Sandhoff disease, GM2-gangliosidosis type II, Hexosaminidases A and B deficiency, Sandhoff disease adult type, Sandhoff disease juvenile type, Sandhoff disease infantile type
Sandhoff disease is a rare inherited lysosomal storage disorder caused by an accumulation of the specific glycosphinogolipid, GM2 ganglioside1, particularly in neurons. This accumulation results in a progressive neurodegenerative disorder clinically indistinguishable from Tay-Sachs disease. Because the buildup of GM2 ganglioside is involved, Sandhoff disease is also termed as a GM2-gangliosidosis.
The estimated prevalence in Europe is about 1/130 0002, 3. Sandhoff disease appears to be more common in the Metis Indians in Saskatchewan (Canada), the Creole population of northern Argentina, and people from Lebanon 2, 3.
The clinical findings of Sandhoff disease are identical to those of Tay-Sachs disease1, with progressive motor and mental deterioration, cherry-red spots on the macula, startle reactions, early blindness, and macrocephaly. Patients may have a specific facial doll-like appearance, hepatosplenomegaly, and recurring respiratory infections.
The most common and severe form of Sandhoff disease becomes apparent in infancy 4. Infants with this disorder typically appear normal until the age of 3 to 6 months, at which time they present with developmental delay and muscle weakness. Affected infants lose motor skills and develop an exaggerated startle reaction to loud noises. With the further progression of the disease, affected children experience seizures, vision and hearing loss, intellectual disability, and paralysis 4. All affected children show a characteristic eye abnormality called a cherry-red spot, which can be identified with an eye examination, and some of them also have hepato- and/or splenomegaly and 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 and are mostly characterized by later onset and milder symptoms, including muscle weakness, loss of muscle coordination, speech abnormalities, and mental problems 1, 4.
Sandhoff disease results from hexosaminidase A and B deficiency, linked to an abnormal beta subunit, while Tay-Sachs disease results from hexosaminidase A deficiency caused by an abnormal alpha subunit of the hexosaminidase enzyme. This protein is encoded by HEXB gene, located on chromosome 5 (5q13).
Pathogenic variants in the HEXB gene disrupt the activity of beta-hexosaminidase A and beta-hexosaminidase B, which prevents these enzymes from breaking down GM2 ganglioside and other molecules. As a result these compounds can accumulate to abnormal and toxic levels, particularly in neurons of the central nervous system. Accumulation of GM2 ganglioside leads to the progressive destruction of the affected neurons, and subsequently the symptoms of Sandhoff disease.
More than 100 pathogenic variants have been reported (HGMD® Professional 2017.4) in the HEXB gene so far, with almost 50% missense, 20% splicing, 20% small deletions, and 10% large deletions 6.
At CENTOGENE we have identified 455 unique HEXB variants in 130 individuals to date 7. The HEXB variants have been identified, classified, and curated on DNA and protein levels and the distribution of variants by the type of variant is illustrated in Figure 1 and Figure 2:
Figure 1: HEXB classified and curated genetic variants types on DNA level identified in cases and carriers (wild type excluded) at CENTOGENE 7
Figure 2: HEXB classified and curated genetic variants types on protein level identified in cases and carriers (wild type excluded) at CENTOGENE 7
Treatment for Sandhoff disease is primarily supportive and directed at providing adequate nutrition and hydration, managing infectious disease, protecting the airway, and controlling seizures. Central nervous system enzyme replacement and neuronal-corrective gene therapy are in experimental considerations.
CENTOGENE offers fluorimetric enzymatic assay for determination of total hexaminidase activity, sequencing, and deletion/duplication analysis of the HEXB gene. The HEXB gene is also part of the following NGS panels:
- Lysosomal storage disease panel
- AllNeuro panel
The differential diagnosis of HEXB-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Tay-Sachs disease
- GM1 gangliosidosis
- Infantile Gaucher disease
- Niemann-Pick disease type A
- Krabbe disease
- Canavan disease
- Alexander disease
To confirm/establish the diagnosis, we offer fluorimetric enzymatic assay for total hexaminidase activity, HEXB gene sequencing, and deletion/duplication testing. We also offer a broad selection of NGS panels which are designed for the molecular diagnostics of related conditions/phenotypes.
Thus, CENTOGENE offers the following testing strategy for HEXB gene testing:
Step 1: Fluorimetric enzymatic assay for determination of total hexaminidase activity.
Step 2: HEXB gene sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter.
Step 3: Deletion/duplication analysis of HEXB
Step 4: If no pathogenic variant is identified after analysis of the HEXB gene, panel testing with related genes or further genetic testing of related genes is available.
Step 5: If no pathogenic variant is identified in any of the panel genes listed, we can offer whole exome sequencing, based on NGS technology
The following individuals are candidates for HEXB gene testing:
- Individuals with a family history of Sandhoff disease and presentation of the most common symptoms (such as cherry-red spot of the fovea centralis of the retina macula)
- Individuals without a positive family history, but with symptoms resembling Sandhoff disease
- Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).
Sequencing, deletion/duplication of the HEXB gene and related genes should be performed in all individuals suspected of having Sandhoff disease. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through HEXB genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the Sandhoff disease, identify at-risk family members, provide information on reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.