Beta Hex Deficiency

Authored by Dr Gurvinder Rull, 18 Mar 2011

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Synonyms: Sandhoff's disease, type II GM2 gangliosidosis, hexosaminidase A and B deficiency

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 GM2A. The products of all 3 genes are required for normal catabolism of the GM2 ganglioside substrate. Abnormal catabolism of this substrate results in accumulation of the substrate inside neuronal lysosomes, leading to cell death, most significantly in the brain and spinal cord.

The products of the 3 genes HEXA, HEXB and GM2A are respectively:

  • Alpha subunits of b-hexosaminidase A: absence or defects of these results in Tay-Sachs disease (TSD) and its variants.
  • Beta subunits of Hex A: absence or defects of these results in Sandhoff's disease (SD) and its variants.
  • GM2 activator protein.

Different mutations give rise to different clinical phenotypes. TSD is the most common of the GM2 gangliosides. Where there are abnormal beta chains both hexosaminidase A and B will be affected. With combined enzyme deficiency, there is more extensive extraneural involvement.

This article is about the latter group of patients, where there is a mutation of the HEXB gene leading to a deficiency of the beta subunit of Hex A and the subunits of Hex B leading to a spectrum of disorders including SD. Patients with these diseases tend to present with developmental delay and progressive neurodegenerative disorders.

  • This is a rare group of disorders affecting approximately 3.22 per million non-Jewish newborns (compared with 1 in a million Jewish newborns - a distinction with TSD where there is an increased prevalence in the Ashkenazi Jewish community).
  • Males and females are equally affected.
  • Clusters of affected children have occurred in Argentina, Portugal,[3] Cyprus (the Maronite community has been highlighted as being at particular risk).[1, 2] and the Lebanon. In the USA, those with an Italian ancestry have been found to be at higher risk of being a carrier for Sandhoff's disease (SD).[4]
  • This group of disorders is transmitted as single gene autosomal-recessive disorders; consanguinity increases risk.

The syndrome usually presents in infancy (typically at about 6 months of age) or in early childhood with signs of:

There are juvenile and adult forms which show delayed onset (between 2 and 10 years old or in adulthood respectively),[1] slower progress and longer survival.[6]

  • Beta Hex enzyme assay can be undertaken in specialist centres. Hexosaminidase activity can be measured in serum, leukocytes, tears and cultivated fibroblasts.
  • DNA typing will confirm the diagnosis.
  • Periodic acid-Schiff (PAS) staining of systemic tissues will differentiate Sandhoff's disease from the other GM2 gangliosidoses.
  • There is currently no specific treatment for patients with these diseases.
  • Treatment is supportive (eg concentration on nutrition, hydration, airway support) and symptomatic (eg anticonvulsants where fitting, treatment of respiratory infections).

Frequent respiratory infections are a common complication.

In general terms, the earlier the presentation, the worse the prognosis. 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 age 6 months. Loss of the swallowing reflex will make the child more vulnerable to aspiration and chest infections. Commonly, death occurs by about the age of 4 years.

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

Further reading and references

  1. Tegay DH; GM2 Gangliosidoses, eMedicine, Nov 2009

  2. Sandhoff Disease, Online Mendelian Inheritance in Man (OMIM), 2007

  3. Pinto R, Caseiro C, Lemos M, et al; Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet. 2004 Feb

  4. Branda KJ, Tomczak J, Natowicz MR; Heterozygosity for Tay-Sachs and Sandhoff diseases in non-Jewish Americans with ancestry from Ireland, Great Britain, or Italy. Genet Test. 2004 Summer

  5. Textbook of Paediatrics, 6th Edition Forfar and Arneil 2003 Churchill Livingstone ISBN 0443071926

  6. Cashman NR, Antel JP, Hancock LW, et al; N-acetyl-beta-hexosaminidase beta locus defect and juvenile motor neuron disease: a case study. Ann Neurol. 1986 Jun

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