What are the other Names for this Condition? (Also known as/Synonyms)

• Beta Hex Deficiency
• Sandhoff's Disease
• Variant 0 of GM2-Gangliosidosis

What is Sandhoff Disease? (Definition/Background Information)

• Sandhoff Disease is a rare, inherited disorder (autosomal recessive) that occurs due to an enzyme deficiency. Young children are affected the most by this disorder
• Enzymes are proteins in the body that allow specific biochemical reactions to occur. During a biochemical reaction, the enzymes act on a particular substrate (a substance) and it results in the production of a particular product (substratum)
• Sandhoff Disease is a disease categorized as a lysosomal storage disorder (LSD)
  • Lysosomes are cellular components present inside the cytoplasm of cells
  • In lysosomal storage disorders, certain enzymes that should be present within the lysosomes are absent (or deficient). This results in the accumulation of a particular substrate
  • The substrate in Sandhoff Disease are GM2 ganglioside and globoside (glycosphingolipids)
  • The excess substrate thus accumulated, affects the function of the cell, and the cell eventually dies, leading to the death of tissues and manifestation of the disorder

• There are several different types of LSD. One among them is a group of disorders called GM2 gangliosidoses (singular - gangliosidosis). The 3 disorders present in this group are:

  • Tay-Sachs disease, where there is a deficiency of enzyme β-hexosaminidase A
  • Sandhoff Disease, where there is deficiency of enzymes β-hexosaminidase A and β-hexosaminidase B
  • GM2 gangliosidosis variant AB, occurring due to deficiency of GM2 activator protein
• Sandhoff Disease is a progressive condition primarily affecting the central nervous system. It has been reported in certain regions and in certain populations
• Presently, there is no curative treatment available for this condition. The prognosis of Sandhoff disease is not favorable; in children, death usually occurs by age 3

Who gets Sandhoff Disease? (Age and Sex Distribution)

• Sandhoff Disease is a rare, genetic disorder. The disorder usually manifests in infants, beginning from ages of 4-6 months (infantile acute). It may also affect children between the ages of 2 to 10 years (late onset sub-acute) and adults (adult chronic)
• Both males and females are affected
• The disorder is more common in non-Jewish population and affects 1 in 300,000 individuals. Among the Jewish population, the incidence is 1 in 1,000,000

Sandhoff Disease was reported in increasing frequency in the following individuals - Creoles (of North Argentina), Metis Indians (of North Saskatchewan Canada), Hispanics (of Mexico, Central America), Maronite (of Cyprus Greece), and in Lebanon, Portugal, Italy, Iran, etc.

What are the Risk Factors for Sandhoff Disease? (Predisposing Factors)

The risk factors of Sandhoff Disease include:

• Individual with a positive family history of the condition
• The individual’s parents may have the condition or can be carriers of the condition. A carrier is an individual who does not have the disorder, but has one defective gene. Two genes have to be abnormal in autosomal recessive disorders for the condition to be manifested
• Consanguineous union (or marriages among close blood-relations) increases the risk of this autosomal recessive disorder

What are the Causes of Sandhoff Disease? (Etiology)

• Sandhoff Disease is caused by the deficiency of 2 enzymes, which include:
  • β-hexosaminidase A and
  • β-hexosaminidase B             
• The deficiency of these enzymes is due to an abnormal (mutated) gene called HEXB. The mutated gene is inherited (passed on to children from parents) in an autosomal recessive manner

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Sandhoff Disease?

The signs and symptoms of Sandhoff Disease include:

• This condition predominantly affects the central nervous system (CNS) and the eye; hence, the signs and symptoms are mostly associated with these systems
• Infantile form of Sandhoff Disease begins to manifest when the infant is 4-5 months of age. The symptoms slowly progress and disables the child, usually resulting in death by age 3-4 years
• Poor eye contact, cherry red spot on the retina (on the inside of the eye, generally noticed using an ophthalmoscope by the healthcare provider)
• Increased ‘startle’ response due to increased sensitivity to sound
• Loss of motor skills, muscle weakness, floppiness
• Decreased attention span
• Delayed growth
• “Doll-like” facial expression
• Fits (seizures), paralysis
• Macroglossia (unusually large tongue)
• Big head (macrocephaly)
• Liver and spleen enlargement
• Deformity of the back

Older children and adults, who present symptoms later, do not have cherry red spot on the retina or liver or spleen enlargement. Additionally, they initially present with balance and speech problems (dysarthria). Also, their prognosis is slightly better than that of infants.

How is Sandhoff Disease Diagnosed?

The following tools may be used in the diagnosis of Sandhoff Disease:

• Complete evaluation of medical history, including family history of this disorder and consanguinity
• Thorough physical examination with special focus on the central nervous system
• Pediatric neurologist and geneticist consultation may be necessary
• Sandhoff Disease (or other lysosomal storage disorders) is suspected in an infant, when they are present with central nervous system abnormalities and cherry red spot on the retina

Following suspicion, the healthcare provider may perform the following tests to confirm Sandhoff Disease

• Urine tests, which may reveal increased oligosaccharide levels
• Blood tests to analyze for leucocyte (white blood cell) enzyme activity for β-hexosaminidase
• Molecular testing for gene analysis; the presence of mutated gene HEXB confirms the diagnosis

• Tissue biopsy: In this procedure, the physician removes a sample of the accessible tissue and sends it to the laboratory for a histopathological examination. The pathologist examines the biopsy under a microscope and arrives at a definitive diagnosis after a thorough evaluation of the clinical and microscopic findings, as well as by correlating the results of special studies on tissues (if required). The microscopic studies may reveal the following:

  • Neurons showing ballooned cytoplasmic vacuoles

  • Periodic Acid-Schiff (PAS) staining of tissues helps in diagnosing and differentiating Sandhoff Disease from the other related lysosomal storage disorders             

What are the possible Complications of Sandhoff Disease?

The possible complications associated with Sandhoff Disease are:

• Deafness
• Blindness
• Impaired speech
• Frequent respiratory infections
• Gradual loss of voluntary movement and motor skills

How is Sandhoff Disease Treated?

Currently, there is no specific cure or treatment available for Sandhoff Disease. Only symptomatic treatment may be offered (available), which include:

• Measures to keep the affected individual as comfortable as possible, which is the primary goal
• Physical therapy and speech language therapy may helpful
• Seizures can be treated with antiepileptic drugs. The dosage may not remain consistent, as seizures tend to gradually get worse over time

How can Sandhoff Disease be Prevented?

• Currently, there are no specific methods or guidelines to prevent Sandhoff Disease, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of Sandhoff Disease? (Outcomes/Resolutions)

• Sandhoff Disease is associated with a poor prognosis. The prognosis of infantile form is poorer than ‘later-onset’ Sandhoff Disease such as juvenile and adult type
• Death typically occurs by age 3-4 years with the infantile form

Additional and Relevant Useful Information for Sandhoff Disease:

• Tay-Sachs disease is an enzyme deficiency, or a complete absence of the enzyme (called beta-hexosaminidase A), disorder

The following article link will help you understand Tay-Sachs disease:

https://www.dovemed.com/diseases-conditions/tay-sachs-disease-tsd/