GM2G2
MCID: SND001
MIFTS: 66

Sandhoff Disease (GM2G2)

Categories: Eye diseases, Genetic diseases, Metabolic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Sandhoff Disease

MalaCards integrated aliases for Sandhoff Disease:

Name: Sandhoff Disease 57 12 73 20 43 53 58 72 36 29 54 6 44 15 37 39 70
Total Hexosaminidase Deficiency 20 43 70
Sandhoff Disease, Infantile, Juvenile, and Adult Forms 57 13
Beta-Hexosaminidase-Beta-Subunit Deficiency 20 43
Hexosaminidase a and B Deficiency Disease 20 43
Hexosaminidases a and B Deficiency 57 58
Sandhoff-Jatzkewitz-Pilz Disease 20 43
Sandhoff Disease, Infantile Form 58 6
Sandhoff Disease, Juvenile Form 58 6
Sandhoff Disease, Adult Form 58 6
Gm2 Gangliosidosis, Type 2 20 43
Hexosaminidases a and B Deficiency, Infantile Form 58
Hexosaminidases a and B Deficiency, Juvenile Form 58
Hexosaminidases a and B Deficiency, Adult Form 58
Infantile Gm2 Gangliosidosis 0 Variant 58
Juvenile Gm2 Gangliosidosis 0 Variant 58
Adult Gm2 Gangliosidosis 0 Variant 58
Hexosaminidase a and B Deficiency 72
Gm2 Gangliosidosis 0 Variant 58
Gm2-Gangliosidosis, Type Ii 57
Sandhoff Jatzkewitz Disease 12
Gm2 Gangliosidosis, Type Ii 43
Gm2-Gangliosidosis 2 72
Gm2g2 72
Sd 72

Characteristics:

Orphanet epidemiological data:

58
sandhoff disease
Inheritance: Autosomal recessive; Prevalence: 1-9/100000 (Portugal),1-9/1000000 (Netherlands),1-9/1000000 (Czech Republic),1-9/1000000 (Australia),1-9/1000000 (Turkey),1-9/1000000 (United States),1-9/1000000 (Europe),1-9/1000000 (Sweden); Age of onset: Adolescent,Adult,Childhood,Infancy; Age of death: adolescent,early childhood,late childhood;

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal recessive with multiple alleles and compounds


HPO:

31
sandhoff disease:
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Rare neurological diseases
Rare eye diseases
Inborn errors of metabolism


Summaries for Sandhoff Disease

MedlinePlus Genetics : 43 Sandhoff disease is a rare inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord.The most common and severe form of Sandhoff disease becomes apparent in infancy. Infants with this disorder typically appear normal until the age of 3 to 6 months, when their development slows and muscles used for movement weaken. Affected infants lose motor skills such as turning over, sitting, and crawling. They also develop an exaggerated startle reaction to loud noises. As the disease progresses, children with Sandhoff disease experience seizures, vision and hearing loss, intellectual disability, and paralysis. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Some affected children also have enlarged organs (organomegaly) or bone abnormalities. Children with the severe infantile form of Sandhoff disease usually live only into early childhood.Other forms of Sandhoff disease are very rare. Signs and symptoms can begin in childhood, adolescence, or adulthood and are usually milder than those seen with the infantile form. Characteristic features include muscle weakness, loss of muscle coordination (ataxia) and other problems with movement, speech problems, and mental illness. These signs and symptoms vary widely among people with late-onset forms of Sandhoff disease.

MalaCards based summary : Sandhoff Disease, also known as total hexosaminidase deficiency, is related to gm1-gangliosidosis, type i and gangliosidosis. An important gene associated with Sandhoff Disease is HEXB (Hexosaminidase Subunit Beta), and among its related pathways/superpathways are Glycosaminoglycan degradation and Other glycan degradation. The drugs Miglustat and Glycoside Hydrolase Inhibitors have been mentioned in the context of this disorder. Affiliated tissues include eye, spinal cord and spleen, and related phenotypes are macrocephaly and failure to thrive

Disease Ontology : 12 A GM2 gangliosidosis that is characterized by an accumulation of GM2 gangliosides, particularly in neurons, and that has material basis in mutation in the beta subunit of hexosaminidase (HEXB) on chromosome 5q13.

GARD : 20 Sandhoff disease is an inherited lipid storage disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord. The most common and severe form of Sandhoff disease becomes apparent in infancy. Infants with this disorder typically appear normal until the age of 3 to 6 months when their development slows and muscles used for movement weaken. Other forms of Sandhoff disease have been described where much milder signs and symptoms begin in childhood, adolescence, or adulthood. These forms are very rare. Sandhoff disease is caused by mutations in the HEXB gene. These mutations cause a deficiency of the enzyme beta-hexosaminidase, which results in the accumulation of certain fats (lipids) in the brain and other organs of the body. Sandhoff disease is inherited in an autosomal recessive manner.

OMIM® : 57 Sandhoff disease is a progressive neurodegenerative disorder characterized by an accumulation of GM2 gangliosides, particularly in neurons, and is clinically indistinguishable from Tay-Sachs disease (272800). (268800) (Updated 05-Apr-2021)

NINDS : 53 Sandhoff disease is a rare, inherited lipid storage disorder that progressively destroys nerve cells in the brain and spinal cord.  It is caused by a deficiency of the enzyme beta-hexosaminidase, which results in the harmful accumulation of certain fats (lipids) in the brain and other organs of the body. Sandhoff disease is a severe form of Tay-Sachs disease, the incidence of which had been particularly high in people of Eastern European and Ashkenazi Jewish descent, but Sandhoff disease is not limited to any ethnic group. Each parent must carry the defective gene and pass it on to the child.  Individuals who carry only one copy of the mutated gene typically do not show signs and symptoms of the disorder. Onset of the disorder usually occurs at 6 months of age. Symptoms may include: progressive nervous system deterioration, problems initiating and controlling muscles and movement, increased startle reaction to sound, early blindness, seizures, spasticity (non-voluntary and awkward movement), myoclonus (shock-like contractions of a muscle, macrocephaly (an abnormally enlarged head), cherry-red spots in the eyes, frequent respiratory infections, doll-like facial appearance, and enlarged liver and spleen.

