Browsing by Issue Date, starting with "2021-03"
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- Targeting transthyretin ‐ Mechanism‐based treatment approaches and future perspectives in hereditary amyloidosisPublication . Dohrn, Maike F.; Ihne, Sandra; Hegenbart, Ute; Medina, Jessica; Züchner, Stephan L.; Coelho, Teresa; Hahn, KatrinThe liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.
- Findings in physical examination of the external genitalia In pediatric age − different is not always pathological - Part II (female)Publication . Teles-Pinto, Nuno; Morais-Costa, Diana; Marinho, Ana Sofia; Moreira-Pinto, JoãoIntroduction: Findings in the physical examination of the external genitalia in children are often a source of concern and anxiety for parents and caregivers. Due to the proximity and role in child’s periodic surveillance, the family physician is in a privileged position to identify and initially provide guidance on these situations, key for the success of future interventions. Objectives: To review available evidence on the main variations and anomalies of the external female genitalia in pediatric age, focusing on diagnosis and clinical approach in primary health care. Results: In most cases, anomalies of the prepubertal female external genitalia are only variants of normal and/or do not significantly affect function, hence not requiring intervention other than clinical surveillance – e.g., fusion of labia minora. However, others require referral to secondary health care − like congenital vaginal obstruction or clitoral hypertrophy –, with early intervention being crucial for the success of implemented measures in some cases. Conclusion: Genital pathology in prepubertal children is most often diagnosed by systematic and careful physical examination and usually has a favorable outcome. It is important to distinguish variants of normal from situations requiring more specialized assessment, in order to optimize health care system resources without overloading it and decrease parental anxiety.
- Long-Term Visual Function Effects of Pan-Retinal Photocoagulation in Diabetic Retinopathy and Its Impact in Real LifePublication . Baptista, Pedro Manuel; Marta, Ana; Marques, Joao Heitor; José, Diana; Almeida, Daniel; Ribeiro, António; Barbosa, IrenePurpose: To address the long-term visual function after bilateral pan-retinal photocoagulation (PRP) and its impact in real life, namely on visual field (VF) legal criteria to drive. To determine potential predictors related to clinical factors and treatment strategies. Patients and methods: Observational cross-sectional study. Eyes from diabetic patients diagnosed with diabetic retinopathy who underwent bilateral PRP, with or without macular treatments and with visual acuity legal criteria for non-professional driving were randomly assigned. Main outcomes were: demographic and clinical data including best corrected visual acuity; binocular visual field (EBST-Esterman Binocular Suprathreshold Test, Humphrey analyzer3®); contrast sensitivity (CS-Metrovision-MonPack3®); light scattering in the retina (HD Analyzer, Visiometrics®). Results: Seventy-one diabetic patients included (44 men and 27 women), with a mean age of 62.2±11.8 years. PRP was performed, on average, 9.7±6.9 years before the study. The average EBST Score was 85.8±17.0 and the average CS (2-5cpd) was 19.5±2.9 dB in photopic and 14.2±4.1 dB in mesopic conditions. Through a multivariate regression model, after adjusting to the clinical and demographic factors as possible confounders, we found that treatment factors associated with worse results were the use of Argon laser for the EBST Score, the very confluent PRP for the number of non-viewed points in the central 30°x20° of the EBST and the presence of macular treatments for the CS tests. According to Portuguese law, 79% (n=56) of patients had minimal EBST amplitudes for non-professional driving. Conclusion: The functional results achieved in our sample are compatible with an active life, allowing most of the patients included to overcome the requirements of Portuguese legislation for driving light vehicles, namely at the level of the binocular visual field. These results highlight the role of PRP in the treatment of diabetic retinopathy in an era with evolving less aggressive laser options.
- Preconceptional immunity and congenital cytomegalovirus infection – A serologic pitfallPublication . Ferreira, Joana; Fonseca, José Luís; Vieira, Maria JoãoCongenital cytomegalovirus infections are the most prevalent intrauterine infections worldwide and result from maternal primary or non-primary infections. Diagnosis of primary cytomegalovirus infection during pregnancy is considered reliable and mainly relies on maternal serology. However, diagnosis of non-primary cytomegalovirus infection is more questionable. Herein is reported the case of a 34-week-old male newborn with congenital cytomegalovirus infection of a mother with preconceptional immunity. The organism was identified in urine by polymerase chain reaction in the first week of life. Maternal peripartum serology was the same as prior to conception. This case highlights the pitfalls of cytomegalovirus serology interpretation in non-primary infection during pregnancy. Clinicians should be aware of this and consider congenital cytomegalovirus infection, particularly when suggestive signs are present.
