Beta hex-brist

Synonyms: Sandhoff's disease, type II G_M2 gangliosidosis, hexosaminidase A and B deficiency

Beskrivning¹

The G_M2 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 G_M2 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 sjukdom (TSD) and its variants.

• Beta subunits of Hex A: absence or defects of these results in Sandhoff's disease (SD) and its variants.

• G_M2 activator protein.

Different mutations give rise to different clinical phenotypes. TSD is the most common of the G_M2 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.

Epidemiologi²

• 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).¹² 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.

Presentation²⁵

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

• Developmental delay and neuromuscular problems: floppy baby, dystonia, ataxia, muscle wasting, myoclonus, anfall.

• Ophthalmological problems: cherry red spots seen at the macula, early blindness.

• They may appear to have a 'doll-like' facial appearance.

• Extraneural involvement: frequent respiratory infections, mild visceromegaly, occasional foamy histiocytes or vacuolated lymphocytes in peripheral blood.

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

Differentialdiagnos

• Other lipid storage diseases such as Tay-Sachs disease.

• Gauchers sjukdom.

• Motor skills disorder.

• The mucopolysaccharidoses.

• Hurler's syndrome.

• Friedreichs ataxi.

• Niemann-Pick disease.

Utredningar

• 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 G_M2 gangliosidoses.

Management

• 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).

Komplikationer

Frequent respiratory infections are a common complication.

Prognos

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 bröstinfektioner. Commonly, death occurs by about the age of 4 years.

Förebyggande

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