KEGG : 36 Sandhoff disease is an autosomal recessive lysosomal storage disorder caused by mutations in HEXB that encodes beta-hexosaminidase subunit beta. Sandhoff disease is characterized by combined deficiency of hexosaminidase A (HexA) and hexosaminidase B (HexB) activities. GM2 ganglioside cannot be hydrolyzed and therefore accumulates primarily in neuronal tissues. This results in progressive neurologic degeneration. The severe form is characterized by an early age of onset and a rapidly progressive clinical course leading to death in early childhood, whereas the juvenile and adult forms start later and generally manifest a less severe course.

UniProtKB/Swiss-Prot : 72 GM2-gangliosidosis 2: An autosomal recessive lysosomal storage disease marked by the accumulation of GM2 gangliosides in the neuronal cells. Clinically indistinguishable from GM2-gangliosidosis type 1, presenting startle reactions, early blindness, progressive motor and mental deterioration, macrocephaly and cherry-red spots on the macula.

Wikipedia : 73 Sandhoff disease, is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to... more...

Related Diseases for Sandhoff Disease

Diseases related to Sandhoff Disease via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 124)
# Related Disease Score Top Affiliating Genes
1 gm1-gangliosidosis, type i 31.2 SMPD1 PSAP NPC2 NPC1 GLB1
2 gangliosidosis 30.9 UGCG PSAP HEXB HEXA GM2A GLB1
3 gm2-gangliosidosis, ab variant 30.9 PSAP OGA HEXB HEXA GM2A GLB1
4 inherited metabolic disorder 30.0 NPC2 NPC1 GLA
5 fabry disease 29.7 UGCG PSAP GLA ARSA
6 lysosomal storage disease 29.6 SMPD1 PSAP NPC2 NPC1 HEXB HEXA
7 scheie syndrome 29.6 NPC2 NPC1 GLB1 GLA ARSA
8 farber lipogranulomatosis 29.4 UGCG SMPD1 PSAP NPC1 GM2A ASAH1
9 tay-sachs disease 28.9 UGCG SMPD1 PSAP OGA NPC2 NPC1
10 mucopolysaccharidosis-plus syndrome 28.9 SMPD1 OGA NPC2 NPC1 HEXB HEXA
11 gaucher's disease 28.7 UGCG SMPD1 PSAP NPC2 NPC1 HEXA
12 gm1 gangliosidosis 28.6 UGCG SMPD1 PSAP OGA NPC2 NPC1
13 gm2 gangliosidosis 28.3 UGCG SMPD1 PSAP OGA NPC2 NPC1
14 gm2 gangliosidosis, 0 variant 11.5
15 generalized gangliosidoses 11.1
16 ataxia and polyneuropathy, adult-onset 10.4
17 motor neuron disease 10.4
18 niemann-pick disease type c, juvenile neurologic onset 10.3 NPC2 NPC1
19 niemann-pick disease type c, adult neurologic onset 10.3 NPC2 NPC1
20 niemann-pick disease type c, severe early infantile neurologic onset 10.3 NPC2 NPC1
21 niemann-pick disease type c, late infantile neurologic onset 10.3 NPC2 NPC1
22 metachromatic leukodystrophy, late infantile form 10.3 PSAP ARSA
23 niemann-pick disease type c, severe perinatal form 10.3 NPC2 NPC1
24 metachromatic leukodystrophy, adult form 10.3 PSAP ARSA
25 gm1-gangliosidosis, type ii 10.2 HEXB GM2A GLB1
26 fazio-londe disease 10.2 HEXA ETFA
27 helix syndrome 10.2
28 charcot-marie-tooth disease, axonal, type 2v 10.2 GM2A ASAH1
29 thalassemia 10.2
30 acid sphingomyelinase deficiency 10.2 SMPD1 NPC1
31 gm1-gangliosidosis, type iii 10.2 HEXB GLB1 GBA2
32 metachromatic leukodystrophy, juvenile form 10.2 PSAP ARSA
33 combined saposin deficiency 10.2 PSAP ARSA
34 malignant pineal area germ cell neoplasm 10.2 NPC2 ASAH1
35 mucolipidosis iv 10.2 NPC2 NPC1 HEXA
36 progressive myoclonus epilepsy 4 10.1 PSAP GBA2
37 skin hemangioma 10.1 UGCG GLA ETFA
38 amyotrophic lateral sclerosis 1 10.1
39 autosomal recessive disease 10.1
40 mitral valve insufficiency 10.1
41 diarrhea 10.1
42 lateral sclerosis 10.1
43 hypotonia 10.1
44 tremor 10.1
45 angiokeratoma 10.1 UGCG GLA ETFA
46 lysosomal and lipase deficiency 10.1 SMPD1 NPC2 NPC1
47 niemann-pick disease, type b 10.1 SMPD1 NPC2 NPC1
48 mucopolysaccharidosis, type iva 10.1 GLB1 GLA ARSA
49 mucopolysaccharidosis, type vi 10.0 GLB1 GLA ARSA
50 lysosomal acid lipase deficiency 10.0 SMPD1 NPC2 NPC1

Graphical network of the top 20 diseases related to Sandhoff Disease:



Diseases related to Sandhoff Disease

Symptoms & Phenotypes for Sandhoff Disease

Human phenotypes related to Sandhoff Disease:

