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- Design and Implementation of a Collaborative Clinical Practice and Research Documentation System Using SNOMED-CT and HL7-CDA in the Context of a Pediatric Neurodevelopmental UnitPublication . Direito, B; Santos, A; Mouga, S; Lima, J; Brás, P; Oliveira, G; Castelo-Branco, MThis paper introduces a prototype for clinical research documentation using the structured information model HL7 CDA and clinical terminology (SNOMED CT). The proposed solution was integrated with the current electronic health record system (EHR-S) and aimed to implement interoperability and structure information, and to create a collaborative platform between clinical and research teams. The framework also aims to overcome the limitations imposed by classical documentation strategies in real-time healthcare encounters that may require fast access to complex information. The solution was developed in the pediatric hospital (HP) of the University Hospital Center of Coimbra (CHUC), a national reference for neurodevelopmental disorders, particularly for autism spectrum disorder (ASD), which is very demanding in terms of longitudinal and cross-sectional data throughput. The platform uses a three-layer approach to reduce components’ dependencies and facilitate maintenance, scalability, and security. The system was validated in a real-life context of the neurodevelopmental and autism unit (UNDA) in the HP and assessed based on the functionalities model of EHR-S (EHR-S FM) regarding their successful implementation and comparison with state-of-the-art alternative platforms. A global approach to the clinical history of neurodevelopmental disorders was worked out, providing transparent healthcare data coding and structuring while preserving information quality. Thus, the platform enabled the development of user-defined structured templates and the creation of structured documents with standardized clinical terminology that can be used in many healthcare contexts. Moreover, storing structured data associated with healthcare encounters supports a longitudinal view of the patient’s healthcare data and health status over time, which is critical in routine and pediatric research contexts. Additionally, it enables queries on population statistics that are key to supporting the definition of local and global policies, whose importance was recently emphasized by the COVID pandemic.
- Phenotyping GABA transaminase deficiency: a case description and literature reviewPublication . Louro, P; Ramos, L; Robalo, C; Cancelinha, C; Dinis, A; Veiga, R; Pina, R; Rebelo, O; Pop, A; Diogo, L; Salomons, GS; Garcia, PGamma-aminobutyric acid transaminase (GABA-T) deficiency is an autosomal recessive disorder reported in only three unrelated families. It is caused by mutations in the ABAT gene, which encodes 4-aminobutyrate transaminase, an enzyme of GABA catabolism and mitochondrial nucleoside salvage. We report the case of a boy, deceased at 12 months of age, with early-onset epileptic encephalopathy, severe psychomotor retardation, hypotonia, lower-limb hyporeflexia, central hypoventilation, and rapid increase in weight and, to a lesser rate, length and head circumference. He presented signs of premature pubarche, thermal instability, and water-electrolyte imbalance. Serum total testosterone was elevated (43.3 ng/dl; normal range <16), as well as serum growth hormone (7.7 ng/ml; normal range <1). Brain magnetic resonance imaging (MRI) showed decreased myelination and generalized brain atrophy, later confirmed by post-mortem examination. ABAT gene sequencing was performed post-mortem, identifying a homozygous variant c.888G > T (p.Gln296His),not previously described. In vitro analysis concluded that this variant is pathogenic. The clinical features of this patient are similar to those reported so far in GABA-T deficiency. However, distinct mutations may have a different effect on enzymatic activity, which potentially could lead to a variable clinical outcome. Clinical investigation aiming for a diagnosis should not end with the patient's death, as it may allow a more precise genetic counselling for the family.
- Identification of a novel deletion in SURF1 gene: Heterogeneity in Leigh syndrome with COX deficiencyPublication . Ribeiro, C; Macário, MC; Viegas, AT; Pratas, J; Santos, MJ; Simões, M; Mendes, C; Bacalhau, M; Garcia, P; Diogo, L; Grazina, MLeigh syndrome (LS) is a rare, progressive neurodegenerative mitochondrial disorder of infancy. It is a genetically heterogeneous disease. The mutations in SURF1 gene are the most frequently known cause. Here two cases of LS likely caused by SURF1 gene variants are reported: a 39-year-old male patient with a novel homozygous deletion (c.-11_13del), and a case of a 6-year-old boy with the same deletion and a nonsense mutation (c.868dupT), both in heterozygosity. Blue native PAGE showed absence of assembled complex IV. This is the first report of a variant that may abolish the SURF1 gene initiation codon in two LS patients.
