Anderson-Fabry's Disease

Author: giulia gay
Date: 24/02/2009


Nicola Corino, Francesco De Amicis, Giulia Gay


Fabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. This enzymatic defect leads to the systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes throughout the body and to a lesser extent of blood group antigen B (of the ABO blood group antigens) derived compounds.
The disease belongs to the family of lysosomal storage diseases (Cartoon)


It's a rare disease (1:40000 live births): estimated incidence at 1:117 000. The true incidence is underestimated, however, as there are paucisintomatic types which occur with isolated or primary involvement setting cardiac, renal, cerebrovascular "variants". Although genetic transmission is linked to the X chromosome, females can be equally affected, often with paucisintomatic features and late onset

Genetics and epidemiology


Alpha-galactosidase A enzyme in physiological conditions determine the enzymatic cleavage of Gb3 to lattosilceramide which will be removed by the reticoloendotelial system; its functional deficit involves the gradual accumulation of neutral glycosphingolipids in any fluid any organ, every cell of the body.
More represented glycosphingolipid in cellular storage is globotriaosylceramide , followed by galabiosilceramide.

Like all enzymes destined for the lysosomes the α-galactosidase A protein is co-translationally modified with mannose-6-phosphate residues. A portion of the phosphorylated enzyme is actually secreted from cells and then taken up by receptor-mediated endocytosis via mannose-6-phosphate receptors on the plasma membrane of cells. This secretion and re-uptake of α-galactosidase A provides the basis for the rationale behind enzyme replacement therapy

Additional Info on phospholipids metabolism


Alpha-galactosidase A gene was identified on the long arm of X-chromosome,on region Xq21, 22.

Fabry Disease

About 75% of gene mutations is represented by point mutations "missense" or "nonsense", usually specific to each family. The severity of the clinical features may, but only in part, be related to the patient's blood group (group AB, B) as a result of glycosphingolipids additional accumulation specifically related to the antigens of the group B.


Diagnosis is based on:
• Biochemical diagnosis obtained with the determination of leukocyte's alpha-galactosidase A activity: it is absent or greatly reduced in males, while in females the activity is often normal or only slightly reduced.
• Research of "cornea verticillata", which, due to the high frequency both in males than in females, it is an important diagnostic aid.
• detection of "cross of Malta" lipid finds in the urinary sediment, examined with an optical microscope with polarized light.
• family history cannot always be useful to diagnosis.
• determination of cerebroside triesossido plasmatic levels that documents the abnormal growth, even with abnormal urinary levels.
• Diagnosis confirmation is obtained through genetic analysis.
Prenatal diagnosis can be made as early as the 14th gestation week through amniocentesis

Differential diagnosis


The clinical manifestations of Fabry disease begin in childhood or adolescence. Classic symptoms include pain and parathesis in the extremities, gastrointestinal disturbances, cardiomyopathy, progressive renal impairment, corneal and lenticular opacities and characteristic skin lesions called angiokeratomata. These symptoms are all due to the deposition of G3b in the walls of small vessels, kidney tubule and glomeular cells, nerves and dorsal root ganglia. The characteristic skin lesions of Fabry disease are the earliest signs that may lead to diagnosis in childhood. Death usually occurs in early adulthood from renal and cardiac complications of the vascular disease. Carrier females are usually asymptomatic but can, in rare cases, be as severely affected as hemizygous males. The most consistent clinical phenotype found in carrier females is corneal opacity.


The clinical onset usually occurs in childhood, although sometimes the first symptoms of the disease can appear in the second or third decade of life.



• burning paroxysmal pain crises to hands palms and feet soles (acroparesthesia) to recede in intensity and frequency with age.
• fever and increase in VES.
• visceral neuropathic symptoms.
• Intolerance to heat and to increases in ambient temperature, due to the skin hypohidrosis.
• skin teleangiectasias in the back headset or other regions.
A 14-year-old Boy with Pain in Hands and Feet,2009

Youth age:

• mainly the presence of cutaneous angiokeratomas with a "swimming costume" distribution.
• ipohidrosis or anhidrosis, leading to collapse from heat or strenuous exercise.
• occasionally persistent proteinuria and isolated effect of an early renal damage, secondary to glomerular disease.
• impaired ability to concentrate urine, secondary to tubule-interstitial disease.
• “cornea verticillata", pathognomonic of corneal dystrophy from sfingolipids accumulation in epithelial cells.


  • gradual and progressive deterioration of renal function to terminal chronic uremia within 40 years of age in male patients.
  • cardiovascular and / or cerebrovascular serious clinical complications (leading cause of death of patients with MAF).
  • The progression of cardiac disease is manifested by:
    • early coronary artery disease
    • Left ventricular hypertrophy by accumulation,
    • very frequent valvulopathy with mitral prolapse,
    • arrhythmias secondary to the progressive damage of the conduction system (paroxysmal atrial fibrillation, atrioventricular block of Wenckebach-Luciani,syndrome Wolff-Parkinson-White, shorter PR range).
  • Neurological clinical manifestations are due to multifocal impairment of cerebral microcirculation and are represented by:
    • Transient ischemic attacks (TIA),
    • tonic-clonic seizures,
    • ischemic or hemorrhagic stroke,
    • parkinsonism.

