Course:MEDG550/Student Activities/Fabry Disease

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Fabry Disease

Fabry Disease (FD), also called alpha-galactosidase A deficiency or Anderson-Fabry disease, is a rare and inherited lysosomal storage disease. It is estimated that 1 in 50 000 to 1 in 117 000 individuals have FD.[1][2] Inherited means being passed down from parent to child. Lysosomes are molecules in the cells of our body that play an important job in breaking down waste and nutrients in the cell. For the lysosome to work properly, it requires different molecules called enzymes to help it participate in its function.

Patients with FD produce a lower amount of a specific enzyme called alpha-galactosidase A (α-Gal), resulting in the buildup of a type of fat substance called globotriaosylceramide and other related compounds in the lysosome. The improper clearance of these fat substances in the cells of the body results in a range of symptoms and causes progressive damage to several organs in the body, including the heart, kidney and brain.[3]

Clinical Characteristics

Patients may not present with every symptom listed, and the symptoms observed also can vary between patients. FD is classified into two types depending on when and which symptoms appear in affected individuals.


Angiokeratoma seen in various parts of the body
Cornea verticillata

Classic Fabry Disease [4][5]

The classic form of FD begins in infancy/childhood and is considered to be more severe than the atypical type. On average, symptoms appear between age 6 and 9.[6]

More common symptoms include:

  • Small dark red or purple raised spots that are present throughout the body (angiokeratoma)
  • Distinctive starburst pattern in the eyes (cornea verticillata)
  • Immense pain in the hands and feet that can be chronic or periodic (neuropathic pain or acroparesthesia)
  • Reduction or absence of sweating (anhidrosis/hypohidrosis)
  • "Fabry cataract" of the eye (lenticular opacity)

Other non-specific symptoms may also be seen:

  • Gastrointestinal problems (abdominal pain, nausea, vomiting, diarrhea, constipation)
  • Heat/cold intolerance
  • Cardiac abnormalities (heart valve problems, heart rhythm abnormalities, thickening of the left ventricle)
  • Poor growth (height/weight gain) in boys

In adulthood, when irreversible damage has been done to different organs, more severe symptoms may occur in the heart, brain and kidneys and lead to death:

  • Cardiac disease
  • Stroke
  • End stage kidney failure


Atypical Fabry Disease

Atypical Fabry disease appears in adulthood and it is usually less severe than classic FD, making it more likely to be underdiagnosed. Symptoms usually involve a single organ, and α-Gal typically measures higher than in classic FD. Atypical Fabry disease subtypes include the renal and cardiac variants.

Renal Variant[7]

The typical early symptoms of classic FD may not appear in individuals with the renal variant of the condition, such as angiokeratoma and cataracts. This variant of FD appears after age 25. Individuals with the renal variant develop renal insufficiency, which can be misdiagnosed as chronic glomerulonephritis.

Cardiac Variant[8][9][10]

Some individuals with unexplained hypertrophic cardiomyopathy over age 40 have been identified to have a cardiac variant of FD. People with the cardiac variant of FD typically only have cardiac symptoms of the condition.

Genetics

X-linked inheritance. The father is affected and will never pass the mutation to his son, but will always pass it to his daughters, making them "carriers" for the mutation.
X-linked inheritance. The mother is a carrier for the mutation, and can pass the mutation to either her son or daughter. If the son receives the mother's X-chromosome that carries the mutation, he will be affected, whereas the daughter becomes a carrier.

DNA is what makes us who we are, and consequently provides instructions for cells in our body to make different molecules. Our DNA are packaged into genes, which are located on chromosomes. Everyone has 23 pairs of chromosomes (22 numbered pairs, and 1 pair of sex chromosomes). Males have an XY pair of sex chromosomes, while females have XX.

The gene that instructs our cells to make α-Gal is called GLA, and is located on the X-chromosome. All patients with FD have mutations, which are genetic changes in this gene that leads to a drastic reduction in the amount of α-Gal enzyme being produced.[3]

Mutations in GLA are extremely diverse, and majority of mutations are unique to individual families.[11] The type of mutation and where it occurred in the gene determines the severity and types of symptoms observed in affected individuals. Thus, individuals with FD are likely to show differences in the progression of their disease.


