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Sandhoff disease

MedGen UID:
11313
Concept ID:
C0036161
Disease or Syndrome
Synonyms: Beta-hexosaminidase-beta-subunit deficiency; GM2 gangliosidosis, type 2; GM2-GANGLIOSIDOSIS, TYPE II; Hexosaminidase A and B deficiency Disease; HEXOSAMINIDASES A AND B DEFICIENCY; Sandhoff-Jatzkewitz-Pilz disease; Total hexosaminidase deficiency
SNOMED CT: Sandhoff disease (23849003); GM>2< gangliosidosis, type 2 (23849003); Hexosaminidase A AND B deficiency (23849003); Total hexosaminidase deficiency (23849003); O variant (23849003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): HEXB (5q13.3)
 
Monarch Initiative: MONDO:0010006
OMIM®: 268800
Orphanet: ORPHA796

Disease characteristics

Excerpted from the GeneReview: Sandhoff Disease
Sandhoff disease comprises a phenotypic continuum encompassing acute infantile, subacute juvenile, and late-onset disease. Although classification into these phenotypes is somewhat arbitrary, it is helpful in understanding the variation observed in the timing of disease onset, presenting manifestations, rate of progression, and life span. Acute infantile Sandhoff disease (onset age <6 months). Infants are generally normal at birth followed by progressive weakness and slowing of developmental progress, then developmental regression and severe neurologic impairment. Seizures are common. Death usually occurs between ages two and three years. Subacute juvenile Sandhoff disease (onset age 2-5 years). After attaining normal developmental milestones, developmental progress slows, followed by developmental regression and neurologic impairment (abnormal gait, dysarthria, and cognitive decline). Death (usually from aspiration) typically occurs in the early to late teens. Late-onset Sandhoff disease (onset older teen years or young adulthood). Nearly normal psychomotor development is followed by a range of neurologic findings (e.g., weakness, spasticity, dysarthria, and deficits in cerebellar function) and psychiatric findings (e.g., deficits in executive function and memory). Life expectancy is not necessarily decreased. [from GeneReviews]
Authors:
Changrui Xiao  |  Cynthia Tifft  |  Camilo Toro   view full author information

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/268800
From MedlinePlus Genetics
Sandhoff disease is a rare inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord (central nervous system). This condition is classified into three major types based on the age at which signs and symptoms first appear: infantile, juvenile, and adult.

The infantile form of Sandhoff disease is the most common and severe form and 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, and intellectual disability. 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 distinctive facial features, enlarged organs (organomegaly), or bone abnormalities. Children with the infantile form of Sandhoff disease usually live only into early childhood.

The juvenile and adult forms of Sandhoff disease are very rare. Signs and symptoms are usually milder than those seen with the infantile form, although they vary widely. The juvenile form can begin between ages 2 and 10.  Characteristic features include speech difficulties, loss of cognitive function (dementia), seizures, and  loss of muscle coordination (ataxia). Adult Sandhoff disease is characterized by problems with movement and psychiatric problems.  https://medlineplus.gov/genetics/condition/sandhoff-disease

