RESUMO
Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience numerous complications, which are exacerbated by inflammatory dysregulation and infection. Understanding the immunological mechanisms is crucial for selecting medications that balance inflammation control and immunocompetence. In this cross-sectional study, aiming to identify potential immunotherapeutic targets and inflammatory biomarkers, we delved into the interrelationship between clinical severity and systemic inflammatory parameters in a representative RDEB cohort. Encompassing 84 patients aged 1-67 and spanning all three Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) severity categories, we analysed the interrelationship of infection history, standard inflammatory markers, systemic cytokines and Ig levels to elucidate their roles in RDEB pathophysiology. Our findings identify C-reactive protein as an excellent biomarker for disease severity in RDEB. A type 2 inflammatory profile prevails among moderate and severe RDEB patients, correlating with dysregulated circulating IgA and IgG. These results underscore the IL4/IL13 pathways as potential evidence-based therapeutic targets. Moreover, the complete inflammatory scenario aligns with Staphylococcus aureus virulence mechanisms. Concurrently, abnormalities in IgG, IgE and IgM levels suggest an immunodeficiency state in a substantial number of the cohort's patients. Our results provide new insights into the interplay of infection and immunological factors in the pathogenesis of RDEB.
Assuntos
Biomarcadores , Proteína C-Reativa , Epidermólise Bolhosa Distrófica , Interleucina-13 , Interleucina-4 , Índice de Gravidade de Doença , Humanos , Estudos Transversais , Biomarcadores/sangue , Criança , Pré-Escolar , Interleucina-4/sangue , Adolescente , Proteína C-Reativa/metabolismo , Adulto , Adulto Jovem , Feminino , Masculino , Lactente , Pessoa de Meia-Idade , Interleucina-13/sangue , Interleucina-13/metabolismo , IdosoRESUMO
BACKGROUND: Genetic defects of monoamine neurotransmitters are rare neurological diseases amenable to treatment with variable response. They are major causes of early parkinsonism and other spectrum of movement disorders including dopa-responsive dystonia. OBJECTIVES: The objective of this study was to conduct proteomic studies in cerebrospinal fluid (CSF) samples of patients with monoamine defects to detect biomarkers involved in pathophysiology, clinical phenotypes, and treatment response. METHODS: A total of 90 patients from diverse centers of the International Working Group on Neurotransmitter Related Disorders were included in the study (37 untreated before CSF collection, 48 treated and 5 unknown at the collection time). Clinical and molecular metadata were related to the protein abundances in the CSF. RESULTS: Concentrations of 4 proteins were significantly altered, detected by mass spectrometry, and confirmed by immunoassays. First, decreased levels of apolipoprotein D were found in severe cases of aromatic L-amino acid decarboxylase deficiency. Second, low levels of apolipoprotein H were observed in patients with the severe phenotype of tyrosine hydroxylase deficiency, whereas increased concentrations of oligodendrocyte myelin glycoprotein were found in the same subset of patients with tyrosine hydroxylase deficiency. Third, decreased levels of collagen6A3 were observed in treated patients with tetrahydrobiopterin deficiency. CONCLUSION: This study with the largest cohort of patients with monoamine defects studied so far reports the proteomic characterization of CSF and identifies 4 novel biomarkers that bring new insights into the consequences of early dopaminergic deprivation in the developing brain. They open new possibilities to understand their role in the pathophysiology of these disorders, and they may serve as potential predictors of disease severity and therapies. © 2020 International Parkinson and Movement Disorder Society.
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Erros Inatos do Metabolismo dos Aminoácidos , Distúrbios Distônicos , Biomarcadores , Humanos , Proteômica , Índice de Gravidade de DoençaRESUMO
Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein, we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. Ann Neurol 2017;82:317-330.
