Diagnosing Fabry Disease

Diagnosis can be challenging, as the signs and symptoms of the disease are diverse and varied and affect a number of different organs.1 While Fabry disease is considered “rare,” the disease manifestations are common. As a result of the multi-organ pathology often seen in patients with Fabry and the number of conditions that mimic the signs and symptoms of the disease, diagnosis may be difficult.2

It is estimated that patients visit an average of 10 different specialists before a Fabry disease diagnosis is confirmed, leading to a delay of approximately 10 years from the onset of first symptoms to diagnosis.3

Diagnosis in males with suspected classic phenotype is confirmed by an in vitro enzymatic assay that demonstrates an absence or very low levels of α-Gal A activity in blood leukocytes or cultured skin fibroblasts.3,4However, genetic sequencing can provide additional insight into a male patient’s mutations that may impact managing and treating his disease.5-8

Diagnosis of female patients with Fabry disease is less straightforward. Due to X-chromosome inactivation (lyonization) of the abnormal chromosome, α-Gal A activity may appear normal in blood leukocytes and cultured fibroblasts, thus masking the presence of Fabry disease.1,4,9 A definitive diagnosis of suspected Fabry disease in females is confirmed by sequencing the alpha-galactosidase A (GLA) gene.4

For families affected by Fabry, GLA gene sequencing and pedigree analysis can characterize the disease-causing mutation and help to identify affected family members.10


Disease Prognosis

The life expectancy of patients with Fabry disease is significantly shorter than that of the general population.1 Lifespans for people with Fabry disease may be shortened to approximately 50 years for untreated men and 70 years for untreated women—a 20- and 10-year reduction, respectively.1

Cardiovascular disease is the most common cause of death for both men and women with Fabry.11 In patients enrolled in The Fabry Registry, sponsored by Genzyme Corporation, the main cause of death was cardiovascular disease, with 53.6% and 50.0% of male and female deaths, respectively, due to this cause.11

The second and third most common causes of death in males were cerebrovascular (12.5%) and renal (10.7%) disease, respectively.11 It has been established that certain genetic variants result in the onset of predictable clinical manifestations. For example, the GLA gene variant IVS4+919G>A has been demonstrated to be associated with a high prevalence of late-onset cardiac symptoms and has been shown to have a high prevalence in Taiwanese Chinese Fabry patient populations.12,13


Impact on Quality of Life

The presence of serious, chronic, and debilitating complications, including cardiovascular and renal complications, and comorbid conditions such as pain can have a significant impact on the psychological well-being of patients with Fabry disease. This, along with the impact on social functioning, means that patients often experience a reduction in quality of life (QoL).14,15

A meta-analysis from 11 studies that included 536 affected patients demonstrated that Fabry disease had a significant impact across multiple QoL domains, including physical functioning, bodily pain, general health, vitality, mental health, and emotional well-being, compared with healthy individuals.15 This pooled analysis also demonstrated that disease severity, the presence of renal disease, and advanced age severely impacted the quality of life of patients with Fabry disease.15

The presence of Fabry disease can also have a serious impact on mood, with many patients experiencing depression.14,16 Analysis of a Fabry disease population in the United Kingdom revealed that the prevalence of depression was 46%, of which 28% were consistent with severe clinical depression.14,16

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  1. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. doi:10.1186/1750-1172-5-30.
  2. Hoffmann B, Mayatepek E. Fabry disease-often seen, rarely diagnosed. Dtsch Arztebl Int. 2009;106(26):440-447.
  3. Rozenfeld PA. Fabry disease: treatment and diagnosis. IUBMB Life. 2009;61(11):1043-1050.
  4. Winchester B, Young E. Laboratory diagnosis of Fabry disease. In: Elstein D, Altarescu G, Beck M, eds. Fabry Disease. Springer Science and Business Media; 2010: Chapter 6.
  5. Laney DA, Bennett RL, Clarke V, et al. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2013;22(5):555-564.
  6. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York, NY: McGraw-Hill; 2001:3733-3774.
  7. Anderson LJ, Wyatt KM, Henley W, et al. Long-term effectiveness of enzyme replacement therapy in Fabry disease: results from the NCS-LSD cohort study. J Inherit Metab Dis. 2014;37(6):969-978.
  8. Biegstraaten M, Arngrímsson R, Barbey F, et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis. 2015;10:36. doi:10.1186/s13023-015-0253-6.
  9. El-Abassi R, Singhal D, England JD. Fabry’s disease. J Neurol Sci. 2014;344(1-2):5-19.
  10. Yousef Z, Elliott PM, Cecchi F, et al. Left ventricular hypertrophy in Fabry disease: a practical approach to diagnosis. Eur Heart J. 2013;34(11):802-808.
  11. Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med. 2009;11(11):790-796.
  12. Chien YH, Lee NC, Chiang SC, Desnick RJ, Hwu WL. Fabry disease: incidence of the common later-onset alphagalactosidase A IVS4+919G–>A mutation in Taiwanese
    newborns–superiority of DNA-based to enzyme-based newborn screening for common mutations. Mol Med. 2012;18:780-784.
  13. Liu HC, Lin HY, Yang CF, et al. Globotriaosylsphingosine (lyso-Gb3) might not be a reliable marker for monitoring the long-term therapeutic outcomes of enzyme replacement therapy for late-onset Fabry patients with the Chinese hotspot mutation (IVS4+919G>A). Orphanet J Rare Dis. 2014;9:111.
  14. Cole AL, Lee PJ, Hughes DA, Deegan PB, Waldek S, Lachmann RH. Depression in adults with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis. 2007;30(6):943-951.
  15. Arends M, Hollak CE, Biegstraaten M. Quality of life in patients with Fabry disease: a systematic review of the literature. Orphanet J Rare Dis. 2015;10:77.
  16. Bolsover FE, Murphy E, Cipolotti L, Werring DJ, Lachmann RH. Cognitive dysfunction and depression in Fabry disease: a systematic review. J Inherit Metab Dis. 2014;37(2):177-187.
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