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The arthropathy of fabry disease.

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Fabry disease, an X-linked recessively inherited
glycosphingolipidosis, results from defective activity of
the lysosomal enzyme ceramide trihexosidase termed agalactosidase A (1). The cumulative deposition of the
substrate ceramide trihexose (CTH) in various tissues
accounts for the clinical manifestations of the disease
(2). Although excruciating pains in the extremities are
frequently present, pains localized in joints are uncommon. There is a characteristic arthropathy of the distal
interphalangeal joints of the fingers with limitation of
extension and degenerative changes which are evident
on radiologic examination (3). Because patients with
Fabry disease have attacks of fever, pains in extremities,
and elevated ESR, rheumatic fever or rheumatoid arthritis is frequently the initial diagnosis (3). We wish to
report synovial and joint capsule biopsies from a male
who was initially diagnosed as having rheumatoid arthritis and was later confirmed to have Fabry disease by
low plasma a-galactosidaselevel.
A 25-year-old white man sought an opinion about his
joint pains and stiffness which involved shoulders, wrists, finFrom the Department of Pediatrics, The Medical College of
Wisconsin, Milwaukee Children’s Hospital, Milwaukee, Wisconsin,
and the Division of Rheumatology. Department of Medicine, Columbia Hospital, Milwaukee, Wisconsin.
Kumudchandra J. Sheth MB, MRCP, DCH, FRCP(C): Assistant Professor of Pediatrics, Medical College of Wisconsin; Gerson
C. Bernhard, MD, FACP Clinical Professor of Medicine, Medical
College of Wisconsin.
Address reprint requests to K. J. Sheth, MB, MRCP, Department of Pediatrics. Medical College of Wisconsin, Milwaukee Children’s Hospital, 1700 West Wisconsin Avenue, Milwaukee, Wisconsin
Submitted for publication January I I , 1979; accepted in revised form February 21, 1979.
Arthritis and Rheumatism, Vol. 22, No. 7 (July 1979)
gers, and knees for 6 years. He did not have morning stiffness.
Arthralgias were worse toward the end of each day. Salicylates and mild analgesics did not help, but codeine afforded
some relief. On a previous occasion he had fever and arthralgias and a diagnosis of acute rheumatic fever was made at
that time. Treatment consisting of rest, penicillin, and salicylates, did not help. His mother had “rheumatism”; his maternal grandmother also had severe arthralgias and died of a
“heart attack” at age fifty.
Examination of the patient showed a tall, thin man
with blood pressure of 150/88 mm Hg. Scattered angiokeratomas were noted on the chest wall and scrotum. The capillaries of the scleral conjunctiva appeared tortuous and beaded.
There was mild swelling with thickening of the proximal interphalangeal joints, without limitation of motion or deformities. There was no swelling or synovial thickening of any
other joints.
Laboratory studies showed a hemoglobin of 12.6 gm/
dl, normal leukocyte and differential count, and a sedimentation rate of 15 mm/hour by the Westergren method. Blood
tests for urea nitrogen, creatinine, electrolytes, protein electrophoresis, calcium, and uric acid gave normal results. He
had negative serum tests for rheumatoid factor (latex), antinuclear antibody (fluorescent), and VDRL. Serum C’3 was
152 mg/dl (normal: 80-150), and C‘4 was 23 mg/dl (normal:
11-47). A 24-hour urine collection showed 3 gm of protein.
An electrocardiogram was normal.
Peripheral nerve conduction velocities in both the ulnar and peroneal nerves were normal, but distal latency was
prolonged and action potentials were markedly complex. On
IVP, the kidneys were large, 16 cm long. Joint radiographs
showed normal findings. By light microscopy a renal biopsy
showed “foam” cells in glomeruli and interstitium (Figure I).
A synovial and joint capsule biopsy of a proximal interphalangeal index finger showed slight proliferation of synovial l i n i n g 4 cell thickness (Figure 2, top arrow)-without
inflammatory cellular infiltration. Subsynovial “foam” cells
were present either directly under the synovial lining unrelated to blood vessels (Figure 2, bottom arrow) or in the small
blood vessel wall (Figure 3).