Assuntos
Deficiência de Tiamina/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Proteínas de Membrana Transportadoras/genética , Proteínas de Transporte da Membrana Mitocondrial , Mutação , Prognóstico , Taxa de Sobrevida , Deficiência de Tiamina/mortalidade , Adulto JovemRESUMO
Mitochondrial diseases are a group of genetic disorders leading to the dysfunction of mitochondrial energy metabolism pathways. We aimed to assess the clinical phenotype and the biochemical cerebrospinal fluid (CSF) biogenic amine profiles of patients with different diagnoses of genetic mitochondrial diseases. We recruited 29 patients with genetically confirmed mitochondrial diseases harboring mutations in either nuclear or mitochondrial DNA (mtDNA) genes. Signs and symptoms of impaired neurotransmission and neuroradiological data were recorded. CSF monoamines, pterins, and 5-methyltetrahydrofolate (5MTHF) concentrations were analyzed using high-performance liquid chromatography with electrochemical and fluorescence detection procedures. The mtDNA mutations were studied by Sanger sequencing, Southern blot, and real-time PCR, and nuclear DNA was assessed either by Sanger or next-generation sequencing. Five out of 29 cases showed predominant dopaminergic signs not attributable to basal ganglia involvement, harboring mutations in different nuclear genes. A chi-square test showed a statistically significant association between high homovanillic acid (HVA) values and low CSF 5-MTHF values (chi-square = 10.916; p = 0.001). Seven out of the eight patients with high CSF HVA values showed cerebral folate deficiency. Five of them harbored mtDNA deletions associated with Kearns-Sayre syndrome (KSS), one had a mitochondrial point mutation at the mtDNA ATPase6 gene, and one had a POLG mutation. In conclusion, dopamine deficiency clinical signs were present in some patients with mitochondrial diseases with different genetic backgrounds. High CSF HVA values, together with a severe cerebral folate deficiency, were observed in KSS patients and in other mtDNA mutation syndromes.
Assuntos
Aminas Biogênicas/líquido cefalorraquidiano , Ácido Homovanílico/líquido cefalorraquidiano , Doenças Mitocondriais/líquido cefalorraquidiano , Doenças Mitocondriais/diagnóstico , Pterinas/líquido cefalorraquidiano , Tetra-Hidrofolatos/líquido cefalorraquidiano , DNA Mitocondrial/genética , Humanos , Doenças Mitocondriais/genética , Mutação Puntual , Deleção de Sequência , Tetra-Hidrofolatos/deficiênciaRESUMO
AIM: Gamma-aminobutyric acid (GABA) is a major modulator in brain maturation and its role in many different neurodevelopmental disorders has been widely reported. Although the involvement of GABA in different disorders has been related to its regulatory function as an inhibitory neurotransmitter in the mature brain, co-transmitter, and signalling molecule, little is known about its role as a clinical biomarker in neuropaediatric disorders. The aim of this study is to report the cerebrospinal fluid (CSF) free-GABA concentrations in a large cohort of patients (n=85) with different neurological disorders. METHOD: GABA was measured in the CSF of neuropaediatric patients using capillary electrophoresis with laser-induced fluorescence detection. Other neurotransmitters (amino acids and monoamines) were also analysed. RESULTS: GABA concentrations in CSF were abnormal, with a greater frequency (44%) than monoamines (20%) in neuropaediatric patients compared with our reference values. Although we included a few patients with inborn errors of metabolism, GABA levels in CSF were more frequently abnormal in metabolic disorders than in other nosological groups. INTERPRETATION: Our work suggests further research into brain GABAergic status in neuropaediatric disorders, which could also lead to new therapeutic strategies. WHAT THIS PAPER ADDS: Homeostasis of GABA seems more vulnerable than that of monoamines in the developing brain. The highest GABA levels are found in the primary GABA neurotransmitter disorder SSADH deficiency. GABA alterations are not specific for any clinical or neuroimaging presentation.
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Epilepsia/líquido cefalorraquidiano , Deficiência Intelectual/líquido cefalorraquidiano , Erros Inatos do Metabolismo/líquido cefalorraquidiano , Doenças Mitocondriais/líquido cefalorraquidiano , Transtornos dos Movimentos/líquido cefalorraquidiano , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Ácido gama-Aminobutírico/líquido cefalorraquidiano , Adolescente , Adulto , Biomarcadores/líquido cefalorraquidiano , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Adulto JovemRESUMO
Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid.
