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Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment

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Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment Published online: 2018-10-29 2 Review Article Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment Heiko Brennenstuhl1 Sabine Jung-Klawitter1 Birgit Assmann1 Thomas Opladen1 1 Division of Neuropediatrics and Metabolic Medicine, Department of Address for correspondence Prof. Dr. Thomas Opladen, MD, Division General Pediatrics, University Children’s Hospital Heidelberg, of Neuropediatrics and Metabolic Medicine, Department of General Heidelberg, Germany Pediatrics, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany (e-mail: [email protected]). Neuropediatrics 2019;50:2–14. Abstract 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. Keywords Classical signs are hypotonia, movement disorders, autonomous dysregulations, and ► inherited monoamine impaired development. Diagnosis depends on quantitative detection of neurotrans- neurotransmitter mitters in cerebrospinal fluid, since peripheral markers in blood or urine are less deficiency reliable. Treatment is based on supplementation of the missing neurotransmitter ► pterin synthesis precursors or restoring deficient cofactors for endogenous enzymatic synthesis. In defect recent years, knowledge about this orphan group of diseases increased substantially ► pediatric movement among clinicians. However, the difficult task of integrating clinical symptoms and disorders laboratory values still leads to a critical delay in diagnosis and therapy for patients. This ► parkinsonism review aims at enhancing the understanding of neurotransmitter disorders and should ► dystonia help practicing clinicians to choose useful diagnostic steps on the way to a valid ► L-dopa diagnosis. Introduction the following neuron or cell. The binding changes the electrical Brain function depends on neuronal connections in circuits, activity of the postsynaptic neuron, which in turn leads to which range in scale from small local neuronal groups to long- further interneuron communication. Subsequently, the stimu- distance projections. Neurons can function in more than one lus is terminated by degradation or re-uptake of the neuro- circuit and communicate with thousands of other neurons transmitter into the pre-synaptic cell. Synaptic connections This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. through synapses. In a single human brain, there are roughly forming neuronal circuitries are highly plastic, constantly more than 100 trillion synapses.1 The classical synaptic orga- respond to stimulation, and adapt to a changing environment. nization consists of a pre-synaptic neuron which, upon sti- The umbrella term “neurotransmitter” subsumes different mulation by an electrical impulse, releases chemical types of chemical substances involved in synaptic transmission substances (“neurotransmitter”) stored in the axon from from cell to cellwithin the central (CNS) and peripheral nervous vesicles into the synaptic cleft. The neurotransmitter binds system (PNS). Neurotransmitters are synthesized in the neuron to specific receptors located on the postsynaptic membrane of and stored within vesicles, are essential for intercellular received © 2019 Georg Thieme Verlag KG DOI https://doi.org/ May 2, 2018 Stuttgart · New York 10.1055/s-0038-1673630. accepted after revision ISSN 0174-304X. August 22, 2018 published online October 29, 2018 Inherited Disorders of Neurotransmitters Brennenstuhl et al. 3 communication, and lay the foundation of basic and complex to dopamine by aromatic amino acid decarboxylase (AADC). biological functions, including muscular movement as well as In noradrenergic neurons and the adrenal medulla, dopa- neuropsychological development.2 Neurotransmitters can be mine-β-hydroxylase (DβH) catalyzes the conversion of dopa- grouped according to their chemical structure into amino acid mine to noradrenalin. In a similar fashion, TPH converts L- transmitters (glycine, glutamate and γ-aminobutyric acid tryptophan to 5-hydroxytryptophan (5-HTP) which is then [GABA]), monoamines/biogenic amine transmitters (with the decarboxylated to its active metabolite serotonin by AADC. subgroup of catecholamines norepinephrine, epinephrine, and The role of DNAJC12, a heat shock co-chaperone of the HSP40 dopamine as well asserotonin), andneuropeptides,classifiedas family, still needs to be elucidated. While an interaction with short proteins or