- Acute liver failure related to inherited metabolic diseases in young childrenPublication . Dias-Costa, F; Moinho, R; Ferreira, S; Garcia, P; Diogo, L; Gonçalves, I; Pinto, CINTRODUCTION: Pediatric acute liver failure (ALF) due to inherited metabolic diseases (IMD) is a rare life-threatening condition with a poor prognosis. Early intervention may be lifesaving. OBJECTIVE: To describe clinical presentation, investigation and outcomes of ALF related to IMD in young children. MATERIAL AND METHODS: Retrospective review of the medical records of children aged up to 24 months, admitted to a tertiary pediatric and neonatal Intensive Care Unit during a 27-year period, fulfilling the ALF criteria, with documented metabolic etiology. RESULTS: From 34 ALF cases, 18 were related to IMD: galactosemia (4), mitochondrial DNA depletion syndrome (MDS) (3), ornithine transcarbamilase deficiency (3), congenital defects of glycosylation (2), tyrosinemia type 1 (2), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (1), hereditary fructose intolerance (1), classic methylmalonic aciduria (1) and citrulinemia type 1 (1). The median age was 1.3 months. At least one previous suggestive sign/symptom of IMD (vomiting, failure to thrive, hypotonia or developmental delay) was observed in 67% of the cases. The most common physical signs at admission included: hepatomegaly (72%), jaundice (67%) and encephalopathy (44%). The peak laboratorial findings were: mean international normalizad ratio 4.5, median lactate 5mmol/L, mean bilirubin 201μmol/L, median alanine aminotransferase (ALT) 137 UI/L and median ammonia 177μmol/L. One patient was submitted to liver transplant in ALF context (MSD). The mortality rate was 44%. DISCUSSION: The identification of IMD as a frequent cause of ALF allowed specific therapeutic measures and adequate family counselling. Particular clinical features and moderated ALT and bilirubin levels can lead to its suspicion.
- Bactérias Multirresistentes Associadas aos Cuidados de Saúde num Hospital Pediátrico: Experiência de Cinco Anos Cuidados de Saúde num Hospital Pediátrico: Experiência de Cinco AnosPublication . Mação, P; Lopes, JC; Oliveira, H; Oliveira, G; Rodrigues, FINTRODUCTION: In recent years there has been an increase of infections caused by multidrug-resistant bacteria. Paediatric data are scarce, particularly at national level. AIMS: To analyse trends of health-care associated multidrug-resistant bacteria infections in a paediatric hospital. MATERIAL AND METHODS: A retrospective incidence study was conducted in medical, surgical and intensive care wards in a level III paediatric hospital, from January 2005 to December 2009. The studied multidrug-resistant bacteria were methicillin-resistant Staphylococcus aureus (MRSA), ESBL-producing bacilli, vancomycin-resistant Enterococcus spp, multidrug-resistant Pseudomonas aeruginosa (PA-MDR) and Acinetobacter baumannii resistant to carbapenems. Demographic, clinical and laboratory data, treatment and presence of risk factors for these infections were analysed. RESULTS: During the study period 106 multidrug-resistant bacteria were identified, related to 72 children, predominantly male (65.3%). The most frequently identified multidrug-resistant bacteria were MRSA (35.8%), PA-MDR (29.2%) and ESBL-producing bacilli (17.9%). Of the 106 multidrug-resistant bacteria, 45 (42.5%) were causing infection. During the study period the annual proportion of infections caused by multidrug-resistant bacteria went up from 32.0% in 2006 to 55.6% in 2009 (p = 0.376). The overall incidence rate of infection was 0.400 per 1 000 hospitalization-days, corresponding to 0.274 infections per 100 admissions, remaining stable over the five years. The most frequent infections were bloodstream (31.1%), intra-abdominal (20.0%), catheter-related (17.8%) and skin and soft tissue (11.1%). All children had risk factors and the most frequently identified were previous antibiotic therapy and underlying chronic disease (> 90%). Six children (13.3%) died during hospitalisation. CONCLUSIONS: During the study period, there was an increase in the proportion of multidrug-resistant bacteria but with no statistical significance. The overall incidence rate of multidrug-resistant bacteria infection remained stable. MRSA were the most frequently identified bacteria, followed by PA-MDR and ESBL-producing bacilli. Bloodstream infections were the most frequent infections, followed by intra-abdominal and catheter-related. All children had risk factors, mainly previous antibiotic therapy and chronic disease.
