Makindo Medical Notes.com

Related Subjects: |Autosomal Dominant |Autosomal Recessive |X Linked Recessive |Osteoporosis

Fabry disease is a rare genetic disorder that affects the body's ability to break down a specific type of fat called globotriaosylceramide (GL-3 or Gb3). This disorder is caused by a deficiency in an enzyme called alpha-galactosidase A (α-GAL A), leading to the accumulation of GL-3 in various organs and tissues, including the kidneys, heart, and nervous system. Fabry disease is part of a group of disorders known as lysosomal storage disorders.

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
• Renal failure: proteinuria, 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
• Enzyme assay: Low levels of alpha-galactosidase A. Males with Fabry disease typically have low or absent enzyme activity.
  • White Cell:10-50 µmol/g/hour
  • Plasma: 3-20 umol/L/hour
  • Blood spot: 6.3-47 pmol/punch/hour
• Genetic Testing: Identifying mutations in the GLA gene can confirm the diagnosis and help identify carrier females.
• Urine Analysis: To detect the presence of GL-3 in the urine. 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 can show a large basilar artery
• Cardiac: 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. Manage cardiac and renal disease and stroke contribute to morbidity and mortality.
• Kidney Care: Medications to control blood pressure and proteinuria, and in advanced cases, dialysis or kidney transplantation may be necessary.
• Pain Management: Medications, including anticonvulsants and antidepressants, can help manage chronic 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 Therapy (ERT): Regular intravenous infusions of synthetic alpha-galactosidase A to help reduce GL-3 buildup in cells.
• Chaperone Therapy: Oral medications that stabilize the function of the mutant enzyme in certain patients.
• Cardiac Care: Regular monitoring and management of heart disease with medications, pacemakers, or other interventions.
• Supportive Care: Physical therapy, dietary modifications, and other supportive measures to manage symptoms and improve quality of life.

References

• Fabry Disease and Early Stroke