58 31 (show all 38)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 macrocephaly 58 31 hallmark (90%) Very frequent (99-80%) HP:0000256
2 failure to thrive 58 31 hallmark (90%) Very frequent (99-80%) HP:0001508
3 ataxia 58 31 hallmark (90%) Very frequent (99-80%) HP:0001251
4 kyphosis 58 31 hallmark (90%) Very frequent (99-80%) HP:0002808
5 hearing impairment 58 31 hallmark (90%) Very frequent (99-80%) HP:0000365
6 blindness 58 31 hallmark (90%) Very frequent (99-80%) HP:0000618
7 cherry red spot of the macula 58 31 hallmark (90%) Very frequent (99-80%) HP:0010729
8 abnormality of movement 58 31 hallmark (90%) Very frequent (99-80%) HP:0100022
9 motor deterioration 58 31 hallmark (90%) Very frequent (99-80%) HP:0002333
10 progressive psychomotor deterioration 58 31 hallmark (90%) Very frequent (99-80%) HP:0007272
11 seizure 31 hallmark (90%) HP:0001250
12 abnormal glycosphingolipid metabolism 31 hallmark (90%) HP:0004343
13 muscle weakness 58 31 frequent (33%) Frequent (79-30%) HP:0001324
14 splenomegaly 58 31 frequent (33%) Frequent (79-30%) HP:0001744
15 hepatomegaly 58 31 frequent (33%) Frequent (79-30%) HP:0002240
16 recurrent respiratory infections 58 31 frequent (33%) Frequent (79-30%) HP:0002205
17 full cheeks 58 31 frequent (33%) Frequent (79-30%) HP:0000293
18 skeletal dysplasia 58 31 occasional (7.5%) Occasional (29-5%) HP:0002652
19 congestive heart failure 58 31 occasional (7.5%) Occasional (29-5%) HP:0001635
20 seizures 58 Very frequent (99-80%)
21 hyperreflexia 31 HP:0001347
22 hyperhidrosis 31 HP:0000975
23 dysarthria 31 HP:0001260
24 macroglossia 31 HP:0000158
25 coarse facial features 31 HP:0000280
26 cardiomegaly 31 HP:0001640
27 skeletal muscle atrophy 31 HP:0003202
28 abnormality of glycosphingolipid metabolism 58 Very frequent (99-80%)
29 hypohidrosis 31 HP:0000966
30 fasciculations 31 HP:0002380
31 chronic diarrhea 31 HP:0002028
32 upper motor neuron dysfunction 31 HP:0002493
33 impotence 31 HP:0000802
34 orthostatic hypotension 31 HP:0001278
35 hepatosplenomegaly 31 HP:0001433
36 urinary incontinence 31 HP:0000020
37 episodic abdominal pain 31 HP:0002574
38 impaired thermal sensitivity 31 HP:0006901

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Cranium:
macrocephaly

Tongue:
macroglossia

G I:
chronic diarrhea
hepatosplenomegaly
episodic abdominal pain

Facies:
coarse facies
doll-like face

Eyes:
early blindness
cherry red spots

Skin:
impaired sweating

Lab:
hexosaminidase b beta chain deficiency

Neuro:
hyperreflexia
dysarthria
fasciculations
orthostatic hypotension
impaired thermal sensitivity
more
Cardiac:
cardiomegaly

G U:
impotence
mild urinary incontinence

Muscle:
muscle wasting
infantile muscle weakness

Skel:
high lumbar gibbus

Misc:
lethal usually by age 3 years
intolerance to heat

Clinical features from OMIM®:

268800 (Updated 05-Apr-2021)

GenomeRNAi Phenotypes related to Sandhoff Disease according to GeneCards Suite gene sharing:

26
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 Decreased viability GR00240-S-1 9.6 ASAH1 GBA2
2 Decreased viability GR00249-S 9.6 ETFA GLA HEXA HEXB
3 Decreased viability GR00381-A-1 9.6 ASAH1 GBA2 GLA SMPD1 UGCG
4 Decreased viability GR00386-A-1 9.6 ASAH1 CCL3 CTBS GBA2 HEXA HEXD
5 Decreased viability GR00402-S-2 9.6 ARSA GLB1

MGI Mouse Phenotypes related to Sandhoff Disease:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 cellular MP:0005384 10.27 ASAH1 CTBS GBA2 GLA GLB1 HEXB
2 behavior/neurological MP:0005386 10.26 ARSA ASAH1 GLA GLB1 GM2A HEXA
3 homeostasis/metabolism MP:0005376 10.25 ARSA ASAH1 CTBS GBA2 GLA GLB1
4 growth/size/body region MP:0005378 10.21 ASAH1 GLA GLB1 HEXA HEXB HHEX
5 immune system MP:0005387 10.11 ARSA ASAH1 CTBS GLA GLB1 HEXB
6 mortality/aging MP:0010768 10.07 ASAH1 GFM2 GLA GLB1 HEXA HEXB
7 liver/biliary system MP:0005370 10.06 ASAH1 CTBS GLA GLB1 HEXA HEXB
8 nervous system MP:0003631 9.97 ARSA ASAH1 GLA GLB1 GM2A HEXA
9 renal/urinary system MP:0005367 9.56 ASAH1 CTBS GLA GLB1 HEXA HEXB
10 respiratory system MP:0005388 9.17 ASAH1 HHEX NPC1 NPC2 OGA PSAP

