Fabry Disease: Insights into a Rare Condition

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Fabry disease is a type of lysosomal storage disease. It is a rare condition in which the body does not make enough of an enzyme called alpha-galactosidase-A (alpha-Gal A). This enzyme breaks down sphingolipids, the fat-like substances in the body.
This condition is more common in males. Females also present with this condition, but it is a milder form. Currently, there’s no cure, but treatments are available to relieve the symptoms and prevent complications.

What is Fabry Disease?

It is a type of genetic disorder caused by a deficiency of a lysosomal enzyme called alpha-galactosidase A (alpha-Gal A). This enzyme is normally present in lysosomes and is responsible for breaking up harmful lipid-like materials in the body.
In people with this disease, their bodies don’t make enough of this enzyme (alpha-galactosidase A), so lipid-like substances build up in cells throughout the body, causing damage to organs and tissues.1Mehta A, Hughes DA. Fabry Disease. 2002 Aug 5 [Updated 2023 Mar 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1292/ This buildup can lead to various symptoms, such as pain and tingling, skin rashes, hearing loss, and heart and kidney dysfunction.

How Does Fabry Disease Occur?

Fabry disease occurs due to genetic mutations in the GLA gene, which provides instructions for producing the enzyme α-galactosidase A. This enzyme is responsible for breaking down a specific type of fat called globotriaosylceramide (Gb3). Mutations in the GLA gene lead to reduced or absent activity of α-galactosidase A. This results in the accumulation of Gb3 in cells throughout the body, causing damage to various organs and tissues.

Pattern of Inheritance

It shows an X-linked recessive inheritance pattern, meaning the mutated gene responsible for Fabry’s disease is on the X chromosome. Since males have only one X chromosome (XY), inheriting one copy of the mutated gene from their carrier mother manifests Fabry disease. Females with two X chromosomes (XX) are usually carriers of the mutated gene.2Wanner, C., Arad, M., Baron, R., Burlina, A., Elliott, P. M., Feldt-Rasmussen, U., Fomin, V. V., Germain, D. P., Hughes, D. A., Jovanovic, A., Kantola, I., Linhart, A., Mignani, R., Monserrat, L., Namdar, M., Nowak, A., Oliveira, J. P., Ortiz, A., Pieroni, M., Spada, M., … Hilz, M. J. (2018). European expert consensus statement on therapeutic goals in Fabry disease. Molecular genetics and metabolism, 124(3), 189–203. https://doi.org/10.1016/j.ymgme.2018.06.004
However, in some cases, females can also develop symptoms if they inherit two copies of the mutated gene or if X-chromosome inactivation leads to significant expression of the mutated gene.
Statistics have shown that around 1 in every 40,000 male babies is born with Fabry disease.3Bokhari SRA, Zulfiqar H, Hariz A. Fabry Disease. [Updated 2023 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK435996/ Some people develop Fabry disease late in life (late-onset Fabry disease), affecting about 1/15,000 men.4Battaglia, Y., Fiorini, F., Azzini, C., Esposito, P., De Vito, A., Granata, A., Storari, A., & Mignani, R. (2021). Deficiency in the Screening Process of Fabry Disease: Analysis of Chronic Kidney Patients Not on Dialysis. Frontiers in medicine, 8, 640876. https://doi.org/10.3389/fmed.2021.640876 The exact number of women with this condition is uncertain because some may not have symptoms or only have mild ones that often go unnoticed.

Fabry Disease – Symptoms

Fabry disease has two phenotypes, each presenting with different signs and symptoms. The symptoms occur due to the deposition of glycolipids in different organs and tissues.

Elderly man suffering from Acroparestheisa due to Fabry disease
Elderly man suffering from Acroparestheisa due to Fabry disease

Type 1 Classic Phenotype:

Type 1 Classic Phenotype typically manifests in childhood or adolescence. It is characterized by progressive glycolipid accumulation in various organs, leading to kidney insufficiency, kidney failure, heart disease, strokes, and other symptoms.

Signs & Symptoms of Type 1

The signs and symptoms of type 1 Fabry disease are:

  • Acroparesthesia: Severe burning pain in hands and feet, known as acroparesthesias or Fabry’s crises. Factors like exercise, fatigue, and fever trigger it.
  • Anhidrosis or Hypohidrosis: Decreased or absent sweat production, leading to discomfort in warm temperatures or during physical activity.
  • Angiokeratomas: Reddish to dark-blue skin rash, especially in the area between hips and knees.
  • Gastrointestinal Problems: Abdominal cramping, frequent bowel movements, and diarrhea, often after meals.
  • Corneal Dystrophy: Abnormal deposits of glycolipids in the corneas. It results in characteristic whorl-like opacity.
  • Additional Symptoms: Chronic fatigue, dizziness, headache, weakness, nausea, vomiting, delayed puberty, sparse hair growth, joint malformations, and lymphedema.

