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Review
. 2017 Jan 18;12(1):12.
doi: 10.1186/s13023-016-0522-z.

Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency

Tessa Wassenberg  1 , Marta Molero-Luis  2 , Kathrin Jeltsch  3 , Georg F Hoffmann  3 , Birgit Assmann  3 , Nenad Blau  4 , Angeles Garcia-Cazorla  5 , Rafael Artuch  2 , Roser Pons  6 , Toni S Pearson  7 , Vincenco Leuzzi  8 , Mario Mastrangelo  8 , Phillip L Pearl  9 , Wang Tso Lee  10 , Manju A Kurian  11 , Simon Heales  12 , Lisa Flint  13 , Marcel Verbeek  1   14 , Michèl Willemsen  1 , Thomas Opladen  15
Affiliations
Review

Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency

Tessa Wassenberg et al. Orphanet J Rare Dis. .

Abstract
in English, German, Spanish

Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurometabolic disorder that leads to a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine. Onset is early in life, and key clinical symptoms are hypotonia, movement disorders (oculogyric crisis, dystonia, and hypokinesia), developmental delay, and autonomic symptoms.In this consensus guideline, representatives of the International Working Group on Neurotransmitter Related Disorders (iNTD) and patient representatives evaluated all available evidence for diagnosis and treatment of AADCD and made recommendations using SIGN and GRADE methodology. In the face of limited definitive evidence, we constructed practical recommendations on clinical diagnosis, laboratory diagnosis, imaging and electroencephalograpy, medical treatments and non-medical treatments. Furthermore, we identified topics for further research. We believe this guideline will improve the care for AADCD patients around the world whilst promoting general awareness of this rare disease.

Der Aromatische L-Aminosäuren Decarboxylase Mangel (AADCD) ist eine seltene autosomal rezessive neurometabolische Störung, die zu einem schweren kombinierten Mangel an Serotonin, Dopamin, Norepinephrin und Epinephrin führt. Die Symptome setzen in einer frühen Phase des Lebens ein. Die klinischen Hauptsymptome sind muskuläre Hypotonie, Bewegungsstörungen (Okkulogyre Krisen, Dystonie und Hypokinesie), Entwicklungsverzögerung und autonome Symptome.

In diesen Konsensus basierten Leitlinien haben Mitglieder der “International Working Group on Neurotransmitter Related Disorders (iNTD)” sowie Patientenvertreter die verfügbare Evidenz für die Diagnose und Behandlung von AADCD ausgewertet und evidenzbasierte Empfehlungen nach den Methoden von SIGN und GRADE formuliert. Stets im Bewusstsein der limitierten Evidenz haben wir praktische Empfehlungen für die klinische Diagnose, Labordiagnose, Bildgebung und EEG, medizinische und nicht medizinische Behandlung formuliert. Des Weiteren haben wir Themen identifiziert, die der weiteren Forschung bedürfen. Wir glauben, dass diese Leitlinie die Behandlung von Patienten mit AADCD verbessert und gleichzeitig das Bewusstsein für diese seltene Erkrankung geschärft wird.

Electronic supplementary material: The online version of this article (doi:10.1186/s13023-016-0522-z) contains supplementary material, which is available to authorized users.

La deficiencia de la descarboxilasa de aminoácidos aromáticos (AADCD) es una enfermedad neurometabólica minoritaria de herencia autosómica recesiva que causa un defecto grave de dopamina, serotonina, epinefrina y norepinefrina. El inicio de la enfermedad es precoz, y sus síntomas principales incluyen hipotonía, trastornos del movimiento (crisis oculógiras, distonía e hipocinesia), retraso del desarrollo y signos disautonómicos.

En esta guía de consenso han participado representantes del grupo de trabajo internacional sobre trastornos de la neurotransmisión (iNTD) y representantes de las asociaciones de pacientes, que han evaluado todas las evidencias existentes en relación al diagnóstico y tratamiento de la AADCD. Las recomnedaciones se han realizado siguiendo la metodología SIGN y GRADE. A pesar de los bajos niveles de evidencia existentes, se han podido establecer recomendaciones prácticas y que pueden ser muy útiles sobre el diagnóstico clínico y de laboratorio, las pruebas de neuroimagen y electroencefalográficas y sobre tratamientos tanto médicos como de soporte. Se han identificado además temas que pueden ser interesantes a desarrollar en el campo de la investigación de la AADCD.

