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标题：Blood, urine and cerebrospinal fluid analysis in TH and AADC deficiency and the effect of treatment
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作者：Tessa Wassenberg ; Ben P.H. Geurtz ; Leo Monnens 等
期刊名称：Molecular Genetics and Metabolism Reports
印刷版ISSN：2214-4269
出版年度：2021
卷号：27
页码：100762
DOI：10.1016/j.ymgmr.2021.100762
出版社：Elsevier B.V.
摘要：Background Aromatic L-amino acid decarboxylase (AADC) deficiency and tyrosine hydroxylase (TH) deficiency are rare inherited disorders of monoamine neurotransmitter synthesis which are typically diagnosed using cerebrospinal fluid examination of monoamine neurotransmitter metabolites. Until now, it has not been systematically studied whether analysis of monamine neurotransmitter metabolites in blood or urine has diagnostic value as compared to cerebrospinal fluid examination, or whether monoamine neurotransmitter metabolites in these peripheral body fluids is useful to monitor treatment efficacy. Methods Assessment, both by literature review and retrospective analysis of our local university hospital database, of monoamine neurotransmitter metabolites in urine, blood and cerebrospinal fluid, and serum prolactin levels, before and during treatment in patients with AADC and TH deficiency. Results In AADC deficiency, 3- O -methyldopa in serum or dried blood spots was reported in 34 patients and found to be (strongly) increased in all, serotonin in serum was decreased in 7/7 patients. Serum prolactin was increased in 34/37 and normal in 3 untreated patients. In urine, dopamine was normal or increased in 21/24 patients, 5-hydroxyindoleacetic acid was decreased in 9/10 patients, and vanillactic acid was increased in 19/20 patients. No significant changes were seen in monoamine neurotransmitter metabolites after medical treatment, except for an increase of homovanillic acid in urine and cerebrospinal fluid after levodopa therapy, sometimes even in absence of a clinical response. After gene therapy, cerebrospinal fluid homovanillic acid increased in most patients (8/12), but 5-hydroxyindoleacetic acid remained unchanged in 9/12 patients. In TH deficiency, serum prolactin was increased in 12/14 and normal in the remaining untreated patients. Urinary dopamine was decreased in 2/8 patients and normal in 6. Homovanillic acid concentrations in cerebrospinal fluid increased upon levodopa treatment, even in the absence of a clear treatment response. Conclusions This study confirms that cerebrospinal fluid is the most informative body fluid to measure monoamine neurotransmitter metabolites when AADC or TH deficiency is suspected, and that routine follow-up of cerebrospinal fluid measurements to estimate treatment response is not needed. 3- O -methyldopa in dried blood spots and vanillactic acid in urine are promising peripheral biomarkers for diagnosis of AADC deficiency. However, in many patients with TH or AADC deficiency dopamine in urine is normal or increased thereby not reflecting the metabolic block. The value of serum prolactin for follow-up of AADC and TH deficiency should be further studied.
关键词：Monoamine neurotransmitter deficiency ; Tyrosine hydroxylase deficiency ; Aromatic L-amino acid decarboxylase deficiency ; Biomarkers ; TH deficiency ; AADC deficiency ; 3-OMD 3- O -methyldopa ; 5-HIAA 5-Hydroxyindoleacetic acid ; 5-HTP 5-Hydroxytryptophan ; AADC Aromatic L-amino acid decarboxylase ; CSF Cerebrospinal fluid ; HVA Homovanillic acid ; MHPG 3-methoxy 4-hydroxyphenylglycol ; TH Tyrosine hydroxylase ; TML Translational Metabolic Laboratory ; VMA Vanillylmandelic acid ; VLA Vanillactic acid