- Autism Spectrum Disorder: FRAXE Mutation, a Rare EtiologyPublication . Correia, F; Café, C; Almeida, J; Mouga, S; Oliveira, GAutism spectrum disorder (ASD) is characterized by impaired social interaction and communication, restricted interests and repetitive behaviors. Fragile X E is associated with X-linked non-specific mild intellectual disability (ID) and with behavioral problems. Most of the known genetic causes of ASD are also causes of ID, implying that these two identities share common genetic bases. We present a child with an ASD with a normal range of intelligence quotient, that later evolved to compulsive behavior. FRAXE locus analysis by polymerase chain reaction revealed a complete mutation of the FMR 2 gene. This report stresses the importance of clinicians being aware of the association between a full mutation of FMR2 and ASD associated with compulsive behavior despite normal intellectual level.
- The impact of the metabotropic glutamate receptor and other gene family interaction networks on the autism spectrum disordersPublication . Hadley, D; Wu, ZL; Kao, C; Kini, A; Mohamed-Hadley, A; AGP Consortium; Oliveira, G; et alAlthough multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P ≤ 2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P ≤ 3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P ≤ 4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.
- Convergence of genes and cellular pathways dysregulated in autism spectrum disordersPublication . Pinto, D; Delaby, E; Merico, D; Barbosa, M; Merikangas, A; Oliveira, G; et alRare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
- Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disordersPublication . Correia, CT; Conceição, IC; Oliveira, B; Coelho, J; Sousa, I; Sequeira, AF; Almeida, J; Café, C; Duque, F; Mouga, S; Roberts, W; Gao, K; Lowe, JK; Thiruvahindrapuram, B; Walker, S; Marshall, CR; Pinto, D; Geschwind, JI; Scherer, SW; Oliveira, G; Vicente, AMBACKGROUND: Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study. METHODS: From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants. RESULTS: The ANXA1 duplication, overlapping the last four exons and 3'UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3'UTR identified 11 novel changes, but no obvious variants with clinical significance. CONCLUSIONS: We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.
- Síndromes de Deficiência Cerebral de CreatinaPublication . Malheiro, R; Diogo, L; Garcia, P; Fineza, I; Oliveira, GIntroduction: Creatine deficiency syndromes are a recently described group of diseases characterized by inborn errors of creatine metabolism. Clinical features include a spectrum of neurodevelopment disorders of diverse severity. They are characterized by low levels of cerebral creatine caused by different pathogenic mutations concerning the genes coding for creatine synthesis enzymes [arginine: glicyne amidinotransferase (AGAT, EC 2.1.4.1) and guanidinoacetate methyltansferase (GAMT, EC 2.1.1.2)], AGAT and GAMT, respectively, or its transporter (CT1 deficiency), SLC6A8. Enzymatic deficiencies are transmitted as autosomal recessive traits, whereas the transporter deficit is X-linked. Objectives: To characterize the clinical and laboratorial presentation, diagnosis and treatment of cerebral creatine deficiency patients, followed in Hospital Pediátrico Carmona da Mota. The awareness of these inborn errors of metabolism as neurological disorders, namely of neurodevelopment, among the medical community is a secondary aim of the present work. Methods and Material: Retrospective analysis of the clinical files of patients followed in our Hospital and diagnosed with cerebral creatine deficiency syndrome. Results: Twelve patients belonging to seven different families were diagnosed with creatine deficiency syndromes. Five presented GAMT deficiency and seven CT1 deficiency. Present ages are 2 to 38 years old. The most common clinical presentations were: global development delay in seven patients (two with epilepsy), and speech delay in two patients. Only one patient had communication and social interaction dysfunction. In all, global development delay in the range of intellectual delay was identified. The pathognomonic pattern of cerebral creatine deficiency in the brain image was demonstrated in eight patients. Pathogenic mutations in GAMT or SLC6A8 genes were identified in all cases. Conclusions: The suspicion of cerebral creatine depletion must be considered in all children presenting unexplained global psychomotor development delay. Pre-symptomatic therapy has shown promising results, especially in GAMT deficiency patients. The high rate of asymptomatic carriers of GAMT mutations in our population makes this disorder eligible to neonatal screening in Portugal.