Makindo Medical Notes

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 deficiency of the lysosomal enzyme alpha-galactosidase A.
• A rare cause of stroke and cardiovascular disease, primarily affecting males but can manifest in females.
• Lysosomal storage disorder with an incidence of approximately 1 in 40,000 males.

Aetiology

• Due to a deficiency of alpha-galactosidase A, leading to the accumulation of GL-3 in lysosomes.
• Causes a buildup of sphingomyelins in vascular cells, leading to cellular dysfunction and damage.
• Accumulation occurs in vascular endothelial and smooth muscle cells, contributing to vascular disease.
• Blood group B individuals are more severely affected, as the enzyme also breaks down blood group B antigens.

Genetics

• The gene responsible for encoding alpha-galactosidase A is located on the X chromosome.
• More than 200 mutations have been identified in the GLA gene.
• While males typically exhibit more severe symptoms, heterozygous females may also present with varying degrees of the disease.

Pathophysiology

• Deficiency of alpha-galactosidase A leads to the accumulation of GL-3 in lysosomes, especially in endothelial and smooth muscle cells.
• This buildup disrupts normal cellular function, leading to widespread vascular dysfunction, inflammation, and fibrosis.
• The progressive accumulation of GL-3 leads to damage in various organs, particularly the kidneys, heart, and central nervous system.

Clinical Features

• Symptoms manifest mainly in males, though females can also be symptomatic.
• Skin: Angiokeratomas, typically found between the knees and umbilicus.
• Nervous System: Acroparaesthesia (painful burning sensations in hands and feet), especially in childhood and adolescence.
• Renal: Proteinuria, polyuria, polydipsia, and progressive renal failure. May present with Fanconi syndrome.
• Cardiac: Cardiomyopathy, arrhythmias, and heart failure. May also have left ventricular hypertrophy (LVH).
• Neurological: Stroke, especially in the posterior circulation. May be ischaemic or, less commonly, haemorrhagic.
• Ocular: Cornea verticillata (whorl-like radial lines), lenticular opacities, and vascular tortuosity visible on slit-lamp examination.
• Others: Lymphoedema, decreased sweating, and osteoporosis.

Fabry disease

Investigations

• Prenatal Diagnosis: Assay of alpha-galactosidase A activity in amniocytes or chorionic villi for early detection.
• Enzyme Assay: Measurement of alpha-galactosidase A activity in blood or tissue samples:
  • White Cells: 10-50 µmol/g/hour
  • Plasma: 3-20 µmol/L/hour
  • Blood Spot: 6.3-47 pmol/punch/hour
• Genetic Testing: Identifies mutations in the GLA gene to confirm diagnosis and identify carriers.
• Urine Analysis: Detects elevated GL-3 levels and proteinuria, often an early marker of renal involvement.
• MRI: Identifies silent lesions, particularly in the posterior circulation, with evidence of white matter changes and pulvinar calcifications.
• Cardiac Assessment: ECG and echocardiography for LVH and conduction abnormalities.
• Renal Biopsy: Used when enzyme assay results are inconclusive, especially in heterozygote females.
• Ophthalmic Exam: Slit-lamp examination reveals characteristic corneal changes.

Management

• Median life expectancy in males ranges from 50 to 57 years, with complications like cardiac, renal disease, and stroke impacting outcomes.
• Enzyme Replacement Therapy (ERT): Intravenous alpha-galactosidase A to reduce GL-3 buildup and improve organ function.
• Chaperone Therapy: Oral medications that stabilize the mutant enzyme, used in specific genetic variants.
• Kidney Care: Management includes blood pressure control, addressing proteinuria, and considering dialysis or renal transplantation for advanced disease.
• Pain Management: Anticonvulsants and antidepressants can help manage neuropathic pain.
• Cardiac Care: Monitoring and managing cardiac complications, including arrhythmias and heart failure, with medications and devices like pacemakers.
• Supportive Care: Includes physical therapy, dietary adjustments, and lifestyle changes to improve quality of life.

References

• Fabry Disease and Early Stroke