Type 2 Later-Onset Phenotype:

Type 2 Later-Onset Phenotype typically presents later in adulthood ( during the third and sixth decade of life). It primarily manifests in renal and cardiac complications without the characteristic early symptoms seen in Type 1.

Signs & Symptoms of Type 2 

The signs and symptoms of type 2 Fabry disease are:

  • Renal Dysfunction: The progressive decrease in renal function due to glycolipid accumulation in the kidneys leads to kidney failure.
  • Cardiac Disease: Heart enlargement, left ventricular hypertrophy, arrhythmias, and heart failure.
  • Cerebrovascular Complications: Ischemic or hemorrhagic strokes occurring typically in the fourth decade of life or later.
  • Respiratory Abnormalities: Interstitial lung disease causing restrictive lung disease, obstructive airway disease, or a mixture of both.
  • Other Pathologies:
    Several pathologies occur potentially due to glycolipid deposition in various organs and include hearing loss, tinnitus, dizziness, vertigo, and depression.
    Both phenotypes share common manifestations like renal and cardiac complications with advancing age.

Fabry Disease Diagnosis & Screening

Diagnosing Fabry disease in males is usually easier than in females and those with different genetic variations. It is because males present with classic Fabry disease symptoms and are diagnosed easily. On the other hand, most women have a mild form of Fabry disease. The condition either goes unnoticed or gets confused with other lysosomal storage diseases like Schindler or Gaucher disease.
Doctors use a detailed history, family background, physical exam, and various tests to diagnose the condition. Physicians diagnose Fabry disease type 1 classic phenotype based on specific clinical findings observed in childhood or adolescence, including episodic pain in fingers and limbs, reduced or increased sweating, characteristic skin lesions (angiokeratoma), gastrointestinal issues, and corneal dystrophy. On the other hand, diagnosis of type 2 later-onset phenotype is often missed initially and may only be made when cardiac or kidney issues become apparent in late adulthood.

Confirmation of Diagnosis:

In both type 1 and 2, diagnosis is confirmed by laboratory tests that demonstrate enzyme deficiency and identify the specific mutation in the GLA gene. The tests include:

Enzyme Assay

This measures the activity of the α-galactosidase A enzyme, which is deficient in this disease. Blood or skin samples may be used for this test. For males suspected of having Fabry disease, doctors check the activity of the alpha-galactosidase A (alpha-GAL) enzyme. This enzyme’s very low activity level is a strong sign of classic Fabry disease.5Schiffmann, R., Fuller, M., Clarke, L. A., & Aerts, J. M. (2016). Is it Fabry disease? Genetics in medicine: Official Journal of the American College of Medical Genetics, 18(12), 1181–1185. https://doi.org/10.1038/gim.2016.55
However, diagnosing Fabry disease in females is complex due to a natural process called X-chromosome inactivation. It can lead to normal enzyme activity levels despite a mutated GLA gene, resulting in a milder or variable disease presentation.

Gene Sequencing

DNA analysis can identify mutations in the GLA gene, which is responsible for producing the α-galactosidase A enzyme. This test can confirm the diagnosis and identify carriers.

Urine Analysis

The presence of certain substances like globotriaosylceramide (Gb3) or lyso-Gb3 in urine can suggest Fabry disease. Lyso-Gb3 is the derivative of Gb3 (Globotriaosylceramide). In Fabry disease, Gb3 gets accumulated due to the deficiency of the enzyme alpha-Gal A.6Niemann, M., Rolfs, A., Störk, S., Bijnens, B., Breunig, F., Beer, M., Ertl, G., Wanner, C., & Weidemann, F. (2014). Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease. Circulation. Cardiovascular genetics, 7(1), 8–16. https://doi.org/10.1161/CIRCGENETICS.113.000249 It’s particularly useful for figuring out the type of Fabry disease a person has, even before they show symptoms.

Cardiac Evaluation

When doctors suspect heart issues in this disease, they typically start with a test called echocardiography. This test allows them to examine the heart using sound waves. They look for specific signs that indicate heart problems, such as thickening of the heart muscle and issues with how the heart fills with blood.
If there are concerns about heart involvement, additional tests, such as magnetic resonance imaging (MRI) or 24-hour heart monitoring, may be recommended to get a clearer picture of the heart’s condition.

