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Amyotrophic Lateral Sclerosis &... Feb 2022Sandhoff disease is an infrequent, genetically caused disorder with a recessive autosomal inheritance pattern. It belongs to the gangliosidosis GM2 group and is produced...
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 leading to reduction in enzymatic activity of enzymes β-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.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Hexosaminidase A; Humans; Male; Motor Neuron Disease; Mutation; Sandhoff Disease
PubMed: 33650927
DOI: 10.1080/21678421.2021.1892146 -
Nihon Rinsho. Japanese Journal of... Sep 1993Lysosomal beta-hexosaminidase occurs as two major isozymes hexosaminidase A and B. The alpha subunit is encoded by the HEXA gene and the subunit by HEXB gene. Defects in... (Review)
Review
Lysosomal beta-hexosaminidase occurs as two major isozymes hexosaminidase A and B. The alpha subunit is encoded by the HEXA gene and the subunit by HEXB gene. Defects in the beta subunit lead to Sandhoff disease. Patients with the defect lack the activity or formation of both hexosaminidase A and B. The disorders are classified according to the age of onset, as infantile, juvenile and adult form. Recent molecular genetic analysis has revealed a 50 kb deletion, 16 kb Alu type deletion, and compound heterozygous with other mutations. In the juvenile or adult type of the disease, point mutation of the HEXB gene, creating a new 3' splice acceptor site. The correlation of the clinical phenotype and the gene abnormalities is discussed.
Topics: Adolescent; Adult; Age of Onset; Hexosaminidase A; Hexosaminidase B; Humans; Infant; Mutation; Sandhoff Disease; beta-N-Acetylhexosaminidases
PubMed: 8411702
DOI: No ID Found -
Acta Pathologica Japonica May 1981An autopsy case of Sandhoff disease in a 2-year-old boy is reported. Diagnosis was established by enzyme assay, which demonstrated total deficiency of hexosaminidase in...
An autopsy case of Sandhoff disease in a 2-year-old boy is reported. Diagnosis was established by enzyme assay, which demonstrated total deficiency of hexosaminidase in the serum. Histochemical examination, using hematoxylin-eosin (H & E) and Luxol fast blue (LFB) stain, showed accumulation of LFB-positive material not only in cells of the cerebrum, cerebellum, spinal cord, and peripheral nervous system, but also in reticuloendothelial cells of the lymph nodes, spleen, thymus, and liver, in podocytes of renal glomeruli, in all types of renal tubular cells, in endothelial cells of small vessels, in fibroblasts, and in epithelial cells of the epididymis and ductus deferens. Electron microscopic examination showed that these deposits contained electrondense membranous bodies. Lipid analysis demonstrated a marked elevation of ganglioside GM2 and its asialo derivative in the brain and liver. Accumulation of globoside was found in the liver, kidney, and spleen. There was complete absence of hexosaminidase in the brain and liver.
Topics: Brain; Child, Preschool; Gangliosides; Globosides; Glycolipids; Hexosaminidases; Humans; Kidney; Liver; Male; Sandhoff Disease; Spinal Cord; Spleen
PubMed: 7270152
DOI: 10.1111/j.1440-1827.1981.tb01391.x -
Journal of Medical Case Reports Aug 2022Infantile Sandhoff disease is a rare inherited disorder that progressively destroys nerve cells in the brain and spinal cord, and is classified under lysosomal storage...
BACKGROUND
Infantile Sandhoff disease is a rare inherited disorder that progressively destroys nerve cells in the brain and spinal cord, and is classified under lysosomal storage disorder. It is an autosomal recessive disorder of sphingolipid metabolism that results from deficiency of the lysosomal enzymes β-hexosaminidase A and B. The resultant accumulation of GM2 ganglioside within both gray matter nuclei and myelin sheaths of the white matter results in eventual severe neuronal dysfunction and neurodegeneration.