Drugs & Therapeutics for Sandhoff Disease

Drugs for Sandhoff Disease (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 43)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Miglustat Approved Phase 4 72599-27-0 51634
2 Glycoside Hydrolase Inhibitors Phase 4
3 Anti-Retroviral Agents Phase 4
4 Antiviral Agents Phase 4
5 Anti-HIV Agents Phase 4
6 Cardiac Glycosides Phase 4
7 Hypoglycemic Agents Phase 4
8
Prednisolone phosphate Approved, Vet_approved Phase 2, Phase 3 302-25-0
9
Prednisolone Approved, Vet_approved Phase 2, Phase 3 50-24-8 5755
10
Methylprednisolone Approved, Vet_approved Phase 2, Phase 3 83-43-2 6741
11
Methylprednisolone hemisuccinate Approved Phase 2, Phase 3 2921-57-5
12
Prednisolone acetate Approved, Vet_approved Phase 2, Phase 3 52-21-1
13
Cyclophosphamide Approved, Investigational Phase 2, Phase 3 50-18-0, 6055-19-2 2907
14
Busulfan Approved, Investigational Phase 2, Phase 3 55-98-1 2478
15
Prednisolone hemisuccinate Experimental Phase 2, Phase 3 2920-86-7
16 Alkylating Agents Phase 2, Phase 3
17 Immunosuppressive Agents Phase 2, Phase 3
18 Antirheumatic Agents Phase 2, Phase 3
19 Immunologic Factors Phase 2, Phase 3
20 Methylprednisolone Acetate Phase 2, Phase 3
21 Antilymphocyte Serum Phase 2, Phase 3
22
leucovorin Approved Phase 1, Phase 2 58-05-9 6006
23
Hydroxyurea Approved Phase 2 127-07-1 3657
24
Melphalan Approved Phase 2 148-82-3 4053 460612
25
tannic acid Approved Phase 2 1401-55-4
26
alemtuzumab Approved, Investigational Phase 2 216503-57-0
27
Clofarabine Approved, Investigational Phase 2 123318-82-1 119182
28
Clotrimazole Approved, Vet_approved Phase 2 23593-75-1 2812
29
Miconazole Approved, Investigational, Vet_approved Phase 2 22916-47-8 4189
30
Benzocaine Approved, Investigational Phase 2 1994-09-7, 94-09-7 2337
31 Antidotes Phase 1, Phase 2
32 Nutrients Phase 1, Phase 2
33 Trace Elements Phase 1, Phase 2
34 Micronutrients Phase 1, Phase 2
35 Protective Agents Phase 1, Phase 2
36 Vitamins Phase 1, Phase 2
37 Cyclosporins Phase 2
38 Antineoplastic Agents, Immunological Phase 2
39 Dermatologic Agents Phase 2
40 Antimetabolites Phase 2
41 Calcineurin Inhibitors Phase 2
42 Antifungal Agents Phase 2
43
Leucine Investigational, Nutraceutical Phase 2 61-90-5 6106

Interventional clinical trials:

(show all 16)
# Name Status NCT ID Phase Drugs
1 Synergistic Enteral Regimen for Treatment of the Gangliosidoses (Syner-G) Recruiting NCT02030015 Phase 4 miglustat
2 Treatment of Lysosomal and Peroxisomal Inborn Errors of Metabolism by Bone Marrow Transplantation Completed NCT00176904 Phase 2, Phase 3 Busulfan, Cyclophosphamide, Antithymocyte Globulin
3 Pharmacokinetics, Safety and Tolerability of Zavesca (Miglustat) in Patients With Infantile Onset GM2 Gangliosidosis: Single and Steady State Oral Doses Completed NCT00672022 Phase 3 Zavesca (Miglustat)
4 A Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Venglustat in Late-onset GM2 Gangliosidosis (Tay-Sachs Disease and Sandhoff Disease) Together With a Separate Basket for Juvenile/Adolescent Late-onset GM2 Gangliosidosis and Ultra-rare Diseases Within the Same and Similar Glucosylceramide-based Sphingolipid Pathway Recruiting NCT04221451 Phase 3 venglustat GZ402671;placebo
5 Proposed Investigator-Initiated Clinical Trial of Pyrimethamine as a Treatment for Late-Onset GM2-gangliosidosis (Tay-Sachs and Sandhoff Disease) Completed NCT01102686 Phase 1, Phase 2 Pyrimethamine;Leucovorin
6 Treatment of High Risk, Inherited Lysosomal And Peroxisomal Disorders by Reduced Intensity Hematopoietic Stem Cell Transplantation Completed NCT00383448 Phase 2 Clofarabine;Melphalan;Alemtuzumab;mycophenylate mofetil;Hydroxyurea
7 Effects of N-Acetyl-L-Leucine on GM2 Gangliosdisosis (Tay-Sachs and Sandhoff Disease): A Multinational, Multicenter, Open-label, Rater-blinded Phase II Study Recruiting NCT03759665 Phase 2 IB1001
8 Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders Active, not recruiting NCT01372228 Phase 1, Phase 2
9 A Two-Stage, Dose-Escalation and Safety & Efficacy Study of Bilateral Intraparenchymal Thalamic and Intracisternal/Intrathecal Administration of AXO-AAV-GM2 in Tay-Sachs or Sandhoff Disease Recruiting NCT04669535 Phase 1
10 Augmentation of Umbilical Cord Blood Transplantation for Inherited Metabolic Diseases With Intrathecal Administration of Human Umbilical Cord Blood-Derived Oligodendrocyte-Like Cells Recruiting NCT02254863 Phase 1
11 A Dose-Escalated, Double-Blind, Placebo-Controlled, Randomized Phase I Clinical Trial of Pyrimethamine in Patients Affected With Chronic GM2 Gangliosidosis (Tay-Sachs or Sandhoff Variants) Withdrawn NCT00679744 Phase 1 Pyrimethamine
12 Gene Therapy for Tay-Sachs Disease (Phase 1: Natural History Data Gather) Completed NCT01869270
13 Eight At One Stroke: Attention Gangliosidoses A Registry Study for Patients With Gangliosidoses Recruiting NCT04624789
14 Longitudinal Study of Neurodegenerative Disorders Recruiting NCT03333200
15 Natural History Study for Pediatric Patients With Early Onset of Either GM1 Gangliosidosis, GM2 Gangliosidoses, or Gaucher Disease Type 2 Recruiting NCT04470713
16 A Natural History Study of the Gangliosidoses Recruiting NCT00668187

Search NIH Clinical Center for Sandhoff Disease

Cell-based therapeutics:


LifeMap Discovery
Data from LifeMap, the Embryonic Development and Stem Cells Database
Read about Sandhoff Disease cell therapies at LifeMap Discovery.

