Tay-Sachs Research Articles

Genetics and Therapies for GM2 Gangliosidosis.

Tay-Sachs disease, caused by impaired β-N-acetylhexosaminidase activity, was the first GM2 gangliosidosis to be studied and one of the most severe and earliest lysosomal diseases to be described. The condition, associated with the pathological build-up of GM2 ganglioside, has acquired almost iconic status and serves as a paradigm in the study of lysosomal storage diseases. Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children. There is no effective treatment beyond palliative care, and while the genetic basis of GM2 gangliosidosis is well established, the molecular and cellular events, from disease-causing mutations and glycosphingolipid storage to disease manifestations, remain to be fully delineated. Several therapeutic approaches have been attempted in patients, including enzymatic augmentation, bone marrow transplantation, enzyme enhancement, and substrate reduction therapy. Hitherto, none of these stratagems has materially altered the course of the disease. Authentic animal models of GM2 gangliodidosis have facilitated in-depth evaluation of innovative applications such as gene transfer, which in contrast to other interventions, shows great promise. This review outlines current knowledge pertaining the pathobiology as well as potential innovative treatments for the GM2 gangliosidoses.

Identification of mutations in HEXA and HEXB in Sandhoff and Tay-Sachs diseases: a new large deletion caused by Alu elements in HEXA

GM2 gangliosides are a group of lysosomal lipid storage disorders that are due to mutations in HEXA, HEXB and GM2A. In our study, 10 patients with these diseases were enrolled, and Sanger sequencing was performed for the HEXA and HEXB genes. The results revealed one known splice site mutation (c.346+1G>A, IVS2+1G>A) and three novel mutations (a large deletion involving exons 6–10; one nucleotide deletion, c.622delG [p.D208Ifsx15]; and a missense mutation, c.919G>A [p.E307K]) in HEXA. In HEXB, one known mutation (c.1597C>T [p.R533C]) and one variant of uncertain significance (c.619A>G [p.I207V]) were identified. Five patients had c.1597C>T in HEXB, indicating a common mutation in south Iran. In this study, a unique large deletion in HEXA was identified as a homozygous state. To predict the cause of the large deletion in HEXA, RepeatMasker was used to investigate the Alu elements. In addition, to identify the breakpoint of this deletion, PCR was performed around these elements. Using Repeat masker, different Alu elements were identified across HEXA, mainly in intron 5 and intron 10 adjacent to the deleted exons. PCR around the Alu elements and Sanger sequencing revealed the start point of a large deletion in AluSz6 in the intron 6 and the end of its breakpoint 73 nucleotides downstream of AluJo in intron 10. Our study showed that HEXA is an Alu-rich gene that predisposes individuals to disease-associated large deletions due to these elements.

Preconception risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease.

Globally, about five per cent of children are born with congenital or genetic disorders. The most common autosomal recessive conditions are thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease, with higher carrier rates in specific patient populations. Identifying and counselling couples at genetic risk of the conditions before pregnancy enables them to make fully informed reproductive decisions, with some of these choices not being available if genetic counselling is only offered in an antenatal setting. This is an update of a previously published review. To assess the effectiveness of systematic preconception genetic risk assessment to improve reproductive outcomes in women and their partners who are identified as carriers of thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease in healthcare settings when compared to usual care. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Registers. In addition, we searched for all relevant trials from 1970 (or the date at which the database was first available if after 1970) to date using electronic databases (MEDLINE, Embase, CINAHL, PsycINFO), clinical trial databases (National Institutes of Health, Clinical Trials Search portal of the World Health Organization, metaRegister of controlled clinical trials), and hand searching of key journals and conference abstract books from 1998 to date (European Journal of Human Genetics, Genetics in Medicine, Journal of Community Genetics). We also searched the reference lists of relevant articles, reviews and guidelines and also contacted subject experts in the field to request any unpublished or other published trials.Date of latest search of the registers: 20 June 2017.Date of latest search of all other sources: 16 November 2017. Any randomised or quasi-randomised controlled trials (published or unpublished) comparing reproductive outcomes of systematic preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease when compared to usual care. We identified 25 papers, describing 16 unique trials which were potentially eligible for inclusion in the review. However, after assessment, no randomised controlled trials of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease were found. No randomised controlled trials of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease were included. One ongoing trial has been identified which may potentially eligible for inclusion once completed. As no randomised controlled trials of preconception genetic risk assessment for thalassaemia, sickle cell disease, cystic fibrosis, or Tay-Sachs disease were found for inclusion in this review, the research evidence for current policy recommendations is limited to non-randomised studies.Information from well-designed, adequately powered, randomised trials is desirable in order to make more robust recommendations for practice. However, such trials must also consider the legal, ethical, and cultural barriers to implementation of preconception genetic risk assessment.

