DOI:10.2214/AJR.05.0019
AJR 2006; 186:1184-1191
© American Roentgen Ray Society
Imaging Features of Fabry Disease
Olivier Lidove1,
Isabelle Klein2,
Jean-Daniel Lelièvre1,
Philippa Lavallée3,
Jean-Michel Serfaty2,
Emmanuel Dupuis4,
Thomas Papo1 and
Jean-Pierre Laissy2
1 Department of Internal Medicine, Hôpital Bichat Claude-Bernard, 46 rue
Henri Huchard, 75722 Paris, Cedex 18, France.
2 Department of Radiology, Hôpital Bichat Claude-Bernard, 75722 Paris,
Cedex 18, France.
3 Department of Neurology, Hôpital Bichat Claude-Bernard, 75722 Paris,
Cedex 18, France.
4 Department of Nephrology, Hôpital Bichat Claude-Bernard, 75722 Paris,
Cedex 18, France.
Received January 6, 2005;
accepted after revision February 25, 2005.
Address correspondence to J.-P. Laissy
(jean-pierre.laissy{at}bch.ap-hop-paris.fr).
Abstract
OBJECTIVE. Our objective was to describe the various imaging
patterns of Fabry disease, including cerebrovascular, renal, cardiac, and
other organ involvement. Fabry disease, an X-linked inborn error of
glycosphingolipid catabolism resulting from a deficient activity of the
hydrolase 
-galactosidase A, displays more complications in men than in
heterozygous women.
CONCLUSION. It is up to radiologists to evoke the diagnosis, help
practitioners in treating patients early with enzyme replacement therapy, and
monitor its efficacy.
Keywords: brain • cardiovascular disease • Fabry disease • genetics • renal disease
Introduction
Fabry disease (OMIM 301 500) is an X-linked inborn error of
glycosphingolipid catabolism resulting from a deficient activity of the
hydrolase -galactosidase A in tissues and fluids of affected patients
[1]. In absence of specific
therapy, the life expectancy is about 50 years in men and 70 years in women.
Enzymatic substitutive therapy has been available since 2001 and has proven
its efficacy [2]. The aim of
this pictorial essay is to describe different radiologic (conventional,
sonography, CT, and MRI) patterns of Fabry disease.
Clinical Symptoms and Physical Inspection Data
Hemizygous men exhibit symptoms of Fabry disease because of extensive
deposition of glycosphingolipids in body fluids and in the lysosomes of
endothelial, perithelial, and smooth-muscle cells of blood vessels
[3]. Heterozygous women are not
only healthy carriers; they can experience symptoms as severe as those
reported in the male population
[4]. Many clinical
manifestations in hemizygous men with no or low detectable
-galactosidase A activity occur during childhood or adolescence, such
as acroparesthesia, angiokeratoma with typical swimsuit distribution, corneal
opacities termed "cornea verticillata," and hypohidrosis with heat
and exercise intolerance.
Imaging Patterns
Neurologic Complications
Apart from acroparesthesia, severe neurologic complications can occur.
There is an unpredictable risk for stroke in young men, predominantly in the
vertebrobasilar system, often leading to deafness and chronic vertigo
[5]. Vascular dementia may
occur after multiple stroke episodes. MRI seems to be the most sensitive
method to detect CNS involvement in Fabry disease and to monitor CNS lesions
under enzyme replacement therapy. Neurologic involvement is based on
small-vessel involvement. Even without neurologic symptoms, patients may
display nonspecific asymmetric, widespread deep white-matter nodules that are
hyperintense on T2-weighted and T2-FLAIR acquisitions (Figs.
1A,
1B,
1C, and
2). In these cases, the
abnormalities are predominantly located in the frontal and parietal lobes. In
some instances, they involve gray matter and white matter in equal proportion.
On T1-weighted imaging, hyperintensity of the deep gray nuclei can be
observed, particularly in the lateral pulvinar. These abnormalities,
previously thought to be related to the accumulation of glycosphingolipids,
may more likely correspond to calcium salt deposits
[6] (Figs.
