Electrocardiographic and vectorcardiographic abnormalities in Fabry's disease Jawahar Mehta, M.D. Naip Tuna, Ph.D., M.D. James H. Moller, M.D. Robert J. Desnick, Ph.D., M.D. Minneapolis, Minn.
Fabry's disease is an X-linked disorder of glycosphingolipid metabolism, related to the defective activity of alpha-galactosidase A. 1 There is deposition of glycosphingolipid, mainly trihexosyl ceramide, in the vascular smooth muscle, myocardium, cells of sympathetic central nervous system, and epithelial cells of renal glomeruli. ~ Because of unusual skin lesions and multiorgan involvement, the disease is also known as angiokeratoma corporis diffusum universale. Involvement of the myocardium and small blood vessels has long been recognized. T M Electrocardiographic (ECG) abnormalities have occasionally been reported2-G, lO. 11 but there is no detailed information regarding the incidence of ECG and vectorcardiographic (VCG) abnormalities in these patients. The purpose of this report is to review the ECG in 32 patients and the VCG in 15 patients with Fabry's disease followed in our institution. Materials and methods
Thirty-two patients between the ages of 6 and 56 years with Fabry's disease {including 21 hemizygotes and 11 heterozygotes) studied at the University of Minnesota Hospitals form the basis From the Departments of Medicine, Pediatrics, and the Dight Institute for Human Genetics, University of Minnesota Medical School, Minneapolis, Minn. 55455. This work was supported in part by a grant (74-915) from the American Heart Association; a grant (1-273) from the National Foundation-March of Dimes; a grant (AM 15174) from the National Institutes of Health; and a grant (RR-400) from the General Clinical Research Center, Program of the Division of Research Resources, National Institutes of Health; Dr. Desnick is a recipient of a National Institutes of Health Career Development Award (1K04-AM00042). Received for publication Jan. 27, 1976. Reprint requests: J. Mehta, M.D., Box J-277, J H M Health Center, University of Florida, Gainsville, Fla. 32610.
June, 1977, Vol. 93, No. 6, pp. 699-705
of this report. The diagnosis of hemizygosity and heterozygosity for Fabry's disease was made by physical examination, corneal changes as seen by slit-lamp examination, skin biopsy, and biochemical studies which included measurement of trihexosyl ceramide concentration in plasma, urinary sediment, and the determination of alpha-galactosidase activity in plasma, leukocytes, and tears. 12"13 In each patient a 12 lead ECG and in 15 a corrected orthogonal VCG was performed. TM More than one ECG was performed in 13 patients over periods ranging from 3 to 12 years. In two of the 13 patients with serial ECG's, cardiac signs and symptoms were present; both of these patients died and necropsy revealed extensive cardiac infiltration with glycosphinogolipid characteristic of Fabry's disease. 15 None of the other patients presented clinical signs or symptoms of cardiac disease and ECG/VCG abnormality, if present, was found only upon routine examination. ECG's were interpreted for rhythm, QRS axis, PR, QRS, and QT intervals and P, QRS, and ST-T morphology according to the New York Heart Association criteria TM and compared with ECG's of age-matched normal subjects. 17 VCG's were recorded on magnetic tape and were analyzed with a minicomputer as previously reported TM and interpreted according to established criteria. 1~ Results
Of 32 patients, there were 11 heterozygous females and 21 hemizygous males. The mean age was 33 {range, 19 to 56) and 22 {range, 6 to 50) years, respectively. Table I shows the genotype and ECG abnormalities noted in these patients.
American Heart Journal
699
Mehta et al.
T a b l e I. E C G ' s i n F a b r y ' s d i s e a s e *
~
~ I
I Age, I
No. Hemizygotes: 1 2 3
G.T. L.C. C.L.
4 5
Rhythm
6M 11M 11M
RSR RSR RSR
L.R.
12M
K.G.
14M
6 7 8 9 10 11 12 13
L.D. B.R. A.H. S.R. S.L. S.J. G.A. D.P.
15M 16M 18M 19M 23M 29M 31M 33M
14
S.W.
15
G.R.
16
~ I
LVH QRS I iPntRr.I
~
Conduct I NS;:~" ~ - - ~ ecL RBBB
~
95 75 100
N N N
140 115 140
. . .
RSR
80
N
120
-
RSR
90
N
130
.
75 75 90 70 90 90 80 85
N N N N N N N N
120 140 160 160 150 140 160
. . . . . . -
33M
RSR RSR RSR RSR RSR AF RSR RSR RSR
95
N
160
--
36M
RSR
80
N
140
.
G.G.
38M
RSR
90
N
140
-
+
.
17
G.D.
40M
RSR
80
N
140
-
-
+
.
18
R.A.
42M
RSR
65
-27
160
+
-
+
-
19 20
C.J. B.C.
47M 50M
RSR RSR
80 70
N N
140 230
+ +
-
+ -
-
21
B.M.
51M
AF
160
N
.
22 23 24 25 26 27 28 29 30 31
K.J. L.C. C.L. M.G. N.M. B.L. A.D. K.B. A.V. S.E.
19F 20F 24F 35F 37F 40F 44F 45F 46F 50F
RSR RSR RSR RSR RSR RSR RSR RSR RSR RSR
60 85 75 85 85 72 90 82 78 80
N N N N N N N N 105 N
130 180 120 130 130 160 150 150 140 160
. . . . . . . . --
32
S.L.
56F
RSR
75
N
160
-
Heterozygotes:
.
. . .
. . .
. . .
+ .
.
.
. . . . .
+
.
.
. . +
.
.
. . .
.
. . . . -
+
+
. . .
m
D
. .
m
+
. .
+
m
+
+ .
.
-
. . .
.
+
.
. . .
.
.
-
.
.
.
. .
-
.
.
. .
.
-
.
. . .
.
.
.
.
. . .
.
.
.
.
+
.
.
.
.
.
.
+
. . . . .
. .
.
.
. . . . .
. .
+
-
.
. . . . .
+ .
. . .
-
.
. . . . .
.
. . .
+
.
. . . . .
.
. . .
.
B
.
-
D
--
--
+
*APC, atrial premature contraction; AF, atrial fibrillation; CHB, complete heart block; IVCD, intraventricular conduction defect; LAE, left atrial enlargement; LVH, left ventricular hypertrophy; MI, myocardial infarction; RVH, right ventricular hypertrophy; RBBB, right bundle branch block; RSR, regular sinus rhythm; RAE, right atrial enlargement; VPC, ventricular premature beat. Rhythm. Thirty patients on initial examination showed regular sinus rhythm
with a rate ranging
f r o m 60 t o 100 p e r m i n u t e . S i x p a t i e n t s r e v e a l e d evidence of atrial and/or ventricular premature
premature than
beats appeared
normal
on
repeated
to be more ECG
frequent
examinations.
T w o p a t i e n t s ( N o s . 11 a n d 21) p r e s e n t e d w i t h atrial fibrillation and three developed atrial fibril-
beats. Two of these had occasional and three had
l a t i o n o n f o l l o w - u p . O n e p a t i e n t ( N o . 19) w h o h a d
frequent atrial premature
sinus rhythm
occasional
and
two
ventricular
premature
beats, whereas two had
had
frequent
beats. Three
multiform patients
in
and left atrial enlargement
observation;
in another
patient
( N o . 20) a t r i a l
this group had both atrial and ventricular beats.
fibrillation was present only intermittently.
Although
year-old male patient
continuous
monitoring
activity was not done, atrial and/or
700
for
ectopic
ventricular
devel-
oped atrial fibrillation during the 3 year period of A 31-
( N o . 12) d e v e l o p e d s i n o a -
trial block followed by atrial fibrillation after 2
June, 1977,Vol.93,No. 6
ECG a n d VCG abnormalities in Fabry's disease
APC
Jr
VPC
MI
Follow-up
--
_
-
-
---
Disappearance of RBB None None
--
+
-
Var. PR interval; SA block, AF
--
--
--
+ +
+ +
--
PR interval 120 msec. PR interval 140 msec.; RBBB; QRS axis -45 ~ Variable PR inter.; AF RBB; PR inter. 360 msec., intermittem AF Wenckebach phenomena-CHB
-
-
PR interval 140 msec. PR interval 140 msec.