Clinical features

From HPO
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
Episodic abdominal pain
MedGen UID:
814352
Concept ID:
C3808022
Finding
An intermittent form of abdominal pain.
Impotence
MedGen UID:
1720680
Concept ID:
CN208474
Finding
Inability to develop or maintain an erection of the penis.
Increased urinary N-acetylglucosamine-rich oligosaccharide level
MedGen UID:
1054680
Concept ID:
CN376631
Finding
Presence of N-acetylglucosamine-rich oligosaccharides in the urine.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Cherry red spot of the macula
MedGen UID:
786046
Concept ID:
C2216370
Finding
Pallor of the perifoveal macula of the retina with appearance of a small circular reddish choroid shape as seen through the fovea centralis due to relative transparancy of the macula.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
Chronic diarrhea
MedGen UID:
96036
Concept ID:
C0401151
Finding
The presence of chronic diarrhea, which is usually taken to mean diarrhea that has persisted for over 4 weeks.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Fasciculations
MedGen UID:
5124
Concept ID:
C0015644
Sign or Symptom
Fasciculations are observed as small, local, involuntary muscle contractions (twitching) visible under the skin. Fasciculations result from increased irritability of an axon (which in turn is often a manifestation of disease of a motor neuron). This leads to sporadic discharges of all the muscle fibers controlled by the axon in isolation from other motor units.
Orthostatic hypotension
MedGen UID:
43803
Concept ID:
C0020651
Disease or Syndrome
A form of hypotension characterized by a sudden fall in blood pressure that occurs when a person assumes a standing position.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
Exaggerated startle response
MedGen UID:
329357
Concept ID:
C1740801
Finding
An exaggerated startle reaction in response to a sudden unexpected visual or acoustic stimulus, or a quick movement near the face.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Upper motor neuron dysfunction
MedGen UID:
333241
Concept ID:
C1839042
Pathologic Function
A functional anomaly of the upper motor neuron. The upper motor neurons are neurons of the primary motor cortex which project to the brainstem and spinal chord via the corticonuclear, corticobulbar and corticospinal (pyramidal) tracts. They are involved in control of voluntary movements. Dysfunction leads to weakness, impairment of fine motor movements, spasticity, hyperreflexia and abnormal pyramidal signs.
Progressive psychomotor deterioration
MedGen UID:
383942
Concept ID:
C1856565
Finding
Impaired temperature sensation
MedGen UID:
866867
Concept ID:
C4021222
Finding
A reduced ability to discriminate between different temperatures.
CNS hypomyelination
MedGen UID:
892446
Concept ID:
C4025616
Finding
Reduced amount of myelin in the central nervous system resulting from defective myelinogenesis.
Myoclonic seizure
MedGen UID:
1385980
Concept ID:
C4317123
Sign or Symptom
A myoclonic seizure is a type of motor seizure characterized by sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Abnormal glycosphingolipid metabolism
MedGen UID:
870889
Concept ID:
C4025350
Finding
An abnormality of glycosphingolipid metabolism.
Reduced beta-hexosaminidase activity
MedGen UID:
1800805
Concept ID:
C5558366
Finding
Diminished activity of the enzyme beta-hexosaminidase in the blood circulation.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
Increased length and width of the tongue.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.
Hypohidrosis
MedGen UID:
43796
Concept ID:
C0020620
Disease or Syndrome
Abnormally diminished capacity to sweat.
Blindness
MedGen UID:
99138
Concept ID:
C0456909
Disease or Syndrome
Blindness is the condition of lacking visual perception defined as a profound reduction in visual perception. On the 6m visual acuity scale, blindness is defined as less than 3/60. On the 20ft visual acuity scale, blindness is defined as less than 20/400. On the decimal visual acuity scale, blindness is defined as less than 0.05. Blindness is typically characterized by a visual field of no greater than 10 degrees in radius around central fixation.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVSandhoff disease
Follow this link to review classifications for Sandhoff disease in Orphanet.

Professional guidelines

PubMed

Mansouri V, Tavasoli AR, Khodarahmi M, Dakkali MS, Daneshfar S, Ashrafi MR, Heidari M, Hosseinpour S, Sharifianjazi F, Bemanalizadeh M
Eur J Neurol 2023 Sep;30(9):2919-2945. Epub 2023 Jun 8 doi: 10.1111/ene.15871. PMID: 37209042
Toro C, Zainab M, Tifft CJ
Neurosci Lett 2021 Nov 1;764:136195. Epub 2021 Aug 25 doi: 10.1016/j.neulet.2021.136195. PMID: 34450229Free PMC Article
Mahdieh N, Soveizi M, Tavasoli AR, Rabbani A, Ashrafi MR, Kohlschütter A, Rabbani B
Sci Rep 2021 Feb 5;11(1):3231. doi: 10.1038/s41598-021-82778-0. PMID: 33547378Free PMC Article