      Heterozygous patients:

      • reduced events with life expectancy and quality of life comparable to general population.
      • cornea verticillata in 70% of patients.
      • cutaneous angiokeratomas in 30% of patients.
      • pain due to peripheral neuropathy in 10% of patients.
      • renal, cardiac and central nervous system involvement are rare in young age, can appear in older patients.



cornea verticillata , corneal dystrophy due to glycosphingolipids deposits dependents of corneal epithelial cells. The corneal opacity color varies from white to golden-brown, initially at headquarters to gradually extend to the periphery.
• on fundus oculi changes in the retinal vessels, due to sfingolipids deposits in endothelial cells.
• conjunctival vascular lesions.
Fabry's cataract, lenticular opacities due to linear deposits of translucent material near the rear capsule of the crystalline lens.

Skin and mucous membrane:

Angiokeratomas : clusters of superficial or slightly detected angiomatous lesions on the skin with dark bluish red color, with possible modest cutaneous hyperkeratosis. It tend to increase progressively over time both in size and number assuming a "swimming costume" distribution for symmetrical involvement of trunk, perineum, scrotum, penis and vulva.
• teleangiectasias also in conjunctiva and oral cavity.
• anhidrosis od ipoanhidrosis, due to sfingolipidic infiltration of sweat glands. This leads to intolerance to heat, to sudden elevation in ambient temperature, until the "heat stroke" due to prolonged physical activity or higher temperature.

Kidneys :

• Ultrasound examination shows increased size due to progressive glycosphingolipids accumulation.
• Renal biopsy shows hypertrophic and visibly vacuoles renal cell due to the presence of intracytoplasmic lipid material.
• isolated proteinuria without deterioration of urinary sediment is an early sign of renal involvement.
• progressive individual cells involvement with progression to glomerular focal and segmental sclerosis up to global sclerosis.
• isosthenuria ed iposthenuria for impaired ability to concentrate urine.
• involvement of the proximal tubule's epithelial cells with Fanconi syndrome (aminoaciduria, tubular acidosis, normoglycemic glycosuria).
• progressive deterioration of anatomical structures with deteriorating renal function till chronic terminal uremia in the third, fourth, fifth decade of life.

Heart and vessels:

• multiple heart disease due to progressive Gb3 accumulation in heart muscle cells, in valvular fibrocells, in the conduction tissue, in coronary vascular endothelium.
hypertrophy and left ventricular overload.
• normal systolic function and preserved for a long time.
• diastolic deficit, one of the most common causes of stress dyspnea.
• shorter PR range.
• cardiac arrhythmias also in young age.
• cardiac valvular abnormalities with mitral valve insufficiency in 60% of cases.
• myocardial ischemia, cardiac strok and diffuse coronary artery disease are leading causes of death.

Cardiac manifestations of Anderson-Fabry disease in children and adolescents,2008

Nervous system:

• acroparesthesias: paroxysmal painful crisis to the ends.
ischemic stroke and ischemic attacks, one of the leading causes of exitus
• cerebral vasculopathy worsened by the coexistence of hypertension and chronic renal failure in dialysis treatment replacement, and severe cardiac involvement.
• Sometimes progressive deterioration of cognitive functions.

Central nervous system involvement in Anderson-Fabry disease: a clinical and MRI retrospective study,2008

Depression in adults with Fabry disease: a common and under-diagnosed problem,2007

Gastrointestinal involvement:

• abdominal pain with alternating constipation and diarrhea.
• presence of glycosphingolipids deposits in the plexus of Meissner's cells, as well as in intestinal vessels endothelial cells .
• abdominal colic

Growth retardation:

with characteristics craniofacial and oral abnormalities like prognathism and maxillar sinus cysts, till to the characteristic "facies acromegalica".

Osteo-articular pathology:

deflection of distal interphalangeal joints with partial functional impotence.


The primary risk factor for Fabry disease is having family members with the disease or who are carriers of the disease.


•Enzyme replacement therapy: with agalsidasi alfa, human DNA recombinant.The enzyme's availability offers the possibility of effective, secure and long-term treatment, with weekly or biweekly administration due to the long half-life of the enzyme.The treatment showed clinical, instrumental and biohumoral improvements of great importance, with insignificant side effects.

Advances in the management of Anderson- Fabry disease: enzyme replacement therapy,2002

Effects of enzyme replacement therapy in patients with Anderson-Fabry disease: a prospective long term cardiac magnetic resonance imaging study,2009

•Gene Therapy: despite the effectiveness of enzyme replacement therapy, treatment will probably be future genetic.Now it still remains a distant hope: even if we know the gene sequence of every absent or lacking protein which cause individual hereditary disorders, one of the major problems of gene therapy is the search for suitable carriers for intracellular transport of a copy of the defective gene.

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