Renal Assessment

Doctors usually begin with blood and urine tests to assess kidney function in Fabry disease patients. These tests help determine how well the kidneys are working.
Additionally, ultrasound imaging may be used to examine the kidneys for any visual abnormalities.
If the initial tests suggest kidney damage, a biopsy, which involves taking a small sample of kidney tissue for examination, may be necessary to provide more detailed information about the extent of the damage.

Neurological Testing

Identifying nerve problems can be challenging since no specific blood tests are available. Instead, doctors rely on recognizing symptoms commonly associated with nerve damage, such as tingling sensations, chronic pain, and abnormalities in sweating patterns. These symptoms and the patient’s history of nerve-related issues guide further neurological diagnostics.
Tests like magnetic resonance imaging (MRI) and visual and hearing assessments are often used to detect nerve damage and evaluate its severity.

Prenatal Diagnosis in Fabry Disease:

Early prenatal diagnosis can be achieved through genetic testing of fetal tissue obtained via procedures like chorionic villus sampling or amniocentesis. This allows for the detection of GLA gene mutations, enabling early intervention if necessary.
Pre-implantation genetic diagnosis is possible when the familial mutation in the GLA gene is known. It allows for the selection of embryos free from the genetic disorder before implantation.7Altarescu, G., Beeri, R., Eiges, R., Epsztejn-Litman, S., Eldar-Geva, T., Elstein, D., Zimran, A., Margalioth, E. J., Levy-Lahad, E., & Renbaum, P. (2012). Prevention of lysosomal storage diseases and derivation of mutant stem cell lines by preimplantation genetic diagnosis. Molecular Biology International, 2012, 797342. https://doi.org/10.1155/2012/797342

Newborn Screening in Fabry Disease:

Newborn screening programs identify affected males by analyzing dried blood spots for reduced α-Gal A enzyme activity. Confirmation is then done through GLA gene sequencing. Screening is important for early intervention and management of the condition.
Since this disease is inherited, screening family members of a known patient can help identify other affected individuals or carriers.

What are the Complications of Fabry Disease?

It can lead to various complications affecting multiple organs and systems in the body. Some common complications include:

  • Chronic kidney disease
  • Renal failure
  • Hypertrophic cardiomyopathy
  • Arrhythmias
  • Heart failure and stroke
  • Transient ischemic attacks (TIAs)
  • Corneal opacities and vision impairment
  • Sensorineural hearing

Fabry Disease Treatment Options

Unfortunately, no treatment is available to cure Fabry Disease. The treatment interventions available focus on addressing its symptoms and preventing complications.

Enzyme replacement Therapy (ERT)

ERT is the primary approach to Fabry disease. It includes giving regular infusions of the missing enzyme (alpha-galactosidase A). This enzyme helps break down fatty substances in the body.8Lenders, M., & Brand, E. (2021). Fabry Disease: The Current Treatment Landscape. Drugs, 81(6), 635–645. https://doi.org/10.1007/s40265-021-01486-1
ERT helps alleviate pain and improves organ function and overall quality of life for individuals with this disease.

Oral Medication

A newer oral medication called migalastat (Galafold) stabilizes enzymes to mitigate the disease’s impact on organs.

Agalsidase Beta, Enzyme replacement therapy (ERT) for Fabry disease
Agalsidase Beta, Enzyme replacement therapy (ERT) for Fabry disease

Chaperone Therapy

Emerging therapies offer promising alternatives. Chaperone therapy aims to enhance the function of existing enzymes. In contrast, gene therapy, though still in clinical trials, holds the potential for correcting the underlying genetic defect responsible for this disease.

Chaperone therapy uses small molecules to act like natural helpers in the body. These molecules help fix or stabilize proteins that are not working correctly.

In Fabry disease, the GLA enzyme needs to work properly in a part of the cell called the lysosome. However, in patients with Fabry disease, this enzyme is broken down too soon by the cell’s quality control system. Chaperone therapy helps stabilize the faulty GLA enzyme, allowing it to fold correctly and reach the lysosome, where it can do its job. Right now, Migalastat is the only chaperone therapy widely approved for Fabry disease.9Weidemann F, Jovanovic A, Herrmann K, Vardarli I. Chaperone Therapy in Fabry Disease. Int J Mol Sci. 2022 Feb 8;23(3):1887. doi: 10.3390/ijms23031887. PMID: 35163813; PMCID: PMC8836454.

Supportive Treatment

Given that Fabry disease affects multiple organs, your doctor may recommend various supportive treatments. These include:

  • Pain-relieving medications for nerve damage
  • Drugs to manage stomach issues like gastroparesis
  • Medications to address heart problems such as irregular heartbeats or high blood pressure.
  • In severe cases of kidney damage, dialysis or kidney transplantation may be necessary.