Fabry disease. The significance of “foam” cells directly
under the synovial lining in the genesis of the joint
pains is not clear. However, the presence of “foam” cells
in the vessel wall (Figure 3), most likely CTH deposition in the endothelium, by narrowing the vessel lumen
leads to ischemia (2). Ischemia certainly plays a major
role in the vaned clinical manifestations of the disease
(2) and would also explain some of the other reported
skeletal manifestations such as avascular necroses or
multiple opacities in the femoral heads and degenerative changes in the interphalangeal joints (3). Similarly,
ischemia to the peripheral nerves due to CTH deposi-
Figure 1. A renal glomerulus showing “foam” cells (arrows)(H & E X
By use of artificial substrate 4-methylumbelliferone agalactoside (4), plasma a-galactosidase level in the patient was
0.31 nanomole/hour/ml. Our normal range estimated in 57
individuals is 11.4 f 3.5 SD nanomole/hour/ml plasma.
Plasma a-galactosidase studies in the family revealed that the
patient’s mother and 2 sisters had intermediate levels (20409”
of normal), one brother had less than 2% of normal value,
while 2 other brothers had normal levels. Assays of four other
lyso+mal enzymes were within normal ranges in all family
members. Oral diphenylhydantoin treatment controlled joint
pains in both the patient and his mother.
The rheumatic signs and symptoms of the storage diseases are of considerable interest since rheumatic
disease is a frequent initial diagnosis, as in this patient.
That our patient has Fabry disease is confirmed by the
angiokeratomas, tortuous conjunctival vessels, “foam”
cells in the renal tissues, and the low plasma a-galactosidase level.
The mechanism Of joint pain in Fabydisease is
not adequately explained. Absence of SYnOvial inflammation excludes synovitis as the cause of joint pains in
Figure 2. Synovial biopsy with slight proliferation of synovial lining
(top arrow). Presence of subsynovial “foam” cells (bottom arrow)
without inflammatory cellular infiltration (H & E x 160).
chemia to peripheral nerves suggests that the joint pains
in Fabry disease may be neuroischemic in nature. This
contention is furthered by relief of joint pains with diphenylhydantoin which stabilizes the hyperexcitable
neurons without reducing CTH levels (6). Additionally,
vasodilatation with a-adrenergic or stellate ganglion
blockade, by improving the peripheral blood flow, relieves ischemia and alleviates pains in Fabry disease (7).
Hence despite dissimilarity between the localized joint
pains in our patient and the typical pains of Fabry disease, the most likely pathogenesis for both seems to be
Figure 3. “Foam” cells in a small blood vessel wall in the subsynovium (arrows) (H& E X 400).
tion in the endothelium of vasa nervorum or the cytoplasm of the nerve cells leads to ischemic neuralgia and
is thought to contribute to Fabry pains. On peripheral
nerve conduction studies, ischemic neuralgia may manifest as delayed distal latency and markedly complex action potential (5). Hence in our patient, the presence of
“foam” cells in the subsynovial and joint capsule capillaries (Figures 2 and 3) together with the evidence of is-
1. Brady RO, Gal AE, Bradley RM, Martensson E,Warshaw
AL, Laster L: Enzymatic defect in Fabry’s disease. Ceramide trihexosidase deficiency. N Engl J Med 276: 1 163-1 167,
2. Desnick RJ,Klionsky B, Sweeley C C Fabry’s disease (agalactosidase A deficiency), The Metabolic Basis of Inherited Disease. Fourth edition. Edited by JB Stanbury, JB
Wyngaarden, DS Frederickson. New York, McGraw-Hill
Book Company, 1978, pp 810-840
3. Wise D, Wallace HG, Jellinek EH: Angiokeratoma corpork dNusum. A clinical study of eight affected families.
Q J Med, New Series 3 1:177-206,1962
4. Desnick RJ, Allen KY, Desnick SJ, Raman MK,Bernlohr
RW, Krivit W Fabry’s disease: enzymatic diagnosis of hemizygotes and heterozygotes. J Lab Clin Med 81:157-171,
5. Swick HM, Sheth KJ, Cataldi M:Nerve conduction studies
in Fabry’s disease (abstract). Fifth Annual Meeting of the
Child Neurology Society. Monterey, California, October
6. Lockman LA, Hunnhghake DB, Krivit W, Desnick RJ:
Relief of pain of Fabry’s disease by dephenylhydantoin.
Neurology 23:87 1-875, 1973
7. Liston EH, Levine MD,Phillippart M:Psychosis in Fabry’s
disease and treatment with phenoxybenzamine. Arch Gen
Psychiatry 29402403, 1973
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arthropathy, fabr, disease
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