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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Unlike the better known infantile and late adolescent variants, chronic GM2 gangliosidosis has variable onset and slow progression, with some surviving into their eighth decade. Most are HEXA compound heterozygotes with less than 10% enzyme activity.
Sandhoff disease/GM2 gangliosidosis/deficiency of Hex A and Hex B subunit deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The clinical phenotype of Sandhoff disease may be indistinguishable from that of Tay-Sachs disease (Chapter 88), but there may be hepatosplenomegaly in Sandhoff disease. The distinction between the two conditions was delineated by Sandhoff et al. [1] in 1968, in a patient who was unusual in that he stored ganglioside not only in the brain but also in other viscera, in contrast to patients with Tay-Sachs disease. The activity of total hexosaminidase was found to be deficient [1]. Hexosaminidase B is a glycoprotein homopolymer with four identical subunits; its structure is designated β2β2 [2, 3]. Hexosaminidase A is a heteropolymer of α and β subunits. Activity of the Hex-A and Hex-B isozymes are defective because of a defective β subunit. The disease has also been referred to as GM2 gangliosidosis (variant O). The Hex-B gene is located on chromosome 5q13 [4]. Heterogeneity has been observed in the mutations in the gene for Hex-B [5]. Most mutations lead to the most severe infantile onset phenotype. The causative mutations in these patients tend to be deletions, nonsense mutations, or splice site mutations. The most common is a 16 kb deletion that includes the promoter, exons 1 to 5, and part of the intron [6].
Paediatric Neurology
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Table 28.7 outlines features of a number of the lipid storage disorders. Tay Sachs disease is the most common of the gangliosidoses. It is inherited in an autosomal recessive manner (with a marked increase in gene frequency in Ashkenazi Jews). It is characterized by loss of motor milestones from around three to six months of age, initially with hypotonia, then spasticity. An exaggerated startle response, progressive macrocephaly and cherry red spot at the macula are typical, but as already noted, non-specific. Sandhoff’s is very similar in presentation, although in this case hexosaminidase A and B are deficient, just hexosaminidase A in Tay-Sachs. A ‘juvenile’ form exists, misleading terminology since the onset is usually in the preschoolage child with gait disturbance followed by ataxia, spasticity and dementia. A ‘chronic’ or ‘adult’ form is more often heralded by speech disturbance (dysarthria), then motor deterioration and psychiatric disorder and may simulate Freidreich’s ataxia. Numerous gene mutations have been identified. The spectrum of phenotypes in GM2 gangliosidosis highlights the relevance of the disorder to paediatric and adult neurological practice.
Sandhoff disease in the elderly: a case study
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
Leidy García Morales, Reinaldo Gaspar Mustelier Bécquer, Laura Pérez Joglar, Tatiana Zaldívar Vaillant
Sandhoff disease is an infrequent genetically-caused disorder with a recessive inheritance pattern. It belongs to the gangliosidosis GM2 group and it is produced by mutations in gen HEXB (chromosome 5q13) leading to reduced activity of enzymes β-hexosaminidase A and B, and deposition of sphingolipids (ganglioside GM2 and globoside) in brain and other organs. Nearly, 40 specific mutations causing this disease have been reported (1). Clinical manifestations and age of onset depend on the enzymatic residual catabolic activity, associated with infantile, juvenile, and adult variants (2). The homozygous state is associated with earlier onset and greater disease severity (1). The clinical manifestations of the adult variant are heterogeneous and poorly characterized. It may appear as a combination of motor neuron disease, spinocerebellar ataxia, neuropathy, autonomic dysfunction, cognitive impairment, movement disorders, and psychiatric manifestations (2–4). At this time, there is no effective treatment for this disease (2).
Ocular Manifestations of Neuronal Ceroid Lipofuscinoses
Published in Seminars in Ophthalmology, 2021
Rohan Bir Singh, Prakash Gupta, Akash Kartik, Naba Farooqui, Sachi Singhal, Sukhman Shergill, Kanwar Partap Singh, Aniruddha Agarwal
Until 1960s, the NCLs were considered to be variants of gangliosidoses such as Tay-Sachs disease owing to their shared symptom complex.7 However, it was found that the substances accumulating in NCLs were not metabolic precursors but physically, chemically and topographically similar to lipofuscin and ceroid (a pathological variant of lipofuscin).8
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Manuel González-Cuesta, Irene Herrera-González, M. Isabel García-Moreno, Roger A. Ashmus, David J. Vocadlo, José M. García Fernández, Eiji Nanba, Katsumi Higaki, Carmen Ortiz Mellet
TSD is the best characterised of the GM2 gangliosidosis, with over 100 HEXA gene mutations categorised (http://www.hgmd.cf.ac.uk/). The frequency of asymptomatic heterozygotes is 1 in 300 live births in the general population (1 in 30 among Ashkenazy Jews), with a predicted frequency of 1 in 360,000 for homozygotes (1 in 2,900 among Ashkenazy Jews). Different genotypes result in different clinical phenotypes (infantile, juvenile or adult/chronic), with severity generally associating with the level of residual HexA activity permitted by different mutations (<0.5% of normal activity for infantile; 2%–5% for late on-set forms)6,7. Based on genotype/phenotype correlations, it has been suggested that 10% of the normal activity could be sufficient to prevent development of clinical symptoms8. Administration of recombinant HexA (enzyme replacement therapy; ERT) is unlikely to be clinically effective due to the inaccessibility imposed by the blood-brain barrier. Gene therapy using viral vectors has shown some promise in animal models9,10, but toxicity issues unveiled in non-human primates and low effectivity in clinical trials may seriously thwart translation to hospital settings11,12. Other approaches, such as the use of gene editing tools or brain permeable inhibitors of glycosphingolipid biosynthesis are under investigation13,14. Since many of the TSD-causative mutations do not compromise the catalytic site, but target the α chain of HexA to endoplasmic reticulum-associate degradation (ERAD), the development of pharmacological chaperones (PCs) that can stabilise the native folding of the protein despite its anomalous conformation and restore activity appears attractive15. Typically, a PC is a small molecule able to bind to the mutant enzyme at the ER, promote the correct folding and restore trafficking to the Golgi apparatus for maturation and then to the final destination. With few exceptions16–18, most reported PCs developed for LSDs are competitive inhibitors of the target enzyme; they however exert an effector action by dissociating from the corresponding mature enzyme: inhibitor complex in the presence of an excess of substrate in the lysosomes of patient cells19–21.