Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ultrastructural and biochemical studies were performed on postmortem material of a 67-year-old woman presenting with proximal muscle weakness in the legs, slurred speech, and mental subnormality. The symptoms began at age 19 and showed extremely slow progression, mimicking progressive muscular dystrophy. A brother suffered from a similar chronic neuromuscular disease, and two sisters died at an early age from unknown "nervous" diseases. Autopsy disclosed abundant lipid accumulation in CNS neurons and severe cerebellar cortical atrophy of the granule cell type. Skeletal muscle showed a terminal stage of denervation atrophy with severe lipomatosis; intrafusal fibers of muscle spindles contained lipid deposits. Complex lamellar cytoplasmic inclusions often resembling membranous cytoplasmic bodies or stacked membranes were seen in cells of the brain. In addition, there were various lipopigment bodies, fingerprint profiles, rare polyglucosan bodies, rodlike structures, and filamentous sheaves, particularly in substantia nigra. Accumulation of gangliosides GM2 and GA2 in the cerebral cortex was demonstrated by thin-layer chromatography. Determination of hexosaminidase activity was not possible (formalin-fixed material). This observation, in addition to the cases reported by Navon et al. [1981] and Johnson [1982], is suggested to represent a new phenotype of adult-onset GM2 gangliosidosis referred to as motor neuron disease phenotype, which can be differentiated from other adult-onset lipidoses and motor neuron disorders. Our paper emphasizes the importance of ultrastructural demonstration of lamellar inclusions for the differential diagnosis of ceroid lipofuscinosis, and the value of biochemical studies in the diagnostic clarification of atypical neuromuscular disorders.
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PMID:Adult GM2 gangliosidosis masquerading as slowly progressive muscular atrophy: motor neuron disease phenotype. 716 18

We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (alpha subunit) or Hexb (beta subunit) genes, respectively, encoding lysosomal beta-hexosaminidase A (structure, alpha) and B (structure, beta beta). Both mutant mice accumulate GM2 ganglioside in brain, much more so in Hexb -/- mice, and the latter also accumulate glycolipid GA2. Hexa -/- mice suffer no obvious behavioral or neurological deficit, while Hexb -/- mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Hexb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2. We propose that Hexa -/- mice escape disease through partial catabolism of accumulated GM2 via GA2 (asialo-GM2) through the combined action of sialidase and beta-hexosaminidase B.
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PMID:Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases. 878 34

Among the numerous congenital disorders of glycosylation concerning glycoproteins, only a single mutation in ganglioside biosynthesis had been reported until a few years ago: one in the ST3GAL5 gene, encoding GM3 synthase. More recently, additional mutations in the same gene were reported, together with several distinct mutations in the B4GALNT1 gene, encoding GM2/GD2/GA2 synthase. Patients suffering from ST3GAL5 deficiency present a devastating syndrome characterized by early onset and dramatic neurological and cognitive impairment, sometimes associated with dyspigmentation and an increased blood lactate concentration. On the other hand, B4GALNT1 mutations give rise to a form of complicated hereditary spastic paraplegia (HSP), previously referred to as HSP26. It is characterized by the late onset of lower limb weakness and mild to moderate intellectual impairment, which is usually not progressive. In addition to the most typical signs, some patients present ocular and endocrine signs, pes cavus, and psychiatric illness. Since the nineties, mice lacking genes for single glycosyltransferases involved in ganglioside biosynthesis, including ST3GAL5 and B4GALNT1, were created and studied. The resulting phenotypes were frequently mild or very mild, so double knock-out animals were created to effectively study the function of gangliosides. The main clinical and biochemical features of patients suffering from GM3 synthase or GM2/GD2/GA2 synthase deficiency, compared with the phenotypes described in mice that are null for single or multiple glycosyltransferase genes, provide suggestions to improve the recognition of novel mutations and potentially related disorders.
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PMID:Diseases of ganglioside biosynthesis: An expanding group of congenital disorders of glycosylation. 2998 10