What Is Sandhoff Disease?

  • Anna BouroulitiPhD Neuroscience, D.U.Th., Democritus University of Thrace, Greece
  • Helen McLachlanMaster of Science in Molecular Biology and Pathology of Viruses (2001)


Sandhoff disease gradually causes cell death in the nervous system. It’s an inherited disease of unknown prevalence, with a manifestation onset at various time points after birth. The time of onset usually affects the life expectancy of affected individuals. Roughly, early onset is associated with a shorter lifespan. Sadly, there is no treatment for Sandhoff disease, but there are specific approaches that treat certain symptoms and signs.1 The following paragraphs further explore the genetic origin of Sandhoff disease and its clinical features, as well as diagnosis and management of the disease.

Genetics, inheritance and molecular mechanism

Mutations in the HEXB gene

Sandhoff disease, along with Tay-Sachs disease, are also termed as GM2 (monosialoganglioside2) gangliosidoses and belong in the category of Lysosomal Storage Diseases (LSDs). The two diseases are of genetic origin, caused by mutations that lead to dysfunction of certain subunits which compose the lysosomal enzymes β-hexosaminidase A (HEXA) and β-hexosaminidase B (HEXB). More specifically, Sandhoff disease is associated with mutations on the enzyme’s β-subunit, which is encoded by the HEXB gene located on the 5th chromosome, while Tay-Sachs disease originates from mutation of the α-subunit, which is encoded by the HEXA gene located on the 15th chromosome.2 Mutations in the β-subunit lead to deficits in both HEXA and HEXB enzymes. Contrary, mutations in the α-subunit only affect the function of the enzyme HEXA. However, the clinical features of the diseases are similar, and they both yield a fatal outcome.3

Inheritance pattern

Both Sandhoff and Tay-Sachs disease are inherited in an autosomal recessive pattern, meaning that the genes responsible for the manifestation of the diseases are located in chromosomes not associated with gender determination, and that in order for the disease to manifest, an individual must carry two copies of the mutated genes. In other words, manifestation of said diseases depends on inherited mutations from both parents.3 As a result, genetic counselling is strongly advised in cases where parents are suspected of carrying a copy of the mutated gene. Such suspicions of parents being carriers arise from manifestation of the disease in other family members. If so, molecular testing can be performed to investigate the possibility that both patients will pass down a copy of the mutated HEXB to their offspring.1

Molecular mechanism of impairment in Sandhoff disease

The enzyme HEXA, which is defective in both Sandhoff and Tay-Sachs disease, is normally involved in catabolism of GM2 ganglioside through hydrolysis of the protein. Mutations that render the enzyme inactive or dysfunctional result in the accumulation of GM2 in cell organelles called the lysosomes. This accumulation is toxic, so in turn, it signals destruction of the cell, and eventually leads to cell death.4


Enzyme activity testing

Activity of the HEXA and HEXB enzymes can be measured to test whether a patient is affected by Sandhoff or Tay-Sachs disease. Testing requires a blood sample, from which either leukocytes or serum can be further analysed in regards to HEX activity. More specifically, the test evaluates HEXA and total HEX activity, so HEXB activity is asserted by the other measurements. The two measured activities also aid in discrimination between Tay-Sachs and Sandhoff disease. As previously noted, Tay-Sachs affects HEXA levels, while Sandhoff disease affects both HEXA and HEXB. As a result, test results from a person with Tay-Sachs would show a decrease in HEXA activity, while results of Sandhoff cases would demonstrate reduced total activity of HEX enzymes.5

Genetic testing

Another method to investigate the possibility that a patient is affected by Sandhoff disease is gene testing, which allows for the finding of HEXB gene variants. If Sandhoff disease is the most likely cause of a patient’s clinical characteristics, and especially if this is also supported by test results of enzymatic activity, then variants of a single gene, HEXB, may be searched. However, if symptoms are common with those of other diseases, then mutations in more than one gene may be investigated by performing analyses based on genome sequencing techniques.1

