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[ 0 => array:2 [ "paginaInicial" => "170" "paginaFinal" => "176" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Cezar Antonio Abreu de Souza, Michelle Rosa Andrade Alves, Rosangelis del Lama Soares, Viviane de Cássia Kanufre, Valéria de Melo Rodrigues, Rocksane de Carvalho Norton, Ana Lúcia Pimenta Starling, Marcos José Burle de Aguiar" "autores" => array:8 [ 0 => array:4 [ "nombre" => "Cezar Antonio Abreu de" "apellidos" => "Souza" "email" => array:1 [ 0 => "cezarabreu35@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Michelle Rosa Andrade" "apellidos" => "Alves" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Rosangelis del Lama" 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"<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 6 => array:3 [ "nombre" => "Ana Lúcia Pimenta" "apellidos" => "Starling" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 7 => array:3 [ "nombre" => "Marcos José Burle de" "apellidos" => "Aguiar" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Universidade Federal de Minas Gerais (UFMG), Hospital das Clínicas, Belo Horizonte, MG, Brazil" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), Belo Horizonte, MG, Brazil" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Universidade Federal de Minas Gerais (UFMG), Department of Pediatrics, Belo Horizonte, MG, Brazil" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Deficiências de BH<span class="elsevierStyleInf">4</span> identificadas em um programa de triagem neonatal para hiperfenilalaninemias" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Hyperphenylalaninemias are manifestations of the genetic defects most frequently involved in amino acid metabolism.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> To date, five defects are known to lead to hyperphenylalaninemia states: defect in the phenylalanine hydroxylase enzyme, causing phenylketonuria, and in four different enzymes involved in the synthesis or regeneration of tetrahydrobiopterin (BH<span class="elsevierStyleInf">4</span>), which is an important cofactor of the enzymes involved in the synthesis of tyrosine, dopamine, serotonin, nitric oxide, and glycerol.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The four BH<span class="elsevierStyleInf">4</span> deficiencies that occur with hyperphenylalaninemia are deficiency of GTP cyclohydrolase I – autosomal recessive form (GTPCH I), 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, dihydropteridine reductase (DHPR) deficiency, and pterin-4α-carbinolamine dehydratase (PCD) deficiency. They account for approximately 2% of cases of hyperphenylalaninemia, with a worldwide prevalence of 1 per 1,000,000 live births.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">As BH<span class="elsevierStyleInf">4</span> is involved in the synthesis of neurotransmitters such as dopamine and serotonin, deficiencies of this cofactor can lead not only to hyperphenylalaninemia states but also neurological symptoms and signs, resulting from the deficiency of these neurotransmitters.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Since these deficiencies occur with hyperphenylalaninemia, their identification is possible through the neonatal screening programs for phenylketonuria, allowing the diagnosis to be made in the first weeks of life<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5,6</span></a> and prompt treatment to be initiated. The current routine of investigating BH<span class="elsevierStyleInf">4</span> deficiencies in every newborn with hyperphenylalaninemia by analyzing pterins and DHPR enzyme activity in blood samples on filter paper, then starting early treatment, has resulted in better intellectual levels in affected patients than were obtained previously to this routine.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The treatment of BH<span class="elsevierStyleInf">4</span> deficiencies should be individualized due to the great inter-individual allelic and non-allelic heterogeneity, a characteristic of the disease.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In Brazil, neonatal screening for hyperphenylalaninemias started in the 1980s. In 2001, the National Neonatal Screening Program was created and since then, neonatal screening for hyperphenylalaninemias has been expanded and now includes the entire country.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> However, most of the states do not systematically screen for BH<span class="elsevierStyleInf">4</span> deficiencies, which leads to delayed diagnosis and treatment onset.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In the state of Minas Gerais, the Neonatal Screening Program (NSPMG) is coordinated by the Action and Research Center in Diagnostic Support (Núcleo de Ações e Pesquisa em Apoio Diagnóstico [NUPAD]) and includes the 853 municipalities. Since its implementation, it has already screened more than 4,300,000 newborns. It aims at the early diagnosis and treatment of sickle cell anemia, cystic fibrosis, congenital hypothyroidism, biotinidase deficiency, and phenylketonuria. Since 2006, it has systematically carried out the screening for BH<span class="elsevierStyleInf">4</span> deficiency. It is, to the best of the authors’ knowledge, the location with the largest number of patients in longitudinal follow-up with these deficiencies in Brazil.