RESUMO Introdução: A doença de Huntington (DH), causada por uma repetição CAG expandida no HTT, não possui tratamento e biomarcadores são necessários para futuros ensaios clínicos. Objetivo: Nosso objetivo foi verificar se os níveis de carnitina livre e aminoácidos de cadeia ramificada se comportam como potenciais biomarcadores na DH. Métodos: Portadores sintomáticos e assintomáticos e controles foram recrutados. Idade, sexo, índice de massa corporal (IMC), idade de início, duração da doença, escores UHDRS e trato CAG expandido foram obtidos; valina, leucina, isoleucina e carnitina livre foram medidas. Foram realizadas análises basal e longitudinal. Resultados: Setenta e quatro portadores sintomáticos, 20 portadores assintomáticos e 22 não portadores foram incluídos. No início do estudo, os níveis de valina estavam reduzidos em portadores de DH sintomáticos e assintomáticos quando comparados aos não portadores. Não foram observadas diferenças nos níveis de carnitina livre ou isoleucina + leucina entre os grupos. O IMC dos indivíduos sintomáticos foi menor que o dos não portadores. Níveis de valina correlacionaram-se com o IMC. Avaliação de acompanhamento foi realizada em 43 indivíduos sintomáticos. A pontuação do escore motor total da UHDRS aumentou 4,8 pontos/ano em média. Não foram observadas reduções significativas no IMC ou na valina, enquanto os níveis de carnitina livre e isoleucina+leucina aumentaram. Conclusões: Embora os níveis de valina tenham sido menores nos portadores de DH e estivessem relacionados às perdas de IMC observadas em indivíduos pré-sintomáticos, nenhum desses metabólitos parece ser biomarcador para a DH.

ABSTRACT Background: Huntington’s disease (HD), caused by an expanded CAG repeat at HTT, has no treatment, and biomarkers are needed for future clinical trials. Objective: The objective of this study was to verify if free carnitine and branched chain amino acids levels behave as potential biomarkers in HD. Methods: Symptomatic and asymptomatic HD carriers and controls were recruited. Age, sex, body mass index (BMI), age of onset, disease duration, UHDRS scores, and expanded CAG tract were obtained; valine, leucine, isoleucine, and free carnitine were measured. Baseline and longitudinal analysis were performed. Results: Seventy-four symptomatic carriers, 20 asymptomatic carriers, and 22 non-carriers were included. At baseline, valine levels were reduced in symptomatic and asymptomatic HD carriers when compared to non-carriers. No difference in free carnitine or isoleucine+leucine levels were observed between groups. BMI of symptomatic individuals was lower than those of non-carriers. Valine levels correlated with BMI. Follow-up evaluation was performed in 43 symptomatic individuals. UHDRS total motor score increased 4.8 points/year on average. No significant reductions in BMI or valine were observed, whereas free carnitine and isoleucine+leucine levels increased. Conclusions: Although valine levels were lower in HD carriers and were related to BMI losses observed in pre-symptomatic individuals, none of these metabolites seem to be biomarkers for HD.

Abstract Phenylketonuria (PKU) is caused by deficient activity of phenylalanine hydroxylase (PAH), responsible for the conversion of phenylalanine (Phe) to tyrosine (Tyr). Monitoring of patients with PKU requires the measurement of Phe in plasma using high-performance liquid chromatography (HPLC) or in dried blood spots (DBS) using different techniques to adjust treatment strategy. The objective of this study was to evaluate Phe levels in DBS measured by two different methods and compare them with Phe levels measured in plasma by HPLC. We analyzed 89 blood samples from 47 PKU patients by two different methods: fluorometric method developed in-house (method A) and the commercially available PerkinElmer® Neonatal Phenylalanine Kit (method B) and in plasma by HPLC. The mean Phe levels by method A, method B, and HPLC were 430.4±39.9μmol/L, 439.3±35.4μmol/L, and 442.2±41.6μmol/L, respectively. The correlation values between HPLC and methods A and B were 0.990 and 0.974, respectively (p < 0.001 for both). Our data suggest that methods A and B are useful alternatives for monitoring Phe levels in patients with PKU, with method A being in closer agreement with the reference standard (HPLC).