- The Role of Multimodal Approach in the Assessment of Glaucomatous Damage in High MyopesPublication . Baptista, Pedro Manuel; Vieira, Rita; Ferreira, André; Figueiredo, Ana; Sampaio, Isabel; Reis, Rita; Menéres, Maria Joãourpose: To compare the optic disc structure and peripapillary retinal function between high myopes with and without glaucoma and to address the differential role of papillary optical coherence tomography angiography (OCT-A) and circumpapillary microperimetry (cpMP) on the diagnosis and prognosis of this patients. Patients and methods: It is a cross-sectional study including 30 high myopic patients (60 eyes), divided into 15 with (GG) and 15 without glaucoma (NGG). Demographic and clinical data were collected from patient records. Papillary structure (peripapillary retinal nerve fiber layer thickness, ppRNFLTs) and vascularization (small vessel densities, SVD´s) were assessed with SD-OCT (RTVue XR Avanti, with AngioVue system, Optovue®). cpMP was carried out with the MP-3 microperimeter (Nidek®). Results: The GG were older, had lower best-corrected visual acuities and higher intraocular pressures and axial lengths (p<0.001). The GG showed lower values in all ppRNFLTs (p<0.05), lower values in all SVDs (p<0.001), except the SVD-inside disc (p=0.638) and lower retinal sensitivities within all cpMPs (p<0.001). The adjusted analysis computing the best two parameters per exam revealed that the anatomical model including the ppRNFLT-inferior and ppRNFLT-temporal and the vascular model including SVD-inferior and SVD-superior had the best discrimination power between groups, with cross-validated AUROCs of 0.9599 and 0.9921, respectively. Conclusion: Despite the apparent superiority of the papillary vascular study, a multimodal approach including the papillary anatomic and circumpapillary microperimetric assessments can be the new way on the diagnosis and prognosis of glaucoma in high myopia.
- Case Report: Pheochromocytoma and Synchronous Neuroblastoma in a Family With Hereditary Pheochromocytoma Associated With a MAX Deleterious VariantPublication . Duarte, Diana Borges; Ferreira, Lia; Santos, Ana P.; Costa, Cláudia; Lima, Jorge; Santos, Catarina; Afonso, Mariana; Teixeira, Manuel R.; Carvalho, Rui; Cardoso, HelenaIntroduction: Pheochromocytomas are rare catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal sympathetic paraganglia. Recent studies have indicated that up to 40% of pheochromocytomas could be attributable to an inherited germline variant in an increasing list of susceptibility genes. Germline variants of the MYC-associated factor (MAX) gene have been associated with familial pheochromocytomas and paragangliomas with an autosomal dominant pattern of inheritance, a median age at onset of 33 years and an overall frequency estimated at 1.9%. We describe a deleterious MAX variant associated with hereditary pheochromocytoma in a family with four affected individuals. Case presentation: The first patient presented with bilateral pheochromocytoma in 1995; genetic testing was proposed to his oldest son, when he was diagnosed with a bilateral pheochromocytoma with a synchronous neuroblastoma. Upon the identification of the MAX variant c.97C>T, p.(Arg33Ter), in the latter individual, his two siblings and their father were tested and the same variant was identified in all of them. Both siblings were subsequently diagnosed with pheochromocytoma (one of them bilateral) and choose to remain on active surveillance before they were submitted to adrenalectomy. All the tumours secreted predominantly norepinephrine, accordingly to the typical biochemical phenotype ascribed to variants in the MAX gene. Conclusion: This case series is, to our knowledge, the one with the largest number of individuals with hereditary pheochromocytoma with a deleterious MAX variant in the same family. It is also the first case with a synchronous pheochromocytoma and neuroblastoma in carriers of a MAX deleterious variant. This report draws attention to some ill-defined features of pheochromocytoma and other malignancies associated with a MAX variant and highlights the importance of understanding the genotype-phenotype correlation in hereditary pheochromocytoma and the impact of oriented genetic testing to detect, survey and treat patients and kindreds at risk.