Cochrane evidence based reviews: sandhoff disease

Genetic Tests for Sandhoff Disease

Genetic tests related to Sandhoff Disease:

# Genetic test Affiliating Genes
1 Sandhoff Disease 29 HEXB

Anatomical Context for Sandhoff Disease

MalaCards organs/tissues related to Sandhoff Disease:

40
Eye, Spinal Cord, Spleen, Brain, Bone Marrow, Heart, Bone

Publications for Sandhoff Disease

Articles related to Sandhoff Disease:

(show top 50) (show all 455)
# Title Authors PMID Year
1
Molecular and functional analysis of the HEXB gene in Italian patients affected with Sandhoff disease: identification of six novel alleles. 57 6 54 61
18758829 2009
2
Sandhoff disease in Argentina: high frequency of a splice site mutation in the HEXB gene and correlation between enzyme and DNA-based tests for heterozygote detection. 57 6 61 54
8076944 1994
3
Sandhoff disease in Cyprus: population screening by biochemical and DNA analysis indicates a high frequency of carriers in the Maronite community. 61 57 6
10982028 2000
4
Molecular basis of an adult form of Sandhoff disease: substitution of glutamine for arginine at position 505 of the beta-chain of beta-hexosaminidase results in a labile enzyme. 61 6 57
8357844 1993
5
Juvenile Sandhoff disease: some properties of the residual hexosaminidase in cultured fibroblasts. 57 6 61
10724 1976
6
Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. 6 57
7550345 1995
7
Adult onset motor neuronopathy in the juvenile type of hexosaminidase A and B deficiency. 57 6
2973515 1988
8
Ganglioside storage, hexosaminidase lability, and urinary oligosaccharides in adult Sandhoff's disease. 6 57
2948136 1987
9
N-acetyl-beta-hexosaminidase beta locus defect and juvenile motor neuron disease: a case study. 6 57
3014997 1986
10
Spinocerebellar degeneration: hexosaminidase A and B deficiency in two adult sisters. 57 6
571983 1979
11
Possible role of autoantibodies in the pathophysiology of GM2 gangliosidoses. 61 57 54
14722612 2004
12
Novel splice site mutation at IVS8 nt 5 of HEXB responsible for a Greek-Cypriot case of Sandhoff disease. 6 54 61
9888387 1999
13
A Pro504 --> Ser substitution in the beta-subunit of beta-hexosaminidase A inhibits alpha-subunit hydrolysis of GM2 ganglioside, resulting in chronic Sandhoff disease. 61 54 6
9694901 1998
14
Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis. 57 61 54
8896570 1996
15
Significance of two point mutations present in each HEXB allele of patients with adult GM2 gangliosidosis (Sandhoff disease) homozygosity for the Ile207-->Val substitution is not associated with a clinical or biochemical phenotype. 6 54 61
8950198 1996
16
Impact of premature stop codons on mRNA levels in infantile Sandhoff disease. 61 54 6
8162015 1994
17
Characterization of two HEXB gene mutations in Argentinean patients with Sandhoff disease. 57 54 61
1390948 1992
18
Two small deletion mutations of the HEXB gene are present in DNA from a patient with infantile Sandhoff disease. 6 54 61
1532910 1992
19
Structure and distribution of an Alu-type deletion mutation in Sandhoff disease. 61 54 6
2147027 1990
20
Distribution and characterization of a Sandhoff disease-associated 50-kb deletion in the gene encoding the human beta-hexosaminidase beta-chain. 61 54 6
1975561 1990
21
Genotype-phenotype correlation of gangliosidosis mutations using in silico tools and homology modeling. 61 6
31367523 2019
22
Clinical presentation and outcome in infantile Sandhoff disease: a case series of 25 patients from Iranian neurometabolic bioregistry with five novel mutations. 61 6
30075786 2018
23
Early cardiac involvement in an infantile Sandhoff disease case with novel mutations. 6 61
27697305 2017
24
Sandhoff disease in two siblings of a Malaysian family: Description of novel beta hexosaminidase mutations, magnetic resonance imaging, and spectroscopic findings. 6 61
28281504 2017
25
Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity. 6 61
27682710 2016
26
Clinical,biochemical and molecular analysis of five Chinese patients with Sandhoff disease. 6 61
27021291 2016
27
Clinical, biochemical and mutation profile in Indian patients with Sandhoff disease. 6 61
26582265 2016
28
Peripheral neuropathy in a family with Sandhoff disease and SH3TC2 deficiency. 6 61
25736553 2015
29
Chaperone therapy for GM2 gangliosidosis: effects of pyrimethamine on β-hexosaminidase activity in Sandhoff fibroblasts. 61 6
24356898 2014
30
Homozygous p.R284* mutation in HEXB gene causing Sandhoff disease with nystagmus. 61 6
24613245 2014
31
[Clinical and molecular characteristics of a child with juvenile Sandhoff disease]. 6 61
24915922 2014
32
Incidence and carrier frequency of Sandhoff disease in Saskatchewan determined using a novel substrate with detection by tandem mass spectrometry and molecular genetic analysis. 61 6
24461908 2014
33
Adult Sandhoff disease with 2 mutations in the HEXB gene presenting as brachial amyotrophic diplegia. 6 61
24263030 2013
34
Molecular pathology of Sandhoff disease with p.Arg505Gln in HEXB: application of simulation analysis. 61 6
23759947 2013
35
Characterization of the mutant β-subunit of β-hexosaminidase for dimer formation responsible for the adult form of Sandhoff disease with the motor neuron disease phenotype. 6 61
23127958 2013
36
Characterization of seven novel mutations on the HEXB gene in French Sandhoff patients. 6 61
23046579 2013
37
GM2 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay-Sachs and 14 Sandhoff patients. 61 6
22789865 2012
38
A polymerase chain reaction-based genotyping assay for detecting a novel Sandhoff disease-causing mutation. 6 61
22191674 2012
39
Sequence and copy number analyses of HEXB gene in patients affected by Sandhoff disease: functional characterization of 9 novel sequence variants. 61 6
22848519 2012
40
Novel Mutations in Sandhoff Disease: A Molecular Analysis among Iranian Cohort of Infantile Patients. 6 61
23113155 2012
41
A mutation of HEXB gene in Sandhoff disease presenting as motor neuron disease. 61 6
21150067 2010
42
New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype. 61 6
20798201 2010
43
Occurrence of an anomalous endocytic compartment in fibroblasts from Sandhoff disease patients. 6 61
19823769 2010
44
Chronic GM2 gangliosidosis type Sandhoff associated with a novel missense HEXB gene mutation causing a double pathogenic effect. 6 54
17251047 2007
45
Western blotting analysis of the beta-hexosaminidase alpha- and beta-subunits in cultured fibroblasts from cases of various forms of GM2 gangliosidosis. 61 6
12027830 2002
46
Molecular pathophysiology in Tay-Sachs and Sandhoff diseases as revealed by gene expression profiling. 57 61
12019216 2002
47
Tay-Sachs and Sandhoff diseases: enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn-screening cards. 61 57
11880123 2002
48
Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin. 57 61
10339597 1999
49
Splicing mutation causes infantile Sandhoff disease. 6 61
9475608 1998
50
Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases. 57 61
9302266 1997