Lifestyle Changes

In addition to medical interventions, a healthy lifestyle is crucial for managing this condition. This entails:

  • Eating nutritious food with dietary restrictions
  • Having a physical activity routine
  • Avoiding binge-drinking
  • Abstaining from smoking cigarettes
  • Effectively managing stress

Regular medical check-ups and close monitoring of organ function are vital for early detection and management of any changes or complications associated with the disease.

What happens to people with Fabry disease in the long run?

It gets worse over time. As you age, the symptoms and chances of serious complications increase.
People with this disease often develop life-threatening complications like arrhythmias and renal dysfunction that shorten their life expectancy.

What is Fabry Disease Life Expectancy?

On average, males with Fabry disease live until their 50s, while women with Fabry disease have a longer life span, comparatively up to 70 years. It may be because women generally have a mild form of Fabry disease and develop fewer complications.
Doctors say that the life expectancy of people with Fabry disease also depends on getting the right treatment promptly. Preventing and treating cardiac and renal complications manages the disease’s severity and helps the patients live longer.

To summarize, Fabry disease is characterized by a deficiency in the alpha-galactosidase A enzyme. This causes the buildup of toxic lipids in the body, affecting many organs and activities. Although there is no cure, therapies, including enzyme replacement therapy and oral medicines, can help manage symptoms and avoid problems. Early identification, genetic testing, and supportive therapy are crucial in enhancing the quality of life and extending the longevity of people with Fabry disease.

Refrences
  • 1
    Mehta A, Hughes DA. Fabry Disease. 2002 Aug 5 [Updated 2023 Mar 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1292/
  • 2
    Wanner, C., Arad, M., Baron, R., Burlina, A., Elliott, P. M., Feldt-Rasmussen, U., Fomin, V. V., Germain, D. P., Hughes, D. A., Jovanovic, A., Kantola, I., Linhart, A., Mignani, R., Monserrat, L., Namdar, M., Nowak, A., Oliveira, J. P., Ortiz, A., Pieroni, M., Spada, M., … Hilz, M. J. (2018). European expert consensus statement on therapeutic goals in Fabry disease. Molecular genetics and metabolism, 124(3), 189–203. https://doi.org/10.1016/j.ymgme.2018.06.004
  • 3
    Bokhari SRA, Zulfiqar H, Hariz A. Fabry Disease. [Updated 2023 Jul 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK435996/
  • 4
    Battaglia, Y., Fiorini, F., Azzini, C., Esposito, P., De Vito, A., Granata, A., Storari, A., & Mignani, R. (2021). Deficiency in the Screening Process of Fabry Disease: Analysis of Chronic Kidney Patients Not on Dialysis. Frontiers in medicine, 8, 640876. https://doi.org/10.3389/fmed.2021.640876
  • 5
    Schiffmann, R., Fuller, M., Clarke, L. A., & Aerts, J. M. (2016). Is it Fabry disease? Genetics in medicine: Official Journal of the American College of Medical Genetics, 18(12), 1181–1185. https://doi.org/10.1038/gim.2016.55
  • 6
    Niemann, M., Rolfs, A., Störk, S., Bijnens, B., Breunig, F., Beer, M., Ertl, G., Wanner, C., & Weidemann, F. (2014). Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease. Circulation. Cardiovascular genetics, 7(1), 8–16. https://doi.org/10.1161/CIRCGENETICS.113.000249
  • 7
    Altarescu, G., Beeri, R., Eiges, R., Epsztejn-Litman, S., Eldar-Geva, T., Elstein, D., Zimran, A., Margalioth, E. J., Levy-Lahad, E., & Renbaum, P. (2012). Prevention of lysosomal storage diseases and derivation of mutant stem cell lines by preimplantation genetic diagnosis. Molecular Biology International, 2012, 797342. https://doi.org/10.1155/2012/797342
  • 8
    Lenders, M., & Brand, E. (2021). Fabry Disease: The Current Treatment Landscape. Drugs, 81(6), 635–645. https://doi.org/10.1007/s40265-021-01486-1
  • 9
    Weidemann F, Jovanovic A, Herrmann K, Vardarli I. Chaperone Therapy in Fabry Disease. Int J Mol Sci. 2022 Feb 8;23(3):1887. doi: 10.3390/ijms23031887. PMID: 35163813; PMCID: PMC8836454.
Dr. Ayesha Maqsood
Dr. Ayesha Maqsood
Dr. Ayesha Maqsood is a practicing medical practitioner. She is an MBBS graduate of National University of Medical Sciences(NUMS). She tries her best to impart her knowledge to benefit mankind as much as she can. Along side being a a physician, she has found her true passion in the world of writing too.

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