Recent clinical studies

Etiology

Mansouri V, Tavasoli AR, Khodarahmi M, Dakkali MS, Daneshfar S, Ashrafi MR, Heidari M, Hosseinpour S, Sharifianjazi F, Bemanalizadeh M
Eur J Neurol 2023 Sep;30(9):2919-2945. Epub 2023 Jun 8 doi: 10.1111/ene.15871. PMID: 37209042
Shaimardanova AA, Solovyeva VV, Issa SS, Rizvanov AA
Int J Mol Sci 2023 Feb 11;24(4) doi: 10.3390/ijms24043627. PMID: 36835039Free PMC Article
Martakis K, Claassen J, Gascon-Bayari J, Goldschagg N, Hahn A, Hassan A, Hennig A, Jones S, Kay R, Lau H, Perlman S, Sharma R, Schneider S, Bremova-Ertl T
Neurology 2023 Mar 7;100(10):e1072-e1083. Epub 2022 Dec 1 doi: 10.1212/WNL.0000000000201660. PMID: 36456200Free PMC Article
García Morales L, Mustelier Bécquer RG, Pérez Joglar L, Zaldívar Vaillant T
Amyotroph Lateral Scler Frontotemporal Degener 2022 Feb;23(1-2):137-138. Epub 2021 Mar 2 doi: 10.1080/21678421.2021.1892146. PMID: 33650927
Leal AF, Benincore-Flórez E, Solano-Galarza D, Garzón Jaramillo RG, Echeverri-Peña OY, Suarez DA, Alméciga-Díaz CJ, Espejo-Mojica AJ
Int J Mol Sci 2020 Aug 27;21(17) doi: 10.3390/ijms21176213. PMID: 32867370Free PMC Article

Diagnosis

Mansouri V, Tavasoli AR, Khodarahmi M, Dakkali MS, Daneshfar S, Ashrafi MR, Heidari M, Hosseinpour S, Sharifianjazi F, Bemanalizadeh M
Eur J Neurol 2023 Sep;30(9):2919-2945. Epub 2023 Jun 8 doi: 10.1111/ene.15871. PMID: 37209042
Martakis K, Claassen J, Gascon-Bayari J, Goldschagg N, Hahn A, Hassan A, Hennig A, Jones S, Kay R, Lau H, Perlman S, Sharma R, Schneider S, Bremova-Ertl T
Neurology 2023 Mar 7;100(10):e1072-e1083. Epub 2022 Dec 1 doi: 10.1212/WNL.0000000000201660. PMID: 36456200Free PMC Article
García Morales L, Mustelier Bécquer RG, Pérez Joglar L, Zaldívar Vaillant T
Amyotroph Lateral Scler Frontotemporal Degener 2022 Feb;23(1-2):137-138. Epub 2021 Mar 2 doi: 10.1080/21678421.2021.1892146. PMID: 33650927
Tim-Aroon T, Wichajarn K, Katanyuwong K, Tanpaiboon P, Vatanavicharn N, Sakpichaisakul K, Kongkrapan A, Eu-Ahsunthornwattana J, Thongpradit S, Moolsuwan K, Satproedprai N, Mahasirimongkol S, Lerksuthirat T, Suktitipat B, Jinawath N, Wattanasirichaigoon D
BMC Pediatr 2021 Jan 7;21(1):22. doi: 10.1186/s12887-020-02481-3. PMID: 33407268Free PMC Article
Tatematsu M, Imaida K, Ito N, Togari H, Suzuki Y, Ogiu T
Acta Pathol Jpn 1981 May;31(3):503-12. doi: 10.1111/j.1440-1827.1981.tb01391.x. PMID: 7270152

Therapy

Mansouri V, Tavasoli AR, Khodarahmi M, Dakkali MS, Daneshfar S, Ashrafi MR, Heidari M, Hosseinpour S, Sharifianjazi F, Bemanalizadeh M
Eur J Neurol 2023 Sep;30(9):2919-2945. Epub 2023 Jun 8 doi: 10.1111/ene.15871. PMID: 37209042
Martakis K, Claassen J, Gascon-Bayari J, Goldschagg N, Hahn A, Hassan A, Hennig A, Jones S, Kay R, Lau H, Perlman S, Sharma R, Schneider S, Bremova-Ertl T
Neurology 2023 Mar 7;100(10):e1072-e1083. Epub 2022 Dec 1 doi: 10.1212/WNL.0000000000201660. PMID: 36456200Free PMC Article
Leal AF, Benincore-Flórez E, Solano-Galarza D, Garzón Jaramillo RG, Echeverri-Peña OY, Suarez DA, Alméciga-Díaz CJ, Espejo-Mojica AJ
Int J Mol Sci 2020 Aug 27;21(17) doi: 10.3390/ijms21176213. PMID: 32867370Free PMC Article
Dogbevia G, Grasshoff H, Othman A, Penno A, Schwaninger M
J Cereb Blood Flow Metab 2020 Jun;40(6):1338-1350. Epub 2019 Jul 29 doi: 10.1177/0271678X19865917. PMID: 31357902Free PMC Article
Gray-Edwards HL, Brunson BL, Holland M, Hespel AM, Bradbury AM, McCurdy VJ, Beadlescomb PM, Randle AN, Salibi N, Denney TS, Beyers RJ, Johnson AK, Voyles ML, Montgomery RD, Wilson DU, Hudson JA, Cox NR, Baker HJ, Sena-Esteves M, Martin DR
Mol Genet Metab 2015 Sep-Oct;116(1-2):80-7. Epub 2015 May 8 doi: 10.1016/j.ymgme.2015.05.003. PMID: 25971245

Prognosis

Johnson AK, McCurdy VJ, Gray-Edwards HL, Maguire AS, Cochran JN, Gross AL, Skinner HE, Randle AN, Shirley JL, Brunson BL, Bradbury AM, Leroy SG, Hwang M, Rockwell HE, Cox NR, Baker HJ, Seyfried TN, Sena-Esteves M, Martin DR
Ann Neurol 2023 Nov;94(5):969-986. Epub 2023 Aug 16 doi: 10.1002/ana.26756. PMID: 37526361Free PMC Article
Blondel A, Kraoua I, Marcelino C, Khrouf W, Schlemmer D, Ganne B, Caillaud C, Fernández-Eulate G, Turki IBY, Dauriat B, Bonnefont-Rousselot D, Nadjar Y, Lamari F
Mol Genet Metab 2023 Feb;138(2):106983. Epub 2022 Dec 26 doi: 10.1016/j.ymgme.2022.106983. PMID: 36709536
Lyn N, Pulikottil-Jacob R, Rochmann C, Krupnick R, Gwaltney C, Stephens N, Kissell J, Cox GF, Fischer T, Hamed A
Orphanet J Rare Dis 2020 Apr 15;15(1):92. doi: 10.1186/s13023-020-01354-3. PMID: 32295606Free PMC Article
Cachon-Gonzalez MB, Zaccariotto E, Cox TM
Curr Gene Ther 2018;18(2):68-89. doi: 10.2174/1566523218666180404162622. PMID: 29618308Free PMC Article
Ozkara HA, Topçu M
Brain Dev 2004 Sep;26(6):363-6. doi: 10.1016/j.braindev.2003.09.006. PMID: 15275696

Clinical prediction guides

Kern J, Böhringer J, Timmann D, Trollmann R, Stendel C, Kamm C, Röbl M, Santhanakumaran V, Groeschel S, Beck-Wödl S, Göricke S, Krägeloh-Mann I, Synofzik M
Neurology 2024 Jan 9;102(1):e207898. Epub 2023 Dec 12 doi: 10.1212/WNL.0000000000207898. PMID: 38165373Free PMC Article
Mansouri V, Tavasoli AR, Khodarahmi M, Dakkali MS, Daneshfar S, Ashrafi MR, Heidari M, Hosseinpour S, Sharifianjazi F, Bemanalizadeh M
Eur J Neurol 2023 Sep;30(9):2919-2945. Epub 2023 Jun 8 doi: 10.1111/ene.15871. PMID: 37209042
Cachón-González MB, Wang S, Cox TM
Hum Mol Genet 2021 Nov 1;30(22):2082-2099. doi: 10.1093/hmg/ddab159. PMID: 34172992Free PMC Article
Tim-Aroon T, Wichajarn K, Katanyuwong K, Tanpaiboon P, Vatanavicharn N, Sakpichaisakul K, Kongkrapan A, Eu-Ahsunthornwattana J, Thongpradit S, Moolsuwan K, Satproedprai N, Mahasirimongkol S, Lerksuthirat T, Suktitipat B, Jinawath N, Wattanasirichaigoon D
BMC Pediatr 2021 Jan 7;21(1):22. doi: 10.1186/s12887-020-02481-3. PMID: 33407268Free PMC Article
Sandhoff K, Christomanou H
Hum Genet 1979;50(2):107-43. doi: 10.1007/BF00390234. PMID: 116955

Recent systematic reviews

Mansouri V, Tavasoli AR, Khodarahmi M, Dakkali MS, Daneshfar S, Ashrafi MR, Heidari M, Hosseinpour S, Sharifianjazi F, Bemanalizadeh M
Eur J Neurol 2023 Sep;30(9):2919-2945. Epub 2023 Jun 8 doi: 10.1111/ene.15871. PMID: 37209042
Ysselstein D, Shulman JM, Krainc D
Mov Disord 2019 May;34(5):614-624. Epub 2019 Feb 6 doi: 10.1002/mds.27631. PMID: 30726573Free PMC Article

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