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Doença de Leigh/dietoterapia , Doença de Leigh/metabolismo , Proteínas de Membrana Transportadoras/deficiência , Tiamina/metabolismo , Tiamina/uso terapêutico , Adolescente , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Humanos , Lactente , Recém-Nascido , Doença de Leigh/sangue , Doença de Leigh/líquido cefalorraquidiano , Doença de Leigh/genética , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Mutação , Complexo Piruvato Desidrogenase/metabolismo , Tiamina/sangue , Tiamina/líquido cefalorraquidiano , Tiamina Pirofosfato/metabolismoRESUMO
Celiac disease (CeD) is an autoimmune condition triggered by gluten in genetically predisposed individuals, affecting all ages. Intestinal permeability (IP) is crucial in the pathogenesis of CeD and it is primarily governed by tight junctions (TJs) that uphold the intestinal barrier's integrity. The protein zonulin plays a critical role in modulating the permeability of TJs having emerged as a potential non-invasive biomarker to study IP. The importance of this study lies in providing evidence for the usefulness of a non-invasive tool in the study of IP both at baseline and in the follow-up of paediatric patients with CeD. In this single-centre prospective observational study, we explored the correlation between faecal zonulin levels and others faecal and serum biomarkers for monitoring IP in CeD within the paediatric population. We also aimed to establish reference values for faecal zonulin in the paediatric population. We found that faecal zonulin and calprotectin values are higher at the onset of CeD compared with the control population. Specifically, the zonulin levels were 347.5 ng/mL as opposed to 177.7 ng/mL in the control population (p = 0.001), while calprotectin levels were 29.8 µg/g stool compared to 13.9 µg/g stool (p = 0.029). As the duration without gluten consumption increased, a significant reduction in faecal zonulin levels was observed in patients with CeD (348.5 ng/mL vs. 157.1 ng/mL; p = 0.002), along with a decrease in the prevalence of patients with vitamin D insufficiency (88.9% vs. 77.8%). We conclude that faecal zonulin concentrations were higher in the patients with active CeD compared with healthy individuals or those following a gluten-free diet (GFD). The significant decrease in their values over the duration of the GFD suggests the potential use of zonulin as an additional tool in monitoring adherence to a GFD.
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Doença Celíaca , Haptoglobinas , Precursores de Proteínas , Humanos , Criança , Dieta Livre de Glúten , Glutens , Biomarcadores , Complexo Antígeno L1 LeucocitárioRESUMO
AIM: To determine the prevalence of dopaminergic abnormalities in 1388 children with neurological disorders, and to analyse their clinical, neuroradiological, and electrophysiological characteristics. METHOD: We studied biogenic amines in 1388 cerebrospinal fluid (CSF) samples from children with neurological disorders (mean age 3y 10mo, SD 4y 5mo; 712 males, 676 females. Correlations among CSF homovanillic acid (HVA) values and other biochemical, clinical, neuroradiological, and electrophysiological parameters were analysed. RESULTS: Twenty-one patients with primary dopaminergic deficiencies were identified. Of the whole sample, 20% showed altered HVA. We report neurological diseases with abnormal CSF HVA values such as pontocerebellar hypoplasia, perinatal asphyxia, central nervous system infections, mitochondrial disorders, and other genetic diseases. Overlapping HVA levels between primary and secondary dopamine deficiencies were observed. Prevalence of low CSF HVA levels was significantly higher in neonatal patients (χ(2) =84.8, p<0.001). Abnormalities in white matter were associated with low CSF HVA (odds ratio 2.3, 95% confidence interval 1.5-3.5). INTERPRETATION: HVA abnormalities are observed in various neurological diseases, but some are probably an unspecific finding. No clear limits for CSF HVA values pointing towards primary diseases can be stated. We report several neurological diseases showing HVA alterations. No neuroimaging traits were associated with low HVA values, except for white matter abnormalities.
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Ácido Homovanílico/líquido cefalorraquidiano , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Adolescente , Algoritmos , Asfixia Neonatal/líquido cefalorraquidiano , Encéfalo/patologia , Infecções do Sistema Nervoso Central/líquido cefalorraquidiano , Criança , Pré-Escolar , Dopamina/líquido cefalorraquidiano , Dopamina/deficiência , Feminino , Humanos , Lactente , Recém-Nascido , Internacionalidade , Imageamento por Ressonância Magnética , Masculino , Doenças Mitocondriais/líquido cefalorraquidiano , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/fisiopatologia , Atrofias Olivopontocerebelares/líquido cefalorraquidiano , Radiografia , Estudos de AmostragemRESUMO
The gluten-free diet (GFD) remains a complex paradigm in managing celiac disease (CeD) in children and adults, and there are many reasons why GFD adherence should be strict to improve outcomes. However, this is a challenging task for patients, since they need to have access to quality healthcare resources that facilitate optimal GFD adherence. Understanding the strengths and weaknesses of the GFD, tackling coexisting nutritional deficiencies, and dealing with complex situations, such as seronegative CeD or non-responsive CeD, all require the involvement of a multidisciplinary team. The short- and long-term follow-up of CeD patients should preferably be performed by a combined Gastroenterology and Nutrition service with well-defined quality standards and the multidisciplinary involvement of physicians, nurses, dietitians, and psychologists. Nutritional advice and counseling by an experienced dietitian can reduce the costs associated with long-term follow-up of CeD patients. Likewise, psychological interventions may be essential in specific scenarios where implementing and sustaining a lifelong GFD can cause a significant psychological burden for patients. This manuscript aims to provide guidelines to improve clinical practice in the follow-up and monitoring of CeD patients and provide information on the nutritional risks of an ill-advised GFD. Clinicians, biochemists, food technologists, dietitians, and psychologists with a global view of the disease have been involved in its writing.
