Final Diagnosis -- Fabry's Disease


On the basis of the kidney biopsy, the patient was diagnosed with a lipid storage disorder, probably Fabry's disease. A blood test confirmed the diagnosis of Fabry's disease, showing an alpha-Galactosidase level in white blood cells of 5 nM/ mg protein/ hour, with the normal range being from 59 to 110. A retrospective review of electron micrographs of the mesenteric lymph nodes (see Images 04, 05 and 06) showed lysosomes within macrophages which contained similar prominent myelin-like bodies similar to those seen in the kidney. A retrospective review of systems revealed a 10 year history of heat and cold intolerance as well as a history of occasional sharp, poorly localized pains that felt "deep inside" to the patient. A retrospective physical examination showed subtle small telangietatic papules on the scrotum, possibly angiokeratomas.

Fabry's disease is a lysosomal storage disease that results from absent or deficient levels of alpha-galactosidase A and leads to the accumulation of neutral glycosphingolipids predominantly in the lysosomes of endothelial cells and smooth muscle cells of blood vessels. This material also accumulates to a lesser extent throughout the body in histiocytic and reticular cells. In vivo, the inclusions are significantly hydrated--swollen with water. Their shriveled appearance ultrastructurally is an artifact due to steps which lead to dehydration during routine processing. These deposits have on their edges macromolecules of uncertain composition which stabilize their structure. It has been hypothesized that deposits cause disease through both a volume effect and through interactions between the edge macromolecules and other cellular constituents. (1) The myelin-like deposits may have different patterns of localization in different organs. In one study, kidney deposits were located within lysosomes, while deposits in the heart were located within the cytoplasm, but apparently not within lysosomes. (1) The disease is transmitted as an X-linked recessive disorder and has a high degree of penetrance. The incidence is estimated to be 1 in 40,000. (2)

A typical presentation of Fabry's disease, as illustrated by this case, is that of a young man with a recurrent febrile illness associated with pain in the extremities or abdomen. In a large series from Europe, the most common presenting signs were proteinuria (90%), angiokeratomas (71%), painful parasthesiae (69%), and intermittent fevers (54%). (3) Angiokeratomas appear as small red papules that are typically clustered in the pelvic and thigh region. Cerebrovascular complications are due to dilative arteriopathy of the vertebrobasilar circulation and are present in up to 67% of hemizygotes. The most frequent signs and symptoms are hemiparesis, vertigo/dizziness, diplopia, and dysarthria. (4) Other clinical manifestations which are variably present include hypohidrosis, corneal opacities, and obstructive pulmonary disease. (2,5) Morbidity and mortality results principally from involvement of the heart, kidneys, and CNS.

The diagnosis of Fabry's disease can be quite difficult to make. Patients typically have undergone extensive evaluations with frequent initial misdiagnoses. Some examples of diagnoses seriously considered in patients who were eventually diagnosed with Fabry's disease include: mitral valve prolapse, glomerulonephritis, idiopathic proteinuria, systemic lupus erythematosus, Whipple's disease (as in this case), acute abdomen, ulcerative colitis, acute intermittent porphyrias, occult malignancies, and many others. (6)

The clinical course of hemizygous males tends to be one of progressive vascular disease leading to heart failure, renal failure, and CNS disease, often with death in early adulthood. However, males with residual alpha-Gal A activity as well as female carriers may have a mild form of the disease which is limited to cardiac involvement manifested by cardiomegaly with particular involvement of the left ventricle and interventricular septum. EKG changes in these cases show cardiomyopathy and myocardial infarctions. (2) Fabry's disease should be considered in the differential diagnosis of any patient with unexplained left ventricular hypertrophy. (7) Fabry's disease can also present as isolated asymptomatic proteinuria. (8)

Mutations in Fabry's disease

Fabry's disease results from many different mutations in the alpha-Gal A gene. The gene is located on Xq22. One report which detailed 35 different mutations found that most cases (67%) were a result of missense mutations. Other types of mutations that were seen included nonsense and splice mutations and two complex rearrangements consisting of a number of adjacent small insertions and deletions. Most mutations tended to be family specific. (9)

Fabry's disease and transplantation

Patients with end-stage renal disease due to Fabry's disease have been treated with renal transplantation. A renal transplant is an attractive therapy in that it both treats the renal failure and could potentially help to treat the underlying enzyme deficiency by providing an organ with normal enzyme activity. Initial reports were discouraging due to both an unacceptably high death rate, largely from sepsis, and evidence for disease recurrence in the graft. (10, 11) These findings led to Fabry's disease being considered a contraindication to renal transplantation by some authors. (10) However, the accumulation of additional experience suggests the possibility of long term survival. (12) The issue remains unsettled, but recently a large European multi-national study on rare kidney diseases discussed 33 patients transplanted for Fabry's disease and reports a survival rate equivalent to patients transplanted for primary renal diseases. They also reported clinical improvement in the parasthesiae and reduced fever in about one half of the patients. Cardiovascular problems showed little improvement. (3)


  1. Simon M, Grey H, Gruler H, et al. Glycolipid storage material in Fabry's disease: a study by electron microscopy, freeze-fracture, and digital image analysis. J Struct Biol 1990; 103:40-47.
  2. Desnik RJ, ioannou YA, Eng CM. (1995) alpha-Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The metabolic and molecular bases of inherited disease, 7th ed. McGraw-Hill, New York, pp 2741-2784.
  3. Tasakiris D, Simpson H, Jones J, et al. Rare diseases in renal replacement therapy in the ERA-EDTA registry. Nephrol Dial Transplant 1996; 11:4-20.
  4. Mitsias P, Lefine Sr. Cerebrovascular complications of Fabry's disease. Ann Neurol 1996; 40:8-17.
  5. Brown LK, Miller A, Bhuptaani A, et al. Pulmonary involvement in Fabry disease. Am J Resp Crit Care Med 1997; 155:1004-1010.
  6. Burkholder P, Updike S, Ware R, et al. Clinicopathologic, enzymatic, and genetic features in a case of Fabry's disease. Arch Pathol Lab Med 1980; 104:17-25.
  7. Nakao S, Takenaka T, Maeda M, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med 1995; 333:288-93.
  8. Ko YH, Kim HJ, Roh yS, et al. Atypical Fabry's disease: an oligosymptomatic variant. Arch Pathol Lab Med 1996;120-86-89.
  9. Eng, C, Ashley G, Burgert T, et al. Fabry disease: thirty-five mutations in the alpha-Galactosidase A gene in patients with classic and variant phenotypes. Molec Med 1997; 3:174-182.
  10. Maizel SE, Simmons Rl, Kjellstrand C, et al. Ten years experience in renal transplantation in Fabry's disease. Transplant Proc 1981; 13:57.
  11. Faraggiana T, Churg J, Grisham E, et al. Light and electron microscopic histochemistry of Fabry's disease. Am J Pathol, 1981; 103:242-262.
  12. Mosnier J, Degott C, Bderossian J, et al. Recurrence of Fabry's disease in a renal allograft eleven years after successful renal transplantation. Transplantation 1991; 51:759-762.

Contributed by Michael Torbenson, MD, James Hanchett, MD, and Sheldon Bastacky, MD


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