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?

Abstract

Two sisters were diagnosed in their adulthood with aromatic l-amino acid decarboxylase (AADC) deficiency (OMIM#608643). They experienced early myasthenia-like manifestations, myoclonic jerks, oculogyric crises, tremors, and developmental delay during childhood; clinical stabilization afterwards; and spontaneous improvement during adolescence and young adulthood. Two novel pathogenic mutations on DDC gene [p.Tyr37Thrfs*5 (c.105delC) and p.F237S (c.710 T>C)] were associated with undetectable enzyme activity in plasma and only a mild reduction of biogenic amines in cerebrospinal fluid (CSF). The increase of both 3-O-methyldopa and 5-hydroxytryptophan on CSF was the most relevant biochemical alteration denoting AADC defect in these subjects. Transdermal rotigotine remarkably improved their gross motor functions and the asthenic status they complained. The present cases broaden the phenotypic spectrum of AADC deficiency and suggest that (1) AADC defect is not a progressive neurological disease and behaves rather as a neurodevelopmental disorder that improves during the second decade of life; (2) treatment-naïve adults can still respond well to neurotransmitter therapy; and (3) the possibility of a mild presentation of AADC deficiency should be considered when examining young adults with asthenic and parkinsonian symptoms.

Competing interests: None declared

Appendices

Compliance with Ethics Guidelines

The work described in the manuscript has been realized in accordance with Italian law and with international ethics guidelines.

Synopsis

AADC deficiency behaves as a neurodevelopmental disorder that improves and responds to neurotransmitter therapy during the second decade of life.

Conflict of Interest

All the authors of this chapter declare that there are no conflicts of interest.

Ethics Approval

Not applicable, not required.

Patient’s Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

Animal Rights

This article does not contain any studies with human or animal subjects performed by any of the authors.

Authors’ Contribution

Vincenzo Leuzzi planned the manuscript and realized the first draft and the final revision. He directed the diagnostic and therapeutic management of the patients since the moment of the diagnosis. He serves as guarantor for the article, he accepts full responsibility for the work and/or the conduct of the study, and he has access to all the related data and controlled the decision to publish.

Mario Mastrangelo took part in the planning of the work described in the manuscript, in its conduct and reporting. He collaborated in the diagnostic and therapeutic management of the patients since the moment of the diagnosis.

Agata Polizzi took part in the reporting of the work described in the manuscript, and she was responsible for the follow-up of the patients since the early infancy.

Cristiana Artiola realized the molecular genetic analysis of DDC gene in all the members of the reported family and the related bioinformatic evaluation that is reported in Fig. 1. She also took part in the conduct and in the reporting of the work described in the manuscript.

André B.P. van Kuilenburg participated in the conduct and in the reporting of the work described in the manuscript and realized AADC enzyme activity and plasma biogenic amine measurement in all the members of the reported family.

Carla Carducci realized the molecular genetic analysis of DDC gene in all the members of the reported family and revised the bioinformatic evaluation that is reported in Fig. 1. She also took part in the conduct and in the reporting of the work described in the manuscript.

Martino Ruggieri took part in the conduct and in the reporting of the work described in the manuscript, and he collaborated in the follow-up of the patients since the early infancy.

Rita Barone took part in the conduct and in the reporting of the work described in the manuscript, and he collaborated in the follow-up of the patients since the early infancy.

Barbara Tavazzi took part in the conduct and in the reporting of the work described in the manuscript and realized biogenic amine urinary measurements in the members of the reported family.

Nico G.G.M. Abeling participated in the conduct and in the reporting of the work described in the manuscript and realized AADC enzyme activity and plasma biogenic amine measurement in all the members of the reported family.

Lida Zoetekouw participated in the conduct and in the reporting of the work described in the manuscript and realized AADC enzyme activity and plasma biogenic amine measurement in all the members of the reported family.

Vito Sofia participated in the conduct and in the reporting of the work described in the manuscript, and he collaborated in the follow-up of the patients in adult age.

Mario Zappia took part in the drafting of the manuscript, and he collaborated in the follow-up of the patients in adult age.

Claudia Carducci participated in the conduct and in the reporting of the work described in the manuscript and realized the cerebrospinal fluid measurements of biogenic amine in the two reported patients.