+
-
Incomplete RBBB; LVH PR interval 150 msec. QRS 90 ~ Sinus bradycardia 45/min.: VPC's
--
-
-
+
y e a r s . A l l five p a t i e n t s w i t h a t r i a l f i b r i l l a t i o n were hemizygous males. One heterozygous female p a t i e n t (No. 31) i n i t i a l l y h a d s i n u s r h y t h m ( h e a r t r a t e 80 p e r m i n u t e ) , a n d l a t e r d e v e l o p e d s i n u s b r a d y c a r d i a ( r a t e o f 45 p e r m i n u t e ) a n d f r e q u e n t premature ventricular beats. One 50-year-old m a l e p a t i e n t (No. 20) d e v e l o p e d c a r d i a c f a i l u r e and preterminally had varying degrees of atriove n t r i c u l a r ( A - V ) c o n d u c t i o n d e f e c t s , i.e., W e n c k e bach phenomenon, A-V junctional escape rhythm, A-V dissociation associated with ventricular tachycardia, and complete heart block. Q R S axis. T h e Q R S axis w a s n o r m a l in 30 o f
American Heart J o u r n a l
t h e 32 p a t i e n t s . I n o n e p a t i e n t (No. 3 0 - h e t e r o z y gous), t h e Q R S axis w a s + 105 ~ i n i t i a l l y a n d l a t e r b e c a m e + 9 0 ~ T h e r e m a i n i n g p a t i e n t (No. 1 8 - h e m i z y g o u s ) f u l f i l l e d t h e E C G c r i t e r i a o f left a n t e r i o r h e m i b l o c k w i t h a c h a n g e in axis f r o m -27 ~ to -45 ~ over a follow-up period of 4 years. I n b o t h t h e s e p a t i e n t s , t h e P R i n t e r v a l w a s 140 msec. a n d t h e l a t t e r p a t i e n t a l s o d e v e l o p e d a r i g h t bundle block pattern. PR i n t e r v a l . I n 26 of 32 p a t i e n t s , t h e P R i n t e r v a l , c o r r e c t e d for a g e a n d h e a r t r a t e , was w i t h i n n o r m a l l i m i t s on i n i t i a l e x a m i n a t i o n . I n f o u r p a t i e n t s t h e P R i n t e r v a l w a s 120 msec. o r less; in t h e r e m a i n i n g t w o i t c o u l d n o t b e c a l c u lated because of the presence of atrial fibrillation. I n 13 p a t i e n t s in w h o m s e r i a l E C G ' s w e r e a v a i l able. t h e P R i n t e r v a l s h o r t e n e d in t w o f r o m 160 t o 140 msec. o v e r a 1 to 3 y e a r p e r i o d ( p a t i e n t s Nos. 18 a n d 27); in o n e ( p a t i e n t No. 17) it s h o r t e n e d f r o m 140 t o 120 msec. o v e r a 3 y e a r f o l l o w - u p p e r i o d . I n t h r e e p a t i e n t s (Nos. 20, 26, 30} f o l l o w e d for 2 t o 5 y e a r s , t h e P R i n t e r v a l p r o l o n g e d a n d o n e of t h e s e t h r e e (No. 2 0 - h e m i z y g o u s ) f i n a l l y developed complete heart block. In two (patients Nos. 12 a n d 19) t h e P R i n t e r v a l w a s v a r i a b l e , a n d t h e y l a t e r d e v e l o p e d a t r i a l f i b r i l l a t i o n ; in five p a t i e n t s t h e P R i n t e r v a l r e m a i n e d u n c h a n g e d . On initial e x a m i n a t i o n , f o u r p a t i e n t s h a d P R i n t e r v a l s of 130 m s e c . ( l o w e r l i m i t o f n o r m a l . 127 msec. for age a n d h e a r t r a t e ) . Conduction defects. S i x p a t i e n t s s h o w e d v e n t r i c u l a r c o n d u c t i o n a b n o r m a l i t i e s . F o u r of t h e s e (Nos. 18 a n d 2 0 - h e m i z y g o u s , a n d Nos. 25 and 29-heterozygous) initially showed nonspecific i n t r a v e n t r i c u l a r c o n d u c t i o n d e f e c t m a n i fested b y Q R S d u r a t i o n o v e r 100 msec. B o t h h e m i z y g o u s p a t i e n t s l a t e r d e v e l o p e d a p a t t e r n of complete right bundle branch block and one h e t e r o z y g o u s p a t i e n t (No. 29) d e v e l o p e d i n c o m plete right bundle branch block. In two other h e m i z y g o u s p a t i e n t s (Nos. 4 a n d 12) i n c o m p l e t e r i g h t b u n d l e b r a n c h b l o c k w a s p r e s e n t on t h e first e x a m i n a t i o n . I n o n e (No. 4), t h e r e w a s n o evidence of block 6 months later. None of the p a t i e n t s h a d left b u n d l e b r a n c h b l o c k . S i n o a t r i a l b l o c k e v o l v e d in one h e m i z y g o u s p a t i e n t (No. 12). C h a m b e r e n l a r g e m e n t . ECG evidence of chamb e r e n l a r g e m e n t w a s m o s t c o m m o n l y s e e n for t h e left v e n t r i c l e . T e n p a t i e n t s s h o w e d a p a t t e r n of left v e n t r i c u l a r h y p e r t r o p h y ( L V H ) , five of t h e s e fulfilling a l l c r i t e r i a i n c l u d i n g s t r a i n . 1'~ I n five
701
M e h t a et al.
Table II. V C G f i n d i n g s i n F a b r y ' s disease
Pt.
Age, sex
PR int. (msec.)
QRS duration
QRS axis
RAE
1 2 3 4
B.R. A.H. S.L. S.J.
16M 18M 23M 29M
134 152 151 -
112 86 101 102
43 58 46 23
. . .
5 6 7 8 9 10 11
S.W. D.P. G.A. G.R. G.G. G.D. R.A.
33M 33M 35M 37M 38M 40M 44M
166 166 139 134 146 132 152
100 100 96 76 89 96 118
33 27 70 29 24 33 -5
+ -
12 13 14 15
K.J.
19F 37F 49F 56F
128 118 158 135
86 93 88 109
48 32 7 15
No.
N.M K. B. S.L.
IVCD
L VH
~-
+ . .
. . .
. . . . . + . . + -
MI
Nonsp. ST chgs.
-
-
. .
.
§ +
. .
. . + +
. .