Variations for Sandhoff Disease

ClinVar genetic disease variations for Sandhoff Disease:

6 (show top 50) (show all 198)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 HEXB nsv513799 Deletion Pathogenic 3873 GRCh37:
GRCh38:
2 HEXB NM_000521.4(HEXB):c.1510C>T (p.Pro504Ser) SNV Pathogenic 3884 rs121907985 GRCh37: 5:74016469-74016469
GRCh38: 5:74720644-74720644
3 HEXB NM_000521.4(HEXB):c.299G>C (p.Arg100Pro) SNV Pathogenic 397589 rs1060499701 GRCh37: 5:73981384-73981384
GRCh38: 5:74685559-74685559
4 HEXB NM_000521.4(HEXB):c.170G>A (p.Trp57Ter) SNV Pathogenic 242876 rs1114167287 GRCh37: 5:73981255-73981255
GRCh38: 5:74685430-74685430
5 HEXB NC_000005.10:g.(?_74685241)_(74697126_?)del Deletion Pathogenic 527972 GRCh37: 5:73981066-73992951
GRCh38: 5:74685241-74697126
6 HEXB NM_000521.4(HEXB):c.171del (p.Trp57fs) Deletion Pathogenic 557707 rs771973471 GRCh37: 5:73981255-73981255
GRCh38: 5:74685430-74685430
7 HEXB NM_000521.4(HEXB):c.333G>A (p.Trp111Ter) SNV Pathogenic 557986 rs761117459 GRCh37: 5:73985186-73985186
GRCh38: 5:74689361-74689361
8 HEXB NM_000521.4(HEXB):c.841C>T (p.Arg281Ter) SNV Pathogenic 623308 rs138914144 GRCh37: 5:74009400-74009400
GRCh38: 5:74713575-74713575
9 HEXB NM_000521.4(HEXB):c.298C>T (p.Arg100Ter) SNV Pathogenic 623479 rs1007338250 GRCh37: 5:73981383-73981383
GRCh38: 5:74685558-74685558
10 HEXB NC_000005.10:g.(?_74685251)_(74697116_?)del Deletion Pathogenic 644276 GRCh37: 5:73981076-73992941
GRCh38: 5:74685251-74697116
11 HEXB NM_000521.4(HEXB):c.171_176delinsCCCCC (p.Trp57fs) Indel Pathogenic 658705 rs1580377261 GRCh37: 5:73981256-73981261
GRCh38: 5:74685431-74685436
12 HEXB NM_000521.4(HEXB):c.839T>G (p.Leu280Ter) SNV Pathogenic 664928 rs1579950499 GRCh37: 5:74009398-74009398
GRCh38: 5:74713573-74713573
13 HEXB NM_000521.4(HEXB):c.1010dup (p.Lys338fs) Duplication Pathogenic 665539 rs1579952143 GRCh37: 5:74011438-74011439
GRCh38: 5:74715613-74715614
14 HEXB NC_000005.10:g.(?_74685261)_(74697106_?)del Deletion Pathogenic 583659 GRCh37: 5:73981086-73992931
GRCh38: 5:74685261-74697106
15 HEXB NM_000521.4(HEXB):c.451_452dup (p.Leu151fs) Duplication Pathogenic 841253 GRCh37: 5:73989467-73989468
GRCh38: 5:74693642-74693643
16 HEXB NM_000521.4(HEXB):c.1021_1023delinsTCAAA (p.Glu342fs) Indel Pathogenic 849280 GRCh37: 5:74011454-74011456
GRCh38: 5:74715629-74715631
17 HEXB NM_000521.4(HEXB):c.64_65del (p.Leu22fs) Deletion Pathogenic 860680 GRCh37: 5:73981149-73981150
GRCh38: 5:74685324-74685325
18 HEXB NM_000521.4(HEXB):c.1481A>G (p.Asp494Gly) SNV Pathogenic 869190 GRCh37: 5:74016316-74016316
GRCh38: 5:74720491-74720491
19 HEXB NM_000521.4(HEXB):c.652_654ATT[1] (p.Ile219del) Microsatellite Pathogenic 870557 GRCh37: 5:73992914-73992916
GRCh38: 5:74697089-74697091
20 HEXB NM_000521.4(HEXB):c.1169+3_1169+10del Deletion Pathogenic 93195 rs398123444 GRCh37: 5:74012500-74012507
GRCh38: 5:74716675-74716682
21 HEXB NM_000521.4(HEXB):c.571_574del (p.Glu191fs) Deletion Pathogenic 952216 GRCh37: 5:73992830-73992833
GRCh38: 5:74697005-74697008
22 HEXB NM_000521.4(HEXB):c.1310_1311del (p.Thr437fs) Microsatellite Pathogenic 960316 GRCh37: 5:74014687-74014688
GRCh38: 5:74718862-74718863
23 HEXB HEXB, 24-BP INS Insertion Pathogenic 3875 GRCh37:
GRCh38:
24 HEXB NM_000521.4(HEXB):c.1367A>C (p.Tyr456Ser) SNV Pathogenic 3877 rs121907982 GRCh37: 5:74014746-74014746
GRCh38: 5:74718921-74718921
25 HEXB NM_000521.3(HEXB):c.185C>T (p.Ser62Leu) SNV Pathogenic 3882 rs820878 GRCh37: 5:73981270-73981270
GRCh38: 5:74685445-74685445
26 HEXB HEXB, PARTIAL DEL Deletion Pathogenic 3883 GRCh37:
GRCh38:
27 HEXB NM_000521.4(HEXB):c.1082+5G>C SNV Pathogenic 3885 rs5030731 GRCh37: 5:74011520-74011520
GRCh38: 5:74715695-74715695
28 HEXB NM_000521.4(HEXB):c.76del (p.Met26fs) Deletion Pathogenic 3886 rs1580377105 GRCh37: 5:73981161-73981161
GRCh38: 5:74685336-74685336