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Doença Celíaca , Adulto , Criança , Humanos , Dieta Livre de Glúten , Cooperação do Paciente , Alimentos , Estado NutricionalRESUMO
The elevation of neopterin in cerebrospinal fluid (CSF) has been reported in several neuroinflammatory disorders. However, it is not expected that neopterin alone can discriminate among different neuroinflammatory etiologies. We conducted an observational retrospective and case-control study to analyze the CSF biomarkers neopterin, total proteins, and leukocytes in a large cohort of pediatric patients with neuroinflammatory disorders. CSF samples from 277 subjects were included and classified into four groups: Viral meningoencephalitis, bacterial meningitis, acquired immune-mediated disorders, and patients with no-immune diseases (control group). CSF neopterin was analyzed with high-performance liquid chromatography. Microbiological diagnosis included bacterial CSF cultures and several specific real-time polymerase chain reactions. Molecular testing for multiple respiratory pathogens was also included. Antibodies against neuronal and glial proteins were tested. Canonical discriminant analysis of the three biomarkers was conducted to establish the best discriminant functions for the classification of the different clinical groups. Model validation was done by biomarker analyses in a new cohort of 95 pediatric patients. CSF neopterin displayed the highest values in the viral and bacterial infection groups. By applying canonical discriminant analysis, it was possible to classify the patients into the different groups. Validation analyses displayed good results for neuropediatric patients with no-immune diseases and for viral meningitis patients, followed by the other groups. This study provides initial evidence of a more efficient approach to promote the timely classification of patients with viral and bacterial infections and acquired autoimmune disorders. Through canonical equations, we have validated a new tool that aids in the early and differential diagnosis of these neuroinflammatory conditions.
Assuntos
Síndrome da Imunodeficiência Adquirida/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Meningites Bacterianas/líquido cefalorraquidiano , Meningoencefalite/virologia , Neopterina/líquido cefalorraquidiano , Viroses/líquido cefalorraquidiano , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Meningoencefalite/líquido cefalorraquidiano , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Enterovirus-A71 causes outbreaks of brainstem encephalitis, ranging from self-limited disease to acute flaccid paralysis. The aim of this study was to assess the role of cerebrospinal fluid (CSF) neopterin as a biomarker of disease severity in children with enterovirus-related brainstem encephalitis. METHODS: A descriptive, prospective cohort study was conducted from April 2016 to March 2017 in a tertiary hospital. Pediatric patients with a diagnosis of brainstem encephalitis with or without myelitis due to enterovirus infection were enrolled. The final study group comprised a convenience sample including all patients with sufficient CSF volume for neopterin determination. The major variables considered in estimating the severity were the diagnosis of encephalomyelitis, the presence of lesions and extensive lesions on brain and spinal magnetic resonance imaging (MRI), hospital stay length greater than seven days, and sequelae at day 30. RESULTS: Of 60 patients, CSF neopterin could be measured in 36. Median age was 26 months (interquartile range: 19 to 32). Thirty-three were diagnosed with brainstem encephalitis and three with encephalomyelitis. Enterovirus-A71 was the only identified genotype (25 of 25). CSF neopterin levels were elevated (>61 nmol/L) in 33 of 36 (92%), with a median of 347 nmol/L (interquartile range: 204 to 525). CSF neopterin was useful to distinguish patients with lesions on MRI (area under the receiver operating characteristic curve = 0.76; P = 0.02) and extensive lesions (area under the receiver operating characteristic curve = 0.76; P = 0.04). CONCLUSIONS: This study suggests an association between CSF neopterin levels and the presence of inflammatory lesions on MRI.
