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.

Background: Tetrahydrobiopterin (BH₄) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH₄biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH₄deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH₄deficiencies.Conclusion: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH₄deficient patients.

Neurotransmitter deficiencies are rare neurological disorders with clinical onset during childhood. The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH₄). With the newly described DNAJC12 deficiency, a chaperon-associated neurotransmitter disorder, the pathophysiological spectrum has been broadened. All deficiencies result in a lack of monoamine neurotransmitters, especially dopamine and its products, with a subset leading to decreased levels of serotonin. Symptoms can occur already in the neonatal period. Classical signs are hypotonia, movement disorders, autonomous dysregulations, and impaired development. Diagnosis depends on quantitative detection of neurotransmitters in cerebrospinal fluid, since peripheral markers in blood or urine are less reliable. Treatment is based on supplementation of the missing neurotransmitter precursors or restoring deficient cofactors for endogenous enzymatic synthesis. In recent years, knowledge about this orphan group of diseases increased substantially among clinicians. However, the difficult task of integrating clinical symptoms and laboratory values still leads to a critical delay in diagnosis and therapy for patients. This review aims at enhancing the understanding of neurotransmitter disorders and should help practicing clinicians to choose useful diagnostic steps on the way to a valid diagnosis. PubMed was used to find English full-text articles published between January 1987 and July 2018 corresponding to the terms “monoamine,” “neurotransmitter,” “pediatric,” and “deficiency.” Articles were carefully read, and distinct reference articles were further investigated for clinically relevant research.

Neurotransmitters are chemical messengers that enable communication between the neurons in the synaptic cleft. Inborn errors of neurotransmitter biosynthesis, breakdown and transport are a group of very rare neurometabolic diseases resulting in neurological impairment at any age from newborn to adulthood. The International Working Group on Neurotransmitter related Disorders (iNTD) is the first international network focusing on the study of primary and secondary neurotransmitter disorders. It was founded with the aim to foster exchange and improve knowledge in the field of these rare diseases. The newly established iNTD patient registry for neurotransmitter related diseases collects longitudinal data on the natural disease course, approach to diagnosis, therapeutic strategies, and quality of life of affected patients. The registry forms the evidence base for the development of consensus guidelines for patients with neurotransmitter related disorders. The iNTD network and registry will improve knowledge and strengthen research capacities in the field of inborn neurotransmitter disorders. The evidence-based guidelines will facilitate standardized diagnostic procedures and treatment approaches.