Can Enzyme Replacement Therapy revert iNKT cell dysfunction in Acid Sphingomyelinase Deficiency patients?

Investigador: Fátima Macedo
PhD in Biomedical Sciences, Senior Researcher, Instituto de Investigação e Inovação em Saúde (i3S) in Porto University

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of the enzyme acid sphingomyelinase (ASM), resulting in an abnormal accumulation of sphingomyelin in lysosomes. The abnormal accumulation of sphingomyelin, a crucial cell membrane component, ultimately impairs pulmonary, hepatic, and neurological functions, with severe forms of the disease being fatal in the first years of life.

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Improve management of MADD patients: a curated database with clinical, molecular and cellular information

Investigador: Bárbara J. Henriques
Ph.D., APhD Senior Researcher, BioISI – Biosystems & Integrative Science Institute Faculty of Sciences, University of Lisbon

Inborn errors of metabolism comprise a class of genetic diseases which affect genes coding for enzymes involved in different cellular pathways. The expansion of the newborn screening program allows the earlier identification of several new cases associated to these rare diseases. Still clinicians and researchers in the field identified an enormous gap, the lack of a unifying depository for molecular and clinical data on patients, with the majority of cases found disperse in literature, and many not even reported in international journal with full access to all.

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Novel insights into treatment strategies for hyperammonemia-associated urea cycle disorders and organic acidurias.

Investigador: Margarida F.B. e Silva
Ph.D., Aux Prof FFUL; Metabolism and Genetics Group at iMed.UL

Hyperammonemia in paediatric patients is mostly related to inborn errors of metabolism (IEM) including urea cycle disorders and certain organic acidurias. The rise of toxic ammonia levels may have devastating consequences on neurodegeneration and neurodevelopment. Preventive strategies of metabolic deterioration and more effective therapeutic options are definitely needed. Few studies have assessed the efficacy of novel therapies, especially tailored to the various phenotypes and IEM. This research proposal puts forward the hypotheses that: 1) hyperammonemia is linked to changes in cofactors or redox status affecting energy metabolism and resulting in mitochondrial dysfunction; 2) drug design profits of associated small molecules to improve their efficacy, reducing levels of toxic ammonia and surpassing the metabolic imbalances associated with the genetic underlying cause of IMD.

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Something stinks’: impaired hydrogen sulfide and cysteine persulfide production by cystathionine β-synthase variants identified in classical homocystinuria patients

Investigador: João B. Vicente
Auxiliary Investigator, ITQB-NOVA

This project aims to shed new lights onto the molecular basis of classical homocystinuria (CHU) due to cystathionine-β-synthase (CBS) deficiency, resulting from CBS gene mutations. The CBS canonical role in the transsulfuration branch of methionine metabolism has been increasingly extended to a major role as an endogenous source of hydrogen sulfide (H2S) source and, secondarily, cysteine persulfide (CysSSH). H2S regulates many physiological processes as a multifaceted ubiquitous signaling molecule. Disturbed H2S metabolism due to aberrant CBS expression is growingly established as an etiologic factor of several pathologies, some with clinical presentations common to CHU, namely cardiovascular disease and neurological impairment. Given that elevated plasma homocysteine does not fully explain the clinical presentations of CHU patients, impaired H2S and/or CysSSH production are likely to underlie the pathogenicity of various CBS mutations.
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Skipping the Pathology in Rare Diseases: Antisense exon-skipping therapy for Mucolipidosis type II

Investigador: Sandra Alves: Research and Development Unit, Department of Human Genetics. National Health Institute Doutor Ricardo Jorge.

Studies will be carried out by the Lysosomal Storage Disease (LSD) research group from Department of Genetics of the National Institute of Health Dr. Ricardo Jorge (INSA-Porto) where all the facilities for the proposed studies are available and well-established. The LSD group has been conducting studies on the mutational spectrum of several rare diseases (namely LSDs) in Portugal addressing also the impact of identified mutations on RNA and protein levels. The development of alternative therapeutic approaches is also a major research focus and recently antisense oligonucleotides-based therapeutic approaches to correct pathogenic effects of some LSDs mutations.