- Dermatology clinical casePublication . Leitão, Cátia; Pereira, Isabel; Tenente, Joana; Vila-Real, Marta; Oliveira, Ana; Leite, Ana LuísaIncontinentia pigmenti is an X-linked neuroectodermal dysplasia. It is a rare genetic disease with multiorgan involvement, and hence a multidisciplinary approach is of paramount importance. Although diagnosis is based on clinical findings, genetic molecular testing can be performed to confirm diagnosis and allow future genetic counselling. The authors describe the case of a 4-month-old girl accidentally diagnosed with incontinentia pigmenti following routine physical examination in the Emergency Department. Timely diagnosis enabled appropriate multidisciplinary approach and follow-up.
- Gait speed in clinical and daily living assessments in Parkinson’s disease patients: performance versus capacityPublication . Atrsaei, Arash; Corrà, Marta; Dadashi, Farzin; Vila Cha, Nuno; Maia, Luis; Mariani, Benoit; Maetzler, Walter; Aminian, KamiarGait speed often referred as the sixth vital sign is the most powerful biomarker of mobility. While a clinical setting allows the estimation of gait speed under controlled conditions that present functional capacity, gait speed in real-life conditions provides the actual performance of the patient. The goal of this study was to investigate objectively under what conditions during daily activities, patients perform as well as or better than in the clinic. To this end, we recruited 27 Parkinson's disease (PD) patients and measured their gait speed by inertial measurement units through several walking tests in the clinic as well as their daily activities at home. By fitting a bimodal Gaussian model to their gait speed distribution, we found that on average, patients had similar modes in the clinic and during daily activities. Furthermore, we observed that the number of medication doses taken throughout the day had a moderate correlation with the difference between clinic and home. Performing a cycle-by-cycle analysis on gait speed during the home assessment, overall only about 3% of the strides had equal or greater gait speeds than the patients' capacity in the clinic. These strides were during long walking bouts (>1 min) and happened before noon, around 26 min after medication intake, reaching their maximum occurrence probability 3 h after Levodopa intake. These results open the possibility of better control of medication intake in PD by considering both functional capacity and continuous monitoring of gait speed during real-life conditions.
- Castleman disease. A rare diagnosis in childhoodPublication . Monteiro-Cunha, Sara; Vasconcelos, Sofia; Neto, Cláudia; Oliva, Tereza; Salgado, MiguelIntroduction: Castleman Disease (CD) is a rare polyclonal lymphoproliferative disorder characterized by massive growth of lymphoid tissue. The most common sites of disease are the chest, abdomen, neck, and axilla. Excisional biopsy is mandatory for diagnosis, and complete surgical resection the gold-standard treatment in unicentric CD. Case report: A ten-year-old girl was observed at the Emergency Department with sore throat and fever. Oropharynx examination revealed inflamed tonsils, with no exudates. Enlarged lymphadenopathy was palpable in the right supraclavicular fossa. Ultrasound revealed right supraclavicular lymphadenopathy with loss of adipose hilum and histopathologic assessment established CD diagnosis. Discussion/Conclusion: Lymphadenopathy is a common presentation in children, usually benign and self-limited. But it may also be a sign of underlying malignancy. Any lymphadenopathy in the supraclavicular fossa is worrisome and requires prompt investigation. CD diagnosis may be challenging, due its rare nature in childhood and nonspecific symptoms.
- Suspecting classical homocystinuria in an adolescent born before the newborn screening programPublication . Carvalho, Fábia; Campos, Teresa; Reis, Joana; Portela, Mariana; Vasconcelos, Carla; Ferreira, Carla; Cerqueira, Arnaldo; Oliveira, Ângela; Vilarinho, Laura; Leão-Teles, Elisa; Rodrigues, EsmeraldaIntroduction: Classical homocystinuria (HCU) is an autosomal recessive disorder caused by a deficiency in the cystathionine beta-synthase enzyme and associated with a high probability of vascular complications. Herein is presented the case of an adolescent diagnosed with HCU during cerebral venous sinus thrombosis (CVST) study. Case Report: A 14-year-old girl presented with thrombophilia screening tests suggestive of HCU during CVST study. After referral to an Inherited Metabolic Diseases Unit, she started supplementation with pyridoxine, folic acid, vitamin B12, betaine anhydrous, and cysteine and was advised to restrict natural proteins and methionine from diet. Genetic analysis revealed a homozygous CBS mutation (c.572C>T (p.T191M) with c.699C>T (p.Y233Y) polymorphism. Discussion: In adolescents born before 2004 (year of implementation of the Portuguese newborn screening program), HCU should be considered when studying hypercoagulability syndromes, as it is a treatable condition and treatment can prevent major morbidity and mortality causes.
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