Abstract Brazil is a country of continental dimensions and most genetic services are concentrated in the Southeast and South, including the Medical Genetics Service of the Hospital de Clínicas de Porto Alegre (MGS/HCPA). As many areas on the country do not have adequate medical genetics support, networks were designed to extend the service of the MGS/HCPA reference center. This paper presents the information and diagnosis networks that have their headquarters at MGS/HCPA: SIAT (National Information System on Teratogenic Agents), SIEM (Information Service on Inborn Errors of Metabolism), Alô Genética (Hello Genetics - Medical Genetics Information Service for Primary Health Care Professionals); Rede MPS Brasil (MPS-Mucopolysaccharidosis Brazil Network); Rede EIM Brasil (IEM-Inborn Errors of Metabolism Brazil Network), Rede NPC Brasil (Niemann-Pick C - NPC Brazil Network), Rede DLD Brasil (LSD-Lysosomal Storage Disorders Brazil Network), Rede DXB (MSUD-Maple Syrup Urine Disease Network), RedeBRIM (Brazilian Network of Reference and Information in Microdeletion Syndromes Project), Rede Neurogenética (Neurogenetics Network), and Rede Brasileira de Câncer Hereditário (Brazilian Hereditary Cancer Network). These tools are very useful to provide access to a qualified information and/or diagnostic service for specialized and non-specialized health services, bypassing difficulties that preclude patients to access reference centers.

Abstract Background: Interest in screening methods for lysosomal storage diseases (LSDs) has increased in recent years, since early diagnosis and treatment are essential to prevent or attenuate the onset of symptoms and the complications of these diseases. In the current work, we evaluated the performance of tandem mass spectrometry (MS/MS) for the detection of some LSDs, aiming the future use of this methodology for the screening of these disorders. Methods: Standard curves and quality control dried blood spots were assayed to evaluate the precision, linearity, and accuracy. A total of 150 controls were grouped according to age and subjected to measurement of lysosomal enzymes deficient in Niemann-Pick A/B, Krabbe, Gaucher, Fabry, Pompe, and Mucopolysaccharidosis type I diseases. Samples from 59 affected patients with a diagnosis of LSDs previously confirmed by fluorimetric methods were analyzed. Results: Data from standard calibration demonstrated good linearity and accuracy and the intra- and interassay precisions varied from 1.17% to 11.60% and 5.39% to 31.24%, respectively. Except for galactocerebrosidase and ?-l-iduronidase, enzyme activities were significantly higher in newborns compared to children and adult controls. Affected patients presented enzymatic activities significantly lower compared to all control participants. Conclusion: Our results show that MS/MS is a promising methodology, suitable for the screening of LSDs, but accurate diagnoses will depend on its correlation with other biochemical and/or molecular analyses.

RESUMO O transplante de células tronco hematopoiéticas (TCTH) é o único tratamento disponível para o envolvimento neurológico de doenças como a leucodistrofia metacromática (MLD), a mucopolissacaridose tipo I-Hurler (MPS-IH) e a adrenoleucodistrofia (CALD). Objetivos Descrever a sobrevida e os desfechos neurológicos após o TCTH nessas doenças. Métodos Sete pacientes CALD, 2 MLD e 2 MPS-IH realizaram TCTH entre 2007 e 2014. Avaliações neurológicas, ressonância nuclear magnética e estudos bioquímicos e moleculares foram feitos no baseline e repetidos quando apropriado. Resultados Desfechos favoráveis foram obtidos em 4/5 TCTH de doadores relacionados e em 3/6 não relacionados. Dois pacientes faleceram de complicações do procedimento. Nove transplantados sobreviveram após uma mediana de 3,7 anos: estabilização neurológica foi obtida em 5/6 CALD, ½ MLD e em um caso MPS-IH. As lesões encefálicas de um caso MPS-IH reduziram-se quatro anos após o TCTH. Conclusão Bons desfechos foram obtidos quando o TCTH foi feito antes da vida adulta, cedo no curso clínico e/ou a partir de um doador relacionado.

ABSTRACT Hematopoietic stem cell transplantation (HSCT) is the only available treatment for the neurological involvement of disorders such as late-onset metachromatic leukodystrophy (MLD), mucopolysaccharidosis type I-Hurler (MPS-IH), and X-linked cerebral adrenoleukodystrophy (CALD). Objective To describe survival and neurological outcomes after HSCT for these disorders. Methods Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated. Results Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT. Conclusion Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor.

Objective: To evaluate serum levels of different biomarkers associated with cardiovascular disease in patients with bipolar disorder (BD). Patients were prospectively evaluated in two separate instances: during acute mania and after remission of manic symptoms. All measurements were compared with those of healthy controls. Methods: The study included 30 patients with BD and 30 healthy controls, matched for gender and age. Biochemical parameters evaluated included homocysteine (Hcy), folic acid, vitamin B12, ferritin, creatine kinase (CK) and C-reactive protein (CRP). Results: Hcy levels were significantly higher in the BD patients, both during mania and after achieving euthymia. When Hcy was adjusted for body mass index, there was no significant difference between patients and controls. Ferritin was the only marker that showed a significant decrease during mania when compared to both euthymic patients and controls. There were no significant differences for folate, vitamin B12, CK and CRP. Conclusions: These findings do not show an association between alterations of markers of cardiovascular risk during manic episodes. Further studies are necessary to determine factors and mechanisms associated with cardiovascular risk in patients with BD.

