Scientific background:

Summary: The alpha-galactosidase A, an enzyme to degrade ceramid into removable compounds, is found in lysosoms. Accumulation of not digestable metabolites results in Fabry disease.

Gene: The GLA gene is about 10kb in size. It is located on X-chromosom (Xq22.1). Mutation relevant for Fabry's disease can be fount on all of the 7 exons.

Pathology: The enzyme is glycosilated. It forms a homodimer. The different types known so far differ in there extend of glycosilation. The enzyme has an important function in cell membrane turn over. It is located in lysosomes degradates here glycosphingolipids. If not degredated these substances accumulate in many organs to result in dysfunction. This takes place in epithelial cells, in glomeruli and tubuli of the kidney, in heart muscel cells, in cells of the ganglions of the peripheral nervous system and in the cornea.

Clinical signs: Hemizygous male patients develop the full blown disease females that are heterozygous develop only few symptomes. Clincal manifestation starts in early adult age. Some patients develop end stage renal disease.

Epidemiology: The prevalance of mutations is from 0,2 per 100.000 in Netherlands up to 0,9 in Australia.

Interpretation: The verification of a mutation is equivalent to a strong confirmation of the diagnosis. Often new mutations will be found. There is a correlation between mutation and clinical picture. The therpy is available.

Test strategy: Patients where biochemical data and family history is suspect for Fabry's diesease.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Multiplex Ligation-Dependent Probe Amplification
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.

Literature: 

Grünfeld JP et al. (2002) Anderson-Fabry disease: its place among other genetic causes of renal disease.
Pastores GM et al. (2002) Biochemical and molecular genetic basis of Fabry disease.
Branton M et al. (2002) Natural history and treatment of renal involvement in Fabry disease.