3A and
3B). No abnormal signal is
present on corresponding T2-weighted images at an early stage of the disease,
which rules out senescent calcifications. These data can be confirmed by the
absence of calcification on CT
[6]. Under therapy, deep white
matter abnormalities usually remain unchanged or worsen, particularly in
patients older than 40 years. In a few cases, they decreased or disappeared
after 12 months. The T1 hypersignal of deep gray nuclei may also disappear; in
some instances, a slight T2 hypersignal can be observed at the early stage of
treatment, assumed to be related to edema.
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Fig. 1A —30-year-old man with pontine and left deep gray nucleus involvement.
Midsagittal T1-weighted images (1.5-T system, 2D gradient-refocused echo;
TR/TE, 24/9; flip angle, 40°; slice thickness, 8 mm). (A) shows
nodular pontine hyposignal (short arrow), which displays slight
hypersignal on corresponding axial (B) and coronal (C)
T2-weighted images (2D fast spin-echo; 4,400/126; slice thickness, 6-7 mm)
(short arrows). CSF-like hyperintensity is also seen in left putamen
(long arrow, C).
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Fig. 1B —30-year-old man with pontine and left deep gray nucleus involvement.
Midsagittal T1-weighted images (1.5-T system, 2D gradient-refocused echo;
TR/TE, 24/9; flip angle, 40°; slice thickness, 8 mm). (A) shows
nodular pontine hyposignal (short arrow), which displays slight
hypersignal on corresponding axial (B) and coronal (C)
T2-weighted images (2D fast spin-echo; 4,400/126; slice thickness, 6-7 mm)
(short arrows). CSF-like hyperintensity is also seen in left putamen
(long arrow, C).
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Fig. 1C —30-year-old man with pontine and left deep gray nucleus involvement.
Midsagittal T1-weighted images (1.5-T system, 2D gradient-refocused echo;
TR/TE, 24/9; flip angle, 40°; slice thickness, 8 mm). (A) shows
nodular pontine hyposignal (short arrow), which displays slight
hypersignal on corresponding axial (B) and coronal (C)
T2-weighted images (2D fast spin-echo; 4,400/126; slice thickness, 6-7 mm)
(short arrows). CSF-like hyperintensity is also seen in left putamen
(long arrow, C).
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Fig. 2 —52-year-old woman with periventricular hyperintense nodules on FLAIR
imaging (1.5-T system; TR/TE, 9,000/146; inversion time, 2,250 msec; slice
thickness, 5 mm). Nodular pattern, although nonspecific, should suggest
disease in nonhypertensive patient and is related to cerebral vasculopathy
involving long perforating arteries.
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Fig. 3A —Deep gray matter involvement seen at various levels in different
patients on T1-weighted images (1.5-T system, 2D spin echo; TR/TE, 520/10;
slice thickness, 5 mm). In every patient, abnormalities are seen as increased
signal. Thalamus involvement is obvious in 40-year-old patient.
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Fig. 3B —Deep gray matter involvement seen at various levels in different
patients on T1-weighted images (1.5-T system, 2D spin echo; TR/TE, 520/10;
slice thickness, 5 mm). In every patient, abnormalities are seen as increased
signal. Bilateral substantia nigra involvement is seen (arrows) in
38-year-old man.
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Cardiac Complications
Cardiac involvement is frequent in Fabry disease, including left
ventricular hypertrophy and short PR interval. Extensive glycosphingolipid
deposition may explain more severe complications, such as angina pectoris,
atrioventricular block, and mitral valve prolapse and thickening with mitral
insufficiency. MRI is useful in the diagnosis and follow-up of cardiac
involvement. It must include cine MRI steady-state free precession sequences
in short-axis, long-axis, and four-chamber views; and delayed-enhanced
T1-weighted sequences in at least the short-axis view. Postprocessing includes
end-diastolic and end-systolic volumes, ejection fraction of the left
ventricle (LV), and LV mass computed from epicardial and endocardial tracings
on each short-axis section (according to the Simpson's method). Almost all
patients display LV hypertrophy (Figs.