. . +
. . -
-
-
+ + -
. . -
+ -
ECG interpretation
Within normal limits Within normal limits Within normal limits Nonspecific ST-T changes, atrial fibrillation LVH by voltage LVH by voltage Incomplete RBBB Nonspecific ST-T changes LVH by voltage, APC's LVH Left axis, IVCD, LVH, LAE Within normal limits Short PR interval Incomplete RBBB. LVH LVH by voltage, APC's
*Anterolateralwall. o t h e r s v o l t a g e c r i t e r i a a l o n e for L V H were m e t . T w o p a t i e n t s (Nos. 20 a n d 29) s u b s e q u e n t l y d e v e l o p e d L V H a f t e r 1 a n d 3 years, r e s p e c t i v e l y . L e f t a t r i a l e n l a r g e m e n t 4LAE) was seen in t h r e e p a t i e n t s . I n o n e p a t i e n t (No. 4) r i g h t v e n t r i c u l a r h y p e r t r o p h y p a t t e r n was p r e s e n t a s s o c i a t e d w i t h L V H . O n l y t w o of 11 h e t e r o z y g o u s f e m a l e s h a d c h a m b e r e n l a r g e m e n t w h e r e a s n i n e of 21 h e m i z y gous m a l e s had o n e or m o r e e n l a r g e d c h a m b e r s (p < 0.05}. Myocardial infarction. O n l y o n e p a t i e n t (No. 21) showed a p a t t e r n of a n t e r o s e p t a l m y o c a r d i a l i n f a r c t i o n , t h o u g h t h e r e was n o c l i n i c a l e v i d e n c e of m y o c a r d i a l d a m a g e . T h i s p a t i e n t , a 5 1 - y e a r - o l d h e m i z y g o t e , h a d , in a d d i t i o n , a t r i a l f i b r i l l a t i o n . N o o t h e r p a t i e n t fulfilled E C G c r i t e r i a of m y o c a r dial i n f a r c t i o n . ST-T c h a n g e s . T h e s e were p r e s e n t i n five p a t i e n t s i n a s s o c i a t i o n w i t h left v e n t r i c u l a r hypertrophy. Three other patients had ST-T c h a n g e s , s u g g e s t i v e in t w o of m y o c a r d i a l ischem i a i n l a t e r a l c h e s t leads. I n o n e p a t i e n t (No. 20) nonspecific S T - T changes preceded d e v e l o p m e n t of left v e n t r i c u l a r h y p e r t r o p h y . T w o of t h e s e t h r e e p a t i e n t s were h e m i z y g o u s a n d o n e h e t e r o zygous. Vectorcardiograms in Fabry's disease. V C G ' s were a v a i l a b l e i n 15 p a t i e n t s . T h e g e n o t y p e s of t h e s e p a t i e n t s a n d t h e i r V C G o b s e r v a t i o n s are
702
s h o w n i n T a b l e II. I n o n l y five p a t i e n t s was t h e V C G n o r m a l . O n e p a t i e n t had a t r i a l f i b r i l l a t i o n (No. 4). A P R i n t e r v a l of less t h a n 120 msec. was seen o n l y in one p a t i e n t (No. 13) a n d six o t h e r s h a d a P R i n t e r v a l b e t w e e n 120 a n d 140 msec. Left ventricular h y p e r t r o p h y and right atrial enlargem e n t were seen in five p a t i e n t s a n d o n e p a t i e n t , r e s p e c t i v e l y . N o n e h a d left a t r i a l e n l a r g e m e n t . F o u r p a t i e n t s had e v i d e n c e of n o n s p e c i f i c S T - T c h a n g e s a n d h a d n o left v e n t r i c u l a r h y p e r t r o p h y . O n e fulfilled c r i t e r i a of a n t e r o l a t e r a l m y o c a r d i a l i n f a r c t i o n o n VCG, b u t n o t o n E C G . A n i n t r a v e n t r i c u l a r c o n d u c t i o n d e f e c t was p r e s e n t in t h r e e patients. Follow-up VCG's. F o l l o w - u p V C G ' s were availa b l e o n six p a t m n t s . I n o n e p a t i e n t (No. 141 i n t r a v e n t r i c u l a r c o n d u c t i o n defect p e r s i s t e d a n d a p a t t e r n of L V H e v o l v e d a f t e r 2 m o n t h s of o b s e r v a t i o n . T h e E C G in this p a t i e n t c o n t i n u e d to s h o w i n c o m p l e t e r i g h t b u n d l e b r a n c h b l o c k a n d left v e n t r i c u l a r h y p e r t r o p h y all along. H o w e v e r , 5 y e a r s e a r l i e r t h e E C G h a d revealed o n l y i n t r a v e n t r i c u l a r c o n d u c t i o n defect. I n a n o t h e r p a t i e n t (No. 11), left a t r i a l e n l a r g e m e n t appeared and intraventricular conduction delay p r o g r e s s e d to right b u n d l e b r a n c h b l o c k a n d n e w left a n t e r i o r h e m i b l o c k a p p e a r e d . S i m i l a r c h a n g e s were also o b s e r v e d i n his E C G as well. Left ventricular hypertrophy disappeared in patient
J u n e , 1977, Vol. 93, No. 6
ECG and VCG abnormalities in Fabry's disease
No. 1 after 1 year and evolved in two patients (No. 10 and 14). The ECG was normal in patient No. 1 all along and revealed LVH with strain in patient NO. 10; VCG in two patients remained unchanged over period of 1 year. Discussion
Ferrans and associates ~ and Becker and associates '~ have described the pathologic and ultrastructural features of the heart in Fabry's disease. They found extensive glyc0sphingolipid deposits in the myocardial fibers, connective tissue of each cardiac valve, conduction system, the endothelium, and smooth muscle of large and small arteries. They postulated t h a t the glycosphingolipid infiltration was responsible for the cardiac abnormalities found in these patients. Mitral and aortic valvular lesions have been described in Fabry's disease ~. 5 9 ~1 and occasionally are responsible for the patient's death. Nevertheless, there have been limited descriptions of the ECG in these patients and include short PR interval. left ventricUlar enlargement, and nonspecific ST-T changes. 2. 3. ~ Atrial fibrillation, complete heart block, left anterior hemiblock, and myocardial infarction patterns have also been occasionally reported. 2. 6. 10. ~ However, morphological proof of infarction has rarely been provided. In our series, six patients (19 per cent) had an abnormal rhythm, either when first seen or during follow-up examination. Five were hemizygotic and one heterozygofic for Fabry's disease. One showed sinus bradycardia, Wenckebach phenomenon, and complete heart block; one heterozygous female developed sinus bradycardia. R h y t h m disturbances and sinoatrial block have been reported by several authors. ~.~, 1~ Chamber enlargement and deposition of glycosphingolipid in the atria and around the conduction system is probably responsible for the rhythm disturbance. Longer duration of the disease in our patients resulted in severe degree of A-V block, probably because of progression of the disease and more extensive deposition Of glycosphingolipid i n and around the conduction pathways. Further proof of more severe degrees of cardiac abnormalities with longer duration of disease comes from the fact t h a t older patients with Fabry's disease had more abnormalities on the ECG's and VCG's (Tables I and II) than their younger counterparts. Ectopic beats arising in the
American Heart Journal
atrium, ventricle or both, probably have their genesis in the same abnormality. A short PR interval has been described in Fabry's disease, 3. 6 Indeed, in our series 13 per cent had a PR interval of 120 msec. or less when first seen. Follow-up ECG's in 13 patients revealed that the PR interval shortened in three, prolonged in three, degenerated into atrial fibrillation in two, and remained unchanged in five patients. In a report by Roudebush and associates, :~ glycosphingolipid accumulation in the conduction system was proposed as a cause of short PR interval in Fabry's disease. In the autopsy study by Becker and associates, 11 deposits of glycosphingolipid were seen in cells of the sinus node, the A-V node, His bundle, and left and right bundle branches. It is likely that lipid deposits in and around the A-V pathway may alter conduction time. However, the presence of a short PR interval in five of 32 patients With Fabry's disease would require the presence of either abnormal short circuiting pathways or supernormal conduction through the normal pathways. Prolongation of PR interval in three of 13 patients on follow-up examination is most likely due to the progression of the disease process; however, progressive shortening in three others cannot be explained by this mechanism, Probably the variations in PR interval result from glycosphingolipid deposition in nerves and nerve membranes causing instability in the conduction process, 2~ Right and left axis deviation were present in one patient each. Six patients (19 per cent) had evidence of intraventricular conduction defects, most frequently right bundle branch block. None of our patients had left bundle branch block. Similar conduction abnormalities have been observed in o t h e r glycosphingolipid storage disorders including Sandhoff's disease 21 and GM,2~ and G~22. gangliosidoses. It is likely that lipid deposits in and around the conduction system in Fabry's disease result in axis shift and conduction defects as in other storage disorders. As is apparent from Tables I and II, the left ventricle is the most common chamber to be enlarged-38 per cent of all patients. Criteria for left atrial enlargement were met in three patients on ECG and right atrial enlargement in one patient on VCG. ST-T segment changes were observed rather frequently in 10 of 32 patients. In
703
M e h t a et al.
