Abstract
Fabry disease is an X-linked lysosomal storage disorder caused by accumulation of glycosphingolipids due to deficiency of the lysosomal enzyme α-galactosidase A. Deposition of substrate results in kidney failure, stroke, and cardiac death. Other disease manifestations include pain, gastrointestinal symptoms, angiokeratoma, and corneal opacities, among others. Life expectancy is reduced in female and male patients. Specific treatment includes intravenous enzyme replacement and oral pharmacologic chaperone therapy.
Keywords
α-galactosidase A, GLA , Fabry disease, chronic kidney disease, stroke, heart failure, enzyme replacement therapy, pharmacologic chaperone, migalastat
Fabry disease (OMIM 301500 ) is an X-linked lysosomal storage disorder that results from absent or deficient activity of the enzyme α-galactosidase A (αGAL; EC 3.2.1.22). This enzyme is encoded by the GLA gene on Xq22 ( Fig. 43.1 ), with more than 800 different mutations so far described. A recent newborn screening study reported the incidence of mutations in GLA to be 1 : 3859 births in Austria. The enzyme defect leads to progressive accumulation of glycosphingolipids, predominantly globotriaosylceramide (Gb3), in all organs ( Fig. 43.2 ).
Early manifestations during childhood include pain, anhidrosis, and gastrointestinal symptoms, among others ( Box 43.1 ). Later, chronic kidney disease (CKD; Fig. 43.3 ) leading to end-stage kidney disease (ESKD), hypertrophic cardiomyopathy ( Fig. 43.4 ), and cerebral events ( Fig. 43.5 ) are the clinically most important organ manifestations resulting in a reduced life span of hemizygous men and heterozygous women. Most male patients develop the classic phenotype with involvement of all organ systems, whereas alterations in X-inactivation lead to highly variable disease expression in women. Furthermore, kidney or heart variant phenotypes with later onset of disease, probably linked to some residual enzyme activity, have also been described. Importantly, because of the nonspecific nature of complaints, there is often a delay of more than 10 to 20 years from the earliest symptoms of disease until the correct diagnosis is established. Therefore it is prudent to include Fabry disease in the differential diagnosis if two or more of the clinical problems indicated in Box 43.2 are present in young adults.
Nervous System
Acroparesthesias, nerve deafness, heat intolerance, tinnitus
Gastrointestinal Tract
Nausea, vomiting, diarrhea, postprandial bloating and pain, early satiety, difficulty gaining weight
Skin
Angiokeratoma, hypohidrosis
Eyes
Corneal and lenticular opacities, vasculopathy (retina, conjunctiva)
Kidneys
Albuminuria, proteinuria, impaired concentrating ability, increased urinary Gb3 excretion
Heart
Impaired heart rate variability, arrhythmias, ECG abnormalities (shortened PR interval), mild valvular insufficiency
ECG , Electrocardiogram; Gb3 , globotriaosylceramide.
a Any combination of two or more of these problems is highly suggestive of Fabry disease in either sex.
- 1.
Acroparesthesia or neuropathic pain in hands or feet beginning in later childhood, precipitated by illness, fever, exercise, emotional stress, or exposure to heat
- 2.
Persistent proteinuria of unknown cause
- 3.
Hypertrophic cardiomyopathy, especially with prominent diastolic dysfunction b
b This may be the only clinical manifestation of Fabry disease in patients of either sex with variants of classical Fabry disease.
- 4.
Progressive CKD
- 5.
Cryptogenic stroke or transient ischemic attack
- 6.
Family history of ESKD, stroke, or hypertrophic cardiomyopathy showing an X-linked pattern of transmission that primarily, but not solely, affects men
- 7.
Vague, persistent, or recurrent abdominal pain associated with nausea, diarrhea, and tenesmus
CKD , Chronic kidney disease; ESKD , end-stage kidney disease.
Beyond screening individuals with a family history of Fabry disease ( Fig. 43.6 ), many cases are identified by means of kidney biopsy on patients referred to nephrologists for proteinuria or other signs of kidney damage. Other cases are found among high-risk populations, such as patients with ESKD, left ventricular hypertrophy, or stroke. Reduced or absent activity of αGAL in leukocytes confirms the diagnosis in male patients. In women, genetic testing is mandatory because αGAL activity may be normal in a significant proportion. Urinary excretion of Gb3 is increased in many instances, and lyso-Gb3 in the plasma is a promising marker for diagnosis and treatment monitoring. Proteomics, the large-scale study of the entire complement of proteins, is another valuable research tool directed at finding biomarkers of diagnosis, disease progression, and responsiveness to therapy in the urine or serum of patients with Fabry disease.
