Disease progression in Sanfilippo type B: Case series of Brazilian patients.

Mucopolysaccharidosis type IIIB (MPS IIIB) is caused by deficiency of alpha-N-acetylglucosaminidase, leading to storage of heparan sulphate. The disease is characterized by intellectual disability and hyperactivity, among other neurological and somatic features. Here we studied retrospective data from a total of 19 MPS IIIB patients from Brazil, aiming to evaluate disease progression. Mean age at diagnosis was 7.2 years. Speech delay was one of the first symptoms to be identified, around 2-3 years of age. Behavioral alterations include hyperactivity and aggressiveness, starting around age four. By the end of the first decade, patients lost acquired abilities such as speech and ability to walk. Furthermore, as disease progresses, respiratory, cardiovascular and joint abnormalities were found in more than 50% of the patients, along with organomegaly. Most common cause of death was respiratory problems. The disease progression was characterized in multiple systems, and hopefully these data will help the design of appropriate clinical trials and clinical management guidelines.

Oral Dantrolene Reduces Myalgia and Hyperckemia in a Child with RYR1-Related Exertional Myalgia/Rhabdomyolysis.

RYR1-related exertional myalgia/rhabdomyolysis (ERM) is an underrecognized condition, which can cause limiting muscle symptoms, and may account for more than one-third of undiagnosed rhabdomyolysis cases. Dantrolene has shown promising results in controlling muscle symptoms in individuals with ERM, however, its use in children remains poorly documented. This case report presents the successful treatment of a 5-year-old patient with ERM using oral dantrolene. The patient experienced notable improvements, including a reduction in the frequency and intensity of myalgia episodes, no hospitalizations due to rhabdomyolysis, a substantial decrease in creatine phosphokinase (CPK) levels, and enhanced performance on the 6-minute walk test. The use of dantrolene was well-tolerated, and no significant adverse effects were observed. This report adds to the existing evidence supporting the effectiveness of oral dantrolene in managing ERM, and, to the best of our knowledge, this is the first report of the use of dantrolene in a pediatric patient for controlling anesthesia-independent muscle symptoms.

A brazilian nationwide multicenter study on deficiency of deaminase-2 (DADA2)

Abstract Introduction The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil. Patients and methods This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho - DASA, São Paulo - Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected. Results Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses. Conclusion The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

Diagnosis and Emerging Treatment Strategies for Mucopolysaccharidosis VII (Sly Syndrome).

Mucopolysaccharidosis VII (MPS VII, Sly syndrome) is an ultra-rare lysosomal disease caused by a deficiency of the enzyme ß-glucuronidase (GUS). The diagnosis is suspected based on a range of symptoms that are common to many other MPS types, and it is confirmed through biochemical and molecular studies. Besides supportive treatment, current and emerging treatments include enzyme replacement therapy, hematopoietic stem cell transplantation, and gene therapy. This review summarizes the clinical manifestations, diagnosis, and emerging treatments for MPS VII.

Clinical trials for genetic diseases in Latin America.

Latin American geneticists have been contributing to the scientific development of Human and Medical Genetics fields since the early 1950s. In the last decades, as Medical Genetics is moving toward a new era of innovative therapies for previously untreatable conditions, the participation of Latin America in clinical trials is also increasing. This review discusses the particularities regarding funding, regulatory, and ethical aspects of conducting clinical trials for genetic diseases in Latin America, with an especial focus on Brazil, the largest country with the highest number of studies. Although there are still several barriers to overcome, the recent development of orphan drug legislation and policies for rare diseases in many Latin American countries indicates a growing opportunity for the participation of the region in international efforts for the development of new therapies for genetic diseases.

Schizophreniform presentation and abrupt neurologic decline in a patient with late-onset mucopolysaccharidosis type IIIB.

