Doença de Tay-Sachs: relato de caso / Tay-Sachs disease: a case report

RESUMO A doença de Tay-Sachs é um distúrbio neurodegenerativo autossômico recessivo, o qual envolve o metabolismo dos lipídios, levando ao acúmulo de gangliosídeos nos tecidos, devido à deficiência da enzima hexosaminidase A. Esse depósito progressivo resulta em perda da função neurológica e, quando acomete as células ganglionares da mácula, causa o achado típico da doença, a "mácula em cereja". A patologia é diagnosticada por meio dos níveis de hexosaminidase A e hexosaminidase total no soro, além análise do DNA do gene HEXA. Este caso relata uma criança com doença de Tay-Sachs cujo diagnóstico foi suspeitado por conta dos achados oftalmológicos.

ABSTRACT Tay-Sachs Disease is an autosomal recessive neurodegenerative disorder, which involves the metabolism of lipids, leading to the accumulation of gangliosides in the tissues, due to the deficiency of the enzyme Hexosaminidase A. This progressive deposit results in loss of neurological function and, when it affects macula ganglion cells, it causes the typical disease finding, the "cherry red spot". The pathology is diagnosed through the levels of Hex A and total Hexosaminidase in the serum, in addition to the analysis of the DNA of the HEXA gene. This case reports a child with Tay-Sachs disease with a suspected diagnosis was through ophthalmologic findings.

Sandhoff disease in the elderly: a case study.

Sandhoff disease is an infrequent, genetically caused disorder with a recessive autosomal inheritance pattern. It belongs to the gangliosidosis GM2 group and is produced by mutations in gen HEXB leading to reduction in enzymatic activity of enzymes ß-hexosaminidase A and B. Adult-onset GM2 gangliosidosis is rare. Here we report a white male who presented at age 69 with a fast-progression, motor neuron disease, mimicking amyotrophic lateral sclerosis (ALS), combined with autonomic dysfunction, sensory ataxia, and exaggerated startle to noise. Enzymatic assays demonstrated deficiency of both Hexosaminidases A and B leading to the diagnosis of Sandhoff disease.

Tay-Sachs disease / Enfermedad de Tay-Sachs

Abstract Introduction: Lysosomal storage disease is caused by the deficiency of a single hydrolase (lysosomal enzymes). GM2 gangliosidoses are autosomal recessive disorders caused by deficiency of β-hexosaminidase and Tay-Sachs disease (TSD) is one of its three forms. Objective: To perform a review of the state of the art on TSD and describe its definition, epidemiology, etiology, physiopathology, clinical manifestations, as well as advances regarding its diagnosis and treatment. Materials and methods: A literature search was carried out in PubMed using the MeSH terms "Tay-Sachs Disease". Results: after the initial search was conducted, 1 233 results were retrieved, of which 53 articles were finally selected. TSD is caused by the deficiency of the lysosomal enzyme β-hexosaminidase A (HexA), and is characterized by neurodevelopmental regression, hypotonia, hyperacusis and cherry-red spots in the macula. Research on molecular pathogenesis and the development of possible treatments has been limited, consequently there is no treatment established to date. Conclusion: TSD is an autosomal recessive neurodegenerative disorder. Death usually occurs before the age of five. More research and studies on this type of gangliosidosis are needed in order to find an adequate treatment.

Resumen Introducción. La deficiencia de una sola hidrolasa (enzimas lisosomales) da como resultado una enfermedad de almacenamiento lisosomal. Las gangliosidosis GM2 son trastornos autosómicos recesivos causados por la deficiencia de β-hexosaminidasa. La enfermedad de Tay-Sachs (TSD, por sus siglas en inglés) es una de las tres presentaciones de este tipo de gangliosidosis. Objetivo. Realizar una revisión del estado del arte de la TSD describiendo su definición, epidemiología, etiología, fisiopatología, manifestaciones clínicas y actualidades en su diagnóstico y tratamiento. Materiales y métodos. Se realizó una búsqueda bibliográfica en PubMed utilizando como único término MeSH "Tay-Sachs Disease". Resultados. Se encontraron 1 233 publicaciones y se seleccionaron 53 artículos. La TSD es originada por la deficiencia de la enzima lisosomal β-hexosaminidasa A (HexA) y se caracteriza por regresión del neurodesarrollo, hipotonía, hiperacusia y manchas maculares rojo cereza. La investigación de la patogenia molecular y el desarrollo de posibles tratamientos han sido limitados y en la actualidad no se cuenta con uno plenamente establecido. Conclusiones. La TSD es un trastorno neurodegenerativo autosómico recesivo y por lo general la muerte se produce antes de los 5 años de edad. Son necesarias más investigaciones y estudios sobre este tipo de gangliosidosis con el fin de encontrar un tratamiento adecuado.

Canine GM2-Gangliosidosis Sandhoff Disease Associated with a 3-Base Pair Deletion in the HEXB Gene.