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Due to their rarity, BH<span class="elsevierStyleInf">4</span> deficiencies are still poorly understood and there are few studies involving patients with this diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">7,9–11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Some signs and symptoms have been described, but the phenotype as a whole is still little known, as well as its clinical evolution. As in Brazil most of the neonatal screening programs for phenylketonuria do not screen for BH<span class="elsevierStyleInf">4</span> deficiencies, the knowledge of the clinical symptoms and the evolution of these patients may contribute to earlier diagnostic suspicion and to anticipate diagnostic and therapeutic measures, improving quality of life. For close relatives, genetic counseling is of great importance in family planning.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The present study aimed to identify the types, general prevalence, and frequency of these deficiencies in newborns with hyperphenylalaninemias screened by NSPMG from its implementation in 1993 until December 2012. Its proposal was to describe the several clinical characteristics of the disease, allowing a better understanding.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0055" class="elsevierStylePara elsevierViewall">A cross-sectional and retrospective study was carried out, after its approval by the Ethics Committee of Universidade Federal de Minas Gerais (UFMG) (CAAE – 04096512.0.0000.5149), which identified all patients screened by the NSPMG, diagnosed with one of the forms of BH<span class="elsevierStyleInf">4</span> deficiency that develops with hyperphenylalaninemia. These diagnoses were performed by the Biochemistry Laboratories of the University Children's Hospital Zürich, in Switzerland, and the Faculté Libre de Medicina, in France, based on the analysis of pterins and the DHPR activity in blood and/or urine sample collected on the day of the first consultation of patients in the Phenylketonuria Outpatient Clinic of Hospital das Clínicas of UFMG and deposited on filter paper that, after dried, was sent by mail.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The calculation of the general prevalence of BH<span class="elsevierStyleInf">4</span> deficiencies was obtained from the ratio between the number of diagnosed cases, since the implantation of the Screening Program until December 2012, and the number of newborns screened in the same period. When calculating the frequency of BH<span class="elsevierStyleInf">4</span> deficiencies among the hyperphenylalaninemias, the denominator used was the number of cases of hyperphenylalaninemias identified in the same period.</p><p id="par0065" class="elsevierStylePara elsevierViewall">After identifying the patients with the deficiencies, their clinical and laboratory characteristics up to December 2012 were recorded, such as delayed neuropsychomotor development, hypotonia, myoclonus, spasticity, seizures, hyperreflexia, hypersalivation, serous coryza, fine tremor, irritability, and serum phenylalanine levels. The time elapsed between treatment onset and symptom improvement or disappearance was an important factor in the comparison between the patients who had been diagnosed by clinical suspicion and those diagnosed by the systematic investigation of BH<span class="elsevierStyleInf">4</span> deficiencies.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Data collection</span><p id="par0070" class="elsevierStylePara elsevierViewall">The databases of the Action and Research Center in Diagnostic Support of Faculdade de Medicina da Universidade Federal de Minas Gerais (NUPAD/FM/UFMG), a referral service of the Screening Program in the State of Minas Gerais, and of the Phenylketonuria Outpatient Clinic of the Special Genetics Service of Hospital das Clínicas of UFMG, were accessed, where data from all patients screened and those who are followed are stored. Patients’ charts were also consulted. The parents of patients with BH<span class="elsevierStyleInf">4</span> deficiency signed the informed consent authorizing study participation.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Inclusion criteria</span><p id="par0075" class="elsevierStylePara elsevierViewall">All patients with hyperphenylalaninemia due to BH<span class="elsevierStyleInf">4</span> deficiency, confirmed by pterin analysis and DHPR activity, were included in the study.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0080" class="elsevierStylePara elsevierViewall">From September 1993 to December 2012, 4,684,515 newborns were screened in Minas Gerais, Brazil. Of these, 586 were identified with hyperphenylalaninemia, of whom 10 were due to BH<span class="elsevierStyleInf">4</span> deficiency, eight of whom were males (80%).