4A,
4B,
4C, and
4D). The underlying mechanism
is mainly focal myocardial fibrosis that is usually more extensive in men than
in women. The hypertrophy of LV myocardium is frequently associated with thick
hyperenhanced bands in men (Fig.
5), whereas it most often displays associated patchy nodular
involvement in women (Figs. 6A
and 6B). Myocardial
involvement occurs mostly in the basal inferolateral wall. Such involvement is
usually not subendocardial, unlike myocardial infarction. Abnormal signal is
thought to be related to myocardial fibrosis
[7]. It is of paramount
importance to measure LV mass at the initial presentation (Figs.
7A,
7B,
7C, and
7D) because its monitoring
during enzyme replacement therapy is a clue for prognosis. Structural valve
abnormalities are frequently associated with LV hypertrophy. Mild thickening
of the aortic valve leaflets has been reported in as many as 25% of patients
(Fig. 8) and should be
regularly monitored, especially in hemodialysis patients.
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Fig. 4A —40-year-old man without hypertension Hypertrophic cardiomyopathy is
seen on short-axis cine MRI views (1.5-T system, 2D steady-state free
precession; TR/TE, 3.6/1.5; slice thickness, 8 mm) in diastole (A) and
systole (B) and in four-chamber cine MRI views in diastole (C)
and systole (D). Ventricular cavity is virtually absent in systole
because of concentric hypertrophy of myocardial fibers.
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Fig. 4B —40-year-old man without hypertension Hypertrophic cardiomyopathy is
seen on short-axis cine MRI views (1.5-T system, 2D steady-state free
precession; TR/TE, 3.6/1.5; slice thickness, 8 mm) in diastole (A) and
systole (B) and in four-chamber cine MRI views in diastole (C)
and systole (D). Ventricular cavity is virtually absent in systole
because of concentric hypertrophy of myocardial fibers.
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Fig. 4C —40-year-old man without hypertension Hypertrophic cardiomyopathy is
seen on short-axis cine MRI views (1.5-T system, 2D steady-state free
precession; TR/TE, 3.6/1.5; slice thickness, 8 mm) in diastole (A) and
systole (B) and in four-chamber cine MRI views in diastole (C)
and systole (D). Ventricular cavity is virtually absent in systole
because of concentric hypertrophy of myocardial fibers.
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Fig. 4D —40-year-old man without hypertension Hypertrophic cardiomyopathy is
seen on short-axis cine MRI views (1.5-T system, 2D steady-state free
precession; TR/TE, 3.6/1.5; slice thickness, 8 mm) in diastole (A) and
systole (B) and in four-chamber cine MRI views in diastole (C)
and systole (D). Ventricular cavity is virtually absent in systole
because of concentric hypertrophy of myocardial fibers.
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Fig. 5 —Cardiac involvement in 38-year-old man. Late-enhancement T1-weighted
cardiac image in short axis (1.5-T system, 3D inversion recovery T1-weighted
multishot gradient echo; TR/TE, 3.9/1.4; flip angle, 25°;
inversion-recovery prepulse delay, 200 msec) shows band of hyperenhancement
assumed to be related to myocardial fibrosis in upper part of septum
(large arrows) and subepicardial nodules in inferior wall (small
arrows). Cine MRI image at same level (not shown) displayed normal
segmental contraction.
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Fig. 6A —Cardiac involvement in 42-year-old woman. Late-enhancement
T1-weighted cardiac images in short axis (same parameters as in
Fig. 5) show nodular
transmural hyperenhancement in anterior wall (arrow, A) and
several patchy, slightly hyperenhancing nodules in inferolateral wall of left
ventricle (arrows, B).
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Fig. 6B —Cardiac involvement in 42-year-old woman. Late-enhancement
T1-weighted cardiac images in short axis (same parameters as in
Fig. 5) show nodular
transmural hyperenhancement in anterior wall (arrow, A) and
several patchy, slightly hyperenhancing nodules in inferolateral wall of left
ventricle (arrows, B).