Progranulin stabilizes hexosaminidase A and is therapeutic in Tay-Sachs disease

Progranulin stabilizes hexosaminidase A and is therapeutic in Tay-Sachs disease

Reclassification of common variants of unknown significance in the hexosaminidase A gene: Implications for Tay-Sachs disease carrier screening

Reclassification of common variants of unknown significance in the hexosaminidase A gene: Implications for Tay-Sachs disease carrier screening

Abnormal GM2 accumulation alters the function of the autophagic pathway in early-onset Tay-Sachs disease mouse model

Attention deficit hyperactivity disorder (ADHD) is the most frequent disorder in childhood and adolescence, and is seen as a public health problem. The recommended treatment includes pharmacological and psychosocial treatment. The aim of this work was to study the changes in the prescribing of the medicines used in ADHD treatment in the Region of Murcia, as well as their socio-demographic variability.A retrospective observational study was conducted using the dispensing of medicines for ADHD treatment by means of prescription in the Region of Murcia from 2010 to 2014. The consumption rates were determined as defined daily doses (DDD) per thousand inhabitants/day (DIDs), stratified by gender and age. The reasons for prevalence of treatment by gender were also determined by comparing male and female consumption rates.The consumption of medicines for ADHD treatment had almost doubled in the period studied, from 5.58 DIDs and 3.39 DIDs in 2010 to 9.34 DIDs and 6.71 DIDs in 2014, for the age range of 10–14 and 15–19, respectively. Boys from 10 to 14 showed the highest consumption rates, showing a high geographical variability with less consumption in rural areas.The results showed a large increase in the use of medicines for ADHD treatment in the Region of Murcia, although the consumption rates are still lower than in other Autonomous Communities or neighbouring countries. A wide geographical variability was found, with a higher consumption in adolescents from urban areas.El trastorno por déficit de atención e hiperactividad (TDAH) es la alteración del comportamiento más frecuente en la infancia y la adolescencia, representando un problema de salud pública. El tratamiento recomendado incluye tratamiento farmacológico y psicosocial. El objetivo de este estudio es analizar la evolución del consumo de los fármacos utilizados para el TDAH en la Región de Murcia y su variabilidad sociodemográfica.Estudio observacional retrospectivo referido a la dispensación de medicamentos para el tratamiento del TDAH mediante receta en la Región de Murcia entre los años 2010 y 2014. Se calcularon las tasas de consumo expresadas en dosis diarias definidas (DDD) por 1.000 habitantes/día (DIDs), estratificadas por sexo y edad y las razones de prevalencia de tratamiento por sexo comparando las tasas de consumo de hombres y de mujeres.Durante el periodo estudiado prácticamente se ha duplicado el consumo de medicamentos para el tratamiento del TDAH, pasando de tasas de 5,58 DIDs y 3,39 DIDs en 2010 a 9,34 DIDs y 6,71 DIDs en 2014, para las franjas de edad de 10 a 14 años y de 15 a 19 años, respectivamente. Los varones de entre 10 y 14 años presentan las tasas de consumo más elevadas, observándose variabilidad geográfica con menores consumos relativos en las zonas rurales.Se ha producido un importante aumento del uso de los medicamentos para el TDAH en la Región de Murcia, si bien las tasas de consumo siguen siendo inferiores a los datos de otras comunidades autónomas o países de nuestro entorno. Se observa una gran variabilidad geográfica con un mayor consumo en adolescentes de zonas urbanas.