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Genetic Substrate Reduction Therapy for Mucopolysaccharidoses Toward a siRNA-containing nanoparticle targeted to brain cells

Investigador: Francisca Coutinho Instituição: Unidade de I&D, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge

Impaired degradation of glycosaminoglycans (GAGs) with consequent intralysosomal accumulation of undegraded products causes a group of lysosomal storage disorders known as mucopolysaccharidoses (MPSs). As it happens for most LSDs, there is no fully effective treatment for MPSs. In fact, even though enzyme replacement therapy does exist for 4 MPSs, this approach is ineffective for the brain since recombinant enzymes are not able to cross the blood brain barrier. This is one of the reasons why other therapies need to be tested for MPSs with central nervous system involvement. Having this in mind, we have designed an RNA-based strategy based upon the selective downregulation of two genes involved in the biosynthesis of GAGs. Our goal is to promote an effective reduction of the accumulating substrate, ultimately decreasing or delaying MPSs’ symptoms. As tools to achieve substrate reduction, we are currently evaluating a specific type of antisense oligonucleotides, which are able to trigger a naturally-occurring post-transcriptional gene silencing process called RNA interference: the small interfering RNAs (siRNAs). So far, the obtained results are quite promising, with marked decreases of the target mRNA levels, which resulted in significant reductions in GAGs’ storage.

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CYP46A1 AS A NEW THERAPEUTIC TARGET IN NIEMANN-PICK TYPE C DISEASE

Investigador: Elsa Rodrigues
Instituição: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de
Lisboa (FF/ULisboa), Lisbon, Portugal

Due to its importance in neuronal function, we have been devoted to the characterization of the molecular pathways involved in the control of brain cholesterol metabolism, focusing on the role of CYP46A1. The neuronal specific cholesterol 24-hydroxylase, encoded by the cytochrome P450 CYP46A1 gene, is responsible for the conversion of cholesterol into 24S-hydroxycholesterol, which accounts for the major elimination pathway of brain cholesterol. Due to its importance in cholesterol elimination we hypothesized that CYP46A1 could be a new therapeutic target in Niemann-Pick type C disease (NPC1 - Rare Disease ORPHA646). NPC disease is a lysosomal
storage disorder, characterized by cholesterol accumulation in the late endosomes/ lysosomes compartment, which results from mutations in NPC1 or NPC2 genes. The most dominant feature is the progressive neurodegeneration leading to premature childhood death.

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Investigador: Isabel Antolin Rivera
Instituição:Grupo Metabolismos e Genética - Research Institute for Medicines (iMed.ILisboa), Faculdade de Farmácia da Universidade de Lisboa

Pyruvate is a key molecule in human metabolism once it links glycolysis to energy production via Krebs cycle and respiratory chain. Nevertheless, the pyruvate oxidation route is an intricate metabolic pathway as it encompasses all the steps mediating the passage of pyruvate from cytoplasm to mitochondrial matrix until its conversion to acetyl-CoA and, additionally, every step is regulated by specific proteins. Accordingly, an insufficient pyruvate turnover in mitochondria ussually originates severe clinical phenotypes.

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Investigador: Paula Peralta
Instituição: Met&Gen, iMed.UL / FFUL – Lisboa

The current universal established PKU treatment relies on a highly restrictive diet of difficult compliance which may compromise the patient’s neurologic outcome and decrease their quality of life. The use of the pharmacological form of the natural hPAH cofactor BH4 has been recently approved by American and European authorities and a pegylated (PEG) form of a recombinant non-mammalian L-Phe degrading enzyme (phenylalanine ammonia lyase; PAL) already reached Phase III clinical trials. However, BH4 supplementation only allow diet liberalization in the restrict group of PKU patients presenting the mild form and PEG-PAL administration has been reported as potentially immunogenic. Therefore, a safety and efficacious treatment for all forms of PKU is still needed.

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Investigador: Manuela Grazina
Instituição: Center for Neuroscience and Cell Biology – CNC, University of Coimbra

LHON is a maternally inherited optic atrophy with acute bilateral loss of central vision, mainly associated to specific mtDNA mutations, affecting MRC-complex I subunits. This study aims to provide new insights on mitochondria networks and alternatives routes for proteins transport into mitochondria.

