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The Utility of CSF for the Diagnosis of Primary and Secondary Monoamine Neurotransmitter Deficiencies A.B

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The Utility of CSF for the Diagnosis of Primary and Secondary Monoamine Neurotransmitter Deficiencies A.B In this issue: Recent Advances in Pediatric Laboratory Medicine The utility of CSF for the diagnosis of primary and secondary monoamine neurotransmitter deficiencies A.B. Burlina1, A. Celato1, G. Polo1, C. Edini1, A.P. Burlina2 1 Division of Inherited Metabolic Diseases, Reference Centre Expanded Newborn Screening, Department of Women’s and Children’s Health, University Hospital, Padova, Italy 2 Neurological Unit, St. Bassiano Hospital, Bassano del Grappa, Italy ARTICLE INFO ABSTRACT Corresponding author: Biogenic amine defects constitute a complex and ex- Alberto Burlina, M.D. Division of Inherited Metabolic Diseases panding group of neurotransmitter disorders affecting Reference Centre Expanded Newborn Screening cognitive, motor and autonomic system development, Department of Women’s and Children’s Health mostly in the pediatric age. In recent years different University Hospital enzymatic defects have been identified impairing the Via Orus 2/B 35129 Padova, Italy tetrahydrobiopterin cofactor pathway and/or biogenic Phone: +39 049 821 3569 ext.7462 amine synthesis, catabolism and transport, with sub- Fax: +39 049 8217474 sequent new disease entities described. The lumbar E-mail: [email protected] puncture, with subsequent withdrawal of cerebrospi- Key words: nal fluid (CSF), remains a key step in the diagnostic monoamine neurotransmitter deficiencies, procedure. Due to the specific nature of CSF, timing cerebrospinal fluid, tetrahydrobiopterin defects of analysis, sample collection and storage, technical issues of the analytic process are still crucial for the diagnosis and follow-up of patients. A progressive approach to the diagnosis of biogenic amine defects is presented, pointing out criticalities and difficulties concerning sample collection and results interpreta- tion, especially due to the increasing reports of sec- ondary neurotransmitter alterations that, at present, constitute a challenge. Page 64 eJIFCC2017Vol28No1pp064-076 A.B. Burlina, A. Celato, G. Polo, C. Edini, A.P. Burlina The utility of CSF for the diagnosis of primary and secondary monoamine neurotransmitter deficiencies major neurotransmitters within the central ner- vous system (CNS). Their regulation is tuned and Abbreviations governed by the rate of neurotransmitter (NT) CSF: cerebrospinal fluid synthesis, packaging, release, re-uptake, degra- PNDs: primary neurotransmitters diseases dation, and by receptor status. Clinically they are Phe: phenylalanine mainly characterized by a range of extrapyramidal AD-GTPCH1: autosomal dominant manifestations including dystonia, hyperkinesia, guanosin triphosphate cyclohydrolase 1 chorea and oculogyric crisis (1,2). These defects AR-GTPCH1: autosomal recessive guanosin are characterized by an elevation of phenylala- triphosphate cyclohydrolase 1 nine, the presence of abnormal monoamines and PTPS: 6-pyruvoyltetrahydropterin synthase deranged monoamine synthesis, degradation SR: sepiapterin reductase and transport (3) (Figure 1). Recently, abnormal PCD: pterin-4a-carbinolamin dehydratase neurotransmitter profiles have been reported in DHPR: dihydropteridin reductase association with other non-metabolic and genet- TH: tyrosine hydroxylase ic diseases, and defined as secondary neurotrans- TPH: Tryptophan hydroxylase mitter abnormalities (4,5) (Table 1). Biochemical AADC: aromatic L-aminoacid decarboxylase distinction between the two groups is difficult MAO: monoamine oxidase due to a considerable overlap in the concentra- DβH: dopamine beta hydroxylase tions of HVA and 5HIAA. Hence, a careful analysis VMAT2: vesicular monoamine transporter of the pattern of all metabolites may be necessary DAT: dopamine transporter to reach the correct diagnosis. Recent discoveries emphasizing the role of NTs in brain development HVA: homovanillic acid have led to the possibility of treating these de- 5-HIAA: 5-hydroxyindolacetic acid fects. Therefore an early and accurate diagnosis 3-OMD: 3 orthomethyldihydroxyphenylalanine of biogenic amine disorder is paramount to an ef- 5-HTP: 5-hydroxytryptophan ficient therapeutic intervention (7). MHPG: 3-methoxy-4-hydroxyphenylglycol BH4: tetrahydrobiopterin In this review, we provide an overview of primary BH2: dihydrobiopterin neurotransmitter diseases (PNDs) by cerebrospi- nal fluid (CSF) investigations. Sample manage- Neo: neopterin ment, analytical methodology, and diagnostic Sep: sepiapterin interpretation are described. Prim: primapterin CLINICAL AND BIOCHEMICAL FEATURES OF MONOAMINE INTRODUCTION NEUROTRANSMITTER DISEASES Monoamine neurotransmitter defects are includ- In all monoamine metabolic disorders, the clini- ed in the group of