Testing Fate: Tay-Sachs Disease and the Right to Be Responsible by Shelley Z. Reuter

Reviewed by: Testing Fate: Tay-Sachs Disease and the Right to Be Responsible by Shelley Z. Reuter Stephen Pemberton Shelley Z. Reuter. Testing Fate: Tay-Sachs Disease and the Right to Be Responsible. Minneapolis: University of Minnesota Press, 2016. 264 pp. Ill. $27.00 (978-0-8166-9996-4). Between 1880 and 1920, physicians in the United States and Great Britain identified a small but concerning number of infants with severe mental and developmental retardation among Jewish immigrant families. Tay-Sachs disease (TSD), as this hereditary condition is known today, has no cure, but it can be effectively prevented through carrier screening or therapeutic abortion. Fortunately, beginning in the 1980s, aggressive carrier screening coordinated by Jewish communities and their medical partners dramatically reduced TSD’s incidence in North America, Western Europe, and Israel. In 2003–4, for instance, only ten such babies were born in the United States, none Jewish. As the latter example suggests, TSD is not an exclusively Jewish disease. Yet, TSD carrier screening among Jewish communities is often hailed today as an exemplar of successful grassroots public health advocacy within an ethnic group—a kind of self-empowerment with [End Page 212] a presumed genetic basis. Shelley Reuter’s thought-provoking book complicates such genetic disease narratives by showing that TSD has always been tied problematically to race. TSD, she argues, is an instructive case of how much choice, if not “freedom,” the racialized and pathologized “Other” can exercise with regard to one’s genetic fate (p. 2). Testing Fate is a work of critical-historical sociology delivered in three parts and driven by Reuter’s determined argument about how Jewish people have been made socioculturally “responsible” for the genetic diseases that presumably affect them. The book’s first part explains how TSD was configured as a “racialized disease” in an age of rampant anti-immigrant sentiment in the United States (chap. 1) and Great Britain (chap. 2). In the British case, Reuter details how Jews combated stigmatizing portraits of disease—inclusive of TSD—by cultivating a “will to health” in the public consciousness. Representing the interests of the British Jewish community, the Jewish Board of Guardians (JBG) worked resolutely to create the impression among Britons that Anglo-Jews set standards of health, parenthood, and sobriety that native Britons should emulate (p. 63). Part 2 of Testing Fate provides finer textual analysis of the Tay-Sachs experience across the decades. It focuses on how TSD has been visually represented first in the printed medical literature (chap. 3) and later in online representations of the malady (chap. 4). The former chapter highlights how visual imagery accompanying medical case reports and studies of TSD throughout the twentieth century “reified” the malady in racialized terms, making medical practitioners complicit in the “Othering” of Jewish people. The latter chapter highlights how the “Othering” of people affected by TSD shifted in the 1990s and 2000s away from explicitly racial terms to highlight the undesirability of this disease-disability. Whereas the older medical literature was tainted by racialism, for Reuter the contemporary “specularism” constituting TSD as a horrific disease/disability also fails the test of inclusiveness. Part 3 stresses the paradoxical efforts to manage TSD through carrier screening from the 1970s into the 2000s (chap. 5). Here, Reuter focuses squarely on the carrier’s “right to be responsible” relative to the growing and, by most accounts, “effective” sociocultural imperative to prevent TSD lives in the age of medical genetics. The successes were more immediate in the United States, where there was early and aggressive cooperation between medical geneticists and Jewish communities. TSD carrier screening in Great Britain advanced more slowly, in part because British advocates did not initially include JBG or Jewish community leaders. Provocatively, Reuter then turns from the controversies surrounding TSD carrier screening to explore the emergence of wrongful birth and wrongful life suits involving TSD. There were eight such cases in the United States between 1977 and 2003, and Reuter interprets them as instances of “responsible personhood” that expose how autonomy in genetic decision making remains severely limited today. The cultures of TSD, even as they have changed over time, continue to be constituted in exclusive terms, leading Reuter to...