Inheritance Pattern of Fabry Disease

The pattern of inheritance for FD occurs in a X-linked manner. Males who inherit the mutated copy of GLA from their parents will be affected with Fabry disease. This is because males only have one X-chromosome. In contrast, females that inherit the mutated copy of GLA are called carriers because they still have a normal copy of GLA on the other X chromosome.

When an affected father carries the FD causing mutation:

  • Daughters have a 100% chance of receiving the mutation, making them carriers (the father will only pass the X chromosome to females)
  • Sons have a 0% chance of receiving the mutation and being affected with FD (the father will only pass the Y chromosome to males)

When a mother is a carrier for the FD causing mutation:

  • Daughters have a 50% chance of receiving the mutation, making them carriers
  • Sons have a 50% chance of receiving the mutation and being affected with FD


It was previously believed that female carriers are not affected with FD as they still have a normal functioning copy of the GLA gene to make normal α-Gal. However, it is now known that some female carriers may have reduced levels of α-Gal, and also the clinical symptoms seen in males with FD.[12]

Diagnosis

Biochemical Testing [13][12]

Biochemical testing for FD involves looking at the level of α-Gal circulating in the blood. Males affected with FD will have decreased levels of α-Gal. FD females however, may have normal or decreased levels of α-Gal, and would require further confirmatory genetic testing.


Genetic Testing [13][12][14][15]

Genetic testing involves reading the DNA to see if a mutation can be found in the GLA gene. As mentioned above, females suspected to have FD will need to have genetic testing for a definitive diagnosis. Individuals from Nova Scotia can have targeted testing for a specific change in GLA that is more common in this population.

Genetic Counselling

Individuals may want to consider genetic counselling if there is a family history of individuals with FD, or have had a previous child that has been diagnosed. Genetic counsellors are trained health professionals that can help individuals assess if there are any other family members or relatives that maybe at risk for the disease and coordinate testing options. In addition, genetic counsellors can provide a better understanding of living with the disease and explore reproductive options. [16]


Reproductive Options [12]

Prenatal diagnosis is an option for parents who have confirmed the specific mutation in the GLA gene. This involves looking at the baby’s DNA to see if it has the same genetic change as identified in its parents.

Parents may want to explore the option of pre-implantation genetic diagnosis (PGD) at an assisted reproduction center. PGD is a technique performed during an in-vitro fertilization (IVF) process to select for healthy embryos that do not carry the known GLA mutation identified in the parents.

Alternatively, parents may want to consider pursuing IVF through an egg or sperm donor.


Psychological and Social Aspects of Living with Fabry Disease

FD patients may have lower psychological wellbeing as a result of living with the symptoms of the disease, such as an increased risk of depression and anxiety.[17][18] Some other feelings may include: [12]

  • Isolation from peers for being unable to participate in activities as a result of pain symptoms
  • Embarrassment and issues of intimacy arising from physical appearance due to presence of angiokeratomas
  • Anger, grief, blame, hopelessness, which are all feelings that commonly are experienced in patients with chronic illnesses

Clinical and Medical Management

Fabry disease patients should be managed by a multidisciplinary specialty team as symptoms can occur in multiple organs. This could comprise a medical geneticist, genetic counsellor, pediatric cardiologist, pain specialist, psychologist and others depending on the specific symptoms that arises. [12]


Neuropathic Pain Management[4]

There are different types of pain medications that may be prescribed for patients, depending on whether the pain is chronic or episodic, and whether the pain is throughout the body or localized to certain areas, and the severity.


Enzyme Replacement Therapy [19][4]

There is currently no cure for FD. However, a treatment called enzyme replacement therapy (ERT) can be used to reduce the severity of symptoms that progress overtime. This involves delivery of the medication directly to the veins, that will help the lysosome break down the buildup of fat substances that causes organ damage.

Not all patients with FD may need ERT, and it is important that patients discuss this option with their doctor. In general, patients that begin presenting with symptoms should consider ERT to prevent the progression of the disease and causing irreversible organ damage. However, asymptomatic patients should discuss with their doctor about the optimal time to start ERT, as there has not been a consensus among doctors for managing this subset of FD patients.

Resources

Patients may find it helpful to review other resources for information regarding FD, or to connect with other individuals or families that are living with the disease. Some starting places are listed below:

Canadian Fabry Association

National Fabry Disease Foundation

Fabry International Network

Canadian MPS Society

References

  1. ↑ Meikle, P. J., Hopwood, J. J., Clague, A. E., & Carey, W. F. (1999). Prevalence of lysosomal storage disorders. Jama, 281(3), 249-254.
  2. ↑ Desnick, RJ; Ioannou, YA; Eng, CM (2001). "Alpha-galactosidase A deficiency: Fabry disease.". The Metabolic and Molecular Bases of Inherited Diseases. New York, NY: McGraw-Hill. pp. 3733–74.
  3. ↑ 3.0 3.1 Germain DP. (2010). Fabry Disease. Orphanet J Rare Dis. 5:30.
  4. ↑ 4.0 4.1 4.2 Hopkin RJ, Jefferies JL, Laney DA, et al. (2016). The management and treatment of children with Fabry disease: A United States-based perspective. Mol Genet Metab. 117: 104-13.
  5. ↑ Laney DA, Peck DS, Atherton AM, et al. (2015). Fabry disease in infancy and early childhood: A systematic literature review. Genet Med. 17: 323-30.
  6. ↑ Hopkin RJ, Bissler J, Banikazemi M, et al. (2008). Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res. 64: 550–555.
  7. ↑ Nakao, S., Kodama, C., Takenaka, T., Tanaka, A., Yasumoto, Y., Yoshida, A., Kanzaki, T., Enriquez, A.L., Eng, C.M., Tanaka, H. and Tei, C. (2003). Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype1. Kidney international, 64(3), 801-807.
  8. ↑ Nakao, S., Takenaka, T., Maeda, M., Kodama, C., Tanaka, A., Tahara, M., Yoshida, A., Kuriyama, M., Hayashibe, H., Sakuraba, H. and Tanaka, H. (1995). An atypical variant of Fabry's disease in men with left ventricular hypertrophy. New England Journal of Medicine, 333(5), 288-293.
  9. ↑ Sachdev, B., Takenaka, T., Teraguchi, H., Tei, C., Lee, P., McKenna, W. J., & Elliott, P. M. (2002). Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation, 105(12), 1407-1411.
  10. ↑ Elliott, P. (2006). Anderson–Fabry disease: an important differential diagnosis in patients with unexplained left ventricular hypertrophy. Arrhythmia and metabolism, 25.
  11. ↑ Desnick RJ, Iouannou YA, & Eng ME. (2007). a-Galactosidase A deficiency: Fabry disease. OMBIDD. p3733-74.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 Laney DA, Bennett RL, Clarke V, et al. (2013). Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns. 22: 555-64.
  13. ↑ 13.0 13.1 Gal S, Hughes DA, & Winchester B. (2011). Towards a consensus in the laboratory diagnostics of Fabry disease – recommendations of a European expert group. J Inherit Metab Dis. 34: 509-14.
  14. ↑ West, M., Lemoine, K., Simms, C., & Dyack, S. (2002). Cross‐sectional analysis of renal disease in the Nova Scotia Fabry disease kindred. Acta Paediatrica, 91, 126-126.
  15. ↑ Sirrs, S. M., Bichet, D. G., Casey, R., Clarke, J. T. R., Lemoine, K., Doucette, S., & West, M. L. (2014). Outcomes of patients treated through the Canadian Fabry disease initiative. Molecular genetics and metabolism, 111(4), 499-506.
  16. ↑ National Society of Genetic Counselors : Who are Genetic Counselors?. Nsgc.org (2017). at <http://www.nsgc.org/page/whoaregcs>
  17. ↑ Cole AL, Lee PJ, Hughes DA, et al. (2007). Depression in adults with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis. 30: 943-51.
  18. ↑ Boisover FE, Murphe E, Cipolotti L, et al. (2014). Cognitive dysfunction and depression in Fabry disease: a systematic review. J Inherit Metab Dis. 37: 177-87.
  19. ↑ Biegstraaten M, Arngrimsson R, Barbey F, et al. (2015). Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. 10: 36.
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