29 HEXB NM_000521.4(HEXB):c.965del (p.Ile322fs) Deletion Pathogenic 557437 rs768438206 GRCh37: 5:74011398-74011398
GRCh38: 5:74715573-74715573
30 HEXB NC_000005.10:g.74713507del Deletion Pathogenic 964994 GRCh37: 5:74009330-74009330
GRCh38: 5:74713505-74713505
31 HEXB NM_000521.4(HEXB):c.283del (p.Glu95fs) Deletion Pathogenic 965677 GRCh37: 5:73981367-73981367
GRCh38: 5:74685542-74685542
32 HEXB NM_000521.4(HEXB):c.1474_1477delinsAA (p.Tyr492fs) Indel Pathogenic 969188 GRCh37: 5:74016309-74016312
GRCh38: 5:74720484-74720487
33 HEXB NM_000521.4(HEXB):c.1514G>A (p.Arg505Gln) SNV Pathogenic 3879 rs121907983 GRCh37: 5:74016473-74016473
GRCh38: 5:74720648-74720648
34 HEXB NM_000521.4(HEXB):c.445+1G>A SNV Pathogenic 633263 rs761197472 GRCh37: 5:73985299-73985299
GRCh38: 5:74689474-74689474
35 HEXB NM_000521.4(HEXB):c.1538T>C (p.Leu513Pro) SNV Pathogenic 929001 GRCh37: 5:74016497-74016497
GRCh38: 5:74720672-74720672
36 HEXB NM_000521.4(HEXB):c.508C>T (p.Arg170Ter) SNV Pathogenic 281002 rs753823903 GRCh37: 5:73989526-73989526
GRCh38: 5:74693701-74693701
37 HEXB NM_000521.4(HEXB):c.1294dup (p.Glu432fs) Duplication Pathogenic 851972 GRCh37: 5:74014671-74014672
GRCh38: 5:74718846-74718847
38 HEXB NM_000521.4(HEXB):c.1250C>T (p.Pro417Leu) SNV Pathogenic 3878 rs28942073 GRCh37: 5:74014629-74014629
GRCh38: 5:74718804-74718804
39 HEXB NM_000521.4(HEXB):c.1250C>T (p.Pro417Leu) SNV Pathogenic 3878 rs28942073 GRCh37: 5:74014629-74014629
GRCh38: 5:74718804-74718804
40 HEXB NM_000521.4(HEXB):c.850C>T (p.Arg284Ter) SNV Pathogenic 3887 rs121907986 GRCh37: 5:74009409-74009409
GRCh38: 5:74713584-74713584
41 HEXB NM_000521.4(HEXB):c.1250C>T (p.Pro417Leu) SNV Pathogenic 3878 rs28942073 GRCh37: 5:74014629-74014629
GRCh38: 5:74718804-74718804
42 HEXB NM_000521.4(HEXB):c.850C>T (p.Arg284Ter) SNV Pathogenic 3887 rs121907986 GRCh37: 5:74009409-74009409
GRCh38: 5:74713584-74713584
43 HEXB NM_000521.4(HEXB):c.1597C>T (p.Arg533Cys) SNV Pathogenic 435415 rs764552042 GRCh37: 5:74016556-74016556
GRCh38: 5:74720731-74720731
44 HEXB NM_000521.4(HEXB):c.552T>G (p.Tyr184Ter) SNV Pathogenic 280067 rs573447174 GRCh37: 5:73992558-73992558
GRCh38: 5:74696733-74696733
45 HEXB NM_000521.4(HEXB):c.94C>T (p.Gln32Ter) SNV Pathogenic 800874 rs1554034434 GRCh37: 5:73981179-73981179
GRCh38: 5:74685354-74685354
46 HEXB NM_000521.4(HEXB):c.115del (p.Val39fs) Deletion Pathogenic 93194 rs398123443 GRCh37: 5:73981199-73981199
GRCh38: 5:74685374-74685374
47 HEXB NM_000521.4(HEXB):c.558+1G>C SNV Pathogenic/Likely pathogenic 853457 GRCh37: 5:73992565-73992565
GRCh38: 5:74696740-74696740
48 HEXB NM_000521.4(HEXB):c.1082+5G>A SNV Pathogenic/Likely pathogenic 354135 rs5030731 GRCh37: 5:74011520-74011520
GRCh38: 5:74715695-74715695
49 HEXB NM_000521.4(HEXB):c.146C>A (p.Ser49Ter) SNV Pathogenic/Likely pathogenic 555683 rs1554034452 GRCh37: 5:73981231-73981231
GRCh38: 5:74685406-74685406
50 HEXB NM_000521.4(HEXB):c.1345del (p.Trp449fs) Deletion Pathogenic/Likely pathogenic 929241 GRCh37: 5:74014723-74014723
GRCh38: 5:74718898-74718898

UniProtKB/Swiss-Prot genetic disease variations for Sandhoff Disease:

72
# Symbol AA change Variation ID SNP ID
1 HEXB p.Ser62Leu VAR_003247 rs820878
2 HEXB p.Cys309Tyr VAR_003250 rs155403664
3 HEXB p.Pro417Leu VAR_003251 rs28942073
4 HEXB p.Tyr456Ser VAR_003252 rs121907982
5 HEXB p.Arg505Gln VAR_003253 rs121907983
6 HEXB p.Cys534Tyr VAR_003254 rs727503960
7 HEXB p.Ser255Arg VAR_011704 rs155403582
8 HEXB p.Pro504Ser VAR_011705 rs121907985
9 HEXB p.Ala543Thr VAR_011706 rs121907984

Copy number variations for Sandhoff Disease from CNVD:

7
# CNVD ID Chromosome Start End Type Gene Symbol CNVD Disease
1 201871 5 73971603 74052869 Deletion HEXB Sandhoff disease

Expression for Sandhoff Disease

Search GEO for disease gene expression data for Sandhoff Disease.