seven, S T - T changes were a s s o c i a t e d with left ventricular h y p e r t r o p h y and in three S T - T changes were seen w i t h o u t left v e n t r i c u l a r hypertrophy. S T - T changes were observed to precede left ventricular h y p e r t r o p h y b o t h b y E C G and VCG in one p a t i e n t . E C G evidence of c h a m b e r enlargement can result from various mechanisms, Left ventricular h y p e r t r o p h y and S T - T changes in m a n y patients m a y result from h y p e r t e n s i o n secondary to renal involvement. Infiltration of endothelium and m y o c a r d i u m by glycosphingolipid 2. 11.15 m a y also result in E C G and VCG evidence of c h a m b e r e n l a r g e m e n t in the absence of hypertension t h r o u g h some y e t unidentified mechanisms. Valvular i n v o l v e m e n t in Fabry's disease 2. 5, ,. 11. 15 m a y also be responsible for c h a m b e r e n l a r g e m e n t by v o l u m e or pressure overloading. Nonspecific S T - T changes m a y be a result of altered repolarization of t h e infiltrated myocardium. E C G evidence of m y o c a r d i a l infarction and ischemia have been occasionally reported in patients with Fabry's disease w i t h o u t clinical or autopsy evidence of c o r o n a r y a r t e r y diseaseY' 6. i6. 11.15 Our patients with either a p a t t e r n of myocardial infarction or ischemic T - w a v e changes had no clinical features o f c o r o n a r y disease: This again illustrates t h a t storage disorders affecting t h e m y o c a r d i u m can mimick myocardial infarction in the E C G and VCG. 24 As would be expected, hemizygosity was asso: ciated with more abnormalities. In 21 hemizygous patients in this study, a short P R interval was present in four patients, l e f t v e n t r i c u l a r hyper: t r o p h y in nine, i n t r a v e n t r i c u l a r conduction defects in four, S T - T changes in 18, sinoatrial and A-V block in one each and left a n t e r i o r hemiblock in one. Only six hemizygous patients had n o r m a l ECG's whereas, of 11 heterozygous patients, five had normal ECG's (p < 0.05). Since Fabry's disease m a y be a m e n a b l e to therapy, 25itis essential to u n d e r s t a n d the n a t u r a l history of electrical changes in t h e m y o c a r d i u m and the mechanisms thereto. Our observations show t h a t glycosphingolipid infiltration in the myocardium, blood vessels, and conduction system results in progression of conduction defects and c h a m b e r enlargement. Occasionally decreases in electrical c o n d u c t i o n time and regression of c h a m b e r e n l a r g e m e n t p a t t e r n s m a y also be apparent, probably due to electrical
704
alterations. N o t unexpectedly, hemizygosity is associated with more severe defects. Summary Fabry's disease has been reported to be associated with ECG abnormalities. T h i r t y - t w o patients with this disease followed in the University of Minnesota had E C G ' s and 15 had VCG's. An a b n o r m a l r h y t h m was observed in two patients on initial e x a m i n a t i o n and four more developed abnormal r h y t h m on follow-up examinations. A short P R interval (120 msec. or less) was seen in five patients. T h i r t e e n others had a PR interval t h a t was less t h a n 140 msec. Conduction abnormalities involving the A-V node or His bundle or its branches were present in 22 per cent of the patients, most f r e q u e n t l y the intraventricular conduction defects progressing to the right bundle b r a n c h block. Atrial or ventricular enlargement was seen in 60 per cent of the patients, left ventricular h y p e r t r o p h y being the most common. S T - T changes with or w i t h o u t chamber enlargement were seen in 10 patients. One patient had an a n t e r i o r m y o c a r d i a l infarction p a t t e r n on his ECG. Hemizygosity was f o u n d to be associated with significantly more abnormalities t h a n heterozygosity. T h e severity of conduction defects also increased with the duration of the disease process. V e c t o r c a r d i o g r a p h y in this study did not provide significant additional information other t h a n t h a t observed on the E C G alone. Since the p a t h o l o g y usually reveals myocardial fibers, conduction system, and blood vessels infiltrated with glycosphingolipid, it is believed t h a t lipid infiltration is responsible for conduction defects, c h a m b e r enlargement, and other abnormalities. Although Fabry's disease is rare, it m a y be amenable to t h e r a p y ; therefore, recognition of cardiac i n v o l v e m e n t is i m p o r t a n t . The authors gratefully appreciate the expert secretarial assistance of Mrs. Frances Wallace in preparation of the manuscript. REFERENCES 1. Sweeley,C. C., Klionsky, B., Krivit, W., et al.: Fabry's disease in Stanbury, J. B., Wyngaarden, J. B., and Fredrickson, 0. S., editors: The metabolic basis of inherited disease, ed. 3, New York, 1972, McGraw-Hill Book Company, Inc., pp. 663-687. 2. Ferrans. V. J., Hibbs, R. G.. and Burda, C. D.: The heart in Fabry's disease. A histochemical and electron microscopic study, Am. J. Cardiol. 26:95, 1969. 3. Roudebush, C. P.. Foerster, J. M., and Bing, O. H. L.: The
J u n e 197~ Vos
No. 6
ECG and VCG abnormalities in Fabry's disease
4. 5. 6. 7.
8.
9.
10.
11. 12.
13.
14.
abbreviated PR interval of Fabry's disease, N. Engl. J. Med. 289:357, 1973. Duncan, C.: Angiokeratoma-a case with gross myocardial involvement, Australas. Ann. Med 19:58, 1970. Leder, A. A., and Boxworth, W. C.: Angiokeratoma corporis diffusum universale (Fabry's disease) with mitral stenosis, Am. J. Med. 38:814, 1965. Wise, D., Wallace, H. J., and Jellinek, E. H.: Angiokeratoma corporis diffusum. A clinical study of eight affected females, Q. J. Med. 31:177, 1962. Ruiter, M., Pompen, A. W. M., and Wyers, H. J. G.: lJber interne und pathologisch-anatomische Befunde bei Angiokeratoma corporis diffusum (Fabry), Dermatologica 94:1, 1947. Pompen, A. W. M., Ruiter, M., and Wyers, H. J. C.: Angiokeratoma corporis diffusum (universale) Fabry as a sign of an unknown internal disease: Two autopsy reports, Acta Med. Scand. 128:235, 1947. Dubach, U. C., and Gloor, F.: Fabry-Kranbeit (angiokeratoma corporis diffusum universale). Posphatidspeicherkrankheit bei zwei Familien, Dtsch. Med. Wohnschr. 91:241, 1966. Parkinson, J. E., and Sunshine, A.: Angiokeratoma corporis diffusum universale (Fabry). Presenting as suspected myocardial infarction and pulmonary infarcts, Am. J. Med. 31:951, 1961. Becker, A. E., Schoorl, R., Balk, A. G., et al.: Cardiac manifestations of Fabry's disease, Am. J. Cardiol. 36:829, 1975. Desnick, R. J., Allen, K. Y., Desnick, S. J., et al.: Fabry's disease: Enzymatic diagnosis of hemizygotes and heterozygotes. Alpha-galactosidase activities in plasma serum, leukocytes and urine, J. Lab. Clin. Med. 81:157, 1973. Johnson, D. L., DelMonte, M. A., Cottier, E., et al.: Fabry's disease: Diagnosis of hemizygotes and heterozygotes by alpha-galactosidase A activity in tears, Clin Chim. Acta 63:81, 1975. Schmitt, O. H., and Simonson, E.: The present status of vectorcardiography, Arch. Intern. Med. 96:574, 1955.
