MPSBase: Comprehensive repository of differentially expressed genes for mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) are lysosomal storage diseases (LSDs) caused by the deficiency of enzymes essential for the metabolism of extracellular matrix components called glycosaminoglycans (GAGs). To understand the physiopathology and alterations due to the lysosomal accumulation resulting from enzymatic deficiencies and their secondary outcomes can improve the diagnosis and treatment of rare genetic diseases. This work presents a database for differentially expressed genes from different public MPS data. We developed our database, including 13 studies previously deposited in the GEO (https://www.ncbi.nlm.nih.gov/geo/). The website is hosted in the UFRGS data processing center (CPD) and is available at . The site was constructed in PHP, and the analyses were performed in R. The organisms represented by the datasets are Canis lupus familiaris, Homo sapiens, Mus musculus, and Rattus norvegicus. The user can search for the differentially expressed genes and ontologies by species, MPS type, or tissue type. For each comparison, a heatmap with the 50 top differentially expressed genes is available as well as dot plots for the 30 top ontologies divided by biological process, cellular component, KEGG pathways, and molecular function. This data is also fully available in tables. There are 54 possible comparisons involving about 5000 to 10,000 genes each. This website is the only specific database for MPS with filtering and presenting their results in a one-click approach to the best of our knowledge. The development of such analytical and automated strategies accessible to health professionals is essential for fostering MPS research. The MPSBase is a web user-friendly, comprehensive repository of differentially expressed genes and ontologies regarding the MPS data.

[Mechanism of action of cell therapy in hereditary diseases]. / Mecanismo de acción de la terapia celular en enfermedades hereditarias.

Inherited metabolism disorders are serious childhood diseases that lead to significant cognitive impairment and regression of psychomotor development. The pathophysiology of the neural progressive deterioration is usually associated with severe neuroinflammation and demyelination, and as a consequence, neurodegeneration. At the moment they have no adequate treatment and require early and aggressive therapeutic approaches, which entail high mortality rates and, very frequently, low degrees of functional improvement and survival. Bone marrow transplantation and bone marrow mesenchymal cells grafts are therapeutic and experimental therapies that improve the course of these diseases through different mechanisms of action: enzyme replacement, membrane exchange and regulation of the inflammatory process.

Los trastornos heredados del metabolismo son enfermedades graves de la infancia que cursan con un gran deterioro cognitivo y del desarrollo psicomotor. La fisiopatología del progresivo deterioro del sistema nervioso suele estar asociada a una severa neuroinflamación y desmielinización, y como consecuencia, neurodegeneración. Por el momento no tienen cura y precisan de actitudes terapéuticas precoces y agresivas, que conllevan altas tasas de mortalidad y, muy frecuentemente, escasos grados de mejoría funcional y supervivencia. El trasplante de médula ósea y de células mesenquimales de médula ósea son terapias de elección y experimentales que consiguen mejorar el curso de estas enfermedades mediante diferentes mecanismos de acción: remplazo de enzima deficiente, intercambio de membranas y regulación del proceso inflamatorio.

Mecanismo de acción de la terapia celular en enfermedades hereditarias / Mechanism of action of cell therapy in hereditary diseases

Los trastornos heredados del metabolismo son enfermedades graves de la infancia que cursan con un gran deterioro cognitivo y del desarrollo psicomotor. La fisiopatología del progresivo deterioro del sistema nervioso suele estar asociada a una severa neuroinflamación y desmielinización, y como consecuencia, neurodegeneración. Por el momento no tienen cura y precisan de actitudes terapéuticas precoces y agresivas, que conllevan altas tasas de mortalidad y, muy frecuentemente, escasos grados de mejoría funcional y supervivencia. El trasplante de médula ósea y de células mesenquimales de médula ósea son terapias de elección y experimentales que consiguen mejorar el curso de estas enfermedades mediante diferentes mecanismos de acción: remplazo de enzima deficiente, intercambio de membranas y regulación del proceso inflamatorio.

Inherited metabolism disorders are serious childhood diseases that lead to significant cognitive impairment and regression of psychomotor development. The pathophysiology of the neural progressive deterioration is usually associated with severe neuroinflammation and demyelination, and as a consequence, neurodegeneration. At the moment they have no adequate treatment and require early and aggressive therapeutic approaches, which entail high mortality rates and, very frequently, low degrees of functional improvement and survival. Bone marrow transplantation and bone marrow mesenchymal cells grafts are therapeutic and experimental therapies that improve the course of these diseases through different mechanisms of action: enzyme replacement, membrane exchange and regulation of the inflammatory process.

Sexual behaviour in a murine model of mucopolysaccharidosis type I (MPS I).