Pathways for Sandhoff Disease

Pathways related to Sandhoff Disease according to KEGG:

36
# Name Kegg Source Accession
1 Glycosaminoglycan degradation hsa00531
2 Other glycan degradation hsa00511

Pathways related to Sandhoff Disease according to GeneCards Suite gene sharing:

(show all 11)
# Super pathways Score Top Affiliating Genes
1
Show member pathways
13.78 UGCG SMPD1 PSAP NPC2 NPC1 HEXD
2
Show member pathways
12.1 UGCG SMPD1 PSAP HEXB HEXA GM2A
3
Show member pathways
11.66 HEXD HEXB HEXA
4
Show member pathways
11.55 HEXB HEXA GLB1
5 11.47 SMPD1 PSAP NPC2 NPC1 HEXB HEXA
6
Show member pathways
11.15 HEXB HEXA GLA
7
Show member pathways
10.99 HEXB HEXA GLB1
8 10.81 HEXD HEXB HEXA GLB1 GBA2
9
Show member pathways
10.8 HEXB HEXA GLB1
10 10.7 SMPD1 CCL3
11
Show member pathways
10.6 NPC2 NPC1

GO Terms for Sandhoff Disease

Cellular components related to Sandhoff Disease according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 extracellular region GO:0005576 10.06 SMPD1 PSAP NPC2 NPC1 HEXB GM2A
2 extracellular space GO:0005615 10.02 SMPD1 PSAP NPC2 HEXB GLB1 CTBS
3 extracellular exosome GO:0070062 10 SMPD1 PSAP NPC2 NPC1 HEXB HEXA
4 lysosomal lumen GO:0043202 9.65 SMPD1 PSAP NPC2 HEXB HEXA GM2A
5 azurophil granule lumen GO:0035578 9.63 NPC2 HEXB GM2A GLB1 GLA ARSA
6 azurophil granule GO:0042582 9.4 HEXB HEXA
7 lysosome GO:0005764 9.4 SMPD1 PSAP NPC2 NPC1 HEXB HEXA

Biological processes related to Sandhoff Disease according to GeneCards Suite gene sharing:

(show all 23)
# Name GO ID Score Top Affiliating Genes
1 lipid metabolic process GO:0006629 10 UGCG PSAP NPC2 NPC1 GM2A GBA2
2 neutrophil degranulation GO:0043312 9.92 PSAP NPC2 HEXB GM2A GLB1 GLA
3 lipid transport GO:0006869 9.8 PSAP NPC2 NPC1 GM2A
4 cholesterol metabolic process GO:0008203 9.78 SMPD1 NPC2 NPC1 GBA2
5 steroid metabolic process GO:0008202 9.76 NPC2 NPC1 GBA2
6 carbohydrate metabolic process GO:0005975 9.7 HEXD HEXB HEXA GLB1 GLA GBA2
7 sphingolipid metabolic process GO:0006665 9.65 UGCG PSAP GM2A GBA2 ASAH1
8 cholesterol efflux GO:0033344 9.61 NPC2 NPC1
9 lipid storage GO:0019915 9.61 HEXB GM2A
10 keratan sulfate catabolic process GO:0042340 9.61 HEXB HEXA GLB1
11 metabolic process GO:0008152 9.61 SMPD1 OGA HEXD HEXB HEXA GLB1
12 low-density lipoprotein particle clearance GO:0034383 9.6 NPC2 NPC1
13 cholesterol transport GO:0030301 9.59 NPC2 NPC1
14 lysosomal transport GO:0007041 9.58 PSAP NPC1
15 oligosaccharide catabolic process GO:0009313 9.58 HEXB GM2A CTBS
16 hyaluronan catabolic process GO:0030214 9.57 HEXB HEXA
17 bile acid metabolic process GO:0008206 9.56 NPC1 GBA2
18 chondroitin sulfate catabolic process GO:0030207 9.55 HEXB HEXA
19 intracellular cholesterol transport GO:0032367 9.54 NPC2 NPC1
20 ganglioside catabolic process GO:0006689 9.54 HEXB HEXA GM2A
21 glycoside catabolic process GO:0016139 9.52 GLA GBA2
22 astrocyte cell migration GO:0043615 9.51 HEXB CCL3
23 glycosphingolipid metabolic process GO:0006687 9.36 UGCG SMPD1 PSAP HEXB HEXA GM2A

Molecular functions related to Sandhoff Disease according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 hydrolase activity GO:0016787 10.03 SMPD1 OGA HEXD HEXB HEXA GM2A
2 N-acetyl-beta-D-galactosaminidase activity GO:0102148 9.5 HEXD HEXB HEXA
3 hydrolase activity, hydrolyzing O-glycosyl compounds GO:0004553 9.5 HEXD HEXB HEXA GLB1 GLA GBA2
4 beta-N-acetylhexosaminidase activity GO:0004563 9.46 HEXD HEXB HEXA GM2A
5 galactoside binding GO:0016936 9.43 GLB1 GLA
6 phospholipase activator activity GO:0016004 9.4 GM2A CCL3
7 beta-galactosidase activity GO:0004565 9.37 PSAP GLB1
8 hydrolase activity, acting on glycosyl bonds GO:0016798 9.28 SMPD1 OGA HEXD HEXB HEXA GLB1

Sources for Sandhoff Disease

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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