American Heart Journal
15. Desnick, R. J., Blieden, L. C., Sharp, H. L., et al.: Cardiac valvular anomalies in Fabry's disease. Clinical morphologic and biochemical studies, Circulation (In press, November, 1976) 16. The Criteria Committee of the New York Heart Association: Nomenclature and criteria for diagnosis of disease of the heart and great vessels, ed. 7, Boston, 1973, Little, Brown & Company. 17. Altman, P. L., and Dittmer, D. S., editors: Respiration and circulation, Bethesda, Md., 1971, Federation of American Societies for Experimental Biology, p. 281. 18. Brohet, C. R., Liedtke, C. E., and Tuna, N.: P wave abnormalities in the orthogonal electrocardiogram: Correlation with ventricular overload in pulmonic and aortic valvular heart disease, J. Electrocardiol. 8:103, 1975. 19. Chou, T. C., and Helm, R. A.: Clinical vectocardiography, New York, 1967, Grune & Stratton, Inc. 20. Ohnishi, A., and Dyck, P. J.: Loss of small peripheral sensory neurons in Fabry's disease, Arch. Neurol. 31:120, 1974. 21. Blieden, L. C., Desnick, R. J., Carter, J. B., et al.: Cardiac involvement in Sandhoff's disease: An inborn error of glycosphingolipid metabolism, Am. J. Cardiol. 34:83, 1974. 22. Hadley, R. N., and Hagstrom, J. W. C.: Cardiac lesions in a patient with familial neurovisceral lipidosis (generalized gangliosidosis), Am. J. Chn. Pathol. 55:237, 1971. 23. Rodriguez-Torres, R., Schneck, L., et al.: Electrocardiographic and biochemical abnormalities in Tay-Sachs disease, Bull. New York Acad. Med. 47:717, 1971. 24. Scholmerich, P.: Myocarditis and weitere Myokardiopathien, in Bergman, G., Frey, W., and Schweiegk, H., editors: Handbuch er Inneren Medizin, Berlin, 1960, Springer Verlag, p. 960. 25. Desnick, R. J., Thorpe, S. R., and Fiddler, M. B.: Towards enzyme therapy for lysosomal storage disease, Phys. Rev. 56:57, 1976.
705
Fabry's disease is an X-linked disorder of glycosphingolipid metabolism, related to the defective activity of alpha-galactosidase A. 1 There is deposition of glycosphingolipid, mainly trihexosyl ceramide, in the vascular smooth muscle, myocardium, cells of sympathetic central nervous system, and epithelial cells of renal glomeruli. ~ Because of unusual skin lesions and multiorgan involvement, the disease is also known as angiokeratoma corporis diffusum universale. Involvement of the myocardium and small blood vessels has long been recognized. T M Electrocardiographic (ECG) abnormalities have occasionally been reported2-G, lO. 11 but there is no detailed information regarding the incidence of ECG and vectorcardiographic (VCG) abnormalities in these patients. The purpose of this report is to review the ECG in 32 patients and the VCG in 15 patients with Fabry's disease followed in our institution. Materials and methods
Thirty-two patients between the ages of 6 and 56 years with Fabry's disease {including 21 hemizygotes and 11 heterozygotes) studied at the University of Minnesota Hospitals form the basis From the Departments of Medicine, Pediatrics, and the Dight Institute for Human Genetics, University of Minnesota Medical School, Minneapolis, Minn. 55455. This work was supported in part by a grant (74-915) from the American Heart Association; a grant (1-273) from the National Foundation-March of Dimes; a grant (AM 15174) from the National Institutes of Health; and a grant (RR-400) from the General Clinical Research Center, Program of the Division of Research Resources, National Institutes of Health; Dr. Desnick is a recipient of a National Institutes of Health Career Development Award (1K04-AM00042). Received for publication Jan. 27, 1976. Reprint requests: J. Mehta, M.D., Box J-277, J H M Health Center, University of Florida, Gainsville, Fla. 32610.
June, 1977, Vol. 93, No. 6, pp. 699-705
of this report. The diagnosis of hemizygosity and heterozygosity for Fabry's disease was made by physical examination, corneal changes as seen by slit-lamp examination, skin biopsy, and biochemical studies which included measurement of trihexosyl ceramide concentration in plasma, urinary sediment, and the determination of alpha-galactosidase activity in plasma, leukocytes, and tears. 12"13 In each patient a 12 lead ECG and in 15 a corrected orthogonal VCG was performed. TM More than one ECG was performed in 13 patients over periods ranging from 3 to 12 years. In two of the 13 patients with serial ECG's, cardiac signs and symptoms were present; both of these patients died and necropsy revealed extensive cardiac infiltration with glycosphinogolipid characteristic of Fabry's disease. 15 None of the other patients presented clinical signs or symptoms of cardiac disease and ECG/VCG abnormality, if present, was found only upon routine examination. ECG's were interpreted for rhythm, QRS axis, PR, QRS, and QT intervals and P, QRS, and ST-T morphology according to the New York Heart Association criteria TM and compared with ECG's of age-matched normal subjects. 17 VCG's were recorded on magnetic tape and were analyzed with a minicomputer as previously reported TM and interpreted according to established criteria. 1~ Results
Of 32 patients, there were 11 heterozygous females and 21 hemizygous males. The mean age was 33 {range, 19 to 56) and 22 {range, 6 to 50) years, respectively. Table I shows the genotype and ECG abnormalities noted in these patients.
American Heart Journal
699
Mehta et al.
T a b l e I. E C G ' s i n F a b r y ' s d i s e a s e *
~
~ I
I Age, I
No. Hemizygotes: 1 2 3
G.T. L.C. C.L.
4 5
Rhythm
6M 11M 11M
RSR RSR RSR
L.R.
12M
K.G.
14M
6 7 8 9 10 11 12 13
L.D. B.R. A.H. S.R. S.L. S.J. G.A. D.P.
15M 16M 18M 19M 23M 29M 31M 33M
14
S.W.
15
G.R.
16
~ I
LVH QRS I iPntRr.I
~
Conduct I NS;:~" ~ - - ~ ecL RBBB
~
95 75 100
N N N
140 115 140
. . .
RSR
80
N
120
-
RSR
90
N
130
.
75 75 90 70 90 90 80 85
N N N N N N N N
120 140 160 160 150 140 160
. . . . . . -
33M
RSR RSR RSR RSR RSR AF RSR RSR RSR
95
N
160
--
36M
RSR
80
N
140
.
G.G.
38M
RSR
90
N
140
-
+
.
17
G.D.
40M
RSR
80
N
140
-
-
+
.
18
R.A.
42M
RSR
65
-27
160
+
-
+
-
19 20
C.J. B.C.
47M 50M
RSR RSR
80 70
N N
140 230
+ +
-
+ -
-
21
B.M.
51M
AF
160
N
.
22 23 24 25 26 27 28 29 30 31
K.J. L.C. C.L. M.G. N.M. B.L. A.D. K.B. A.V. S.E.
19F 20F 24F 35F 37F 40F 44F 45F 46F 50F
RSR RSR RSR RSR RSR RSR RSR RSR RSR RSR
60 85 75 85 85 72 90 82 78 80
N N N N N N N N 105 N
130 180 120 130 130 160 150 150 140 160
. . . . . . . . --
32
S.L.
56F
RSR
75
N
160
-
Heterozygotes:
.
. . .
. . .
. . .
+ .
.
.
. . . . .
+
.
.
. . +
.
.
. . .
.
. . . . -
+
+
. . .
m
D
. .
m
+
. .
+
m
+
+ .
.
-
. . .
.
+
.
. . .
.
.
-
.
.
.
. .
-
.
.
. .
.
-
.
. . .
.
.
.
.
. . .
.
.
.
.
+
.
.
.
.
.
.
+
. . . . .
. .
.
.
. . . . .
. .
+
-
.
. . . . .
+ .
. . .
-
.
. . . . .
.
. . .
+
.
. . . . .
.
. . .
.
B
.
-
D
--
--
+
*APC, atrial premature contraction; AF, atrial fibrillation; CHB, complete heart block; IVCD, intraventricular conduction defect; LAE, left atrial enlargement; LVH, left ventricular hypertrophy; MI, myocardial infarction; RVH, right ventricular hypertrophy; RBBB, right bundle branch block; RSR, regular sinus rhythm; RAE, right atrial enlargement; VPC, ventricular premature beat. Rhythm. Thirty patients on initial examination showed regular sinus rhythm
with a rate ranging
f r o m 60 t o 100 p e r m i n u t e . S i x p a t i e n t s r e v e a l e d evidence of atrial and/or ventricular premature
premature than
beats appeared
normal
on
repeated
to be more ECG
frequent
examinations.
T w o p a t i e n t s ( N o s . 11 a n d 21) p r e s e n t e d w i t h atrial fibrillation and three developed atrial fibril-
beats. Two of these had occasional and three had
l a t i o n o n f o l l o w - u p . O n e p a t i e n t ( N o . 19) w h o h a d
frequent atrial premature
sinus rhythm
occasional
and
two
ventricular
premature
beats, whereas two had
had
frequent
beats. Three
multiform patients
in
and left atrial enlargement
observation;
in another
patient
( N o . 20) a t r i a l
this group had both atrial and ventricular beats.
fibrillation was present only intermittently.
Although
year-old male patient
continuous
monitoring
activity was not done, atrial and/or
700
for
ectopic
ventricular
devel-
oped atrial fibrillation during the 3 year period of A 31-
( N o . 12) d e v e l o p e d s i n o a -
trial block followed by atrial fibrillation after 2
June, 1977,Vol.93,No. 6
ECG a n d VCG abnormalities in Fabry's disease
APC
Jr
VPC
MI
Follow-up
--
_
-
-
---
Disappearance of RBB None None
--
+
-
Var. PR interval; SA block, AF
--
--
--
+ +
+ +
--
PR interval 120 msec. PR interval 140 msec.; RBBB; QRS axis -45 ~ Variable PR inter.; AF RBB; PR inter. 360 msec., intermittem AF Wenckebach phenomena-CHB
-
-
PR interval 140 msec. PR interval 140 msec.
+
-
Incomplete RBBB; LVH PR interval 150 msec. QRS 90 ~ Sinus bradycardia 45/min.: VPC's
--
-
-
+
y e a r s . A l l five p a t i e n t s w i t h a t r i a l f i b r i l l a t i o n were hemizygous males. One heterozygous female p a t i e n t (No. 31) i n i t i a l l y h a d s i n u s r h y t h m ( h e a r t r a t e 80 p e r m i n u t e ) , a n d l a t e r d e v e l o p e d s i n u s b r a d y c a r d i a ( r a t e o f 45 p e r m i n u t e ) a n d f r e q u e n t premature ventricular beats. One 50-year-old m a l e p a t i e n t (No. 20) d e v e l o p e d c a r d i a c f a i l u r e and preterminally had varying degrees of atriove n t r i c u l a r ( A - V ) c o n d u c t i o n d e f e c t s , i.e., W e n c k e bach phenomenon, A-V junctional escape rhythm, A-V dissociation associated with ventricular tachycardia, and complete heart block. Q R S axis. T h e Q R S axis w a s n o r m a l in 30 o f
American Heart J o u r n a l
t h e 32 p a t i e n t s . I n o n e p a t i e n t (No. 3 0 - h e t e r o z y gous), t h e Q R S axis w a s + 105 ~ i n i t i a l l y a n d l a t e r b e c a m e + 9 0 ~ T h e r e m a i n i n g p a t i e n t (No. 1 8 - h e m i z y g o u s ) f u l f i l l e d t h e E C G c r i t e r i a o f left a n t e r i o r h e m i b l o c k w i t h a c h a n g e in axis f r o m -27 ~ to -45 ~ over a follow-up period of 4 years. I n b o t h t h e s e p a t i e n t s , t h e P R i n t e r v a l w a s 140 msec. a n d t h e l a t t e r p a t i e n t a l s o d e v e l o p e d a r i g h t bundle block pattern. PR i n t e r v a l . I n 26 of 32 p a t i e n t s , t h e P R i n t e r v a l , c o r r e c t e d for a g e a n d h e a r t r a t e , was w i t h i n n o r m a l l i m i t s on i n i t i a l e x a m i n a t i o n . I n f o u r p a t i e n t s t h e P R i n t e r v a l w a s 120 msec. o r less; in t h e r e m a i n i n g t w o i t c o u l d n o t b e c a l c u lated because of the presence of atrial fibrillation. I n 13 p a t i e n t s in w h o m s e r i a l E C G ' s w e r e a v a i l able. t h e P R i n t e r v a l s h o r t e n e d in t w o f r o m 160 t o 140 msec. o v e r a 1 to 3 y e a r p e r i o d ( p a t i e n t s Nos. 18 a n d 27); in o n e ( p a t i e n t No. 17) it s h o r t e n e d f r o m 140 t o 120 msec. o v e r a 3 y e a r f o l l o w - u p p e r i o d . I n t h r e e p a t i e n t s (Nos. 20, 26, 30} f o l l o w e d for 2 t o 5 y e a r s , t h e P R i n t e r v a l p r o l o n g e d a n d o n e of t h e s e t h r e e (No. 2 0 - h e m i z y g o u s ) f i n a l l y developed complete heart block. In two (patients Nos. 12 a n d 19) t h e P R i n t e r v a l w a s v a r i a b l e , a n d t h e y l a t e r d e v e l o p e d a t r i a l f i b r i l l a t i o n ; in five p a t i e n t s t h e P R i n t e r v a l r e m a i n e d u n c h a n g e d . On initial e x a m i n a t i o n , f o u r p a t i e n t s h a d P R i n t e r v a l s of 130 m s e c . ( l o w e r l i m i t o f n o r m a l . 127 msec. for age a n d h e a r t r a t e ) . Conduction defects. S i x p a t i e n t s s h o w e d v e n t r i c u l a r c o n d u c t i o n a b n o r m a l i t i e s . F o u r of t h e s e (Nos. 18 a n d 2 0 - h e m i z y g o u s , a n d Nos. 25 and 29-heterozygous) initially showed nonspecific i n t r a v e n t r i c u l a r c o n d u c t i o n d e f e c t m a n i fested b y Q R S d u r a t i o n o v e r 100 msec. B o t h h e m i z y g o u s p a t i e n t s l a t e r d e v e l o p e d a p a t t e r n of complete right bundle branch block and one h e t e r o z y g o u s p a t i e n t (No. 29) d e v e l o p e d i n c o m plete right bundle branch block. In two other h e m i z y g o u s p a t i e n t s (Nos. 4 a n d 12) i n c o m p l e t e r i g h t b u n d l e b r a n c h b l o c k w a s p r e s e n t on t h e first e x a m i n a t i o n . I n o n e (No. 4), t h e r e w a s n o evidence of block 6 months later. None of the p a t i e n t s h a d left b u n d l e b r a n c h b l o c k . S i n o a t r i a l b l o c k e v o l v e d in one h e m i z y g o u s p a t i e n t (No. 12). C h a m b e r e n l a r g e m e n t . ECG evidence of chamb e r e n l a r g e m e n t w a s m o s t c o m m o n l y s e e n for t h e left v e n t r i c l e . T e n p a t i e n t s s h o w e d a p a t t e r n of left v e n t r i c u l a r h y p e r t r o p h y ( L V H ) , five of t h e s e fulfilling a l l c r i t e r i a i n c l u d i n g s t r a i n . 1'~ I n five
701
M e h t a et al.
Table II. V C G f i n d i n g s i n F a b r y ' s disease
Pt.
Age, sex
PR int. (msec.)
QRS duration
QRS axis
RAE
1 2 3 4
B.R. A.H. S.L. S.J.
16M 18M 23M 29M
134 152 151 -
112 86 101 102
43 58 46 23
. . .
5 6 7 8 9 10 11
S.W. D.P. G.A. G.R. G.G. G.D. R.A.
33M 33M 35M 37M 38M 40M 44M
166 166 139 134 146 132 152
100 100 96 76 89 96 118
33 27 70 29 24 33 -5
+ -
12 13 14 15
K.J.
19F 37F 49F 56F
128 118 158 135
86 93 88 109
48 32 7 15
No.
N.M K. B. S.L.
IVCD
L VH
~-
+ . .
. . .
. . . . . + . . + -
MI
Nonsp. ST chgs.
-
-
. .
.
§ +
. .
. . + +
. .
. . +
. . -
-
-
+ + -
. . -
+ -
ECG interpretation
Within normal limits Within normal limits Within normal limits Nonspecific ST-T changes, atrial fibrillation LVH by voltage LVH by voltage Incomplete RBBB Nonspecific ST-T changes LVH by voltage, APC's LVH Left axis, IVCD, LVH, LAE Within normal limits Short PR interval Incomplete RBBB. LVH LVH by voltage, APC's
*Anterolateralwall. o t h e r s v o l t a g e c r i t e r i a a l o n e for L V H were m e t . T w o p a t i e n t s (Nos. 20 a n d 29) s u b s e q u e n t l y d e v e l o p e d L V H a f t e r 1 a n d 3 years, r e s p e c t i v e l y . L e f t a t r i a l e n l a r g e m e n t 4LAE) was seen in t h r e e p a t i e n t s . I n o n e p a t i e n t (No. 4) r i g h t v e n t r i c u l a r h y p e r t r o p h y p a t t e r n was p r e s e n t a s s o c i a t e d w i t h L V H . O n l y t w o of 11 h e t e r o z y g o u s f e m a l e s h a d c h a m b e r e n l a r g e m e n t w h e r e a s n i n e of 21 h e m i z y gous m a l e s had o n e or m o r e e n l a r g e d c h a m b e r s (p < 0.05}. Myocardial infarction. O n l y o n e p a t i e n t (No. 21) showed a p a t t e r n of a n t e r o s e p t a l m y o c a r d i a l i n f a r c t i o n , t h o u g h t h e r e was n o c l i n i c a l e v i d e n c e of m y o c a r d i a l d a m a g e . T h i s p a t i e n t , a 5 1 - y e a r - o l d h e m i z y g o t e , h a d , in a d d i t i o n , a t r i a l f i b r i l l a t i o n . N o o t h e r p a t i e n t fulfilled E C G c r i t e r i a of m y o c a r dial i n f a r c t i o n . ST-T c h a n g e s . T h e s e were p r e s e n t i n five p a t i e n t s i n a s s o c i a t i o n w i t h left v e n t r i c u l a r hypertrophy. Three other patients had ST-T c h a n g e s , s u g g e s t i v e in t w o of m y o c a r d i a l ischem i a i n l a t e r a l c h e s t leads. I n o n e p a t i e n t (No. 20) nonspecific S T - T changes preceded d e v e l o p m e n t of left v e n t r i c u l a r h y p e r t r o p h y . T w o of t h e s e t h r e e p a t i e n t s were h e m i z y g o u s a n d o n e h e t e r o zygous. Vectorcardiograms in Fabry's disease. V C G ' s were a v a i l a b l e i n 15 p a t i e n t s . T h e g e n o t y p e s of t h e s e p a t i e n t s a n d t h e i r V C G o b s e r v a t i o n s are
702
s h o w n i n T a b l e II. I n o n l y five p a t i e n t s was t h e V C G n o r m a l . O n e p a t i e n t had a t r i a l f i b r i l l a t i o n (No. 4). A P R i n t e r v a l of less t h a n 120 msec. was seen o n l y in one p a t i e n t (No. 13) a n d six o t h e r s h a d a P R i n t e r v a l b e t w e e n 120 a n d 140 msec. Left ventricular h y p e r t r o p h y and right atrial enlargem e n t were seen in five p a t i e n t s a n d o n e p a t i e n t , r e s p e c t i v e l y . N o n e h a d left a t r i a l e n l a r g e m e n t . F o u r p a t i e n t s had e v i d e n c e of n o n s p e c i f i c S T - T c h a n g e s a n d h a d n o left v e n t r i c u l a r h y p e r t r o p h y . O n e fulfilled c r i t e r i a of a n t e r o l a t e r a l m y o c a r d i a l i n f a r c t i o n o n VCG, b u t n o t o n E C G . A n i n t r a v e n t r i c u l a r c o n d u c t i o n d e f e c t was p r e s e n t in t h r e e patients. Follow-up VCG's. F o l l o w - u p V C G ' s were availa b l e o n six p a t m n t s . I n o n e p a t i e n t (No. 141 i n t r a v e n t r i c u l a r c o n d u c t i o n defect p e r s i s t e d a n d a p a t t e r n of L V H e v o l v e d a f t e r 2 m o n t h s of o b s e r v a t i o n . T h e E C G in this p a t i e n t c o n t i n u e d to s h o w i n c o m p l e t e r i g h t b u n d l e b r a n c h b l o c k a n d left v e n t r i c u l a r h y p e r t r o p h y all along. H o w e v e r , 5 y e a r s e a r l i e r t h e E C G h a d revealed o n l y i n t r a v e n t r i c u l a r c o n d u c t i o n defect. I n a n o t h e r p a t i e n t (No. 11), left a t r i a l e n l a r g e m e n t appeared and intraventricular conduction delay p r o g r e s s e d to right b u n d l e b r a n c h b l o c k a n d n e w left a n t e r i o r h e m i b l o c k a p p e a r e d . S i m i l a r c h a n g e s were also o b s e r v e d i n his E C G as well. Left ventricular hypertrophy disappeared in patient
J u n e , 1977, Vol. 93, No. 6
ECG and VCG abnormalities in Fabry's disease
No. 1 after 1 year and evolved in two patients (No. 10 and 14). The ECG was normal in patient No. 1 all along and revealed LVH with strain in patient NO. 10; VCG in two patients remained unchanged over period of 1 year. Discussion
Ferrans and associates ~ and Becker and associates '~ have described the pathologic and ultrastructural features of the heart in Fabry's disease. They found extensive glyc0sphingolipid deposits in the myocardial fibers, connective tissue of each cardiac valve, conduction system, the endothelium, and smooth muscle of large and small arteries. They postulated t h a t the glycosphingolipid infiltration was responsible for the cardiac abnormalities found in these patients. Mitral and aortic valvular lesions have been described in Fabry's disease ~. 5 9 ~1 and occasionally are responsible for the patient's death. Nevertheless, there have been limited descriptions of the ECG in these patients and include short PR interval. left ventricUlar enlargement, and nonspecific ST-T changes. 2. 3. ~ Atrial fibrillation, complete heart block, left anterior hemiblock, and myocardial infarction patterns have also been occasionally reported. 2. 6. 10. ~ However, morphological proof of infarction has rarely been provided. In our series, six patients (19 per cent) had an abnormal rhythm, either when first seen or during follow-up examination. Five were hemizygotic and one heterozygofic for Fabry's disease. One showed sinus bradycardia, Wenckebach phenomenon, and complete heart block; one heterozygous female developed sinus bradycardia. R h y t h m disturbances and sinoatrial block have been reported by several authors. ~.~, 1~ Chamber enlargement and deposition of glycosphingolipid in the atria and around the conduction system is probably responsible for the rhythm disturbance. Longer duration of the disease in our patients resulted in severe degree of A-V block, probably because of progression of the disease and more extensive deposition Of glycosphingolipid i n and around the conduction pathways. Further proof of more severe degrees of cardiac abnormalities with longer duration of disease comes from the fact t h a t older patients with Fabry's disease had more abnormalities on the ECG's and VCG's (Tables I and II) than their younger counterparts. Ectopic beats arising in the
American Heart Journal
atrium, ventricle or both, probably have their genesis in the same abnormality. A short PR interval has been described in Fabry's disease, 3. 6 Indeed, in our series 13 per cent had a PR interval of 120 msec. or less when first seen. Follow-up ECG's in 13 patients revealed that the PR interval shortened in three, prolonged in three, degenerated into atrial fibrillation in two, and remained unchanged in five patients. In a report by Roudebush and associates, :~ glycosphingolipid accumulation in the conduction system was proposed as a cause of short PR interval in Fabry's disease. In the autopsy study by Becker and associates, 11 deposits of glycosphingolipid were seen in cells of the sinus node, the A-V node, His bundle, and left and right bundle branches. It is likely that lipid deposits in and around the A-V pathway may alter conduction time. However, the presence of a short PR interval in five of 32 patients With Fabry's disease would require the presence of either abnormal short circuiting pathways or supernormal conduction through the normal pathways. Prolongation of PR interval in three of 13 patients on follow-up examination is most likely due to the progression of the disease process; however, progressive shortening in three others cannot be explained by this mechanism, Probably the variations in PR interval result from glycosphingolipid deposition in nerves and nerve membranes causing instability in the conduction process, 2~ Right and left axis deviation were present in one patient each. Six patients (19 per cent) had evidence of intraventricular conduction defects, most frequently right bundle branch block. None of our patients had left bundle branch block. Similar conduction abnormalities have been observed in o t h e r glycosphingolipid storage disorders including Sandhoff's disease 21 and GM,2~ and G~22. gangliosidoses. It is likely that lipid deposits in and around the conduction system in Fabry's disease result in axis shift and conduction defects as in other storage disorders. As is apparent from Tables I and II, the left ventricle is the most common chamber to be enlarged-38 per cent of all patients. Criteria for left atrial enlargement were met in three patients on ECG and right atrial enlargement in one patient on VCG. ST-T segment changes were observed rather frequently in 10 of 32 patients. In
703
M e h t a et al.