ALS Mimics

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Most patients die within 2–5 years of symptom onset due to the lack of effective therapy options. A diagnostic delay is encountered quite often, since disease progression as well as site and speed of onset may vary significantly. Some diseases can mimic features of ALS, especially in early stages. It is very important to differentiate those mimics from ALS as potentially treatable conditions might be missed otherwise. ALS typically affects the upper as well as the lower motor neuron, which implies that diseases sharing at least one of these clinical features have to be considered in the differential diagnosis. The following conditions should be taken into account as a differential diagnosis for ALS with predominant affection of the lower motor neuron: Immune mediated neuropathies such as multifocal motor neuropathy (MMN) with pronounced distal paresis without striking atrophy signs and conduction blocks in electroneurography, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with common signs of sensibility disturbances, areflexia and cytoalbuminologic dissociation in the cerebrospinal fluid (CSF). Sporadic inclusion body myositis (sIBM) with typical biopsy findings and clinically predominant affection of the finger flexors. Spinal and bulbar muscular atrophy (SBMA), in which androgen receptor (AR-)gene testing and clinical signs of androgen insensitivity will help to differentiate the disease from ALS. Hirayama disease shows cold paresis; a cervical MRI scan and a normal neurography will help to confirm the diagnosis. In benign fasciculation syndrome, there is no muscle paresis or atrophy, and acute denervation cannot be detected in the EMG. In spinal muscular atrophy (SMA), testing for the SMN gene will help to differentiate the condition from ALS; furthermore, SMA is a very rare disease in adults. As a differential diagnosis for ALS with both clinical affection of the upper and lower motor neuron e. g. metabolic diseases such as adrenoleukodystrophy, metachromatic leukodystrophy and Tay-Sachs disease should be taken into account. Here, laboratory tests are the most important steps for a correct diagnosis. Cervical myelopathy is also capable of affecting the upper and lower motor neuron, but can easily be differentiated by a cervical MRI scan. As a differential diagnosis of ALS with predominant affection of the upper motor neuron, we discuss hereditary spastic paraparesis (HSP) which presents with a symmetric spasticity of the legs. The MRI often shows atrophy of the spinal cord, and SPG gene testing is done to differentiate HSP from ALS.

Choroba Taya-Sachsa – w oparciu o opis przypadku klinicznego

Choroba Taya-Sachsa – w oparciu o opis przypadku klinicznego

Induced Pluripotent Stem Cell Technology: A Paradigm Shift in Medical Science for Drug Screening and Disease Modeling.

Induced Pluripotent Stem Cell (IPSC) Technology is the most advanced research as it offers an attractive alternative for establishing patient-specific IPSCs to recapitulate phenotypes of not only monogenic diseases (viz. Thalassaemia, Sickle cell anemia, Haemophilia, Tay-Sachs disease), but also late-onset polygenic diseases (viz. Parkinson's disease, Alzheimer's disease, schizophrenia). Over the hindsight, numerous studies of the past and current scientists have led to the production, maturation and understanding of induced pluripotent stem cell technology and its use in basic and clinical research. A systematic search of peer-reviewed scientific literature and clinical trials in public databases were carried out to summarize the evidence on the use of IPSC. Current review sheds light upon the use of patient-derived iPSC models in drug toxicity, screening and discovery which have been derived after referring to more than 200 articles in literature. Furthermore, their use as disease models was also studied signifying the versatility of iPSC lines. Through this review, we describe the advent of iPSC technology, where we comprehensively cover the generation of iPSCs and their characterization along with their prospective applications using IPSC banks in disease modeling and drug screening.

