Diagnosis

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Fabry disease is challenging to diagnose; partly because the multisystemic signs and symptoms associated with the condition overlap with those from a number of other diseases;1,2 and also because of the variability in disease progression. Fabry disease is a rare condition; therefore, it is not automatically considered by physicians when patients present with non-specific multisystemic symptoms.1,2

Misdiagnosis is common; 25% of patients in the Fabry Outcome Survey (FOS) were initially misdiagnosed.1 The mean length of time between the onset of symptoms and diagnosis is 13.7 years for males and 16.3 years for females.1 The longer delay in the diagnosis of females has been attributed to inconsistent markers of disease, genetic variation, slower disease progression and misconceptions surrounding disease prevalence.1–4

The different specialists typically involved in the diagnosis of Fabry disease, by frequency consulted

piechart image on the different specialists typically involved in the diagnosis of fabry disease - mobile
Figure adapted from Beck, 20062

Establishing a diagnosis

Few of the signs and symptoms of Fabry disease are specific to the condition. However, some signs and symptoms are highly suggestive of Fabry disease and should always be investigated further, especially where more than one of them is present.

Signs and symptoms used to help diagnose Fabry disease1,2

Fabry disease diagnosis in the human body. A body image

Heart

Conduction
abnormalities,
arrhythmia,
left ventricular
hypertrophy,
ischaemia

Kidney

Cysts, albuminuria,
proteinuria,
progressive
renal failure

Gastrointestinal tract

Abdominal pain,
nausea, vomiting,
constipation,
diarrhoea

Skin

Angiokeratomas

Central nervous system

Transient ischaemic
attacks, stroke,
neuropsychiatric
problems, fatigue

Peripheral nervous system

Acroparesthesia,
hypohidrosis,
temperature
sensitivity

Eyes

Cornea verticillata,
tortuous retinal
blood vessels

Ears

Hearing impairment,
vertigo, tinnitus

Fabry disease diagnosis - Cornea verticillata in a patient

Cornea verticillata in a patient with Fabry disease3

Image reproduced with kind permission from Dr A Sodi
Fabry disease diagnosis - Typical angiokeratoma on the skin

Typical angiokeratoma on the skin (thigh and buttock) of a patient with Fabry disease

Image reproduced with kind permission from Dr T Jansen
Fabry disease diagnosis - MRI of the heart of a patient with Fabry disease

MRI of the heart of a patient with Fabry disease, showing marked left ventricular hypertrophy

LA, left atrium; LV, left ventricle; MRI, magnetic resonance imaging; RV, right ventricle

Image reproduced with kind permission from Dr A Linhart2

Confirming a diagnosis

The gold standard procedures for the diagnosis of Fabry disease in the laboratory are measurement of α-Gal A activity in the leucocytes of a patient and molecular analysis of the GLA gene (see figure below). Progressive accumulation of Gb3 in tissues has historically been regarded as a major feature of Fabry disease;1 therefore, chromatography, enzyme-linked immunosorbent assays and mass spectrometry have been used to measure Gb3 in plasma and urine.2 It has, however, been questioned whether or not the accumulation of Gb3 is exclusively responsible for the clinical symptoms of Fabry disease. The reliability of Gb3 as a biomarker of Fabry disease is therefore questionable.1,3,4

Male patients:

  • Patients with the classic Fabry disease phenotype can be reliably diagnosed based on the presence of only negligible α-Gal A activity.
  • Patients with attenuated phenotypes may demonstrate considerable residual α-Gal A activity, while still exhibiting levels below the normal reference range. A mutation analysis of the GLA gene should be performed in these patients.4

confirming a fabry disease diagnosis in male patients
Figure adapted from Gal et al. J Inherit Metab Dis 2011; 34:509–14 (© The Authors 2011) with permission of Springer

Female patients:

  • α-Gal A activity may be within the normal range in heterozygous females (owing to one functional chromosome and lyonisation). Measurement of α-Gal A activity is therefore not a reliable method for the diagnosis of Fabry disease in females.
  • Identification of a disease-relevant, heterozygous mutation in the GLA gene confirms a Fabry diagnosis in heterozygous females.4
confirming a fabry disease diagnosis in female patients
Figure adapted from Gal et al. J Inherit Metab Dis 2011; 34:509–14 (© The Authors 2011) with permission of Springer

Importance of early diagnosis

Early diagnosis of Fabry disease is essential so that specific treatment and symptomatic management can be initiated, with the aim of limiting potentially irreversible organ damage.1,2 Prompt diagnosis may also benefit relatives of the patient in whom the disease is yet to be diagnosed; as many as five additional cases of Fabry disease may be identified within a family through pedigree analysis.3

Diagnosis involves many different tests, performed by a multidisciplinary team with a wide range of clinical specialties.1 In males, diagnosis is made by testing α-Gal A activity and is confirmed by genetic tests; in females, diagnosis must be based on genetic tests because α-Gal A activity may be within the normal range.4,5

Delay in the diagnosis and treatment of Fabry disease may have substantial clinical consequences for both male and female patients including irreversible organ damage, vital organ dysfunction, and early mortality.1 If left untreated, Fabry disease can reduce life expectancy by approximately 20 years in men and 15 years in women.6–8

Improving diagnosis

Misdiagnosis

Misdiagnoses are common in Fabry disease.1 In an analysis of patients with Fabry disease, 25% were initially misdiagnosed, with a mean time of over 13 years between the onset of symptoms and diagnosis.2 The clinical course of the disease is highly variable resulting in a broad range of possible differential diagnoses.1 Common misdiagnoses of Fabry disease include rheumatological diseases and rheumatic fever, arthritis, neuropsychological disease, and multiple sclerosis.2 Fabry disease should be included in the list of differential diagnoses for unclear pathologies and those taking an atypical course.1

Percentage of misdiagnoses (%)

Percentage Misdiagnosis Chart

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