According to studies conducted in different countries, it is estimated that approximately 30% to 50% of people with mental health problems are not recognized by the general practitioner. Given this situation, it has been proposed that the practitioner at the primary care services must play a decisive role in the early detection of cases by establishing a definitive diagnostic and a timely treatment. Several organizations have pointed out that one of the first actions that need to be implemented to fulfill the aims in the care of people with mental disorders is to prepare the first-contact doctors and to have a brief, low cost, self-applied, valid and reliable scale. The studies mention that using screening tests at the primary care level is crucial for the success of the programs. The detection and recognition of psychiatric symptomatology rates vary depending on the type of scale applied. The tools that have been widely used are the Goldberg's General Health Questionnaire (GHQ), Zung Self-Rating Depression Scale, Beck Depression Inventory, the Depression Symptom Checklist (DS 20), the Hopkins Symptom Checklist (SCL), the Hamilton Depression Scale, the Center for Epidemiologic Studies Depression Scale (CES-D), the Montgomery-Asberg Depression Rating Scale, the Geriatric Depression Scale (GDS), the self-administered computerized assessment (PROQSY), the criteria of the 3rd revised edition of the Diagnostical and Statistical Manual of Mental Disorders (DSM-III-R), the Structured Clinical Interview for DSM-IV (SCID), and the criteria of the Symptom Driven Diagnostic System for Primary Care (SDDS-PC), among others. The preliminary results confirm the existence of a high percentage of possible psychiatric cases (46.9%), but only 4% of cases are referral. The low capability of the general practitioner at the primary care level in detecting these pathologies has been confirmed as well. These scales have been applied in different scenarios and to different types of population. Although the dominating criteria for choosing the tool are sensitivity and specificity, some authors mention that strategies for adequately handling cases, such as the confirmation of the diagnosis and follow-up of the patients, are required once the treatment has started. In this paper, we present the psychometric characteristics of the Kessler (K-10) scale in detecting depression and anxiety disorders in the primary care. Material and methods The study is a methodological process that aims to validate the Kessler Psychological Distress scale (K-10). It was conducted in two health care centers of primary care level in Mexico City. The subjects were 280 individuals who requested attention at the mentioned centers and to whom the K-10 test was applied after giving their informed consent. Later on, the computerized version of the International Neuropsychiatric Interview (MINI), which uses the diagnostic criteria of the DSM-IV, was applied to the subjects in order to confirm the diagnostics for depression and anxiety. The MINI is a version adapted to Latin American Spanish by the National Institute of Psychiatry Ramon de la Fuente Muñiz. The diagnostic accuracy was processed following the MINI diagnoses for depression and anxiety closely, and the scores on the scale K-10 as a predictor. The sensitivity and specificity were calculated for all possible cut points in order to establish the optimal cut off point. The efficiency and maximum likelihood ratios were also calculated. The area under the ROC curve as well as the probability quotients, positive and negative (LR+ and LR-), were also calculated. The K-10 is a brief screening tool that can be easily applied by the primary care personnel which measures the psychological distress of a person during the four weeks prior to the application. It consists of ten questions with Likert-like answers that range from 1 to 5 and are categorized in a five level ordinal scale: Always, Very Often, Sometimes, Rarely, Never; where «Never» has an assigned value of 1, and «Always» has assigned value of 5. It has a minimum score of 10 and a maximum of 50. The ranges of the instrument are four levels: low (10-15), moderate (16-21), high (22-29) and very high (30-50). The instrument showed an internal consistency of 0.90 and it has been used in various population studies promoted by the World Health Organization as well as government organizations in Australia, Spain, Colombia and Peru. Results Out of 280 individuals to whom the tool was applied, 78.9% (221) were female and 21.1% (59) male. These values represent the proportion of patients attending the primary care services (95% confidence interval=±5.4%). The mean age of women was 39 years, and the mean age of men was 41. The 70.6% of the women manifested more psychological distress than men (52.5%)[χ2(1)=6.05,p=0.014. No other socio-demographic variable showed significant differences. The instrument is highly precise, it can detect up to 87% of depression cases, and 82.4% of anxiety cases. The scale was compared with the MINI and it presented a prevalence of 26.8% and 10.6%, respectively. Of the total of depression cases, 26.4% also presented anxiety; these represent a co-morbidity of 5.4%. The construct validity presented one factor alone that explains the 53.4% of the total variance, this is why the scale is considered as one-dimensional. In other words, the scale only measures the construct of the psychological distress. The internal consistency was α=0.901. Once the sensitivity and specificity for all cut off points had been determined using the MINI as a golden rule, it was observed that the cut off point for maximum sensitivity and specificity corresponded to 21 for the diagnosis of depression, and 22 for anxiety. Conclusions The K-10 is a good instrument for the detection of depression and anxiety cases at the primary care level which meets the criteria of validity and reliability. However, given that only one diagnosis was considered for all the range of anxiety disorders, the scale must be chosen carefully for all the other disorders that are not included in this paper. The use of the instrument is recommended for the general practitioners at the primary care level, mainly for diagnosing depression. Various studies in which other screening instruments have been used for the detection of depressive disorder at primary care point out that any screening method are useful in making the diagnosis. By using these instruments, the depression diagnosis at primary care level increases from 10% to 47%. The latter supports the fact that the selection of a good instrument turns out to be effective in detection, treatment and clinical outcomes of the entity. Since this recommendation is only one of the activities required in primary care level for good handling of detected cases, it is noteworthy to mention that a comprehensive care model that encompasses both the detection as well as the pharmacological and psychosocial treatments is required.