Due to their low frequency and some atypical presentations, inborn errors of metabolism are frequently misdiagnosed or underdiagnosed, which hinders the correct management of these patients. To illustrate that, here we present a patient that, at early school age, had learning disabilities compared to her classmates, especially for writing. She completed basic education in a regular school and was transferred to a secondary school for students with special needs. At 18 years of age, she presented a first psychiatric abrupt outbreak: she spent a month screaming and without sleeping. Behavioral problems then became apparent, especially hyperactivity, destructive and chaotic behavior, anxiety, and auto-aggressivity and hetero-aggressivity. A diagnosis of schizophreniform disorder was established. Clinical genetic evaluation revealed coarse face, macroglossia, coarse thick hair, and mild hepatomegaly, and the hypothesis of mucopolysaccharidosis-III was raised. Laboratory tests indicated high levels of urinary glycosaminoglycans and almost undetectable NAGLU activity, confirming the diagnosis. Sequencing of the NAGLU gene revealed the c.1318G>C (p.Gly440Arg) and c.1834A>G (p.Ser612Gly) mutations.

Progression of Cardiovascular Manifestations in Adults and Children With Mucopolysaccharidoses With and Without Enzyme Replacement Therapy.

Background: Cardiovascular involvement is among the main features of MPS disorders and it is also a significant cause of morbidity and mortality. The range of manifestations includes cardiac valve disease, conduction abnormalities, left ventricular hypertrophy, and coronary artery disease. Here, we assessed the cardiovascular manifestations in a cohort of children and adults with MPS I, II, IV, and VI, as well as the impact of enzyme replacement therapy (ERT) on those manifestations. Methods: We performed a chart review of 53 children and 23 adults with different types of MPS that had performed echocardiograms from January 2000 until October 2018. Standardized Z scores were obtained for heart chamber sizes according to the body surface area. When available, echocardiographic measurements that were performed before ERT and at least 18 months after that date were used for the assessment of pre- and post-treatment parameters. Results: Left side valvular disease was a frequent finding, with mitral and aortic thickening being reported in most patients in all four MPS types. Left atrium dilatation was present in 26% of the patients; 25% had increased relative wall thickness; 28% had pulmonary hypertension. The cardiovascular involvement was, in general, more prevalent and more severe in adults than in children, including conduction disorders (40 vs. 16%), mitral stenosis (26 vs. 6%), aortic stenosis (13 vs. 4%), and systolic dysfunction (observed in only one adult patient). ERT promoted a significant reduction of the left ventricular hypertrophy parameters, but failed to improve valve abnormalities, pulmonary hypertension, and left atrial dilatation. Conclusions: Adult patients with MPS may develop severe cardiovascular involvement, not commonly observed in children, and clinicians should be aware of the need for careful monitoring and timely management of those potentially life-threatening complications. Our results also confirm the impact of long-term ERT on left ventricular hypertrophy and its limitations in reversing other prevalent cardiovascular manifestations.

Cardiovascular findings in classic homocystinuria.

OBJECTIVE: describe cardiovascular findings from echocardiograms and electrocardiograms in patients with Classic Homocystinuria. METHODS: this retrospective exploratory study evaluated fourteen subjects with Classic Homocystinuria (median age = 27.3 years; male n = 8, B6-non-responsive n = 9 patients), recruited by convenience sampling from patients seen Hospital de Clínicas de Porto Alegre (Brazil), between January 1997 and July 2020. Data on clinical findings, echocardiogram and electrocardiogram were retrieved from medical records. RESULTS: Eight patients presented some abnormalities on echocardiogram (n = 6) or electrocardiogram (n = 5). The most frequent finding was mild tricuspid regurgitation (n = 3), followed by mitral valve prolapse, mild mitral regurgitation, enlarged left atrium and aortic valve sclerosis (n = 2 patients each). Aortic root ectasia was found in one patient. Venous thrombosis was reported in six patients: deep vein thrombosis of lower limbs (n = 3), ischaemic stroke (n = 1), cerebral venous sinus thrombosis (n = 1) and pulmonary vein thrombosis (n = 1). CONCLUSION: mild valvulopathies seen to be common in patients with Classic Homocystinuria, but more studies regarding echocardiogram and electrocardiogram in this population are needed to draw absolute conclusions.

Lysosomal diseases: Overview on current diagnosis and treatment.