Testing Fate: Tay-Sachs Disease and the Right to Be Responsible

Testing Fate: Tay-Sachs Disease and the Right to Be Responsible

Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study.

BackgroundGM1-gangliosidosis and GM2-gangliosidosis (Tay-Sachs disease and Sandhoff disease) are unrelenting heritable neurodegenerative conditions of lysosomal ganglioside accumulation. Although progressive brain atrophy is characteristic, longitudinal quantification of specific brain structures has not been systematically studied.ObjectivesThe goal of this longitudinal study has been to quantify and track brain MRI volume changes, including specific structure volume changes, at different times in disease progression of childhood gangliosidoses, and to explore quantitative brain MRI volumetry (qMRI) as a non-invasive marker of disease progression for future treatment trials.MethodsBrain qMRI studies were performed in 14 patients with gangliosidoses (9 infantile, 5 juvenile) yearly. Cerebellar cortex and white matter, caudate, putamen, corpus callosum, ventricles, total brain, and intracranial volumes were measured, as well as total brain volume. Age-matched controls were available for the patients with the juvenile phenotype.ResultsThe infantile phenotype of all gangliosidoses showed a consistent pattern of macrocephaly and rapidly increasing intracranial MRI volume with both (a) brain tissue volume (cerebral cortex and other smaller structures) and (b) ventricular volume (P < 0.01 for all). In contrast to apparent enlargement of the total brain volume, and chiefly the enlarged cerebral cortex, a subset of smaller brain substructures generally decreased in size: the corpus callosum, caudate and putamen became smaller with time. The volume of cerebellar cortex also decreased in patients with infantile GM1-gangliosidosis and juvenile GM1- and GM2-gangliosidosis; however, infantile GM2-gangliosidosis cerebellar cortex was the exception, increasing in size. Elevated intracranial pressure (estimated by lumbar spinal pressure) was a common finding in infantile disease and showed continued increases as the disease progressed, yet lacked MRI signs of hydrocephalus except for increasing ventricular size. Notably, in patients with juvenile gangliosidosis, macrocephaly and elevated intracranial pressure were absent and total brain volume decreased with time compared to controls (P = 0.004).ConclusionsThe disease course of infantile versus juvenile gangliosidoses is clearly distinguished by the rate of brain disease progression as characterized by qMRI. Assessments by qMRI represent a robust non-invasive method for monitoring CNS changes in the clinical course of gangliosidoses and is ideally suited to monitor effects of novel CNS-directed therapies in future clinical trials.

Late Onset Tay-Sachs Disease in a Non-Jewish Patient: Case Report

Abstract Tay-Sachs disease (TSD) is a rare, inherited, autosomal rececessive lysosomal storage disease. The late-onset form is an uncommon condition among non-Jewish population. We present the case of a 32 years old male patient without Jewish origins, in whom the disease began in adolescence and was initially diagnosed with spinal muscular atrophy. He developed progressively protean neurological symptomatology, including tetraparesis, cerebellar and extrapyramidal syndromes. The diagnosis was based on the cerebral MRI, showing severe cerebellar atrophy and the determination of the Hexosaminidase A activity, revealing low level. In patients showing signs of lower motor neuron involvement, cerebellar and pyramidal signs and marked cerebellar atrophy the late-onset TSD should be suspected, and the first step in establishing the diagnosis should be to determine the serum activity of Hexosaminidase A.

Enzymatic properties of β-N-acetylglucosaminidases.

β-N-Acetylglucosaminidases (GlcNAcases) hydrolyse N-acetylglucosamine-containing oligosaccharides and proteins. These enzymes produce N-acetylglucosamine (GlcNAc) and have a wide range of promising applications in the food, energy, and pharmaceutical industries, such as synergistic degradation of chitin with endo-chitinases and using GlcNAc to produce sialic acid, bioethanol, single-cell proteins, and pharmaceutical therapeutics. GlcNAcases also play an important role in the dynamic balance of cellular O-linked GlcNAc levels, catabolism of ganglioside storage in Tay-Sachs disease, and bacterial cell wall recycling and flagellar assembly. In view of these important biological functions and the wide range of industrial applications of GlcNAcases, this review aims to provide a better understanding of various advances for these enzymes. It focuses on enzymatic properties of GlcNAcases, including substrate specificity, catalytic activity, pH optimum, temperature optimum, thermostability, the effects of various metal ions and organic reagents, and transglycosylation.