Assuntos
Tronco Encefálico , Encefalite Viral/líquido cefalorraquidiano , Encefalomielite/líquido cefalorraquidiano , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/líquido cefalorraquidiano , Neopterina/líquido cefalorraquidiano , Tronco Encefálico/patologia , Tronco Encefálico/fisiopatologia , Tronco Encefálico/virologia , Pré-Escolar , Encefalite Viral/patologia , Encefalite Viral/fisiopatologia , Encefalite Viral/virologia , Encefalomielite/patologia , Encefalomielite/fisiopatologia , Encefalomielite/virologia , Infecções por Enterovirus/patologia , Infecções por Enterovirus/fisiopatologia , Infecções por Enterovirus/virologia , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Cerebrospinal fluid (CSF) metabolomic investigations are a powerful tool for studying neurometabolic diseases. We aimed to assess the effect of CSF contamination with blood on the concentrations of selected biomarkers. METHODS: CSF samples were spiked in duplicate with increasing volumes of whole blood under two conditions: (A) pooled CSF spiked with fresh whole blood and frozen to cause red blood cell (RBC) lysis; (B) pooled CSF spiked with fresh blood and centrifuged (the supernatant with no RBCs was frozen until the moment of analysis). CSF concentrations of amino acids, biogenic amines, pterins, and vitamins were analysed by HPLC coupled with tandem mass spectrometry, electrochemical and fluorescence detection. RESULTS: Aspartate, glutamate, taurine, ornithine, glycine, citrulline, pyridoxal 5´-phosphate, 5-methyltetrahydrofolate, and thiamine showed higher values when RBCs were lysed when compared with those of CSF with no RBC, while arginine, 5-hydroxyindoleacetic and homovanillic acids showed lower values. When RBCs were removed from CSF, only some amino acids, thiamine and pyridoxal 5´-phosphate showed moderately higher values when compared with the non-spiked CSF sample. CONCLUSIONS: CSF-targeted metabolomic analysis is feasible even when substantial RBC contamination of CSF has occurred since CSF centrifugation to remove RBC prior to freezing eliminated most of the interferences observed.
Assuntos
Aminas Biogênicas/análise , Análise Química do Sangue , Líquido Cefalorraquidiano , Pterinas/análise , Vitaminas/análise , HumanosRESUMO
The presence of monoamines and their cofactors (the pterins and vitamin B6 (pyridoxal phosphate (PLP))) in human cerebrospinal fluid (CSF) can be used as indicators of the biosynthesis and turnover of dopamine and serotonin in the brain. In addition, abnormalities in the CSF levels of these molecules are associated with various neurological diseases, including genetic diseases leading to dopamine and serotonin deficiency. Here, we provide a set of quantitative high-performance liquid-chromatography (HPLC) approaches to determine CSF levels of monoamines and their cofactors. This protocol describes step-by-step procedures for CSF sample preparation for the analysis of different molecules, HPLC calibration and analysis, and data quantification and interpretation. Unlike plasma/tissue/blood samples, CSF requires minimal sample preparation: in this protocol, only the analysis of PLP requires mixing with trichloroacetic acid to release the protein-bound vitamin, centrifugation, and mixing of the supernatant with phosphate buffer and sodium cyanide for derivatization in alkaline conditions. Monoamines are analyzed by HPLC with coulometric electrochemical detection (ED), pterins are analyzed by HPLC with coupled coulometric electrochemical and fluorescence detection, and PLP is analyzed by HPLC with fluorescence detection. The quantification of all compounds is achieved by external calibration procedures, and internal quality control and standards are analyzed in each run. We anticipate that investigation of dopamine and serotonin disturbances will be facilitated by measurements of these compounds in human CSF and other biological samples. The estimated time for the different procedures primarily depends on the electrochemical detector stabilization. Overnight stabilization of this detector is advised, and, after that step, preanalytical equilibration rarely exceeds 3 h.
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Monoaminas Biogênicas/líquido cefalorraquidiano , Cromatografia Líquida de Alta Pressão/métodos , Pterinas/líquido cefalorraquidiano , Vitamina B 6/líquido cefalorraquidiano , Calibragem , Humanos , Controle de QualidadeRESUMO
Melatonin is synthesized from serotonin and it is excreted as sulphatoxymelatonin in urine. We aim to evaluate urinary sulphatoxymelatonin as a biomarker of brain serotonin status in a cohort of patients with mutations in genes related to serotonin biosynthesis. We analized urinary sulphatoxymelatonin from 65 healthy subjects and from 28 patients with genetic defects. A total of 18 patients were studied: 14 with autosomal dominant and recessive guanosine triphosphate cyclohydrolase-I deficiency; 3 with sepiapterin reductase deficiency; and 1 with aromatic L-amino acid decarboxylase deficiency. Further 11 patients were studied after receiving serotoninergic treatment (serotonin precursors, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitors): 5 with aromatic L-amino acid decarboxylase deficiency; 1 with sepiapterin reductase deficiency; 3 with dihydropteridine reductase deficiency; and 2 with 6-pyruvoyltetrahydropterin synthase deficiency. Among the patients without therapy, 6 presented low urinary sulphatoxymelatonin values, while most of the patients with guanosine triphosphate cyclohydrolase-I deficiency showed normal values. 5 of 11 patients under treatment presented low urine sulphatoxymelatonin values. Thus, decreased excretion of sulphatoxymelatonin is frequently observed in cases with severe genetic disorders affecting serotonin biosynthesis. In conclusion, sulphatoxymelatonin can be a good biomarker to estimate serotonin status in the brain, especially for treatment monitoring purposes.
Assuntos
Aminas Biogênicas/metabolismo , Melatonina/análogos & derivados , Serotonina/metabolismo , Adolescente , Adulto , Biomarcadores/urina , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Melatonina/metabolismo , Melatonina/urina , Redes e Vias Metabólicas , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/urina , Pessoa de Meia-Idade , Valores de Referência , Adulto JovemRESUMO
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.
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Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Descarboxilases de Aminoácido-L-Aromático/deficiência , Idade de Início , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Erros Inatos do Metabolismo dos Aminoácidos/líquido cefalorraquidiano , Descarboxilases de Aminoácido-L-Aromático/sangue , Descarboxilases de Aminoácido-L-Aromático/líquido cefalorraquidiano , Antagonistas Colinérgicos/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Guias como Assunto , Humanos , Inibidores da Monoaminoxidase/uso terapêutico , Prolactina/sangue , Prolactina/líquido cefalorraquidiano , Fosfato de Piridoxal/uso terapêuticoRESUMO
Pyridoxal phosphate (PLP) is the active form of vitamin B6 and a cofactor in many enzyme reactions including neurotransmitter metabolism. PLP metabolism disturbances may mostly lead to refractory seizures. In this report, we review the main pathophysiological factors related with PLP deficiency and our experience in PLP treatment in pediatric patients with low-normal cerebrospinal fluid PLP values who presented epilepsy. Only one case had a definite diagnosis (Phelan-McDermid syndrome). The results of extensive metabolic workups and targeted genetic studies were normal for all patients. In 5 cases, the response to PLP supplementation (10-30mg/kg/d) was initially positive. PLP adverse reactions were noticed in 4 patients and PLP was discontinued; however, one of the most noticeable symptoms was an asymptomatic increase in liver enzymes. These negative results with PLP supplementation are worth reporting, to improve the information we use to treat our patients.
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Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Fosfato de Piridoxal/deficiência , Fosfato de Piridoxal/farmacologia , Complexo Vitamínico B/farmacologia , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Fosfato de Piridoxal/administração & dosagem , Fosfato de Piridoxal/efeitos adversos , Resultado do Tratamento , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/efeitos adversosRESUMO
In this article, we review the state-of-the-art analysis of different biomarkers in the cerebrospinal fluid for the diagnosis of genetically conditioned, rare, neurometabolic diseases, including glucose transport defects, neurotransmitter (dopamine, serotonin, and gamma-aminobutyric acid) and pterin deficiencies, and vitamin defects (folate, vitamin B6, and thiamine) that affect the brain. The analysis of several key metabolites are detailed, which thus highlights the preanalytical and analytical factors that should be cautiously controlled to avoid misdiagnosis; moreover, these factors may facilitate an adequate interpretation of the biochemical profiles in the context of severe neuropediatric disorders. Secondary disturbances in these biomarkers, which are associated with other genetic or environmental conditions, are also detailed. Importantly, the early biochemical identification of biochemical disturbances in the cerebrospinal fluid may improve the clinical outcomes of a remarkable number of patients, who may exhibit good neurologic outcomes using the available therapies for these disorders.
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Biomarcadores/líquido cefalorraquidiano , Encefalopatias Metabólicas Congênitas/líquido cefalorraquidiano , HumanosRESUMO
INTRODUCTION: Thiamine is a key cofactor for energy metabolism in brain tissue. There are four major genetic defects (SLC19A2, SLC19A3, SLC25A19 and TPK1) involved in the metabolism and transport of thiamine through cellular and mitochondrial membranes. Neurological involvement predominates in three of them (SLC19A3, SCL25A19 and TPK1), whereas patients with SLC19A2 mutations mainly present extra-neurological features (e.g. diabetes mellitus, megaloblastic anaemia and sensori-neural hearing loss). These genetic defects may be amenable to therapeutic intervention with vitamins supplementation and hence, constitutes a main area of research. AREAS COVERED: We conducted a literature review of all reported cases with these genetic defects, and focused our paper on treatment efficacy and safety, adverse effects, dosing and treatment monitoring. Expert commentary: Doses of thiamine vary according to the genetic defect: for SLC19A2, the usual dose is 25-200 mg/day (1-4 mg/kg per day), for SLC19A3, 10-40 mg/kg per day, and for TPK1, 30 mg/kg per day. Thiamine supplementation in SLC19A3-mutated patients restores CSF and intracellular thiamine levels, resulting in successful clinical benefits. In conclusion, evidence collected so far suggests that the administration of thiamine improves outcome in SLC19A-2, SLC19A3- and TPK1-mutated patients, so most efforts should be aimed at early diagnosis of these disorders.
Assuntos
Anemia Megaloblástica , Proteínas de Membrana Transportadoras , Encéfalo/metabolismo , Humanos , Mutação , Tiamina/genética , Tiamina/uso terapêuticoRESUMO
Cerebral folate deficiency is defined as any neurological condition associated with low cerebrospinal fluid folate concentrations. It is becoming increasingly associated with several neurological diseases, either genetic or environmental. Treatment of cerebral folate deficiency by folate supplementation is generally effective, improving the neurological outcome of some patients. However, to treat cerebral folate deficiency, the proper choice of one of the available folate forms is essential. The distinct brain folate metabolism features compared with peripheral folate metabolic pathways strongly suggest the investigation of different folate forms, such as the biologically active folinic acid and 5-methyltetrahydrofolate, since they are efficiently transported to the brain. Regarding the oral doses of the different folate forms, despite the fact that there are some recommendations, there is no general consensus. Further investigation and designing clinical trials are advisable to elucidate these aspects.
Assuntos
Doenças Cerebelares/etiologia , Doenças Cerebelares/terapia , Ácido Fólico/metabolismo , Deficiência de Vitaminas do Complexo B/complicações , Humanos , Deficiência de Vitaminas do Complexo B/metabolismoRESUMO
OBJECTIVE: The mechanisms of the ketogenic diet remain unclear, but several predictors of response have been proposed. We aimed is to study the relationship between the etiology of epilepsy, cerebrospinal fluid neurotransmitters, pterins, and amino acids, and response to a ketogenic diet. METHODS: We studied 60 patients who began classic ketogenic diet treatment for refractory epilepsy. In 24 of 60 individuals, we analyzed cerebrospinal fluid neurotransmitters, pterins, and amino acids in baseline conditions. Mean age at epilepsy onset was 24 months, 83.3% were focal epilepsies, and in 51.7% the etiology of the epilepsy was unknown. RESULTS: Six months after initiating the ketogenic diet, it was effective (greater than a 50% reduction in seizure frequency) in 31.6% of patients. We did not find a link between rate of efficacy for the ketogenic diet and etiologies of epilepsy, nor did we find a link between the rate of efficacy for the ketogenic diet and cerebrospinal fluid pterins and biogenic amines concentrations. However, we found statistically significant differences for lysine and arginine values in the cerebrospinal fluid between ketogenic diet responders and nonresponders, but not for the other amino acids analyzed. SIGNIFICANCE: The values of some amino acids were significantly different in relationship with the ketogenic diet efficacy; however, the epilepsy etiology and the cerebrospinal fluid biogenic amine and pterin values were not.