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Fig. 7A —MRI follow-up of hypertrophic cardiomyopathy in 43-year-old man.
Short-axis cine MRI views (same parameters as in Figs.
4A,
4B,
4C, and
4D) in diastole (A) and
systole (B) at middle portion of left ventricle (LV) before initiation
of enzyme replacement therapy. Left ventricle myocardial mass is estimated at
136 g/m2. End-diastolic and end-systolic LV thicknesses are 13 mm
and 28 mm, respectively.
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Fig. 7B —MRI follow-up of hypertrophic cardiomyopathy in 43-year-old man.
Short-axis cine MRI views (same parameters as in Figs.
4A,
4B,
4C, and
4D) in diastole (A) and
systole (B) at middle portion of left ventricle (LV) before initiation
of enzyme replacement therapy. Left ventricle myocardial mass is estimated at
136 g/m2. End-diastolic and end-systolic LV thicknesses are 13 mm
and 28 mm, respectively.
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Fig. 7C —MRI follow-up of hypertrophic cardiomyopathy in 43-year-old man.
Corresponding cine MRI images 6 months later show decrease in LV hypertrophy,
with LV mass estimated at 115 g/m2, with end-diastolic and
end-systolic LV thicknesses of 12 mm and 26 mm, respectively.
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Fig. 7D —MRI follow-up of hypertrophic cardiomyopathy in 43-year-old man.
Corresponding cine MRI images 6 months later show decrease in LV hypertrophy,
with LV mass estimated at 115 g/m2, with end-diastolic and
end-systolic LV thicknesses of 12 mm and 26 mm, respectively.
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Fig. 9A —40-year-old man on hemodialysis for 6 years. Sonograms show
bilateral kidney involvement. Long-axis diameter of right (A) and left
kidney (not shown) is nearly normal, with normal external contours.
Corticosinusal thickness seems normal. Both kidneys contain cysts and appear
hyperechogenic.
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Fig. 9B —40-year-old man on hemodialysis for 6 years. Sonograms show
bilateral kidney involvement. Noncontrast CT shows some degree of renal
atrophy and confirms presence of multiple cysts, some of them displaying
peripheral high attenuation values (short arrows). Some dense
calcifications are present along right renal sinus.
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Renal Complications
Kidney involvement heralded by proteinuria appears during adolescence.
End-stage renal failure is typically reached after the fourth decade in men.
On sonography, the most common findings are cysts (cortical or parapelvic),
increased echogenicity, and decreased cortical thickness despite a normal
kidney size [8]
(Fig. 9A). The small and
homogeneous size of cysts and their predilection for subcapsular locations
strongly suggest Fabry disease, compared with those seen in autosomal-dominant
polycystic kidney disease. The cysts are also identified with CT
(Fig. 9B) and MRI. The main
MRI pattern of the disease is a decreased corticomedullary differentiation.
The presence of MRI abnormalities is not correlated with the serum creatinine
level. Women generally display fewer abnormalities than men.
Other Sites
Lung involvement is underestimated and chronic obstructive pulmonary
disease-like symptoms may occur, with bronchial thickening in nonsmoker
patients (Fig. 10).
Sympathetic system involvement may trigger digestive manifestations,
leading to abdominal pain and abnormal gastric peristalsis.
Specific avascular necrosis of the femoral head has been described in Fabry
disease.
Lymph node infiltration by glycosphingolipids may be responsible for
lymphedema.
In conclusion, complications are usually widespread in men with Fabry
disease. Heterozygous women are not completely protected from visceral,
cerebrovascular, renal, or cardiac involvement. It is up to radiologists to
evoke the diagnosis, help practitioners in treating patients early with enzyme
replacement therapy, and monitor its efficacy. Indeed, the capacity to monitor
therapy is a very important function of these radiologic procedures.
Acknowledgments
We thank all patients and their families; Professor Samson, Neurovascular
Unit, Pitié-Salpêtrière Hospital, Paris; and Dr.
Delahousse, Nephrology Unit, Foch Hospital, Suresnes, France.
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Abstract
Introduction