Expression of the GM2 activator protein in mouse testis

The GM2-activator protein (GM2-AP), revealed by Li et al. in 1973 in human liver, was initially identified as a protein cofactor that stimulated β-hexosaminidase A to hydrolyze N-acetylgalactosamine from GM2 ganglioside. This cofactor was found to be missing in human variant AB Tay-Sachs disease. Over the years, the GM2-AP has also been shown to be involved in kidney vesicular transport, lipid presentation by CD1 molecule to T-cells, and interaction of human sperm with zona pellucida. Since the expression of the GM2-AP via mRNA detection in mouse tissues was found to be the highest in testis, we became interested in the localization of the GM2-AP at cellular level in mouse testis during spermatogenesis. Using immunohistochemical analysis and electron microscopy, we found that the GM2-AP was predominantly localized in the basal cytoplasm and the attenuated processes of Sertoli cells. The stained structure appeared to be lysosomes. The most interesting finding was the association of the GM2-AP with the acrosomal apparatus in early spermatids. A modest to intense staining was observed in some acrosomal granules and acrosomal caps. The GM2-AP seemed to disappear from acrosomal caps in the later stage of spermatids, in which the nucleus became elongated and condensed. These results suggest that the GM2-AP may be involved in the normal functions of Sertoli cells and play important roles during the development of acrosomal caps in the early spermatids.

Testing Fate: Tay-Sachs Disease and the Right to be Responsible

Testing Fate: Tay-Sachs Disease and the Right to be Responsible

Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease

Tay-Sachs disease is a severe lysosomal storage disorder caused by mutations in Hexa, the gene that encodes for the α subunit of lysosomal β-hexosaminidase A (HEXA), which converts GM2 to GM3 ganglioside. Unexpectedly, Hexa−/− mice have a normal lifespan and show no obvious neurological impairment until at least one year of age. These mice catabolize stored GM2 ganglioside using sialidase(s) to remove sialic acid and form the glycolipid GA2, which is further processed by β-hexosaminidase B. Therefore, the presence of the sialidase (s) allows the consequences of the Hexa defect to be bypassed. To determine if the sialidase NEU3 contributes to GM2 ganglioside degradation, we generated a mouse model with combined deficiencies of HEXA and NEU3. The Hexa−/−Neu3−/− mice were healthy at birth, but died at 1.5 to 4.5months of age. Thin-layer chromatography and mass spectrometric analysis of the brains of Hexa−/−Neu3−/− mice revealed the abnormal accumulation of GM2 ganglioside. Histological and immunohistochemical analysis demonstrated cytoplasmic vacuolation in the neurons. Electron microscopic examination of the brain, kidneys and testes revealed pleomorphic inclusions of many small vesicles and complex lamellar structures. The Hexa−/−Neu3−/− mice exhibited progressive neurodegeneration with neuronal loss, Purkinje cell depletion, and astrogliosis. Slow movement, ataxia, and tremors were the prominent neurological abnormalities observed in these mice. Furthermore, radiographs revealed abnormalities in the skeletal bones of the Hexa−/−Neu3−/− mice. Thus, the Hexa−/−Neu3−/− mice mimic the neuropathological and clinical abnormalities of the classical early-onset Tay-Sachs patients, and provide a suitable model for the future pre-clinical testing of potential treatments for this condition.

Adeno-Associated Virus Gene Therapy in a Sheep Model of Tay-Sachs Disease.