De acuerdo con estudios realizados en diferentes países se estima que aproximadamente hay entre 30% a 50% de personas que presentan algún problema de salud mental que no es reconocido por el médico general. En virtud de esta situación se ha propuesto como estrategia a la atención primaria como base del sistema de salud, lo que permitiría la detección temprana de pacientes con algún trastorno psiquiátrico. Diferentes organismos señalan que una de las primeras acciones para cumplir con los objetivos en la atención de personas con algún trastorno mental, consiste en contar con una escala breve, autoaplicable, válida y confiable y de bajo costo. En este trabajo se presentan las características psicométricas de la escala Kessler (K-10) para detectar trastornos depresivos y ansiosos. La K-10 es un instrumento de tamizaje breve y de fácil aplicación por el personal del primer nivel de atención y ha sido utilizada en diferentes estudios a nivel poblacional. En Australia, en 1997, se aplicó la K-10 en una encuesta de salud, por medio del Consejo Nacional de Encuestas de Salud Mental. Material y métodos Se trata de un estudio de proceso metodológico, cuyo objetivo fue la validación de la escala de malestar psicológico K-10 de Kessler. El estudio se llevó a cabo en dos Centros de Salud del primer nivel de atención en la Ciudad de México. Los participantes fueron 280 personas que acudieron a la consulta externa de dichos centros. Se utilizaron los criterios del DSM-IV para la confirmación del diagnóstico de depresión y de ansiedad, por medio de la Mini International Neuropsychiatric Interview (MINI), en su versión computarizada, adaptada al español latinoamericano en el Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz. La validez diagnóstica se procesó utilizando los diagnósticos de la MINI para depresión y ansiedad como regla de oro y las puntuaciones obtenidas en la escala K-10 como predictor. Se calculó la sensibilidad y especificidad para todos los posibles puntos de corte con el fin de establecer el óptimo. Se calculó adicionalmente la eficiencia y las razones de máxima verosimilitud, así como el área bajo la curva ROC y los cocientes de probabilidad, positivo y negativo (LR+ y LR-). Resultados Del total de personas a quiénes se les aplicó la escala, el 78.9% (221) fueron mujeres y 21.1% (59) hombres. Estos valores representan la proporción en que los pacientes acuden a los servicios de primer nivel (IC 95%=±5.4%). El 70.6% de las mujeres presentaron mayor malestar psicológico en comparación con los hombres que representaron el 52.5% [χ²(1)=6.05,p=0.014]. En ninguna otra variable socio-demográfica se presentaron diferencias significativas. El instrumento tiene una alta precisión, ya que puede detectar hasta el 87% de los casos de depresión y un 82.4% de los casos de ansiedad. La escala se comparó con el MINI en español y presentó una prevalencia de 26.8% y 26.4%, respectivamente. Conclusiones El instrumento cumple con los criterios de validez y confiabilidad, por lo que se recomienda su uso por los médicos generales en el primer nivel de atención. Dado que esta recomendación sólo es una de las actividades que se requieren en la atención primaria para un buen manejo de los casos que se detecten, es necesario señalar que se requiere de un modelo de atención integral que incorpore tanto la detección como el tratamiento farmacológico y psicosocial.