screening programs was advocated with high clinical priority.

References

Chien Y, Lee N, Tseng S, Tai C, Muramatsu S, Byrne B . Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. 2018; 1(4):265-273. DOI: 10.1016/S2352-4642(17)30125-6. View

Manti F, Mastrangelo M, Battini R, Carducci C, Spagnoli C, Fusco C . Long-term neurological and psychiatric outcomes in patients with aromatic l-amino acid decarboxylase deficiency. Parkinsonism Relat Disord. 2022; 103:105-111. DOI: 10.1016/j.parkreldis.2022.08.033. View

Hwu W, Muramatsu S, Tseng S, Tzen K, Lee N, Chien Y . Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012; 4(134):134ra61. DOI: 10.1126/scitranslmed.3003640. View

Hyland K, Clayton P . Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology. Clin Chem. 1992; 38(12):2405-10. View

Himmelreich N, Montioli R, Bertoldi M, Carducci C, Leuzzi V, Gemperle C . Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook. Mol Genet Metab. 2019; 127(1):12-22. DOI: 10.1016/j.ymgme.2019.03.009. View

Lee N, Chien Y, Hu M, Liu W, Chen P, Wang W . Treatment of congenital neurotransmitter deficiencies by intracerebral ventricular injection of an adeno-associated virus serotype 9 vector. Hum Gene Ther. 2013; 25(3):189-98. PMC: 3955971. DOI: 10.1089/hum.2013.170. View

Kojima K, Nakajima T, Taga N, Miyauchi A, Kato M, Matsumoto A . Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency. Brain. 2019; 142(2):322-333. PMC: 6377184. DOI: 10.1093/brain/awy331. View

Brennenstuhl H, Kohlmuller D, Gramer G, Garbade S, Syrbe S, Feyh P . High throughput newborn screening for aromatic ʟ-amino-acid decarboxylase deficiency by analysis of concentrations of 3-O-methyldopa from dried blood spots. J Inherit Metab Dis. 2019; 43(3):602-610. DOI: 10.1002/jimd.12208. View

Burlina A, Giuliani A, Polo G, Gueraldi D, Gragnaniello V, Cazzorla C . Detection of 3-O-methyldopa in dried blood spots for neonatal diagnosis of aromatic L-amino-acid decarboxylase deficiency: The northeastern Italian experience. Mol Genet Metab. 2021; 133(1):56-62. DOI: 10.1016/j.ymgme.2021.03.009. View

10.

Brun L, Ngu L, Keng W, Chng G, Choy Y, Hwu W . Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology. 2010; 75(1):64-71. DOI: 10.1212/WNL.0b013e3181e620ae. View

11.

Pearson T, Gilbert L, Opladen T, Garcia-Cazorla A, Mastrangelo M, Leuzzi V . AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients. J Inherit Metab Dis. 2020; 43(5):1121-1130. PMC: 7540529. DOI: 10.1002/jimd.12247. View

12.

Graziano C, Wischmeijer A, Pippucci T, Fusco C, Diquigiovanni C, Noukas M . Syndromic intellectual disability: a new phenotype caused by an aromatic amino acid decarboxylase gene (DDC) variant. Gene. 2015; 559(2):144-8. DOI: 10.1016/j.gene.2015.01.026. View

13.

Pearson T, Pons R, Ghaoui R, Sue C . Genetic mimics of cerebral palsy. Mov Disord. 2019; 34(5):625-636. DOI: 10.1002/mds.27655. View

14.

Fusco C, Leuzzi V, Striano P, Battini R, Burlina A, Spagnoli C . Aromatic L-amino Acid Decarboxylase (AADC) deficiency: results from an Italian modified Delphi consensus. Ital J Pediatr. 2021; 47(1):13. PMC: 7819234. DOI: 10.1186/s13052-021-00954-4. View

15.

Rizzi S, Spagnoli C, Frattini D, Pisani F, Fusco C . Clinical Features in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Systematic Review. Behav Neurol. 2022; 2022:2210555. PMC: 9578880. DOI: 10.1155/2022/2210555. View

16.

Dai W, Lu D, Gu X, Yu Y . Aromatic L-amino acid decarboxylase deficiency in 17 Mainland China patients: Clinical phenotype, molecular spectrum, and therapy overview. Mol Genet Genomic Med. 2020; 8(3):e1143. PMC: 7057092. DOI: 10.1002/mgg3.1143. View

17.

Leuzzi V, Mastrangelo M, Polizzi A, Artiola C, van Kuilenburg A, Carducci C . Report of two never treated adult sisters with aromatic L-amino Acid decarboxylase deficiency: a portrait of the natural history of the disease or an expanding phenotype?. JIMD Rep. 2014; 15:39-45. PMC: 4270864. DOI: 10.1007/8904_2014_295. View

18.

Manegold C, Hoffmann G, Degen I, Ikonomidou H, Knust A, Laass M . Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. J Inherit Metab Dis. 2009; 32(3):371-80. DOI: 10.1007/s10545-009-1076-1. View

19.

Rizzi S, Spagnoli C, Bellini M, Cesaroni C, Spezia E, Bergonzini P . Aromatic L-Amino-Acid Decarboxylase Deficiency Screening by Analysis of 3-O-Methyldopa in Dried Blood Spots: Results of a Multicentric Study in Neurodevelopmental Disorders. Genes (Basel). 2023; 14(9). PMC: 10530573. DOI: 10.3390/genes14091828. View

20.

Chien Y, Chen P, Lee N, Hsieh W, Chiu P, Hwu W . 3-O-methyldopa levels in newborns: Result of newborn screening for aromatic l-amino-acid decarboxylase deficiency. Mol Genet Metab. 2016; 118(4):259-63. DOI: 10.1016/j.ymgme.2016.05.011. View