</p><p id="par0085" class="elsevierStylePara elsevierViewall">The prevalence found was 2.1 for every 1,000,000 live births and the frequency was 1.71% among the hyperphenylalaninemia cases.</p><p id="par0090" class="elsevierStylePara elsevierViewall">All patients were followed through regular consultations, whose frequency varied from two to six months.</p><p id="par0095" class="elsevierStylePara elsevierViewall">The distribution, by type of deficiency, is shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Three patients died before 6 years of age: two with PTPS deficiency (at 5 and at 10 months of age) and one with GTPCH I deficiency (at 5 years of age). These were deaths without known cause and occurred in their homes.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The first six patients, all before 2006, were initially diagnosed as phenylketonuria cases, but did not adequately respond to dietary treatment, and started to show clinical signs suggestive of BH<span class="elsevierStyleInf">4</span> deficiencies. After 2006, when the systematic screening for BH<span class="elsevierStyleInf">4</span> deficiencies was established, four more patients were identified.</p><p id="par0110" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes the signs and symptoms of each patient, according to the type of deficiency. These clinical characteristics emerged before treatment started and none after treatment was implemented.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3 and 4</a> show (for patients with a diagnosis based on clinical suspicion and for patients diagnosed by neonatal screening, respectively) the ages of the first symptoms, at the diagnosis and treatment onset, and at the beginning of clinical improvement.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">The frequency of BH<span class="elsevierStyleInf">4</span> deficiencies varies greatly worldwide. More than half of patients are Caucasians (52.9%); 37.2% are Turks; 12% are Arabs; 10.4% are Chinese; 2.1% are Indians; 2.7% are Japanese.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> However, it is a very rare disease, corresponding in most countries to 2% of screened hyperphenylalaninemias.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The phenotype description of the several types of BH<span class="elsevierStyleInf">4</span> deficiency is important, since it is a rare disease with a prevalence of 1:10<span class="elsevierStyleSup">6</span> and with few descriptions of patients, especially during long observation periods.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">7,9–11</span></a> In Brazil, this is even more important, since pterin analyses are not yet performed in the country and the diagnosis depends on sending the biological material abroad. This fact makes several states that carry out the neonatal screening for phenylketonuria depend on clinical evaluation for diagnosis and treatment.</p><p id="par0130" class="elsevierStylePara elsevierViewall">In a literature review, only two case reports described in Brazil were found, both in the state of Rio Grande do Sul, by the same team. In 1983, Giugliani et al. described two patients with hyperphenylalaninemia who did not progress well with the dietary treatment for phenylketonuria. After the pterin analysis, the diagnosis of BH<span class="elsevierStyleInf">4</span> deficiency was confirmed.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">12</span></a> In 1994, Jardim et al. described five cases of PTPS deficiency in patients with a diagnostic suspicion of inborn errors of metabolism.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The present study was carried out at the Phenylketonuria Outpatient Clinic of the Special Genetics Service of Hospital das Clínicas of Universidade Federal de Minas Gerais, where all patients with hyperphenylalaninemia in the state of Minas Gerais are followed.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Until 2006, the identification of BH<span class="elsevierStyleInf">4</span> deficiencies was performed based on clinical suspicion in patients who did not have a satisfactory response to dietary treatment for phenylketonuria, despite adhering to it. From that year on, screening for BH<span class="elsevierStyleInf">4</span> deficiencies started to be systematically performed, with pterin measurement and assessment of DHPR enzyme activity in all patients screened with hyperphenylalaninemia, in the first consultation at the service. It is possible that some were lost because they had phenylalanine levels below the cutoff value used (240<span class="elsevierStyleHsp" style=""></span>μmol/L or 4<span class="elsevierStyleHsp" style=""></span>mg/dL). However, as patients with transient hyperphenylalaninemia are followed for six months and those with permanent hyperphenylalaninemia up to six years, with girls returning at puberty,<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> the losses are likely to be minimal.