En conclusión, pensamos que esta guía aumentará la calidad en los cuidados de los pacientes con AADCD en todo el mundo, y que aumentará el conocimiento de esta rara enfermedad.

Electronic supplementary material: The online version of this article (doi:10.1186/s13023-016-0522-z) contains supplementary material, which is available to authorized users.

Keywords: AADC deficiency; Aromatic l-amino acid decarboxylase deficiency; Dopamine; GRADE; Guideline; Infantile dystonia-parkinsonism; Neurotransmitter; SIGN; Serotonin.

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Figures

Fig. 1
Fig. 1
Biosynthesis and breakdown of serotonin and the catecholamines, and the metabolic block in AADC deficiency. Simplified scheme of the biosynthesis and breakdown of serotonin and the catecholamines (dopamine, norepinephrine and epinephrine), and melatonin synthesis. Cofactors (BH4, PLP, Cu) and methyldonor (SAM) are connected to the respective enzyme with dashed lines. Dashed arrows do not show intermediate steps. The metabolic block caused by AADC deficiency is shown as a red bar. Metabolites above the block are increased, metabolites below the block are decreased, indicated by red arrows. The implication of 5-MTHF in L-dopa to 3-OMD metabolism is shown in a simplified manner. Norepinephrine and epinephrine are broken down to NMET and MET only in the periphery. In CSF, the main metabolite of norepinephrine and epinephrine is MHPG. Abbreviations: AADC: aromatic l-amino acid decarboxylase; BH4: tetrahydrobiopterin; COMT: catechol O-methyl transferase; CSF: cerebrospinal fluid; Cu: cupper; DβH: dopamine beta hydroxylase; DOPAC: dihydroxyphenylacetic acid; HCys: homocysteine; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTP: 5-hydroxytryptophan; HVA: homovanillic acid; L-Dopa: 3,4-dihydroxyphenylalanine; MAO: monoamine oxidase; MET: metanephrine; Met: metionine; MHPG: 3-methoxy 4-hydroxyphenylglycol; 3MT: 3-Metyramine; 5-MTHF: methyltetrahydrofolate; NMET: normetanephrine; 3-OMD: 3-O-methyldopa (=3-methoxytyrosine); Phe: phenylalanine; PhH: phenylalanine hydroxylase; PNMT: phenylethanolamine N-methyltransferase; SAH: S-adenosylhomocysteine; SAM: s-adenosylmethionine; TH: tyrosine hydroxylase; TrH: tryptophan hydroxylase; Tryp: tryptophan; Tyr: tyrosine; VLA: vanillactic acid; VMA: vanillmandelic acid: Vit B6 vitamin B6 (pyridoxine)
Fig. 2
Fig. 2
Treatment algorithm in AADC deficiency. This figure reflects a possible treatment scheme for a newly diagnosed AADCD patient. Drug dose and escalating schemes are given in Table 4. At the left, first line treatment is depicted in which pyridoxine is started at diagnosis (step (1)), followed after two weeks by step (2): either one of the dopamine agonists in escalating scheme or one of the MAO-inhibitors. After two months of treatment at target dose, step (3) is added: either a dopamine agonist or a MAO-inhibitor. The order of introducing dopamine agonist or MAO-inhibitors is interchangeably. Dose escalation depends on effect and tolerability. If an agent is not effective or has too many side effects, consider replacing it with another agent from the same class before going to the next step. In case of intolerable side effects, treatment should be stopped. After about 1 year in stable treatment regimen, reassessment should take place: consider to discontinue drugs (only 1 at a time) without clear treatment effect. Frequent assessment is then again necessary, and agents should be reinstated in case of deterioration. At the right, additional symptomatic treatment is depicted, with different drug classes that could be added for specific symptoms. Always avoid starting more than 1 agent at the time. Assess tolerability and effect frequently, and discontinue drugs that have no clear effect, or give intolerable side effects. Treatment in special situations (L-Dopa, folinic acid) is not depicted in this figure (see text). Abbreviations: DA-agonist: dopamine agonist; MAOI: MAO-inhibitor; OGC: oculogyric crisis
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