Lysosomal diseases (LDs), also known as lysosomal storage diseases (LSDs), are a heterogeneous group of conditions caused by defects in lysosomal function. LDs may result from deficiency of lysosomal hydrolases, membrane-associated transporters or other non-enzymatic proteins. Interest in the LD field is growing each year, as more conditions are, or will soon be treatable. In this article, we review the diagnosis of LDs, from clinical suspicion and screening tests to the identification of enzyme or protein deficiencies and molecular genetic diagnosis. We also cover the treatment approaches that are currently available or in development, including hematopoietic stem cell transplantation, enzyme replacement therapy, small molecules, and gene therapy.

Aortic root dilatation in patients with mucopolysaccharidoses and the impact of enzyme replacement therapy.

Mucopolysaccharidoses (MPS) are disorders characterized by impaired glycosaminoglycan (GAG) catabolism as a consequence of a deficiency or the absence of lysosomal enzymes directly involved in their degradation. Multiple organ systems are involved in MPS, including the cardiovascular system. Recently, aortic root dilatation (ARD) has been described in these patients. Thus, we reviewed aortic root diameter measurements in 69 MPS patients from a single center from 2000 to 2016. Aortic root diameter z scores were calculated based on data published by Colan et al. according to the body surface area (BSA) determined using the Haycock formula. The overall incidence of ARD in MPS patients was 39.1%. Higher mean z scores were present in patients with MPS IVA and VI when compared to MPS I and II. Aortic root z scores were higher in older MPS IVA patients, which may suggest a progressive ARD change in this MPS type. No significant differences were found before and after enzyme replacement therapy (ERT) in 11 patients with available data (2 with MPS I; 4 with MPS II; 2 with MPS IVA, and 3 with MPS VI). This work provides further evidence that ARD is common in different types of MPS, being especially evident in MPS IVA, but with a significant occurrence also in MPS VI.

Long-term restoration of alpha-L-iduronidase activity in fibroblasts from patients with mucopolysaccharidosis type I after non-viral gene transfer

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by deficiency of alpha-L-iduronidase (IDUA). Limitations such as the need for weekly injections, high morbidity and mortality, and high cost of current treatments show that new approaches to treat this disease are required. In this study, we aimed to correct fibroblasts from a patient with MPS I using non-viral gene therapy. Using a plasmid encoding the human IDUA cDNA, we achieved stable high IDUA levels in transfected fibroblasts up to 6 months of treatment. These results serve as proof of concept that a non-viral approach can correct the enzyme deficiency in cells of patients with lysosomal storage disorders, which can be used as a research tool for a series of disease aspects. Future studies should focus on showing if this approach can be useful in small animals and clinical trials (AU)

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome.

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.

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome / Desfechos neurológicos após transplante de células tronco hematopoiéticas na adrenoleucodistrofia ligada ao X, forma cerebral, na leucodistrofia metacromática de início tardio e na síndrome de Hurler

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.

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.

Increasing demonstration of angiogenic markers in skin neoplastic lesions.

BACKGROUND: Skin cancer represents the most common worldwide malignancy. Angiogenesis is an important factor in tumor growth and metastasis. Given these facts, the purpose of the current study was to compare the levels of angiogenic proteins in the context of the most common malignant and premalignant skin lesions. METHODS: Immunohistochemistry of CD31, HIF1A, VEGFR1 and VEGFR2 was performed in basal cell carcinoma (BCC), actinic keratosis (AK) and squamous cell carcinoma of the skin (SCCS). RESULTS: SCCS presented with increased levels of HIF1A, VEGFR1 and VEGFR2 in comparison to AK. In addition, SCCS also demonstrated increased levels of HIF1A to BCCLR or BCCHR. BCC presented with more vessels than AK. However, no correlation was observed among CD31, HIF1A, VEGFR1 and VEGFR2. CONCLUSIONS: SCCS presented with higher levels of HIF1A, VEGFR1 and VEGFR2, while BCC demonstrated an increased number of vessels in relation to AK. These data suggest that antiangiogenic therapy might be useful for skin cancer treatment.

Bioinformatics, interaction network analysis, and neural networks to characterize gene expression of radicular cyst and periapical granuloma.

