Related Subjects:
| Autosomal Dominant
| Autosomal Recessive
| X Linked Recessive
Related Subjects:
|Osteoporosis
Anderson-Fabry disease is an X-linked recessive inborn error of glycosphingolipid metabolism caused by deficiency of alpha-galactosidase A
About
- X Linked recessive efficiency of lysosomal enzyme alpha-galactosidase A
- A rare cause of stroke and cardiovascular disease
- Lysosomal storage disorder seen in 1 in 40,000 males
Aetiology
- Lysosomal storage diseases due to deficiency of alpha-galactosidase A
- Deposition of sphingomyelins in plasma and lysosomes of vascular cells
- There is a vascular endothelial accumulation of globotriaosylceramide GL-3
- Increased vascular disease as endothelial and smooth muscle cells affected
- Worse if blood group B as the enzyme breaks down Blood group B substances (B for BAD!)
Genetics
- The gene responsible for alpha-galactosidase is located on the long arm of the X chromosome.
- There have been almost 200 mutations identified.
- Manifestations seen in males and females
- Affects 1 in 55,000 males in the classical form
Clinical
- Clinical signs seen mainly in affected males
- Angiokeratomas between knees and umbilicus
- Acroparaesthesia. Childhood and adolescents get severe burning limb pains
- Suspect in those with cardiac disease (LVH)
- End stage renal failure - polyuria and polydipsia and Fanconi syndrome
- Stroke - may be ischaemic or less commonly haemorrhagic (Posterior circulation)
- Eye changes - cornea verticillata (whorl-like radial lines emanating from a single vortex, visible on slit-lamp examination), distinctive lenticular opacities, and vascular tortuosity of the conjunctiva and retina
- Lymphoedema, Osteoporosis, Decreased sweating
- Heterozygous females usually asymptomatic but may have corneal opacities
Fabry disease
Investigations
- Prenatal assay of alpha galactosidase activity in amniocytes or chorionic villi
- Low levels of alpha-galactosidase A
- White Cell:10-50 µmol/g/hour
- Plasma: 3-20 umol/L/hour
- Blood spot: 6.3-47 pmol/punch/hour
- Proteinuria is usually the earliest biological marker of renal involvement
- MRI shows numerous silent lesions, increasing with age, mainly in small perforant arteries and pulvinar calcifications, due to an increase in cerebral perfusion with impaired cerebral autoregulation, secondary to the glycosphingolipid storage in vascular endothelial cells. Usually, multiple lesions located in the deep white matter and in the subcortical grey matter of both hemispheres. Symmetrical deep white matter disease and large vessel strokes also
- MRA : large basilar artery
- Measure alpha Galactosidase A activity
- ECG: LVH and conduction abnormalities.
- Echocardiography shows LVH
- Renal biopsy: may be needed where alpha-galactosidase A levels are not diagnostic e.g. heterozygote females
- Slit lamp examination shows eye and corneal changes
Management
- Male median life expectancy between 50 and 57 years. In females, there is also eye signs and cardiac disease and cerebral white matter lesions which contribute to morbidity and mortality.
- Supportive for symptoms such as fever and pain.
- Survival is greatly reduced in males with classic Fabry disease usually with end-stage renal failure which can be managed with renal replacement/transplantation
- Enzyme replacement with recombinant alpha-galactosidase A. Enzyme replacement therapy with intravenous infusion of r-h alpha-GAL-A has been found to consistently decrease GL-3 levels in plasma and clear lysosomal inclusions from vascular endothelial cells. However, there have been no definitive trials and pressure to treat means that outcomes are being determined by ongoing Fabry's registry.
References