polypeptides (for example, the hypothalamic PAH has been identified, the suspected influence on TH and hormones oxytocin and vasopressin or orexins). Atypical neu- TPH is based on in silico studies (►Fig. 1).4,5 rotransmitters have either unusual chemical properties or are BH4 is an essential cofactor for PAH, TH, and TPHs. In addition, less extensively studied and understood. They include the it plays a crucial role in the formation of nitric oxide by nitric purinergic neurotransmitters adenosine and adenosine tripho- oxide synthases (NOS).6 It is synthesized from GTP in the sphate (ATP), endogenous cannabinoids and opioids, diffusible following three distinct steps: (1) GTP cyclohydrolase I (GTPCH) gases-like nitric oxide (NO) and carbon monoxide (CO) and converts GTP to 7,8-dihydroneopterin triphosphate (BH2)which 1 families of neurotrophic factors and cytokines, and others. represents the rate-limiting step in BH4 synthesis; (2) 6-pyr- Inherited disorders of neurotransmitters are rare meta- uvoyltetrahydropterin synthase (PTPS) catalyzes the conversion bolic diseases caused by impaired biosynthesis, breakdown of BH2 to 6-pyruvoyltetrahydropterin; and the last step is or transport of neurotransmitters, or of essential cofactors in catalyzed by (3) sepiapterin reductase (SR) via NADPH-depen- their biosynthesis, such as tetrahydrobiopterin (BH4). They dent reduction of 6-pyruvoyltetrahydropterin to BH4 (►Fig. 1). result in a variety of clinical presentations ranging from late- Primary monoamine neurotransmitter disorders can onset moderate movement disorders to early-onset lethal thereby be clustered into five distinct subgroups: (1) disorders 2 encephalopathies. of BH4 synthesis or recycling with or without hyper- Clinical symptoms occurring in patients with inherited phenylalaninemia, (2) primary enzyme defects in monoamine disorders of monoamine and pterin metabolism often over- biosynthesis, (3) monoamine catabolism disorders (4) mono- lap with features seen in other neurological syndromes, such amine transporter defects, and (5) chaperon-associated dis- as cerebral palsy or epileptic encephalopathies, which partly orders (►Table 1). results in significant delayed diagnosis.3 Conventional and functional brain imaging studies are typically normal. Since BH4 Cofactor Deficiencies without tetrahydrobiopterin (BH4) is the essential cofactor not only Hyperphenylalaninemia for tyrosine hydroxylase (TH) and tryptophan hydroxylases (TPH) but also for phenylalanine hydroxylase (PAH), hyper- Autosomal Dominant GTPCH I Deficiency (Segawa phenylalaninemia (HPA) can be present already in newborn Disease, Dopa-Responsive Dystonia, DYT5a, DYT/ screening (NBS), guiding the way to diagnosis. Differential PARK-GCH1)7 diagnosis is essentially based upon clinical assessment, Adeficiency of GTPCH I results in reduced BH4 availability, and blood tests (plasma and dried blood spots [DBS]), urine subsequently, because of its role as the cofactor for TH and TPH, sampling, and cerebrospinal fluid (CSF) investigation. Cor- in decreased levels of dopamine and serotonin. With an rect handling of the specimen to avoid preanalytical errors is incidence of 0.5 per 100.000 people, it is a rare condition crucial as is the final interpretation of the analyses with caused by dominant mutations in the GCH1 gene.8,9 The same regard to age-adjusted reference values. mutation in GCH1 can cause a wide phenotypic spectrum.10 This review will focus on primary disorders of monoamine Key symptoms usually present within the first decade of life synthesis, transport, and breakdown. It summarizes the cur- revealing dystonia of the lower extremities that asymmetri- rent knowledge on diagnostic tools, discusses rational treat- cally progresses to the other limbs. Symptoms can show a mentapproaches,andgives anoverviewonnew model systems circadian fluctuation with worsening during the day and This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. for basic research on neurotransmitter-related disorders. improvement of the symptoms after sleep.8,11 “Parkinsonian” symptoms such as tremor, bradykinesia, and impaired fine motor skills can be present, especially evolving later in the Primary Monoamine Neurotransmitter fi 12 Disorders course due to insuf cient treatment. Neuropsychiatric man- ifestations such as sleep disturbance, anxiety, or depression are Monoamine and Pterin Metabolism more and more included in the clinical phenotype of Segawa The term “monoamine neurotransmitter”
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