BACKGROUND: GM2-gangliosidosis is a fatal neurodegenerative lysosomal storage disease (LSD) caused by deficiency of either ß-hexosaminidase A (Hex-A) and ß-hexosaminidase B (Hex-B) together, or the GM2 activator protein. Clinical signs can be variable and are not pathognomonic for the specific, causal deficiency. OBJECTIVES: To characterize the phenotype and genotype of GM2-gangliosidosis disease in an affected dog. ANIMALS: One affected Shiba Inu and a clinically healthy dog. METHODS: Clinical and neurologic evaluation, brain magnetic resonance imaging (MRI), assays of lysosomal enzyme activities, and sequencing of all coding regions of HEXA, HEXB, and GM2A genes. RESULTS: A 14-month-old, female Shiba Inu presented with clinical signs resembling GM2-gangliosidosis in humans and GM1-gangliosidosis in the Shiba Inu. Magnetic resonance imaging (MRI) of the dog's brain indicated neurodegenerative disease, and evaluation of cerebrospinal fluid (CSF) identified storage granules in leukocytes. Lysosomal enzyme assays of plasma and leukocytes showed deficiencies of Hex-A and Hex-B activities in both tissues. Genetic analysis identified a homozygous, 3-base pair deletion in the HEXB gene (c.618-620delCCT). CONCLUSIONS AND CLINICAL IMPORTANCE: Clinical, biochemical, and molecular features are characterized in a Shiba Inu with GM2-gangliosidosis. The deletion of 3 adjacent base pairs in HEXB predicts the loss of a leucine residue at amino acid position 207 (p.Leu207del) supporting the hypothesis that GM2-gangliosidosis seen in this dog is the Sandhoff type. Because GM1-gangliosidosis also exists in this breed with almost identical clinical signs, genetic testing for both GM1- and GM2-gangliosidosis should be considered to make a definitive diagnosis.

Listeria monocytogenes induces mast cell extracellular traps.

Mast cells play an essential role in different immunological phenomena including allergy and infectious diseases. Several bacteria induce mast cell activation leading to degranulation and the production of several cytokines and chemokines. However, mast cells also have different microbicidal activities such as phagocytosis and the release of DNA with embedded granular proteins known as Mast Cell Extracellular Traps (MCETs). Although previous reports indicate that extracellular bacteria are able to induce MCETs little is known if intracellular bacteria can induce these structures. In this work, we evaluated MCETs induction by the intracellular bacteria Listeria monocytogenes. We found that mast cells released DNA after stimulation with L. monocytogenes, and this DNA was complexed to histone and tryptase. Before extracellular DNA release, L. monocytogenes induced modifications to the mast cell nuclear envelope and DNA was detected outside the nucleus. L. monocytogenes stimulated mast cells to produce significant amounts of reactive oxygen species (ROS) and blocking NADPH oxidase diminished DNA release by mast cells. Finally, MCETs showed antimicrobial activity against L. monocytogenes that was partially blocked when ß-hexosaminidase activity was inhibited. These results show that L. monocytogenes induces mast cells to produce microbicidal MCETs, suggesting a role for mast cells in containing infection beyond the induction of inflammation.

Seminal plasma hexosaminidase in patients with normal and abnormal spermograms.

BACKGROUND: Glycosidases profusion in male reproductive fluids suggests a possible relationship with sperm function. Although Hexosaminidase (Hex) is the most active glycosidase in epididymal fluid and seminal plasma, as well as in spermatozoa, Glucosidase is considered a marker for epididymal function and azoospermia. OBJECTIVE: The aim of this study was to determine Hex activity in seminal plasma from patients with normal and abnormal spermograms and analyze its correlation with seminal parameters. MATERIALS AND METHODS: In this cross sectional study, seminal plasma from azoospermic, asthenozoospermic, teratozoospermic, and normozoospermic patients was analyzed for the activity of: total Hex, HexA isoform, and glucosidase. Besides, hexosamine levels were determined, and the amount of Hex was quantified by immunoblot with a specific antibody. Correlation of Hex activity with seminal parameters was also analyzed. RESULTS: Hex activity, like glucosidase, was significantly reduced in azoospermic samples (44, 49, and 60% reduction for total Hex, HexA and glucosidase, respectively). A reduced amount of Hex in azoospermic samples was confirmed by western immunoblot. Hex activity was negatively correlated with round cells in azoospermic samples and positively correlated with motility in asthenozoospermic ones. CONCLUSION: The results suggested that Hex activity was reduced in azoospermic samples and this was due to a lower amount of enzyme. The correlation to seminal parameters related to particular pathologies suggests a possible relationship of Hex with fertilizing capacity.

Hydroxytyrosol and oleuropein of olive oil inhibit mast cell degranulation induced by immune and non-immune pathways.

The aim of this study was to determine whether hydroxytyrosol and oleuropein, the major phenols found in olives and olive oil, inhibit mast cell activation induced by immune and non-immune pathways. Purified peritoneal mast cells were preincubated in the presence of test compounds (hydroxytyrosol or oleuropein), before incubation with concanavalin A, compound 48/80 or calcium ionophore A23187. Dose-response and time-dependence studies were carried out. Comparative studies with sodium cromoglycate, a classical mast cell stabilizer, were also made. After incubation the supernatants and pellets were used to determine the ß-hexosaminidase content by colorimetric reaction. The percentage of ß-hexosaminidase release in each tube was calculated and taken as a measure of mast cell activation. Other samples of cell pellets were used for cell viability studies by the trypan blue dye exclusion test, or fixed for light and electron microscopy. Biochemical and morphological findings of the present study showed for the first time that hydroxytyrosol and oleuropein inhibit mast cell degranulation induced by both immune and non-immune pathways. These results suggest that olive phenols, particularly hydroxytyrosol and oleuropein, may provide insights into the development of useful tools for the prevention and treatment of mast cell-mediated disorders.