Types of Sandhoff disease

There are three types of Sandhoff disease, differentiated from each other by their time of onset. The first type is the most common2 and is referred to as acute infantile Sandhoff disease.1 As its name indicates, the disease manifests in infants, and according to literature, it is regarded as infantile onset if it manifests by the age of 6 to 12 months.1,2 While the infants appear to be healthy at birth, they gradually begin to show severe symptoms of impaired neuronal development.1 Symptoms include seizures, vision and psychomotor deficits.2 Unfortunately, life expectancy in such early onset cases usually does not exceed 2 to 3 years of age.1,2

The second type of Sandhoff disease is called subacute juvenile Sandhoff disease and is characterised by an early onset at 2 to 5 years of age.1 According to other sources, cases of onset at an age under 18 years old, are also considered to belong in the category of subacute juvenile Sandhoff.2 Again, as in the first type of acute infantile onset, symptoms are related to deficits in neuronal development, such as seizures, cognitive impairment, and problems in coordination.1,2 Life expectancy is also short, as children with Sandhoff disease might not reach adulthood1.

The third type of Sandhoff disease has the latest onset of the three and is called adult, or late-onset Sandhoff disease.1,2 With a late onset around adulthood, people with Sandhoff disease have passed through the years when neuronal development is more critical. As such, symptoms are not as severe and life expectancy is not reduced. Symptoms in late-onset Sandhoff may be related to motor or cognitive function impairments, such as spasticity and memory deficits.1

Clinical characteristics

In cases of early onset Sandhoff disease in infants of around 6 to 12 months old, physical development is slow, but what might prompt parents or caregivers to consult a doctor are deficits noted in the infant’s visual system. Sandhoff disease has been associated with blindness, and early signs of eyesight impairment may include abnormal eye movements and inability to follow motion with eyes. Ophthalmological testing by an expert might reveal red cherry spots in the eye’s macula area. Along with vision problems, motor deterioration is also evident in early onset Sandhoff disease. Seizures are also noted, and they gradually worsen with age. A later clinical feature of Sandhoff infant cases, which is usually observed after the first year of age, is enlargement of the head. At around two years of age symptoms have significantly worsened, and the infant may be unresponsive, unable to swallow, and have developed respiratory deficits. Addressing the last two symptoms with medical assistance, may increase life span for a few years.

Contrary to acute infantile Sandhoff disease, in subacute juvenile Sandhoff visual impairments are part of the later stages in disease progression. First symptoms in children of more than 2 years of age usually include motor and speech dysfunctions due to developmental issues. On top of that, already developed cognitive and motor functions gradually exhibit deficits. In the next years more symptoms, such as spasticity, seizures, and neuropathic pain manifest as well. Aspiration is the usual cause of death, while its proper management may have a positive effect on life span.

Late-onset Sandhoff disease is characterised by slow progression in severity of symptoms. Neuropathy manifests in most cases of Sandhoff disease. Movement and cognitive deficiencies also constitute symptoms observed in patients with late-onset Sandhoff. In addition, psychiatric conditions, namely depression and anxiety, have been associated with the disease. Notably, the above symptoms are not considered as factors that may directly affect life expectancy of patients. However, dysphagia and subsequent physical damage caused by other symptoms may have a negative effect on life span.1

Treatment and management

As there is no cure for Sandhoff disease, management of its clinical features relies on the treatment and management of specific symptoms that manifest in each individual. For instance, seizures are addressed by a doctor by administration of proper medications; occupational and physical therapy approaches are followed in order to manage mobility deficits; and a gastrostomy tube is utilised to aid difficulties in swallowing and aspiration and thereby increase life expectancy. In addition, other pharmaceutical treatments and cognitive therapy help to manage psychiatric symptoms in late-onset Sandhoff disease. In any case, nursing and family support are needed to treat Sandhoff disease.1

Potential therapies

There is ongoing research on the subject of treating Sandhoff disease and GM2 gangliosidoses in general. Certain components and therapeutic approaches are either in early phases of research or have entered clinical studies.1 There is also evidence that indicates gene therapy as a potential treatment, though more research on the subject is necessary.4,5