neurometabolic syndromes cal symptoms are strictly related to the effects of attributable to disturbances of neurotransmitter dopamine and serotonin deficiency. Signs of do- metabolism/transport and cofactors (i.e. tetra- pamine deficiency include Parkinsonism, dysto- hydrobiopterin) synthesis/regeneration. Biogenic nia, chorea, oculogyric crisis, ptosis, hypersaliva- amines, serotonin and all catecholamines (do- tion, and myoclonic epilepsy. The manifestations pamine, epinephrine and norepinephrine) are of serotonin deficiency are less well defined, and Page 65 eJIFCC2017Vol28No1pp064-076 A.B. Burlina, A. Celato, G. Polo, C. Edini, A.P. Burlina The utility of CSF for the diagnosis of primary and secondary monoamine neurotransmitter deficiencies include temperature instability, sweating, aggres- Defect of tetrahydrobiopterin (BH4) with conse- sive behaviour, irritability and sleeping distur- quent dopamine and serotonin deficiency are as- bance. Non-specific symptoms include epileptic sociated with an increased plasma phenylalanine encephalopathy, mental retardation, microceph- (Phe) concentration (8). BH4 acts as a cofactor or aly, swallowing difficulties, and pyramidal tract co-substrate in a range of biochemical reactions features mimicking cerebral palsy. A potential including the hydroxylation of aromatic amino defect in biogenic amine should be considered in acids (Phe, tyrosine and tryptophan) by the cor- an infant presenting with any of the above symp- responding hydroxylases. De novo biosynthesis toms, which may appear in isolation or together of BH4 from GTP requires 3 enzymes (GTPCH, (8). Furthermore clinical monitoring of these PTPS and SR), while dihydropteridine reductase patients could be challenging. Firstly, symptoms (DHPR) regenerates BH4 from q-dihydrobiopter- can fluctuate according to last medication with in (qBH2). Overall BH4 synthesis, as such, is thus on-off effects. Secondly, high doses of L-Dopa complex, and not completely understood as yet. inhibit postsynaptic receptors, resulting in symp- In autosomal recessive and autosomal dominant toms (e.g., involuntary movements, dyskinesia, GTP cyclohydrolase 1 (GTPCH1), 6-pyruvoyltet- irritability, insomnia and opisthotonus) that are rahydropterin synthase (PTPS), and DHPR, the indistinguishable from the one resulting from measurement of blood and CSF pterins facili- under-treatment and/or dopamine deficiency. tates the diagnosis. Noteworthy, all disorders Figure 1 Biochemical pathways involving dopamine, serotonin, epinephrine, norepinephrine, and the cofactor BH4 Page 66 eJIFCC2017Vol28No1pp064-076 A.B. Burlina, A. Celato, G. Polo, C. Edini, A.P. Burlina The utility of CSF for the diagnosis of primary and secondary monoamine neurotransmitter deficiencies Legend Figure 1: Biochemical pathways (p. 66 above) The monoamines consist of catecholamines (for instance dopamine, norepinephrine and epinephrine) and serotonin. The amines are synthesized throughout a complex multienzymatic pathway which con- verts, tryptophan and tyrosine into serotonin and dopamine respectively, through reactions catalysed by tryptophan hydroxylase (TPH, EC 1.14.16.4), tyrosine hydroxylase (TH, EC 1.14.16.2) and aromatic L-aminoacid decarboxylase (AADC, EC 4.1.1.28). This latter enzyme acts as a common converging de- carboxylating system for active neurotransmitter biosynthesis. In the case of AADC deficiency, the dopamine precursor (L-dihydroxyphenylalanine, DOPA) is metabolized into 3-Orthomethyldihydroxy- phenylalanine (3-OMD) and vanillactic acid (VLA). Both TPH and TH require tetrahydrobiopterin (BH4) as cofactor, while AADC needs vitamin B6 (pyridoxine). In noradrenergic neurons, dopamine is further converted by dopamine beta hydroxylase (DBH) into norepinephrine and epinephrine by phenyletha- nolamine N-methyltransferase (PNMT). Since BH4 is crucial in serotonin and dopamine biosynthesis, a large subset of monoamine defects is to be referred to pterins build up and regeneration mostly pre- senting hyperphenylalaninemia as a characterizing hallmark. The biosynthesis and regeneration of BH4 is carried out by a complex system of enzymes starting from guanosine triphosphate cyclohydrolase 1 (GTPCH1), the rate limiting enzyme for BH4 biosynthesis, which is responsible for the hydrolysis of gua- nosine triphosphate into 7,8-dihydroneopterin triphosphate (H2NP3), thus releasing neopterin. H2NP3 is further metabolized into 6-pyruvoyltetrahydropterin (6-PTP) by 6-pyruvoyltetrahydropterin synthase (PTPS), the second critical enzyme for BH4 build up. 6-PTP is used to form BH4 through sepiapterin (SPT) by a two step enzymatic pathway of aldose reductase (AR) and sepiapterin reductase (SR). BH4 is the basic cofactor of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) and once it links with this enzyme it is then released as tetrahydrobiopterin-4a-carbinolamine. Tetrahydrobiopterin-4a- carbinolamine
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