CASE PRESENTATION
We evaluated a 3.5-year-old Comorian girl from the United Arab Emirates who presented with repeated chest infections with heart failure due to ventricular septal defect, neuroregression, recurrent seizures, and cherry-red spots over macula. She had macrocephaly, axial hypotonia, hyperacusis, and gastroesophageal reflux. Organomegaly was absent. Brain magnetic resonance imaging, metabolic tests, and genetic mutations confirmed the diagnosis. Despite multidisciplinary therapy, the girl succumbed to her illness.
CONCLUSION
Though early cardiac involvement can be seen with novel mutations, it is extremely rare to find association of ventricular septal defect in infantile Sandhoff disease. Neuroregression typically starts around 6 months of age. We report this case because of the unusual association of a congenital heart disease with underlying infantile Sandhoff disease and symptomatic heart failure in the first month of life with eventual fatal outcome.
Topics: Brain; Child, Preschool; Female; Heart Failure; Heart Septal Defects, Ventricular; Humans; Mutation; Sandhoff Disease
PubMed: 36002893
DOI: 10.1186/s13256-022-03550-0 -
Annals of Neurology Nov 2023GM2 gangliosidosis is usually fatal by 5 years of age in its 2 major subtypes, Tay-Sachs and Sandhoff disease. First reported in 1881, GM2 gangliosidosis has no...
OBJECTIVE
GM2 gangliosidosis is usually fatal by 5 years of age in its 2 major subtypes, Tay-Sachs and Sandhoff disease. First reported in 1881, GM2 gangliosidosis has no effective treatment today, and children succumb to the disease after a protracted neurodegenerative course and semi-vegetative state. This study seeks to further develop adeno-associated virus (AAV) gene therapy for human translation.
METHODS
Cats with Sandhoff disease were treated by intracranial injection of vectors expressing feline β-N-acetylhexosaminidase, the enzyme deficient in GM2 gangliosidosis.
RESULTS
Hexosaminidase activity throughout the brain and spinal cord was above normal after treatment, with highest activities at the injection sites (thalamus and deep cerebellar nuclei). Ganglioside storage was reduced throughout the brain and spinal cord, with near complete clearance in many regions. While untreated cats with Sandhoff disease lived for 4.4 ± 0.6 months, AAV-treated cats lived to 19.1 ± 8.6 months, and 3 of 9 cats lived >21 months. Correction of the central nervous system was so effective that significant increases in lifespan led to the emergence of otherwise subclinical peripheral disease, including megacolon, enlarged stomach and urinary bladder, soft tissue spinal cord compression, and patellar luxation. Throughout the gastrointestinal tract, neurons of the myenteric and submucosal plexuses developed profound pathology, demonstrating that the enteric nervous system was inadequately treated.
INTERPRETATION
The vector formulation in the current study effectively treats neuropathology in feline Sandhoff disease, but whole-body targeting will be an important consideration in next-generation approaches. ANN NEUROL 2023;94:969-986.
Topics: Child; Animals; Cats; Humans; Sandhoff Disease; Multiple Organ Failure; Genetic Vectors; Central Nervous System; Gangliosidoses, GM2; Genetic Therapy
PubMed: 37526361
DOI: 10.1002/ana.26756 -
Neuromuscular Disorders : NMD Aug 2021Defects in the HEXB gene which encodes the β-subunit of β-hexosaminidase A and B enzymes, cause a GM2 gangliosidosis, also known as Sandhoff disease, which is a rare...
Defects in the HEXB gene which encodes the β-subunit of β-hexosaminidase A and B enzymes, cause a GM2 gangliosidosis, also known as Sandhoff disease, which is a rare lysosomal storage disorder. The most common form of the disease lead to quickly progressing mental and motor decline in infancy; however there are other less severe forms with later onset that can also involve lower motor neurons. The diagnosis of this disease is based on low serum β-hexosaminidases A and B levels and confirmed using genetic test. We report two siblings with compound heterozygous HEXB mutations whose phenotype was extremely mild consisting in stuttering in both cases associated to mild proximal weakness in one of the cases, broadening the clinical spectrum of late onset Sandhoff disease.