INTRODUCTION: Bioinformatics has emerged as an important tool to analyze the large amount of data generated by research in different diseases. In this study, gene expression for radicular cysts (RCs) and periapical granulomas (PGs) was characterized based on a leader gene approach. METHODS: A validated bioinformatics algorithm was applied to identify leader genes for RCs and PGs. Genes related to RCs and PGs were first identified in PubMed, GenBank, GeneAtlas, and GeneCards databases. The Web-available STRING software (The European Molecular Biology Laboratory [EMBL], Heidelberg, Baden-Württemberg, Germany) was used in order to build the interaction map among the identified genes by a significance score named weighted number of links. Based on the weighted number of links, genes were clustered using k-means. The genes in the highest cluster were considered leader genes. Multilayer perceptron neural network analysis was used as a complementary supplement for gene classification. RESULTS: For RCs, the suggested leader genes were TP53 and EP300, whereas PGs were associated with IL2RG, CCL2, CCL4, CCL5, CCR1, CCR3, and CCR5 genes. CONCLUSIONS: Our data revealed different gene expression for RCs and PGs, suggesting that not only the inflammatory nature but also other biological processes might differentiate RCs and PGs.

Gorlin-Goltz syndrome: case report and review of literature

Description of a case report of Gorlin-Goltz Syndrome diagnosed in a male newborn who presented increased head circumference and bifid ribs. Mother and grandmother presented typical physical findings of the syndrome, including palmar pits, odontogenic cysts, and history of multiple skin cancer resections. The diagnosis was based on clinical findings of three relatives. A literature review is also presented.

Septic shock inppatient with disseminated histoplasmosis associated with aids: a case report / Choque septico em paciente com histoplasmose disseminada associada a AIDS: relato de caso

SUMMARY Histoplasmosis is a systemic mycosis caused by Histoplasma capsulatum, which may present itself as a serious infection in immunocompromised individuals. We present a case of 31-year-old female with newly diagnosed HIV infection and history of fever, general and respiratory symptoms and diffuse hyperchromic papules through the body. She was admitted, with rapid progression to septic shock, and the presence of neutrophils filled with yeast-like organisms was detected on peripheral blood smear hematoscopia on the third day of hospitalization. The following is a brief review on the clinical picture and management of histoplasmosis. .

RESUMO A histoplasmose é micose sistêmica causada por Histoplasma capsulatum, a qual pode se apresentar de forma grave em indivíduos imunocomprometidos. Neste trabalho, apresenta-se o caso de paciente feminino, 31 anos, com diagnóstico recente de infecção por HIV e quadro de febre, sintomas gerais e respiratórios e pápulas hipercrômicas difusas pelo corpo. Foi internada, apresentando progressão rápida para choque séptico, sendo detectada a presença de leveduras inclusas em neutrófilos à hematoscopia no terceiro dia de internação. Apresenta-se uma revisão breve sobre a apresentação e o manejo clínico da histoplasmose. .

Actinomycosis affecting the spinal cord: a case report.

Actinomycosis is a rare, chronic, suppurative, granulomatous infection caused by a group of gram-positive anaerobic bacteria belonging to the natural flora of the oral cavity and gastrointestinal and urogenital tracts. It may involve several organs. This case study refers to pulmonary actinomycosis with chest wall involvement and cord compression in a 29-year-old male who presented with fever, cough, hemoptysis, neck pain, and paresis and plegia of the lower limbs of 5-month duration.

Actinomycosis affecting the spinal cord: a case report / Actinomicose comprometendo a medula espinhal: um relato de caso

Actinomycosis is a rare, chronic, suppurative, granulomatous infection caused by a group of gram-positive anaerobic bacteria belonging to the natural flora of the oral cavity and gastrointestinal and urogenital tracts. It may involve several organs. This case study refers to pulmonary actinomycosis with chest wall involvement and cord compression in a 29-year-old male who presented with fever, cough, hemoptysis, neck pain, and paresis and plegia of the lower limbs of 5-month duration.

A actinomicose é uma infecção rara, crônica, supurativa e granulomatosa, causada por um grupo de bactérias anaeróbias Gram-positivas que pertencem à flora natural da cavidade oral, do aparelho gastrointestinal e urogenital. Pode envolver diversos órgãos. O estudo refere-se à actinomicose pulmonar com envolvimento da parede torácica e compressão medular em um paciente masculino com 29 anos que apresentava febre, tosse, hemoptise e cervicalgia, além de paresia e plegia em membros inferiores com cinco meses de evolução.