Mucopolysaccharidosis Type I (MPS I) is a rare genetic lysosomal storage disease caused by a mutation of IDUA gene. IDUA codes for α-L-iduronidase (IDUA), a lysosomal hydrolase that degrades glycosaminoglycans (GAGs): heparan sulphate and dermatan sulphate. GAGs are structural and signalling molecules that have a crucial role in controlling a variety of cell functions and their interaction with the extracellular matrix. Because of GAG's widespread action in cellular metabolism, MPS I is a progressive and disabling multisystemic disorder. Nowadays, the therapies available allowed patients to reach the adult life and the consequences of the disease in their reproductive system are mostly unknown. We aimed to investigate whether IDUA disruption influences sexual behaviour and sexual steroid production in male and female MPS I mice. We used 3 and 6-month-old male and 3-month-old female Idua+/_ and Idua-/- mice to evaluate typical rodent copulatory behaviours. In males we observed the frequency and latency of mounts, intromissions and ejaculations. In females, we evaluated the lordosis quotient. We also analysed the locomotor capacity of mice in the open field test, since mobility is essential for copulatory behaviour. We also quantified steroidal hormonal levels in plasmatic samples. We detected an increase in the latencies of intromissions in Idua-/- males when compared to Idua+/_. However, the number of intromissions was not statistically different between groups. No parameter of female sexual behaviour was statistically different between control and knockout females. In both sexes, we detected diminished mobility in Idua-/- mice. Plasma hormone levels did not differ between Idua+/_ and Idua-/- mice, both in males and females. Although the motor disability predicted to MPS I animals, we concluded that in the considered time point of MPS I progression studied, mice are able to perform sexual behaviour.

Is Parkinson's disease a lysosomal disorder?

Common forms of Parkinson's disease have long been described as idiopathic, with no single penetrant genetic factor capable of influencing disease aetiology. Recent genetic studies indicate a clear association of variants within several lysosomal genes as risk factors for idiopathic Parkinson's disease. The emergence of novel variants suggest that the aetiology of idiopathic Parkinson's disease may be explained by the interaction of several partially penetrant mutations that, while seemingly complex, all appear to converge on cellular clearance pathways. These newly evolving data are consistent with mechanistic studies linking α-synuclein toxicity to lysosomal abnormalities, and indicate that idiopathic Parkinson's disease resembles features of Mendelian lysosomal storage disorders at a genetic and biochemical level. These findings offer novel pathways to exploit for the development of disease-altering therapies for idiopathic Parkinson's disease that target specific components of the lysosomal system.

DNAJB6 myopathy: a vacuolar myopathy with childhood onset.

INTRODUCTION: DNAJB6 mutations cause an autosomal dominant myopathy that can manifest as limb-girdle muscular dystrophy (LGMD1D/1E) or distal-predominant myopathy. In the majority of patients this myopathy manifests in adulthood and shows vacuolar changes on muscle biopsy. METHODS: Clinical, electrophysiological, pathological, and molecular findings are reported. RESULTS: We report a 56-year-old woman, who, like 3 other family members, became symptomatic in childhood with slowly progressive limb-girdle muscle weakness, normal serum creatine kinase (CK) values, and myopathic electromyographic findings. Muscle biopsy showed vacuolar changes and congophilic inclusions, and molecular analysis revealed a pathogenic mutation in the DNAJB6 gene. Differences and similarities with previously described cases are assessed. CONCLUSIONS: Childhood-onset of DNAJB6 myopathy is more frequent than previously believed; congophilic inclusions may be present in the muscle of these patients.

Non-immune hydrops fetalis: A prospective study of 53 cases.

Non-immune hydrops fetalis (NIHF) is a symptom caused by a heterogeneous group of conditions. Diagnostic investigations may constitute a real challenge. This study aimed to evaluate prospectively and systematically a series of NIHF cases using a research protocol expanded for studying inborn errors of metabolism (IEM) during 2 years-2010 and 2011. We also reviewed the frequency of IEM among the NIHF reported in literature. A clinical or etiopathogenic diagnosis was reached in 46 (86.8%) of the 53 studied cases. The main diagnostic groups were chromosomal anomalies (28.3%), syndromic (18.9%), isolated cardiovascular anomaly (7.5%) and congenital infection (7.5%). Metabolic causes were found in 5.7%, all lysosomal storage disorders (LSD). In seven (13.2%), no diagnosis was found in part because of incomplete evaluation. The hydrops was identified prenatally in 90.5% of cases. In 5.7% a spontaneous and complete resolution of the hydrops occurred during pregnancy. Overall mortality was 75.5%. The IEM frequency in the present study (5.7%) was higher than that usually reported. We suggest performing studies directed to IEMs if the more common causes are excluded.

