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Fabry Disease - Causes, Symptoms, Diagnosis, and Treatment

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Fabry disease is an X-linked inherited genetic disorder caused due to alterations in the GAL gene, which prevents the normal production of GAL enzymes.

Medically reviewed by

Dr. Kaushal Bhavsar

Published At September 21, 2022
Reviewed AtApril 21, 2023

What Is Fabry Disease?

Fabry’ disease is a genetically inherited disorder that results in a buildup of fat and lipids in the body. Patients suffering from the disease lack the enzyme alpha-galactosidase A, which breaks down the lipids of fats in the body. These enzymes hinder sphingolipids from depositing in the blood vessels and tissues. Without the alpha GAL enzyme, toxic levels of sphingolipids get collected in the blood vessels and tissues. Decreased activity of alpha-galactosidase, an effect in lysosomal accumulations of glycosphingolipids and globotriaosylceramide GL-3. The disease affects the heart, brain, central nervous system, kidneys, and skin. It is also called Anderson-Fabry disease.

What Causes Fabry Disease?

Fabry disease is caused by mutations in the gene for alpha GAL A enzyme located on the X chromosome. It is a metabolic defect that requires alpha GAL A enzyme for the breakdown of terminal galactose from globotriaosylceramide (Gb3). Gb3 accumulates in various cells and tissues, including the skin, kidney, eye, heart, brain, and peripheral nervous system. Increased endothelial proliferation leads to vascular accumulation manifesting as vascular occlusion, ischemia, and infarction. Common sites of Gb3 accumulation include dorsal root ganglia, autonomic ganglia, renal glomerular, tubular interstitial cells, cardiac muscles, valvular fibrous sites, cardiac conduction fibers, cornea, and vascular smooth muscle cells. Gb3 deposits in the kidney occur in the glomerulus, distal tubule, and tubular interstitial cells.

What Are the Symptoms of Fabry Disease?

  • Proteinuria - The deposition of Gb3 in the glomerulus and the distal tibial results in proteinuria. Proteinuria is the loss of protein in the urine.

  • Polyuria - Increased frequency of urination.

  • Polydipsia - Increased thirst is called polydipsia.

  • Renal Failure - Progressive accumulation of glycolipid with swelling and proliferation of endothelial cells can lead to renal failure in the third to fourth decade of life.

  • Cardiac Disease - Cardiac involvement in patients with cerebral events is associated with myocardial infarction. Cardiac conduction and valvular defects, and other neurological symptoms can be seen in the third and fourth decades of life.

  • Stroke - Abnormalities in the brain can lead to stroke and eventually death at an early stage of life.

  • Angiokeratoma Corporis Diffusum - It is a typical form of skin lesion and is linked to renal involvement, especially proteinuria.

  • Painful Acroparesthesia - A painful sensation of tingling, burning, or numbness in the hands and feet.

  • Hypohidrosis - It is a condition when the body has trouble cooling down by sweating.

  • Gastrointestinal Symptoms - Abdominal cramps and diarrhea are the common symptoms.

  • Lymphadenopathy - Swelling of the lymph nodes.

  • Skin - Skin manifestations include microvascular lesions that can appear as small petechiae around the umbilicus.

  • Eye - Eye manifestations include lenticular opacity and corneal dystrophy.

What Are the Types of Fabry Disease?

Fabray’s disease is divided into two types depending upon the age of onset of the symptoms of the disease.

  • Classic Type - The symptoms of the disease start to appear during childhood or the teenage years. The symptoms include a painful burning sensation in the hands and feet which can be noticed at the age of one or two. Symptoms get worse over time.

  • Atypical or Late-Onset Type - Symptoms generally do not appear until the age of 30. The indication of the disease can be heart disease or kidney failure.

How Is Fabry Disease Diagnosed?

  • DNA Sequencing - The GAL enzyme levels in the woman are normal even with the disease. DNA sequencing or genetic testing to identify the GLA gene mutation needs to be done.

  • Enzyme Assay - This test is used to measure the levels of alpha GAL in the blood. Measurements of one percent or lower indicate the presence of disease. The test should not be used in females and is only reliable in males.

  • Newborn Screenings - The enzyme test is included as a part of routine screening in the newborn.

  • Metabolic Profile - A basic test for electrolyte and renal profile and urine sediment for oval fat bodies can be done.

  • Electrocardiogram (ECG) - An ECG can be done to check for conduction and structural abnormalities in the heart.

  • Radiographic Examination - X-ray, computed tomography (CT) scan, and magnetic resonance imaging (MRI) can be done for neurological features.

  • Renal Biopsy - Glycolipid deposits can be very well characterized in the biopsy. Microscopic examination of the renal biopsy can show the presence of concentric layers of inclusions called myeloid or zebra bodies.

What Are the Complications of Fabry Disease?

  • Angiokeratoma - It is a type of skin lesion created when an open capillary gets deposited by extra layers of skin cells.

  • Arrhythmia - An irregular heartbeat occurs when the electrical signals that coordinate the heartbeats do not work properly.

  • Acroparesthesia - Tingling or numbness sensation in hands and feet.

  • Cardiomegaly - Enlarged heart is seen as a condition after the disease.

  • Vertigo - A sensation that involves spinning the environment around a person is vertigo.

  • Altered Sweating - The body feels to manage the body heat by sweating.

  • Corneal Verticillata - The formation of gray opacity is in the corneal epithelium.

How Is Fabry Disease Treated?

Fabry disease cannot be cured. Medications for pain and gastrointestinal problems can lessen symptoms. The treatment should focus on the prevention of the buildup of fatty substances to prevent heart problems, kidney disease, and other life-threatening complications.

  1. Enzyme Replacement Therapy - A lab-made agalsidase beta enzyme is infused intravenously once every two weeks. This replaced enzyme functions as the alpha GAL enzyme so that fatty substances do not accumulate. Antihistamine medications are given prior to the treatment in order to prevent an allergic reaction.

  2. Oral Chaperon Therapy - Chaperones are tiny molecules that repair faulty alpha GAL enzymes. The faulty enzymes can then break down the fatty substances and prevent accumulation in the body. The medication can be taken every other day to stabilize the faulty alpha GAL enzyme. Not everyone with the disease can be treated with oral chaperon therapy. It depends on a specific mutation in the GLA gene, which provides eligibility for this treatment.

Conclusion :

New therapies to treat the disease using genetic engineering and stem cell technologies are actively developing. Fabry disease is a mutated gene disease that passes from parent to child. A process called pre-implantation genetic diagnosis (PGD) identifies embryos that can carry the mutated gene. This can help in the early diagnosis and treatment of the newborn. PGD confirms that the embryo does not have the mutated gene or get Fabry disease. The physician implants a healthy embryo during in-vitro fertilization.

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Dr. Kaushal Bhavsar
Dr. Kaushal Bhavsar

Pulmonology (Asthma Doctors)

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