Sandhoff disease is an inherited condition with low life expectancy in cases of early onset of symptoms. Such cases of early onset refer to symptom manifestation in infants, toddlers or children. Infants diagnosed with Sandhoff disease are not expected to live beyond their first 2 or 3 years. On the other hand, Sandhoff disease with a later onset around adulthood, is generally considered not to affect life span.Reduced life expectancy of Sandhoff patients and the genetic origin of the disease point out the need for genetic counselling of parents. If parents are tested and found to carry a mutated copy of the gene responsible for Sandhoff disease manifestation, then it is possible that their child will inherit two copies of the mutated gene, one from each parent, and thus develop symptoms1. The Mutation disrupts molecular mechanisms in neurons, thus leading to cell death.4 Neuronal cell death in turn leads to development of symptoms such as blindness, seizures, neuropathy, mobility and cognitive impairments. Sadly, there is no treatment to cure the disease, but rather only to manage individual symptoms. Current research studies aim to develop treatments that target Sandhoff disease, and will hopefully yield favourable results in the future.1


  1. Xiao C, Tifft C, Toro C. Sandhoff Disease. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993-2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993.  Available from: https://pubmed.ncbi.nlm.nih.gov/35420740/ 
  2. Yin JH, Hu WZ, Huang Y. Clinical and genetic features of a case with juvenile onset sandhoff disease. BMC neurology. 2023;23(1):240. Available from: https://pubmed.ncbi.nlm.nih.gov/37344817/ 
  3. Cachon-Gonzalez MB, Zaccariotto E, Cox TM. Genetics and Therapies for GM2 Gangliosidosis. Current gene therapy. 2018;18(2):68-89. Available from: https://pubmed.ncbi.nlm.nih.gov/29618308/ 
  4. Vyas M DN, Osmon KJL, Chen Z, Ahmad I, Kot S, Thompson P, Richmond C, Gray SJ, Walia JS. Efficacy of Adeno-Associated Virus Serotype 9-Mediated Gene Therapy for AB-Variant GM2 Gangliosidosis. International journal of molecular sciences. 2023;24(19). Available from: https://pubmed.ncbi.nlm.nih.gov/37834060/ 
  5. Hall P, Minnich S, Teigen C, Raymond K. Diagnosing Lysosomal Storage Disorders: The GM2 Gangliosidoses. Current protocols in human genetics. 2014;83:17.6.1-8. Available from: https://pubmed.ncbi.nlm.nih.gov/25271840/ 
  6. Shaimardanova AA, Solovyeva VV, Issa SS, Rizvanov AA. Gene Therapy of Sphingolipid Metabolic Disorders. International journal of molecular sciences. 2023;24(4). Available from: https://pubmed.ncbi.nlm.nih.gov/36835039/
This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

Get our health newsletter

Get daily health and wellness advice from our medical team.
Your privacy is important to us. Any information you provide to this website may be placed by us on our servers. If you do not agree do not provide the information.

Anna Bourouliti

PhD Neuroscience, D.U.Th., Democritus University of Thrace, Greece

Back when I was a curious little creature, I was fascinated by science and aspired to work in a laboratory. To satisfy my thirst for scientific knowledge, I pursued studies in Molecular Biology and Genetics, entered the field of Health Sciences, and eventually fulfilled my dream of conducting research. This journey began with my undergraduate studies and progressed to obtaining an MSc and later, a PhD degree in Neurosciences. I have now left hands-on experiments behind, and I currently work as a medical writer, monitoring advancements in health sciences from a close perspective.

Leave a Reply

Your email address will not be published. Required fields are marked *

my.klarity.health presents all health information in line with our terms and conditions. It is essential to understand that the medical information available on our platform is not intended to substitute the relationship between a patient and their physician or doctor, as well as any medical guidance they offer. Always consult with a healthcare professional before making any decisions based on the information found on our website.
Klarity is a citizen-centric health data management platform that enables citizens to securely access, control and share their own health data. Klarity Health Library aims to provide clear and evidence-based health and wellness related informative articles. 
Klarity / Managed Self Ltd
Alum House
5 Alum Chine Road
Westbourne Bournemouth BH4 8DT
VAT Number: 362 5758 74
Company Number: 10696687

Phone Number:

 +44 20 3239 9818