Compromiso cardíaco en pacientes con enfermedad de Fabry / Cardiac involvement in patients with fabry's disease

Antecedentes: La enfermedad de Fabry (EF) es un desorden lisosomal de transmisión ligada al cromosoma X debido al déficit de la enzima alfa galactosidasa A, con acumulación multisistémica de globotriaosilceramida (GB3). La afectación cardíaca reduce expectativa y calidad de vida. Objetivo: Describir compromiso cardiológico de 38 pacientes con EF, diagnosticados y estudiados multidisciplinariamente. Destacar alta prevalencia en esta región. Método: A partir de caso índice, se aplica encuesta y elabora familiograma de 5 familias. Estudio genético y enzimático de 65 sospechosos confirma 38 afectados (25 Mujeres y 13 hombres) evaluados multidisciplina-riamente con Electrocardiograma, Ecocardiograma y exámenes de laboratorio. Resultado: Compromiso cardiológico en 66 por ciento de adultos, no presente en niños. Cardiopatía hipertrófica (CH) fue el hallazgo cardiológico más frecuente (56 por ciento de adultos) presente en 63 por ciento de los hombres y en 52 por ciento de las mujeres. En mayores de 40 años, 100 por ciento de hombres y 82 por ciento de mujeres están afectados. La edad promedio fue 38 en hombres y 57 en mujeres. Cardiopatía dilatada 26 por ciento en su mayoría asociado a CH. Insuficiencia valvular mitral leve en 47 por ciento, con predominio femenino, PR corto en 7 mujeres, fibrilación auricular 2 mujeres y 1 hombre, TPSV 1 mujer, BAV completo 1 hombre. Sin eventos coronarios. Conclusión: La afectación cardíaca en nuestro grupo es similar a la reportada internacionalmente. Dada la alta prevalencia que tiene esta patología en nuestro medio, frente a un paciente no hipertenso con hipertrofia ventricular debería descartarse EF. Evaluación dermatológica y oftalmológica apoyaría diagnóstico presuntivo antes de confirmación enzimática o estudio genético.

Aim: Fabry's disease (FD) is a lysosomal disorder with an X chromosome linkage. It is related to a deficiency of alphagalactosidase A, leading to multisystemic accumulation of globotriasocyl ceramyde (GB3). Cardiac compromise reduces life expectancy. Herein we describe cardiac and systemic findings in 38 patients with FD. Methods: A genetic and enzymatic characterization was obtained in all patients. FD was identified in 38 out of 65 screened subjects (25 females and 13 males), which belonged to 5 families identified from index cases. ECG and echocardiography was used to evaluate cardiac involvement. Results: Cardiac involvement was present in 66 per cent of adults and absent in all children. HVI was the most frequent abnormality observed in 56 of adults (63 per cent in males, 52 per cent in females). The prevalence of HVI increased with age reaching 100 per cent in males and 82 per cent in females aged 40 and older. Among other findings, cardiac dilatation was observed in 26 per cent, mild mitral insufficiency in 47 per cent and atrial fibrillation in 3 cases. No case of coronary artery disease was identified Conclusion: Fabry's disease is more prevalent than usually suspected. Cardiac involvement is frequent, especially the presence of HVI. It should be investigated in all subjects with unexplained LVH, especially when associated to characteristic dermatologic and ophtalmologic findings. Confirmation of the diagnosis may be obtained through enzymatic and genetic studies.

Lectin-histochemistry: glycogenosis in cattle.

Ten out of 47 calves that were born in a small Brahman herd from southern Brazil developed progressive muscular weakness and tremors, lethargy and poor body condition. Necropsy was performed on three affected animals. The only gross lesion detected was paleness of the muscles of the trunk and limbs. Multiple cytoplasm vacuoles located in different tissues were the principal microscopic lesions. Vacuoles were particularly evident in skeletal muscles and myocardium. PAS-positive granules were numerous in skeletal muscle fibres and Purkinje fibres of the myocardium, but were also observed in the neurons of the brain and spinal cord, and in the vascular smooth muscle fibres from all the examined tissues. Pretreatment with diastase completely abolished the PAS reactivity. The vacuoles reacted strongly to Griffonia simplicifolia II and Concanavalia ensiformes lectins, whose biding pattern has been reported as useful for demonstration of glycogen. Examination of the electron micrographs revealed that glycogen was free within the cytoplasm or accumulated in membrane-bound granules of several tissues, especially in striated muscle, liver and neurons of the CNS. These findings were consistent with generalized glycogenosis.

Aspectos genéticos e clínico-terapêuticos da Doença de Tay-Sachs / Genetic and clinical therapeutics aspects of Tay-Sachs disease

A doença de Tay-Sachs apresenta uma freqüência elevada em determinados grupos étnicos, sobretudo nos judeus ashkenazi. É uma desordem neurodegenerativa, presente principalmente em crianças, decorrente de uma atividade deficiente da enzima lisossomal hexosaminidase A, acarretando um acúmulo intracelular de substratos e um progressivo déficit neurológico. O tratamento é discutível, entretanto, resultados promissores têm sido obtidos com a utilização da NB-DNJ e, principalmente, com a terapia genética

Excessive infantile growth and early pubertal growth spurt: typical features in patients with aspartylglycosaminuria.

Rapid infantile growth was the first clinical sign in patients (n = 51) with aspartylglycosaminuria, a lysosomal storage disorder. Even if young children with aspartylglycosaminuria were tall for their age, an early but weak pubertal growth spurt in both sexes resulted in reduced adult heights.