Tay-Sachs disease (TSD) is a fatal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase A (HexA). TSD also occurs in sheep, the only experimental model of TSD that has clinical signs of disease. The natural history of sheep TSD was characterized using serial neurological evaluations, 7 Tesla magnetic resonance imaging, echocardiograms, electrodiagnostics, and cerebrospinal fluid biomarkers. Intracranial gene therapy was also tested using AAVrh8 monocistronic vectors encoding the α-subunit of Hex (TSD α) or a mixture of two vectors encoding both the α and β subunits separately (TSD α + β) injected at high (1.3 × 1013 vector genomes) or low (4.2 × 1012 vector genomes) dose. Delay of symptom onset and/or reduction of acquired symptoms were noted in all adeno-associated virus-treated sheep. Postmortem evaluation showed superior HexA and vector genome distribution in the brain of TSD α + β sheep compared to TSD α sheep, but spinal cord distribution was low in all groups. Isozyme analysis showed superior HexA formation after treatment with both vectors (TSD α + β), and ganglioside clearance was most widespread in the TSD α + β high-dose sheep. Microglial activation and proliferation in TSD sheep-most prominent in the cerebrum-were attenuated after gene therapy. This report demonstrates therapeutic efficacy for TSD in the sheep brain, which is on the same order of magnitude as a child's brain.

Testing Fate: Tay-Sachs Disease and the Right to Be Responsible. By Shelley Z. Reuter. Minneapolis: University of Minnesota Press, 2016. Pp. 264. $94.00 (cloth), $27.00 (paper).

Previous articleNext article No AccessBook ReviewTesting Fate: Tay-Sachs Disease and the Right to Be Responsible. By Shelley Z. Reuter. Minneapolis: University of Minnesota Press, 2016. Pp. 264. $94.00 (cloth), $27.00 (paper).Jennifer ReichJennifer ReichUniversity of Colorado, Denver Search for more articles by this author PDFPDF PLUSFull Text Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinkedInRedditEmail SectionsMoreDetailsFiguresReferencesCited by American Journal of Sociology Volume 123, Number 2September 2017 Article DOIhttps://doi.org/10.1086/692775 Views: 96Total views on this site For permission to reuse a book review printed in the American Journal of Sociology, please contact [email protected]PDF download Crossref reports no articles citing this article.

Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides.

Gangliosides (sialylated glycolipids) play an essential role in the CNS by regulating recognition and signaling in neurons. Metabolic blocks in processing and catabolism of gangliosides result in the development of severe neurologic disorders, including gangliosidoses manifesting with neurodegeneration and neuroinflammation. We demonstrate that 2 mammalian enzymes, neuraminidases 3 and 4, play important roles in catabolic processing of brain gangliosides by cleaving terminal sialic acid residues in their glycan chains. In neuraminidase 3 and 4 double-knockout mice, GM3 ganglioside is stored in microglia, vascular pericytes, and neurons, causing micro- and astrogliosis, neuroinflammation, accumulation of lipofuscin bodies, and memory loss, whereas their cortical and hippocampal neurons have lower rate of neuritogenesis in vitro Double-knockout mice also have reduced levels of GM1 ganglioside and myelin in neuronal axons. Furthermore, neuraminidase 3 deficiency drastically increased storage of GM2 in the brain tissues of an asymptomatic mouse model of Tay-Sachs disease, a severe human gangliosidosis, indicating that this enzyme is responsible for the metabolic bypass of β-hexosaminidase A deficiency. Together, our results provide the first in vivo evidence that neuraminidases 3 and 4 have important roles in CNS function by catabolizing gangliosides and preventing their storage in lipofuscin bodies.-Pan, X., De Britto Pará De Aragão, C., Velasco-Martin, J. P., Priestman, D. A., Wu, H. Y., Takahashi, K., Yamaguchi, K., Sturiale, L., Garozzo, D., Platt, F. M., Lamarche-Vane, N., Morales, C. R., Miyagi, T., Pshezhetsky, A. V. Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides.