Clinical presentation

Fabry disease is a multisystem disease with a wide spectrum of heterogeneous clinical phenotypes. Classical and non-classical (also known as atypical or late-onset) variants of Fabry disease have been described. In ‘classical’ Fabry disease, the onset of symptoms and clinical signs often start in childhood or adolescence. In contrast, in non-classical disease, signs and symptoms appear later in life, although these can vary remarkably. The wide variety of clinical phenotypes documented for both of these forms of the disease make diagnosis a significant challenge. Desnick R.J., Ioannou Y.A., Eng C.M. (2014). α-Galactosidase A Deficiency: Fabry Disease. In Valle D, Beaudet A.L., Vogelstein B, Kinzler K.W., Antonarakis S.E., Ballabio A, Gibson K, Mitchell G (Eds).<br /> Germain DP. Fabry Disease. Orphanet J Rare Dis. 2010;5:30.<br />

In patients with Fabry disease, progressive accumulation of globotriaosylceramide GL-3 starts early in life and continues for decades. Desnick R.J., Ioannou Y.A., Eng C.M. (2014). α-Galactosidase A Deficiency: Fabry Disease. In Valle D, Beaudet A.L., Vogelstein B, Kinzler K.W., Antonarakis S.E., Ballabio A, Gibson K, Mitchell G (Eds).<br /> Germain DP. Fabry Disease. Orphanet J Rare Dis. 2010;5:30.<br />  The early clinical course of Fabry disease typically involves symptoms primarily affecting quality of life as shown in the figure below. Progressive accumulation of GL-3 in multiple cell types throughout the body can lead to life-threatening manifestations involving the kidneys, heart, and nervous system and cerebrovascular system. Desnick R.J., Ioannou Y.A., Eng C.M. (2014). α-Galactosidase A Deficiency: Fabry Disease. In Valle D, Beaudet A.L., Vogelstein B, Kinzler K.W., Antonarakis S.E., Ballabio A, Gibson K, Mitchell G (Eds).<br /> <br />  More serious renal, cardiac, and cerebrovascular complications, which may become life-threatening, typically occur by the third to fifth decade. <br /> Germain DP. Fabry Disease. Orphanet J Rare Dis. 2010;5:30.<br />  The broad spectrum and non-specific nature of the signs and symptoms of Fabry disease may be overlooked and/or attributed to other causes. This can result in a diagnostic delay whereupon end-organ damage may already be present. Desnick R.J., Ioannou Y.A., Eng C.M. (2014). α-Galactosidase A Deficiency: Fabry Disease. In Valle D, Beaudet A.L., Vogelstein B, Kinzler K.W., Antonarakis S.E., Ballabio A, Gibson K, Mitchell G (Eds).<br /> <br />  Earlier diagnosis may facilitate appropriate management of disease and symptoms.

Analysis of data from the first 1765 patients enrolled in the Fabry Registry shows the typical age at symptom onset and diagnosis are 9 and 23 years (males) and 13 and 32 years (females), respectively, indicating diagnostic delays in both genders. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 2001;38:769–75.<br /> MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet 2001;38:750–60.<br />

One or more clinical findings from the list below could point to Fabry disease. If present, Fabry disease should be included in the differential diagnosis:

  • Angiokeratomas
  • Cardiac dysfunction
  • Gastrointestinal symptoms
  • Heat and cold intolerance
  • Hypohidrosis/anhidrosis
  • Neurological manifestations
  • Ocular findings
  • Pain
  • Renal manifestations
  • Fatigue and exercise intolerance
  • Episodes of fever
  • Acroparesthesia

Fabry disease can also be associated with a range of more general signs and symptoms of variable intensity, including reduced well-being and quality of life, school/work performance, and engagement in leisure activities; psychosocial and behavior deficits; and poor weight gain. Germain DP. Fabry Disease. Orphanet J Rare Dis. 2010;5:30.

Early presentation and late complications of Fabry disease