Fabry disease is a genetic lysosomal storage disorder.1 The disease results from the progressive accumulation of glycosphingolipids, in particular globotriaosylceramide, in tissues and organs throughout the body.2,3 This is caused by a deficiency in (or absence of) the enzyme α-galactosidase A, owing to a mutation in the Xq22 region of the X chromosome, which controls enzyme production.4–7
The estimated prevalence of Fabry disease is 1 in 117 000 live births,1,8 and the estimated incidence is 1 in 40 000–60 000 males9 and 1 in 20 000 females.10
The most common mutations found in Fabry disease are point mutations (missense, 55.9%; nonsense, 11.2%), followed by rearrangements of <60 nucleotides (26.8%).4 Larger rearrangements of bases arise more rarely (1.9%) and involve deletions and duplications.4
Fabry disease has previously been classified as an X-linked, recessive genetic disorder; however, females who carry the Fabry gene may show signs and symptoms of Fabry disease. Fabry disease is therefore now described as ‘following X-linked inheritance’3 and the use of the term ‘carrier’ for females with the Fabry gene may no longer be appropriate.11
Cardiovascular disease is one of the most frequent causes of death in patients with Fabry disease;12 it is therefore important to identify signs of Fabry cardiomyopathy early and treat them before they progress and cause more severe disease.
The most common cardiac defects observed in Fabry disease are left ventricular hypertrophy, ischaemia, enlarged left atrium, heart valve abnormalities, conduction disturbances and arrhythmias.13,14 These defects cause a range of symptoms,13 which can be observed in patients with Fabry disease as young as 12 years old.15,16
Proteinuria, hematuria, reduced renal function, nephrotic syndrome and chronic kidney failure are the most frequently reported renal abnormalities in Fabry disease.16 These abnormalities occur less frequently in women than in men.14
Studies have shown that a reduced glomerular filtration rate occurs early in life in a significant proportion of children, in many females, and in almost all male patients with Fabry disease.17
Pain is considered the clinical hallmark of Fabry disease and has a significant impact on the patient’s health-related quality of life.18 It can be addressed by Fabry-specific medication, such as enzyme replacement therapy, or by using appropriate pain-relieving medication. Neuropathic pain is regarded as an indication to start enzyme replacement therapy. A number of triggers are known to cause pain in patients with Fabry disease (e.g. hot weather, physical exercise, stress, alcohol intake or high temperature) and care should be taken to avoid these.14,18
Neuropathic pain typically presents as acroparesthesia,19 which may be chronic, or may occur as episodic, agonising crises known as Fabry crises.14 It has been reported in approximately 77% of male patients and 70% of female patients.18,20
Although there are very few signs or symptoms that are specific to Fabry disease, the presence of one or more of the following should always prompt further investigation: angiokeratoma, left ventricular hypertrophy, cornea verticillata, acroparesthesia, and/or stroke (in patients aged 18–55 years).13,14
A Fabry disease diagnosis is confirmed in the laboratory by measurement of α-galactosidase A activity in the patient’s leucocytes, and molecular analysis of the GLA gene.21
Diagnostic testing should be considered in the following populations who may be at a greater risk of Fabry disease: patients over 30 years of age with a confirmed diagnosis of hypertrophic cardiomyopathy or unexplained left ventricular hypertrophy 13 mm or more;22 patients presenting with end-stage renal disease undergoing dialysis23,24,25,26 or renal transplant27,28; and all patients who have had a stroke and are aged 18–55 years.29,30
Very few Fabry disease signs and symptoms are specific to the condition. Screening for Fabry disease should be performed in all patients with cardiac defects above the age of 30 years with a confirmed diagnosis of hypertrophic cardiomyopathy or unexplained left ventricular hypertrophy of 13 mm or more.22
Screening for Fabry disease should be performed in all patients with end-stage renal disease undergoing dialysis 23,24,25,26 or renal transplant.27,28
Fabry disease should be considered for all patients with a family history of stroke; patients who report episodes of acroparesthesia associated with fever, stress and/or exercise; and young adults who have had a stroke and are aged 18–55 years.29,30
Early diagnosis of Fabry disease is essential so that specific Fabry disease treatment and symptomatic management can be initiated to try to limit potentially irreversible organ damage.3,31 Prompt Fabry disease diagnosis may also benefit relatives of the patient in whom the disease is yet to be diagnosed.
A pedigree analysis enables early detection of disease by identifying any other family members who may have Fabry disease or carry the Fabry gene.32 This information is also important for informed decision making for family planning because it will allow the proband and other family members to understand the risk of passing on this condition to their children. If the pedigree analysis identifies a potential diagnosis of Fabry disease in specific family members then this will help to ensure that the appropriate care can be provided as soon as possible.
Genetic counselling is essential to help the patient and family members understand the diagnosis and potential Fabry disease treatment options. Aside from the benefits listed below (follow the link at the end of this question), genetic counselling is also helpful to explain the risks, benefits and limitations associated with different genetic tests, and can be used to explain the results of these tests. Finally, genetic counselling is a valuable opportunity to provide information about patient support groups.32,33
Enzyme replacement therapy is available for all patients.34,35 Chaperone therapy is available for patients with a so-called “amenable” α-galactosidase A gene mutation (the specific mutation carried by your patient must be confirmed via genetic testing to ensure that they are eligible for treatment).36 Fabry disease can affect multiple organs and results in a spectrum of symptoms. The patient may also have psychosocial issues resulting from diagnosis and disease. Thus, a multidisciplinary approach to Fabry disease treatment is required, and the patient will require ongoing symptomatic treatment even after enzyme replacement therapy has been initiated.