Tay‐Sachs' disease with visceral involvement and its relationship to Niemann‐Pick's disease

Norman, R. M.; Urich, H.; Tingey, A. H.; Goodbody, R. A.

doi:10.1002/path.1700780208

Cited by 82 publications

(8 citation statements)

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“…Altered calcium homeostasis is a common feature of lysosomal storage diseases [40, 41], and elevated cytosolic calcium has been shown in SD mice and attributed to an endoplasmic reticulum defect [42]. Hepatic disease, as suggested in Figure 5, is present in both human [43] and feline [6] SD, and is a potential cause of albumin reduction. The precise role of albumin remains unknown, but interestingly human serum albumin has been suggested to promote neuronal survival through production of glutamate [44], to prevent formation of amyloid β self-association in Alzheimer's disease [45], and to improve outcomes in models of focal cerebral ischemia [46-48].…”

Section: Discussionmentioning

confidence: 99%

Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease

Bradbury

Gray‐Edwards

Shirley

et al. 2015

Experimental Neurology

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The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated GM2 patients and those in future clinical trials.

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Section: Discussionmentioning

confidence: 99%

Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease

Bradbury

Gray‐Edwards

Shirley

et al. 2015

Experimental Neurology

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“…These include cherry-red macular spots, vertebral changes characteristic of the Hurler syndrome, pitting oedema, since birth, upper respiratory tract obstruction and a progressive course with early death. Cardiac enlargement, however, which is characteristic of some storage diseases due to lysosomal enzyme deficiency, has not been reported in other infants with GM1-gangliosidosis (Craig, Clarke and Banker, 1959;Norman et al, 1959;Landing et al, 1964;O'Brien et al, 1965;Gonatas and Gonatas, 1965;Sacrez et al, 1967;Scott, Lagunoffand Trump, 1967;Attal et al, 1967;Grossman and Danes, 1968;Seringe et al, 1968).…”

Section: Discussionmentioning

confidence: 98%

GM1-generalized gangliosidosis variant with cardiomegaly

Benson

Brown

Babarik

et al. 1976

Postgraduate Medical Journal

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A female infant with generalized GM1-gangliosidosis differing in several aspects from previously reported cases is described. Clinically she is the first case to have cardiomegaly, unilateral congenitial dislocation of the hip and normal facial appearance. She had a higher residual leucocyte β-galactosidase activity towards two synthetic substrates, namely p-nitrophenyl-β-D-galactoside (PNP-β-gal) and 4-methylumbelliferyl-β-D-galactoside (MU-β-gal) than in previously reported cases. Total β-hexosaminidase activity was raised in cultured fibroblasts, leucocytes, brain, kidneys and liver of the patient, and in fibroblasts from the parents. The parents' leucocytes had normal β-galactosidase activity towards PNP-β-gal but slightly reduced activity towards MU-β-gal. The parents' cultured fibroblast enzyme, however, had moderately low activities towards both substrates. It is suggested that she may represent a genetic variant of generalized GM1-gangliosidosis and that assay of leucocyte β-galactosidase activity should be added to the list of investigations for infantile cardiomegaly of unknown origin.

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“…Empty vacuoles were a conspicuous feature of the cells of the liver and renal tubules, and foam cells, also devoid of lipid, were present in the pulmonary alveoli and their walls. More extensive visceral involvement of the same type was described by Norman, Urich, Tingey, and Goodbody (1959) in their case of infantile amaurotic idiocy. This child had shown typical macular changes and also came from a non-Jewish family.…”

mentioning

confidence: 60%

“…The brain had been fixed in 10bo formol saline for 14 months. Comparison has been made with a normal control (16 month-old child; brain 12 months in formalin), and with our previous case of Tay-Sachs' disease in which visceral involvement had also been found (17 months at death; brain 18 hours in formalin, Norman et al, 1959).…”

Section: Cbe-istmentioning

confidence: 95%