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Adapting protein homeostasis in inborn errors of metabolism: treatment of severe forms of phenylketonuria 

Investigador: João Leandro
Instituição: Met&Gen, Faculdade de Farmácia de Lisboa

The aim of this study is to modulate the cytosolic proteostasis network to treat severe forms of phenylketonuria, caused by misfolding of phenylalanine hydroxylase.

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Investigador: Lígia S. Almeida
Instituição: Departamento de Genética – INSA, Porto

Este estudo tem como objetivo a implementação de uma nova estratégia para a sequenciação completa do mtDNA usando as novas tecnologias de sequenciação massiva e definição de um algoritmo de análise.

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Investigador: Isabel Antolin Rivera
Instituição: Met&Gen, iMed.UL / FFUL – Lisboa

Os principais objectivos deste estudo são a elucidação dos mecanismos patogénicos subjacentes às mutações de splicing detectadas em doentes galactosémicos da população Portuguesa, bem como o estudo do efeito de sondas oligonucleotídicas anti-sense na recuperação da anomalia introduzida pelas mutações de splicing.

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Investigador: Hugo Daniel Carvalho de Azevedo Rocha
Instituição: Departamento de Genética – INSA, Porto

O objectivo global deste projecto é definir as consequências dos défices múltiplos das desidrogenases (défices de ETF e ETF:QO) no proteoma mitocondrial, gerando novos dados que permitam compreender a patofisiologia associada a esta doença metabólica.

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Investigador: Maria de Fátima Vieira Ventura
Instituição: Met&Gen, iMed.UL / FFUL – Lisboa

Neste projecto pretende-se avaliar funcional e estruturalmente as duas novas variantes de MCAD. Pretende-se igualmente proceder à caracterização de proteínas híbridas de modo a avaliar a ocorrência de uma eventual complementação interalélica.

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Investigador:  Patrícia Gaspar Silva 
Instituição: Serviço de Pediatria do Hospital Divino Espírito Santo de Ponta Delgada, E.P.E.R.

Investigador:  Ana de Carmo Campos  
Instituição: Hospital Pulido Valente, Centro Hospitalar e Universitário de Lisboa Norte.

Investigador:  Patrícia Lipari Pinto  
Instituição: Hospital de Santa Maria, Centro Hospitalar e Universitário de Lisboa Norte.

Investigador: João Durães
Instituição: Centro de Referência DHM, Centro Hospitalar e Universitário de Coimbra

Investigador: Inês Luz Romão
Instituição: Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra

Investigador: Joana Correia
Instituição: Centro Materno Infantil do Norte, Centro Hospitalar e Universitário do Porto

Vencedores Abril 2023

Investigador: Helena Santos
Instituição: Centro Hospitalar de Vila Nova de Gaia/Espinho, EPE
Formação: Genetic therapies, a realizar entre 22/06/2023 e 24/06/2023.

Vencedores Janeiro 2023

Investigador: Cristina Florindo
Instituição: Met&Gen, Faculdade de Farmácia, Universidade de Lisboa, Lisboa Portugal
Formação: SSIEM ETAC Academy que se irá realizar em Manchester a 24 e 25 de abril de 2023.

Vencedores Janeiro 2023

Investigador: Isabel Rivera
Instituição: Professora Auxiliar com agregação da , Faculdade de Farmácia, Universidade de Lisboa, Lisboa Portugal
Formação: PSSIEM Annual Symposium, que irá decorrer de 29 de agosto e 1 de setembro em Jerusalem, Israel e a Reunião satélite da rede GalNet (European Galactosemia Network), da qual é membro da comissão executiva

Vencedores Abril 2022

Investigador: Célia Nogueira
Instituição: INSA, Instituto Nacional de Saúde Ricardo Jorge, Porto, Portugal.
Formação: Para apoiar a realização de um estágio de curta duração de 20 a 26 de Novembro de 2022, na Unidade de Medicina Moleculare per la Malattie Neuro degenerative do Instituto IRCCS Fondazione Stella Maris, Pisa, I tália.

Vencedores Abril 2022

Investigador:  Fátima Macedo
Instituição: Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal
Formação: Participação no  Workshop EMBO CD1/MR1 r estricted T lymphocytes de 22 a 26 de Maio em Gothenburgo, Suécia, onde irá apresentar o trabalho intitulado Human iNKT cells induce activation and subset dependent cell death of macrophages em relação com o projeto “Fabry disease Natural Killer Tcells".

Vencedores Abril 2022

Investigador: Filipa Carvalho
Instituição: BioISI - Biosystems & Integrative Sciences Institute, Chemistry and Biochemistry Department, Faculty
of Science, University of Lisbon, Lisbon, Portugal
Formação: Participação no congresso internacional Annual Symposium of the Society for the Study of Inborn Errors of Metabolism SSIEM 2022com a apresentação do trabalho “Mitochondria phenotype and metabolomic signature in MADD patient derived fibroblasts”.

Vencedores Fevereiro 2020

Investigador: Isabel Rivera
Instituição: Instituto de Investigação do Medicamento (iMed.ULisboa) - Metabolism & Genetics Group. Faculdade Farmácia, Universidade Lisboa
Formação: Participação no congresso internacional Annual Symposium of the Society for the Study of Inborn Errors of Metabolism SSIEM 2020 e representação de Portugal na reunião satélite da rede GalNet (European Galactosemia Network), Freiburg.

Vencedores Maio 2019

Investigador: Bárbara Joana de Almeida Henriques
Instituição: Faculdade de Ciências Universidade de Lisboa BioISI - Biosystems & Integrative Sciences Formação: Apresentação de trabalho no Congresso Internacional "57 Annual Symposium of the Society for the Study of Inborn Errors of Metabolism SSIEM", Rotterdam.

Vencedor Janeiro 2019

Investigador: Cristina Florindo 
Instituição: Lab. Met&Gen. Faculdade Farmácia, Universidade de Lisboa, Lisboa
Formação: Estágio laboratorial - Treino de curta duração no laboratório da VU, Amesterdão, Holanda, Dir. Prof. Gajja Salomons  

Consulte Grelha de Avaliação

Investigador: Isabel Rivera
Instituição: Faculdade Farmácia, Universidade de Lisboa, Lisboa
Formação: Ida ao congresso internacional "56 Annual Symposium of the Society for the Study of Inborn Errors of Metabolism SSIEM" e representação de Portugal na reunião satélite da rede GalNet, Atenas.

Investigador: Olga Amaral
Instituição: INSA, Instituto Nacional de Saúde Ricardo Jorge, Porto
Formação: Apresentação de comunicação oral no "50º congresso da Sociedade Europeia de Genética
Humana", Dinamarca 

Investigador: Helena Caldeira Araújo
Instituição: Unidade de Ciências Médicas, Universidade da Madeira
Formação: Apresentação de comunicação no “SSIEM International Symposium”, Birmingham, UK.

Investigador: Rúben José Jesus Faustino Ramos
Instituição: Met&Gen, iMed.UL / FFUL – Lisboa
Formação: Participação no “SSIEM Academy”, Amsterdam, The Netherlands.

Validation of a questionnaire to assess eating disorders in inherited metabolic disease patients requiring dietary treatment

Investigador: Inês Curvelo Mendes 
Instituição: Hospital Divino Espírito Santo EPER., Ponta Delgada, São Miguel, Azores, Portugal

Abstract
Diet-therapy represents an elective approach to the treatment of several inherited metabolic diseases (IMD). Studies suggest that living with chronic diseases which are treated with dietary management may adversely affect eating attitudes and behaviors and may increase susceptibility to the development of eating disturbances, and subsequently nutritional unbalances. Eating disorders (ED) are a group of psychopathological disorders that affect the patient's relationship with food and his own body and that are manifested mainly in adolescence and in young-adult age. The identification of eating-related problems is important because deviations in dietary adherence are associated with worst outcomes, for most IMD patients.
Morgan et al., developed and tested a tool for detecting ED in community settings— SCOFF questionnaire. Several other questionnaires are available for screening ED in community settings and some have been applied to patients in hospital settings. In the clinical practice, health professionals feel the need to screen for this ED in specific patients, who have higher risk for ED, especially those patients who have to follow strict dietary treatments. An example of this is the IMD patients. To our knowledge, in Portugal there is not available a validated questionnaire to screen for ED in IMD patients. This project aims to translate the SCOFF questionnaire for the Portuguese language, including cultural adaptation, and validation in IMD patients that require dietary management.
In the first phase of the project, we intend to proceed with the Portuguese translation and cultural adaptation of the SCOFF questionnaire, following the recommended steps by the World Health Organization: “Process of translation and adaptation of instruments”. The final version of the questionnaire will be applied to approximately 30 IMD patients that require dietary treatment and attend to the nutrition appointment in the Reference Center of Centro Hospitalar Universitário do Porto and in the Treatment Centers of Hospital Divino Espírito Santo and Hospital de Santo Espírito da Ilha Terceira, in Azores. In the second phase, we intend to proceed with the statistical validation of the questionnaire. This protocol will be presented to the Ethic Committee of Centro Hospitalar Universitário do Porto, Hospital Divino Espírito Santo and Hospital de Santo Espírito da Ilha Terceira.
We expect that this instrument could be validated for this specific group of patients that globally have high risk of developing eating disorders. This tool can identify ED early and allow a rapid initiation of treatment, which will improve the prognosis of IMD patients. It is also expected that, subsequently in the future, this tool could be used to others IMD patients at the Portuguese Reference/Treatment Centers.

Diet quality and saproterin dihydrochloride (BH4) use in children with phenylketonuria (PKU)

Investigador: Maria Inês Gama
Instituição: Nutrition & Metabolism, NOVA Medical School, Faculty of Medical Sciences, University of Lisbon, Lisbon, Portugal

Abstract

Phenylketonuria (PKU) is a rare metabolic disorder. Mutations in the enzyme phenylalanine hydroxylase (PAH), impair phenylalanine (Phe) metabolism into tyrosine, and a Phe build up in the brain causes neurological deterioration and consequently brain damage and developmental delay, if treatment is not initiated early. Treatment consists of a low protein diet restricted in the amino acid Phe. Diet is based on low protein foods, usually fruits and vegetables, together with a protein substitute to secure protein needs and special low protein foods to attain energy requirements. Sapropterin dihydrochloride (BH4), is a synthetic form of the co-factor tetrahydrobiopterin, necessary for the PAH activity. Patients who respond to the drug can increase Phe tolerance, leading to diet relaxation and consequently more natural protein introduction in the diet, and/or can improve metabolic control of patients. However, reports of patients’ food patterns in PKU are scarce, with existing ones reporting increase intake of known familiar foods and neophobia to new protein sourced foods. This could lead to nutritional imbalances, particularly in micronutrient status. A retrospective observational longitudinal study will be performed in a cohort of paediatric (0-17 years) PKU patients followed at the BCH, and their caregivers. Data from patients records (age, gender, diagnosis, weight, height, BMI, metabolic control) food frequency and food neophobia questionnaires will be collected. From caregivers an anxiety and depression questionnaire will be applied. We expect these results to be of extreme importance to characterize food patterns and food choices in children treated with BH4 treatment as well as their caregivers’ burden.

Bone health and micronutrients status evaluation in phenylalanine dietary restricted patients

Investigador: Sandra Mexia
Instituição: Metabolic Unit, Reference Center for Metabolic Diseases, CHULN-HSM, Lisbon, Portugal

Abstract

Phenylketonuria (PKU) dietary management involving protein restriction remains an effective treatment of the disease preventing neurocognitive compromise. The goal is to limit the accumulation of toxic amounts of phenylalanine (Phe), an essential amino acid. A combination of natural protein and Phe-free, tyrosine rich formulas are needed to provide adequate amounts of tyrosine for growth and neurotransmitter synthesis, with just enough Phe for anabolism. Although, long term protein restricted diets can lead to suboptimal bonne health outcomes, potentially leading to growth failure and fractures.
Authors intend to perform a retrospective study to evaluate the bonne health of PKU patients followed at Lisbon Reference Center for Inborn Errors of Metabolism, CHULN, concerning bonne mineralization and fracture risk.
The clinical charts of all PKU patients summitted to dual energy X-ray absorptiometry (DEXA) evaluation will be reviewed regarding:
1. Mineral bonne density by DEXA, according to patient´s age and gender;
2. Demographic data regarding gender, age, puberty status, dietary compliance, type, duration and frequency of exercise and fracture occurrence;
3. Energy, protein (natural and synthetic), calcium, phosphorus, magnesium and vitamin D daily intake in the patient´s diet and pharmacological supplementation, previous to DEXA evaluation;
4. Plasma biochemical evaluation of calcium, phosphorus, magnesium, alkaline phosphatase, vitamin D, parathyroid hormone (PTH), median Phe levels and urinary calcium excretion, previous to DEXA evaluation;
5. Anthropometric data (weight, height and body mass index), according to World Health Organization (WHO) percentiles and z-scores to gender and age, at the time of DEXA evaluation;
6. Calcium content of amino acid mixtures, glycomacropeptide (GMP) intake and Kuvan supplementation will also be addressed.

There is no animal testing.

Does phenylalanine restricted diet impacts microbiota in patients with phenylketonuria?

Investigador: Catarina Isabel dos Santos Rodrigues.
Instituição: Nutrition and Metabolism, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal. CINTESIS - Center for Health Technology and Services Research, Porto, Portugal.

ABSTRACT: Phenylketonuria (PKU) is a rare autosomal recessive inborn error of phenylalanine (Phe) metabolism due to a deficiency of the hepatic-based enzyme phenylalanine hydroxylase. Dietary treatment is the cornerstone of therapy and its goal is to prevent excessive Phe accumulation in the blood.

The gut microbiota plays a major role in the maintenance of the host health, including intestinal health and function. It is influenced by several factors, including dietary pattern, antibiotic exposure, mode of delivery of a neonate, among others. However, dietary pattern is one of the most important, as it strongly influences the composition of gut microbiota. This may be particularly relevant in PKU patients, since their special Phe- restricted diet begins in the neonatal period and is maintained throughout life, possibly modifying gut microbiota composition and affecting gut homeostasis.

This study aims to i) characterize the gut microbiota of adult PKU patients; ii) compare gut microbiota of adult PKU patients with healthy adult population; and iii) understand the role of the Phe-restricted diet as a potential inducer of gut dysbiosis.

This will be an observational, cross-sectional study. A total of 24 participants will be recruited from the National Reference Centre in Hereditary Metabolic Disorders, Centro Hospitalar de Lisboa Norte. Anthropometric data of the population will be collected, and body composition will be assessed by bioimpedance, after overnight fasting. Faecal samples will be collected, as well as food records from the three days prior to faecal sample collection. Data from medical records will also be collected, including prescribed protein substitutes, natural and total daily protein intakes, median blood Phe concentrations in the previous year preceding the study, and clinical relevant data.

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Melhoramento das novas tabelas de composição do teor e dos aminoácidos a utilizar como ferramenta para o tratamento das doenças hereditárias do metabolismo proteico

Investigador:  Carla Vasconcelos
Instituição:  Unidade de Nutrição e Dietética do Centro Hospitalar São João. Centro de Referência de Doenças Metabólicas do Centro Hospitalar Universitário São João

As Doenças Hereditárias do Metabolismo (DHM) são patogênicas raras de natureza genética em que uma metabolização pode ser destruída. A proteína é uma proteína enzimática, que é uma variável via metabólica, tendo uma acumulação de compostos (muitas vezes tóxicos) e uma produção diminuída ou um produto biológico importante (Scriver et al., 2001). A deficiência enzimática é devida a uma mutação numérica de vários genes codificantes para o passo metabólico em causa. Como aminoácidos e ácidos orgânicos, tais como aminoácidos e sob o ponto de vista fisiológico são incluídos no grupo de intoxicação por doenças, ou seja, doenças que causam sintomas de intoxicação aguda e progressiva, por acumulação de metabolismo tóxico ao aumento do bloqueio enzimático.
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The effect of the nitrogen source on metabolism in Phenylketonuria

Investigador: Maria João Pena, PhD Student, FMUPorto  
Instituição: Faculdade de Medicina da Universidade do Porto, Porto

Since Phenylketonuria’s (PKU) treatment introduction in 1950’s by Dr. Horst Bickel, many advances were made. In fact, one of the major contributions to PKU was the implementation of a phenylalanine (Phe)-restricted diet, remaining the cornerstone of treatment. The Phe-restricted diet consists of natural protein supplemented with protein substitutes (PS). Phe-free amino acid mixtures (AAM) are still the most common PS used to treat patients with PKU, despite the recent emergence of glycomacropeptide-based PS (GMP). GMP is an intact protein derived from cheese making process. There may be metabolic discrepancies between AAM and GMP, particularly at gycidic metabolism level. Several mechanisms can explain these differences, such as, the incretins release and the gut microbiota. Nevertheless, the scientific evidence is still scarce. This project comprises animal and clinical studies.
The main objective of the present research is to understand the effect of different nitrogen sources used for the treatment of PKU on metabolism.

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Challenges in long-term management of MSUD: a prospective study by assessment of clinical, Biochamical and Anthropometric Parameters

Investigador: Sandra Mexia
Instituição: Centro Hospitalar de Lisboa Norte, Hospital de Santa Maria

Maple syrup utine disease (MSUD - OMIM # 24860) is a rare unherited sidorder of branched-chain amino acids (BCAAs) - leucine (Leu), isoleucine (lLe) and valine (Val), displaying an autosomal recessive pattern of inheritance, and caused by deficiency of branched-chain aketo acid dehydrogenase, the enzymatic complex responsible for the breaking down of byproducts of the BCAAs transmination reactioin, the corresponding branched-chain a-keto-acids (BCKA).
The disruption of this metabolic pathway results in the accumulation of BCAAs and BCKA in cells and fluis of the body, which present neurotoxic, especially Leu and the corresponding a-keto-acid, the a-keto-isocaproic acid (KIC). To avoid life-threatening complications, treatment must promptly be strated. MSUD's treatment, primarily nutritional, is based on manipulation of a restricted natural protein diet with reduced BCAAs content and supplementation eith synthetic formulas for the supplying of essential amino acids and micronutrients, pivotal for ensuring normal grosth and psychomotor development of effected children.

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Estado de micronutrientes e ingestão de misturas de aminoácidos isentas de fenilalanina, em doentes fenilcetonúricos 

Investigador: Paula Cristina Ramos
Instituição: Centro de Genética Médica, Centro Hospitalar do Porto, Porto

Consulte Grelha de Avaliação

Investigador: Carla Vasconcelos
Instituição: Unidade de Doenças Metabólicas do Centro Hospitalar São João, Porto

Uma das importantes fontes proteicas dos planos alimentares dos doentes com Doenças Hereditárias do Metabolismo Proteico são os produtos hortícolas e as leguminosas. Este estudo procura atualizar os dados referentes às alterações no mercado alimentar português e, simultaneamente, sistematizar essa informação em bases de dados ou tabelas de composição, possibilitando aos doentes uma melhor escolha, em prol da sua saúde.

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Investigador: Maria João Pena
Instituição: FMUP – Porto

Neste estudo procura-se estabelecer relação entre a dieta particular utilizada nos doentes com PKU e alguns parâmetros metabólicos, ainda não estudados nesta patologia. Em particular, pretende-se determinar se a mistura de aminoácidos livre de fenilalanina é responsável pela diminuicão dos níveis plasmaticos de glicose em ratos.

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Exploring Lysosomal dysfunction in Neuronal Ceroid Lipofuscinosis 

Investigador: Maria do Carmo Macário
Instituição: CHUC / CNC, Coimbra

The loss of progranulin (PGRN) expression has been directly linked with neurodegeneration in the form of neuronal ceroid lipofuscinosis 11 (NCL11), a lysosomal storage disease observed in homozygous GRN mutation carriers, or frontotemporal lobar degeneration (FTLD), an early-onset dementia present in individuals with heterozygous mutations in this gene. We recently identified a NCL11 patient bearing a homozygous GRN mutation which is one of three described cases in the world and the first one identified as a member of a family with several cases of FTLD with genetic and neuropathological confirmation. Despite recent efforts, it is still unclear how alterations in PGRN levels contribute to neuronal loss in this two pathologies, which have completely different phenotypes.

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The effect of Globotriaosylceramide on invariant Natural Killer T cell activation 

Investigador: Maria de Fátima Macedo
Instituição: UniLiPe – IBMC, Porto

Fabry disease is a lysosomal storage disease (LSD) characterized by the accumulation of globotriaosylceramide (Gb3). The aim of this project is to investigate whether Gb3 is a regulator of the immune response through a direct effect in Invariant Natural Killer T (iNKT) cell regulation, which may contribute to the definition of a new mechanism explaining the iNKT cell abnormalities found in other LSDs.

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Development of a U1 snRNA-adapted gene therapeutic strategy to correct 5’ splicing defects in lysosomal storage disorders

Investigador: Liliana Matos
Instituição: Departamento de Genética Humana – INSA, Porto

In this work, an antisense-snRNA therapeutic strategy will be developed for mutations present in Mucopolysaccharidosis 1 and Mucolipidosis III patients.

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Molecular and cellular defects of cystatin B – from cell to population 

Investigador: Ana Joana Duarte
Instituição: Departamento de Genética – INSA, Porto

Este trabalho foca-se na caracterização mutacional do gene Cystatin B na população Portuguesa e identificação da distribuíção subcelular da Cystatin B em doentes com a doença de Unverricht-Lundborg, de modo a melhor compreender a sua patofisiologia.

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Cytokine production by inkt cells in Fabry disease 

Investigador: Maria de Fátima Macedo
Instituição: IBMC – Porto

O objetivo deste projeto é determinar a produção de citocinas pelas células iNKT e subpopulações de células iNKT em doentes com doença de Fabry, bem como no modelo animal de doença de Fabry.

O apoio financeiro concedido por este prémio contribuiu para o trabalho apresentado na seguinte publicação:
Pereira CS, Azevedo O, Maia ML, Dias AF, Sa Miranda MC, Macedo MF. Invariant Natural Killer T cells are phenotypically and functionally altered in Fabry disease. Mol Genet Metab. 2013 108 (4) 241-248

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Acquired Vitamin B12 Deficiency in Newborns: Positive Impact on Newborn Health through Early Detection

Investigador: Patrícia Lipari Pinto
Instituição: Hereditary Metabolic Disease Reference Center, Metabolic Unit, Pediatric Department, Santa Maria’s Hospital-Lisbon North University Hospital Center, EPE, Pediatric University Clinic,Faculty of Medicine, University of Lisbon, 1600-190 Lisbon, Portugal

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MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile

Investigador: Sandra Jacinto
Instituição: Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal | Serviço de Neurologia Pediátrica, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central-EPE, Lisboa, Portugal

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Functional Recovery of a GCDH Variant Associated to Severe Deflavinylation—Molecular Insights into Potential Beneficial Efects of Riboflavin Supplementation in Glutaric Aciduria-Type I Patients, Int. J. Mol. Sci. 2020, 21, 7063.

Investigador: Bárbara Henriques
Instituição: Faculdade de Ciências Universidade de Lisboa, BioISI - Biosystems & Integrative Sciences Institute, Lisbon, Portugal

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Investigador: Sandra Mexia
Instituição: Metabolic Unit, Reference Center for Metabolic Diseases, CHULN-HSM, Lisbon, Portugal

Projeto: Redes europeias de referência: a gestão do conhecimento na melhoria de cuidados de saúde nas doenças raras

Investigador: Teresa Campos
Instituição: Centro de Referências Hereditárias do Metabolismo, Centro Hospitalar Universitário de São João, Porto, Portugal

Projeto: Programa Doutoral em Investigação Clínica e em Serviços de Saúde

Investigador: Sandra Mexia
Instituição: Metabolic Unit, Reference Center for Metabolic Diseases, CHULN-HSM, Lisbon, Portugal

Projeto: Redes europeias de referência: a gestão do conhecimento na melhoria de cuidados de saúde nas doenças raras

Investigador: Sónia Moreira
Instituição: Serviço de Medicina Interna do CHUC, Coimbra, Portugal

Projeto: Long-term cardiovascular outcome in long-chain fatty acid -oxidation disorders