Topics: Adult; Female; Hexosaminidase A; Humans; Male; Middle Aged; Motor Neuron Disease; Mutation; Phenotype; Sandhoff Disease; Stuttering
PubMed: 34210542
DOI: 10.1016/j.nmd.2021.04.011 -
Journal of Molecular Neuroscience : MN Apr 2020Infantile Sandhoff disease is an autosomal recessive inherited disease primarily characterized by cherry red spots in the retina, muscle weakness, seizure, truncal... (Review)
Review
Infantile Sandhoff disease is an autosomal recessive inherited disease primarily characterized by cherry red spots in the retina, muscle weakness, seizure, truncal hypotonia, hyperacusis, developmental delay and regression. The pathogenic genetic defects of the HEXB gene, which encodes the β subunit of the hexosaminidase A (ɑβ) and hexosaminidase B (ββ) enzymes, cause deficiency of both the Hex A and Hex B enzymes, resulting in the deposition of GM2 ganglion glycerides in the lysosomes of the central nervous system and somatic cells. The aim of this study was to discover disease-causing variants of the HEXB gene in two Chinese families through the use of exome sequencing. By characterizing three novel variants by molecular genetics, bioinformatics analysis, and three-dimensional structure modeling, we showed that all these novel variants influenced the protein structure. The results broaden the variant spectrum of HEXB in different ethnic groups. Furthermore, not all patients diagnosed with infantile Sandhoff disease had characteristic cranial imaging findings, which can only be used as supplementary information for diagnosis. The results of this study may contribute to clinical management, genetic counseling, and gene-targeted treatments for Sandhoff disease.
Topics: Brain; Female; Fundus Oculi; Humans; Infant; Mutation; Protein Domains; Sandhoff Disease; beta-Hexosaminidase beta Chain
PubMed: 31919734
DOI: 10.1007/s12031-019-01409-6 -
Neuropediatrics Dec 2020
Topics: Child; Gait; Humans; Leucine; Male; Sandhoff Disease; Treatment Outcome
PubMed: 32892336
DOI: 10.1055/s-0040-1715486 -
Yakugaku Zasshi : Journal of the... 2023Sandhoff disease (SD) is a glycosphingolipid storage disease resulting from a genetic mutation in HEXB and associated deficiency in β-hexosaminidase activity. This...
Sandhoff disease (SD) is a glycosphingolipid storage disease resulting from a genetic mutation in HEXB and associated deficiency in β-hexosaminidase activity. This defect causes abnormal accumulation of ganglioside GM2 and related glycolipids in lysosomes, resulting in progressive deterioration of the central nervous system. Hexb-knockout (Hexb) mice, an established animal model, show abnormalities similar to the severe phenotype seen in human infants. We used iPS cells derived from this mouse model (SD-iPSCs) to examine abnormal neuronal lineage differentiation and development in vitro during the asymptomatic phase of SD. Differentiation ability along the time axis appears to be altered in SD-iPSCs in which the differentiation ability of neural stem cells is promoted and differentiation into neurons is completed earlier, while the timing of differentiation into astrocytes is accelerated. This abnormal differentiation was suppressed by introducing the Hexb gene. These results indicate that the abnormal differentiation of SD-iPSCs into the nervous system reflects the pathogenesis of SD. Analysis using Hexb mice revealed that activated microglia causes astrogliosis at the early stage of development that can be ameliorated via immunosuppression. Furthermore, reactive astrocytes in the cortex of Hexb mice express adenosine A receptors in the late inflammatory phase. Inhibition of this receptor resulted in a decrease in activated microglial cells and inflammatory cytokines/chemokines. These results suggest that the astrocyte A receptor is important as a sensor that regulates microglial activation in the late inflammatory phase. Thus, our results provide new insights into the complex pathogenesis of SD.
Topics: Humans; Mice; Animals; Sandhoff Disease; Mice, Knockout; Neurons; Astrocytes; Neural Stem Cells; Disease Models, Animal
PubMed: 36596541
DOI: 10.1248/yakushi.22-00167