</p><p id="par0145" class="elsevierStylePara elsevierViewall">After 2006, with the systematic screening for BH<span class="elsevierStyleInf">4</span> deficiencies in all patients with hyperphenylalaninemia, the losses, if any, should have been even lower. Possible biases, especially regarding research, may have occurred due to the small number of cases found. Nonetheless, considering the total number of screened patients and the lack of sample selection, it is possible that the results are representative of the population.</p><p id="par0150" class="elsevierStylePara elsevierViewall">The prevalence found was slightly higher than that described; however, the percentage of patients among the cases of hyperphenylalaninemia was similar to that described in the literature.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1,15,16</span></a> In 1994, Jardim et al.,<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> in the state of Rio Grande do Sul, Brazil, studying patients with suspected inborn errors of metabolism, found a very high prevalence of PTPS deficiency. This is explained by the fact that it is a study of selected patients with suspected diagnosis of related diseases. Although the present study population was large (4,684,515 screened patients) and the prevalence (2.1:10<span class="elsevierStyleSup">6</span>) higher than that described, the number of cases was relatively small. Nevertheless, to the best of the authors’ knowledge, it represents the largest number of cases with longitudinal follow-up in Brazil.</p><p id="par0155" class="elsevierStylePara elsevierViewall">Similar to what was described in the literature,<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> PTPS deficiency was the most common in the present study, although with a lower percentage (40%) than described (approximately 60%).<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> After that, the most frequently identified deficiencies were DHPR (30%) and GTPCH I (30%). Although the first deficiency showed a frequency similar to the one described,<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">3,17</span></a> the second showed a much lower percentage (4–5%) in the literature.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">3,17</span></a> No cases of PCD deficiency were identified, which the literature reports as rare (3–4% of cases).<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">3,17</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Symptom onset in all patients with BH<span class="elsevierStyleInf">4</span> deficiency occurred between two and four months, as described in the literature.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1,3,17–19</span></a> No difference was observed regarding the age at symptom onset of the different types.</p><p id="par0165" class="elsevierStylePara elsevierViewall">In eight patients, phenylalanine levels at the screening were compatible with the diagnoses of mild or classical phenylketonuria. Patient # 7 had a phenylalanine level compatible with the probable diagnoses of transient or permanent hyperphenylalaninemia. Patient #10, however, had a phenylalanine level below the cutoff value and would not have been diagnosed if her twin (patient # 9) had not been, too. These facts warn that BH<span class="elsevierStyleInf">4</span> deficiencies may show low phenylalanine levels at the neonatal screening and reinforce the need for its investigation in all patients, even those with slightly increased phenylalanine levels.<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">20,21</span></a> They also alert to the possibility of false negative results, even when the screening is used for diagnosis.</p><p id="par0170" class="elsevierStylePara elsevierViewall">All signs and symptoms appeared before treatment was implemented. All patients showed developmental delay and muscle hypotonia, as described in the literature.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> The third most frequent sign was serous coryza (70% of patients), followed by fine tremor, hyperreflexia, and spasticity, present in 50% of the patients. Irritability, myoclonus, seizures, and hypersalivation were present in 30% of the patients. These data, all described in the literature,<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">19,23–28</span></a> warn that the combination of signs and symptoms may be variable, and that neurological assessment helps in the diagnostic suspicion.</p><p id="par0175" class="elsevierStylePara elsevierViewall">Death occurred in 30% of patients, a higher rate than described (approximately 13%),<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> demonstrating the disease severity.<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">18,29</span></a> Of these patients, two had PTPS deficiency and one had GTPCH I deficiency. One patient died before it was possible to start the therapy. The exact cause of death is unknown. In the literature, cases of death due to BH<span class="elsevierStyleInf">4</span> deficiency are attributed to sudden death, with no precise specification of the cause.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">All patients who died were diagnosed before the systematic study of the pterins and DHPR activity.</p><p id="par0185" class="elsevierStylePara elsevierViewall">Patients who were diagnosed after clinical suspicion had confirmation and started treatment later, between 5 and 11 months. Despite this, treatment showed good results, especially in relation to the dystonic pictures, even in a patient with PTPS deficiency (#4), whose diagnosis was made eight years after symptom onset. He had a severe neurological condition, but currently, he can walk, speak with difficulty, and maintain good interaction with the environment, although he is still very dependent regarding activities of daily living.</p><p id="par0190" class="elsevierStylePara elsevierViewall">This patient had a suspected diagnosis since he was five months old; however, his mother did not want to continue the investigation; she had another child, equally affected. She only returned to the clinic eight years later, due to the eldest son's death. This fact alerts to the importance of the family's emotional reaction when an early diagnosis is not attained and the patient does not respond well to the implemented therapy.</p><p id="par0195" class="elsevierStylePara elsevierViewall">Treatment response was somewhat slower in patients whose diagnosis was made after clinical suspicion. These patients, despite a good clinical response, persisted with some degree of developmental delay, demonstrating early brain impairment. It is suspected that neuronal development, early functional synapse maturation, and myelination are altered by BH<span class="elsevierStyleInf">4</span> deficiencies during critical periods of brain development.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Patients whose diagnoses were obtained after the systematic study of pterins and DHPR activity had a shorter time between treatment onset and the start of symptom improvement (approximately one month). They also showed better neuropsychomotor development, and two of them (#7 and #8) had an apparently normal development until the end of this study. Two female twin patients (#9 and #10), despite good motor development, have been showing speech delay. Their mother's pregnancy was complicated by preeclampsia, toxoplasmosis, and preterm labor. Due to maternal toxoplasmosis, the patients were treated for this disease up to one year of age. It is important to consider the overlap of toxoplasmosis with speech difficulty.</p><p id="par0205" class="elsevierStylePara elsevierViewall">The early treatment of BH<span class="elsevierStyleInf">4</span> deficiencies is only possible if the differential diagnosis of the hyperphenylalaninemia types is performed as soon as possible, preferably within the first month of life.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> Although treatment is yet to be started within this period, since the diagnosis is still made outside of the country, the satisfactory evolution of the diagnosed patients justifies this recommendation.</p><p id="par0210" class="elsevierStylePara elsevierViewall">Patients with DHPR deficiency showed the best clinical outcome, although this is described as the most severe form of BH<span class="elsevierStyleInf">4</span> deficiency.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> Early treatment probably contributed to this finding.</p><p id="par0215" class="elsevierStylePara elsevierViewall">No patient showed any adverse drug reactions.</p><p id="par0220" class="elsevierStylePara elsevierViewall">Sapropterin (synthetic BH<span class="elsevierStyleInf">4</span>) was not regularly used due to the difficulty in obtaining the medication in Brazil, since it has not been licensed by the Brazilian National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária [ANVISA]). Only two patients (#2 and #3) with GTPCH I deficiency used it, for a short time. The medication is available in only a few countries and its importation is very expensive. The medication acquisition was only possible through a lawsuit. In the absence of medication, hyperphenylalaninemia was controlled with a specific diet, with good results. Genetic counseling was offered to all parents.</p><p id="par0225" class="elsevierStylePara elsevierViewall">The number of cases identified was larger than expected, but still small for more definitive conclusions. The sample size may explain the disagreements with the percentages described in the literature. This study reinforces the opinion of the European Phenylketonuria Group of March 2011, which states that after neonatal screening for phenylketonuria, every newborn, even those with slightly elevated serum phenylalanine levels, should be screened for BH<span class="elsevierStyleInf">4</span> deficiency.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">This is the group's current recommendation to neonatal screening services, supported by Han et al., who emphasize that early diagnosis and treatment influence the disease prognosis and help maximize the potential for development.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> It also emphasizes the need for these tests to be performed in Brazil, which will allow even earlier diagnosis and genetic counseling.</p><p id="par0235" class="elsevierStylePara elsevierViewall">As these are very rare diseases, many health professionals are unaware of their characteristics and their forms of treatment. It is expected that this study will contribute to a better understanding of the clinical and epidemiological aspects of BH<span class="elsevierStyleInf">4</span> deficiencies in the state of Minas Gerais.</p><p id="par0240" class="elsevierStylePara elsevierViewall">The results were consistent with the scientific literature. Specific mutations have already been described in a small number of cases, but genotype-phenotype associations are still not consistent. This may be an interesting line for future studies in Brazil as well.</p><p id="par0245" class="elsevierStylePara elsevierViewall">The authors expect, in the near future, to be able to conduct the tests that identify BH<span class="elsevierStyleInf">4</span> deficiencies in Brazil, allowing even earlier diagnoses and treatments, with important improvement in the clinical evolution of affected patients.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of interest</span><p id="par0250" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1415655" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1295480" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1415654" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusões" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1295481" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Data collection" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Inclusion criteria" ] ] ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-10-24" "fechaAceptado" => "2017-03-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1295480" "palabras" => array:4 [ 0 => "Phenylketonuria" 1 => "Neonatal screening" 2 => "Intellectual disability" 3 => "Rare diseases" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec1295481" "palabras" => array:4 [ 0 => "Fenilcetonúria" 1 => "Triagem neonatal" 2 => "Deficiência intelectual" 3 => "Doenças raras" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To show the general prevalence and to characterize tetrahydrobiopterin (BH<span class="elsevierStyleInf">4</span>) deficiencies with hyperphenylalaninemia, identified by the Neonatal Screening Program of the State of Minas Gerais.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Descriptive study of patients with BH<span class="elsevierStyleInf">4</span> deficiency identified by the Neonatal Screening Program of the State of Minas Gerais.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The prevalence found was 2.1 for 1,000,000 live births, with a frequency of 1.71% among hyperphenylalaninemias. There were four cases (40%) with 6-pyruvoyl-tetrahydropterin synthase deficiency, three with GTP cyclohydrolase I – autosomal recessive form deficiency, and three with dihydropteridine reductase deficiency (30% each). Six patients were diagnosed due to clinical suspicion and four cases due to systematic screening in neonatal screening. After the start of the treatment, patients identified by neonatal screening had rapid improvement and improved neuropsychomotor development compared to those diagnosed by the medical history.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The prevalence of BH<span class="elsevierStyleInf">4</span> deficiencies in Minas Gerais was slightly higher than that found in the literature, but the frequency among hyperphenylalaninemias was similar. Although rare, they are severe diseases and, if left untreated, lead to developmental delays, abnormal movements, seizures, and premature death. Early treatment onset (starting before 5 months of age) showed good results in preventing intellectual disability, justifying the screening of these deficiencies in newborns with hyperphenylalaninemia identified at the neonatal screening programs for phenylketonuria.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Apresentar a prevalência geral e caracterizar as deficiências de tetrahidrobiopterina - BH<span class="elsevierStyleInf">4</span> - com hiperfenilalaninemia, identificadas pelo Programa de Triagem Neonatal do Estado de Minas Gerais.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudo descritivo de pacientes com deficiência de BH<span class="elsevierStyleInf">4</span> do Programa de Triagem Neonatal do Estado de Minas Gerais.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">A prevalência encontrada foi de 2,1 para 1.000.000 recém-nascidos vivos e a frequência de 1,71%, dentre as hiperfenilalaninemias. Quatro casos (40%) com deficiência de 6-piruvoil-tetrahidropterina sintase, três com deficiência de GTP ciclohidrolase I e três com deficiência de dihidropteridina redutase (30% cada um). Seis pacientes foram diagnosticados por suspeita clínica e quatro pela pesquisa sistemática na triagem neonatal. Após o início do tratamento, os pacientes identificados pela triagem neonatal tiveram melhora rápida e melhor desenvolvimento neuropsicomotor em comparação com aqueles diagnosticados pela história clínica.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusões</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A prevalência das deficiências de BH<span class="elsevierStyleInf">4</span> em Minas Gerais foi um pouco maior que a encontrada na literatura, mas a frequência, entre as hiperfenilalaninemias, foi semelhante. Embora raras, são graves e, se não tratadas, levam a atraso de desenvolvimento, movimentos anormais, convulsões e morte precoce. O tratamento precoce (início antes dos 5 meses) mostrou bons resultados na prevenção de deficiência intelectual, justificando a pesquisa dessas deficiências nos recém-nascidos com hiperfenilalaninemia pelos programas de triagem neonatal para fenilcetonúria.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusões" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Souza CA, Alves MR, Soares RD, Kanufre V, Rodrigues VM, Norton RC, et al. BH<span class="elsevierStyleInf">4</span> deficiency identified in a neonatal screening program for hyperphenylalaninemia. J Pediatr (Rio J). 2018;94:170–176.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Study carried out at Universidade Federal de Minas Gerais (UFMG), Hospital das Clínicas, Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), Belo Horizonte, MG, Brazil.</p>" ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Deficiency \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Number of patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PTPS deficiency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DHPR deficiency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GTPCH I deficiency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PCD deficiency \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Zero \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2429072.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Frequency of BH<span class="elsevierStyleInf">4</span> deficiencies in Minas Gerais.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Patient # \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">GTPCH I deficiency1–4</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="4" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PTPS deficiency5–7</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DHPH deficiency8–10</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">1 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">3 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">4 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">5 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">6 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">7 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">8 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">9 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">10 \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Developmental delay \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypotonia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Myoclonus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Spasticity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Seizures \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hyperreflexia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypersalivation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serous coryza \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fine tremor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Irritability \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Death \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phenylalanine at neonatal screening (μmol/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1461 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">616.30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">743.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">730.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2582 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2359.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">538.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1400 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">626 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">161.2 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2429073.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Signs and symptoms found in patients with BH<span class="elsevierStyleInf">4</span> deficiency in Minas Gerais: (+) present symptoms (−) absent symptoms.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">BH<span class="elsevierStyleInf">4</span> deficiency (patient #) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Symptom onset \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diagnostic confirmation and age at start of the treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Onset of clinical improvement (months after start of the treatment) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GTPCH I#1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 months (died at 5 years of age) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GTPCH I#2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2–3 months \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GTPCH I#3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 months (severe symptoms) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 months \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PTPS#4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 years \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 months \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PTPS#5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Died at 5 months of age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PTPS#6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 months (died at 10 months of age) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2429074.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Age at onset of symptoms/signs, diagnostic confirmation, and clinical improvement onset in patients with BH<span class="elsevierStyleInf">4</span> deficiency, identified based on the clinical suspicion of the disease.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">BH<span class="elsevierStyleInf">4</span> deficiency (patient #) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Symptom onset \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diagnostic confirmation and age at the start of the treatment \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical improvement onset (months after the start of the treatment) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PTPS #7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 month \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DHPR #8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 month \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DHPR #9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 month \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DHPR #10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 month \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2429075.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Age at onset of symptoms/signs, diagnostic confirmation, and clinical improvement onset in patients with BH<span class="elsevierStyleInf">4</span> deficiency, identified at the neonatal screening for the disease.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Disorders of tetrahydrobiopterin and related biogenic amines" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "N. 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Year/Month | Html | Total | |
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2024 November | 5 | 1 | 6 |
2024 October | 30 | 11 | 41 |
2024 September | 39 | 24 | 63 |
2024 August | 58 | 30 | 88 |
2024 July | 52 | 34 | 86 |
2024 June | 20 | 15 | 35 |
2024 May | 20 | 19 | 39 |
2024 April | 27 | 23 | 50 |
2024 March | 22 | 22 | 44 |
2024 February | 23 | 27 | 50 |
2024 January | 21 | 23 | 44 |
2023 December | 15 | 33 | 48 |
2023 November | 23 | 38 | 61 |
2023 October | 23 | 40 | 63 |
2023 September | 27 | 38 | 65 |
2023 August | 16 | 14 | 30 |
2023 July | 21 | 18 | 39 |
2023 June | 16 | 8 | 24 |
2023 May | 25 | 17 | 42 |
2023 April | 16 | 10 | 26 |
2023 March | 30 | 19 | 49 |
2023 February | 25 | 16 | 41 |
2023 January | 21 | 23 | 44 |
2022 December | 39 | 34 | 73 |
2022 November | 31 | 24 | 55 |
2022 October | 50 | 34 | 84 |
2022 September | 58 | 41 | 99 |
2022 August | 52 | 36 | 88 |
2022 July | 25 | 35 | 60 |
2022 June | 41 | 34 | 75 |
2022 May | 29 | 72 | 101 |
2022 April | 67 | 41 | 108 |
2022 March | 51 | 49 | 100 |
2022 February | 37 | 26 | 63 |
2022 January | 23 | 22 | 45 |
2021 December | 9 | 18 | 27 |
2021 November | 12 | 18 | 30 |
2021 October | 22 | 24 | 46 |
2021 September | 4 | 13 | 17 |
2021 August | 8 | 8 | 16 |
2021 July | 6 | 6 | 12 |
2021 June | 9 | 6 | 15 |
2021 May | 12 | 12 | 24 |
2021 April | 17 | 8 | 25 |
2021 March | 19 | 28 | 47 |
2021 February | 13 | 6 | 19 |
2021 January | 11 | 13 | 24 |
2020 December | 22 | 9 | 31 |
2020 November | 19 | 13 | 32 |
2020 October | 15 | 8 | 23 |
2020 September | 17 | 10 | 27 |
2020 August | 6 | 1 | 7 |
2020 July | 10 | 5 | 15 |
2020 June | 20 | 10 | 30 |
2020 May | 24 | 6 | 30 |
2020 April | 29 | 9 | 38 |
2020 March | 18 | 7 | 25 |
2020 February | 21 | 12 | 33 |
2020 January | 27 | 20 | 47 |
2019 December | 17 | 13 | 30 |
2019 November | 13 | 4 | 17 |
2019 October | 19 | 13 | 32 |
2019 September | 12 | 6 | 18 |
2019 August | 17 | 7 | 24 |
2019 July | 15 | 8 | 23 |
2019 June | 17 | 9 | 26 |
2019 May | 22 | 12 | 34 |
2019 April | 28 | 15 | 43 |
2019 March | 26 | 14 | 40 |
2019 February | 24 | 10 | 34 |
2019 January | 20 | 8 | 28 |
2018 December | 25 | 14 | 39 |
2018 November | 36 | 4 | 40 |
2018 October | 122 | 28 | 150 |
2018 September | 62 | 10 | 72 |
2018 August | 15 | 5 | 20 |
2018 July | 26 | 8 | 34 |
2018 June | 20 | 6 | 26 |
2018 May | 46 | 21 | 67 |
2018 April | 28 | 17 | 45 |
2018 March | 19 | 17 | 36 |
2018 February | 0 | 3 | 3 |
2018 January | 2 | 3 | 5 |
2017 December | 6 | 0 | 6 |
2017 November | 1 | 5 | 6 |
2017 October | 1 | 13 | 14 |
2017 September | 0 | 11 | 11 |
2017 August | 0 | 2 | 2 |