Beta Hex Deficiency

Synonyms: Sandhoff disease, Gangliosidosis GM2 type 2

The GM2 gangliosidoses are a group of lipid storage diseases caused by a mutation in at least one of three recessive genes(HEXA, HEXB or GM2A2,3) which result in abnormal forms of the 2 isoenzymes of hexosaminidase - hexosaminidase A (contains alpha chains only) and hexosaminidase B (alpha and beta chains)¹. Hexosaminidase's normal function is to break down gangliosides so the varied mutations result in accumulation of GM2 ganglioside which causes cell death, most significantly in the brain and spinal cord. Different mutations give rise to different clinical phenotypes.

• Tay-Sachs disease is the most common of the GM2 gangliosides and is caused by a mutation in HEX A affecting the alpha subunit of hexosaminidase A.
• Beta-hex deficiency is caused by a mutation of the HEXB gene. Abnormal beta chains will affect both hexosaminidase A and B. With combined enzyme deficiency, there is more extensive extraneural involvement.

Patients with these diseases present with neuromuscular disorders. The earlier the presentation, the worse is the prognosis in general terms, and presentations in infancy frequently lead to death by early childhood

• Beta-Hex deficiency and Sandhoff disease are extremely rare disorders affecting approximately 1 in 1.3 million newborns.
• Males and females are equally affected.
• Clusters of affected children have occurred in Argentina, Portugal³, Cyprus and the Lebanon. Unlike Tay-Sachs disease, there is no increased incidence in the Ashkenazi jewish community. In the US, those with an italian ancestry have been found to be at higher risk of being a carrier for Sandhoff Disease.⁴

Beta-Hex deficiency and Sandhoff disease are both transmitted as single gene autosomal recessive disorders. Consanguinity increases risk.

The syndrome often presents in infancy or early childhood with signs of:

• Developmental delay.
• Muscle wasting
• Floppy baby
• Dystonia
• Ataxia
• Early blindness
• Myoclonus.
• 'Doll-like' facial appearance
• Frequent respiratory infections
• Seizures
• Cherry red spots seen at the macula
• Extraneural involvement - mild visceromegaly, occasional foamy histiocytes or vacuolated lymphocytes in peripheral blood

Juvenile and adult forms show delayed onset, slower progress and longer survival⁶.

• Other lipid storage diseases such as Tay Sachs disease
• Gaucher disease
• Motor skills disorder
• The mucopolysaccharidoses
• Hurler's syndrome
• Freidrichs ataxia
• Niemann-Pick disease

• Beta-Hex enzyme assay can be undertaken in specialist centres. Hexominidase activity can be measured in serum, leukocytes, tears and cultivated fibroblasts.
• DNA typing will confirm the diagnosis
• PAS staining of systemic tissues will differentiate Sandhoff Disease from the other GM2 gangliosidoses

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• There is currently no specific treatment for patients with Beta-hex deficiency or Sandhoff disease.
• Treatment is supportive (for example, concentration on nutrition, hydration, airway support), and symptomatic(for example, anticonvulsants where fitting, treatment of respiratory infections).

Frequent respiratory infections are a common complication .

The prognosis for all forms of Beta-hex deficiency is poor, with most sufferers dying in childhood. Neonates appear normal, but increasing motor weakness is usually evident by about 6 months, loss of a swallow reflex will make the child more vulnerable to aspiration and chest infections and commonly death occurs by about the age of 4.

Genetic counselling - prenatal diagnosis and carrier status can be determined where mutations are known.