seven, S T - T changes were a s s o c i a t e d with left ventricular h y p e r t r o p h y and in three S T - T changes were seen w i t h o u t left v e n t r i c u l a r hypertrophy. S T - T changes were observed to precede left ventricular h y p e r t r o p h y b o t h b y E C G and VCG in one p a t i e n t . E C G evidence of c h a m b e r enlargement can result from various mechanisms, Left ventricular h y p e r t r o p h y and S T - T changes in m a n y patients m a y result from h y p e r t e n s i o n secondary to renal involvement. Infiltration of endothelium and m y o c a r d i u m by glycosphingolipid 2. 11.15 m a y also result in E C G and VCG evidence of c h a m b e r e n l a r g e m e n t in the absence of hypertension t h r o u g h some y e t unidentified mechanisms. Valvular i n v o l v e m e n t in Fabry's disease 2. 5, ,. 11. 15 m a y also be responsible for c h a m b e r e n l a r g e m e n t by v o l u m e or pressure overloading. Nonspecific S T - T changes m a y be a result of altered repolarization of t h e infiltrated myocardium. E C G evidence of m y o c a r d i a l infarction and ischemia have been occasionally reported in patients with Fabry's disease w i t h o u t clinical or autopsy evidence of c o r o n a r y a r t e r y diseaseY' 6. i6. 11.15 Our patients with either a p a t t e r n of myocardial infarction or ischemic T - w a v e changes had no clinical features o f c o r o n a r y disease: This again illustrates t h a t storage disorders affecting t h e m y o c a r d i u m can mimick myocardial infarction in the E C G and VCG. 24 As would be expected, hemizygosity was asso: ciated with more abnormalities. In 21 hemizygous patients in this study, a short P R interval was present in four patients, l e f t v e n t r i c u l a r hyper: t r o p h y in nine, i n t r a v e n t r i c u l a r conduction defects in four, S T - T changes in 18, sinoatrial and A-V block in one each and left a n t e r i o r hemiblock in one. Only six hemizygous patients had n o r m a l ECG's whereas, of 11 heterozygous patients, five had normal ECG's (p < 0.05). Since Fabry's disease m a y be a m e n a b l e to therapy, 25itis essential to u n d e r s t a n d the n a t u r a l history of electrical changes in t h e m y o c a r d i u m and the mechanisms thereto. Our observations show t h a t glycosphingolipid infiltration in the myocardium, blood vessels, and conduction system results in progression of conduction defects and c h a m b e r enlargement. Occasionally decreases in electrical c o n d u c t i o n time and regression of c h a m b e r e n l a r g e m e n t p a t t e r n s m a y also be apparent, probably due to electrical
704
alterations. N o t unexpectedly, hemizygosity is associated with more severe defects. Summary Fabry's disease has been reported to be associated with ECG abnormalities. T h i r t y - t w o patients with this disease followed in the University of Minnesota had E C G ' s and 15 had VCG's. An a b n o r m a l r h y t h m was observed in two patients on initial e x a m i n a t i o n and four more developed abnormal r h y t h m on follow-up examinations. A short P R interval (120 msec. or less) was seen in five patients. T h i r t e e n others had a PR interval t h a t was less t h a n 140 msec. Conduction abnormalities involving the A-V node or His bundle or its branches were present in 22 per cent of the patients, most f r e q u e n t l y the intraventricular conduction defects progressing to the right bundle b r a n c h block. Atrial or ventricular enlargement was seen in 60 per cent of the patients, left ventricular h y p e r t r o p h y being the most common. S T - T changes with or w i t h o u t chamber enlargement were seen in 10 patients. One patient had an a n t e r i o r m y o c a r d i a l infarction p a t t e r n on his ECG. Hemizygosity was f o u n d to be associated with significantly more abnormalities t h a n heterozygosity. T h e severity of conduction defects also increased with the duration of the disease process. V e c t o r c a r d i o g r a p h y in this study did not provide significant additional information other t h a n t h a t observed on the E C G alone. Since the p a t h o l o g y usually reveals myocardial fibers, conduction system, and blood vessels infiltrated with glycosphingolipid, it is believed t h a t lipid infiltration is responsible for conduction defects, c h a m b e r enlargement, and other abnormalities. Although Fabry's disease is rare, it m a y be amenable to t h e r a p y ; therefore, recognition of cardiac i n v o l v e m e n t is i m p o r t a n t . The authors gratefully appreciate the expert secretarial assistance of Mrs. Frances Wallace in preparation of the manuscript. REFERENCES 1. Sweeley,C. C., Klionsky, B., Krivit, W., et al.: Fabry's disease in Stanbury, J. B., Wyngaarden, J. B., and Fredrickson, 0. S., editors: The metabolic basis of inherited disease, ed. 3, New York, 1972, McGraw-Hill Book Company, Inc., pp. 663-687. 2. Ferrans. V. J., Hibbs, R. G.. and Burda, C. D.: The heart in Fabry's disease. A histochemical and electron microscopic study, Am. J. Cardiol. 26:95, 1969. 3. Roudebush, C. P.. Foerster, J. M., and Bing, O. H. L.: The
J u n e 197~ Vos
No. 6
ECG and VCG abnormalities in Fabry's disease
4. 5. 6. 7.
8.
9.
10.
11. 12.
13.
14.
abbreviated PR interval of Fabry's disease, N. Engl. J. Med. 289:357, 1973. Duncan, C.: Angiokeratoma-a case with gross myocardial involvement, Australas. Ann. Med 19:58, 1970. Leder, A. A., and Boxworth, W. C.: Angiokeratoma corporis diffusum universale (Fabry's disease) with mitral stenosis, Am. J. Med. 38:814, 1965. Wise, D., Wallace, H. J., and Jellinek, E. H.: Angiokeratoma corporis diffusum. A clinical study of eight affected females, Q. J. Med. 31:177, 1962. Ruiter, M., Pompen, A. W. M., and Wyers, H. J. G.: lJber interne und pathologisch-anatomische Befunde bei Angiokeratoma corporis diffusum (Fabry), Dermatologica 94:1, 1947. Pompen, A. W. M., Ruiter, M., and Wyers, H. J. C.: Angiokeratoma corporis diffusum (universale) Fabry as a sign of an unknown internal disease: Two autopsy reports, Acta Med. Scand. 128:235, 1947. Dubach, U. C., and Gloor, F.: Fabry-Kranbeit (angiokeratoma corporis diffusum universale). Posphatidspeicherkrankheit bei zwei Familien, Dtsch. Med. Wohnschr. 91:241, 1966. Parkinson, J. E., and Sunshine, A.: Angiokeratoma corporis diffusum universale (Fabry). Presenting as suspected myocardial infarction and pulmonary infarcts, Am. J. Med. 31:951, 1961. Becker, A. E., Schoorl, R., Balk, A. G., et al.: Cardiac manifestations of Fabry's disease, Am. J. Cardiol. 36:829, 1975. Desnick, R. J., Allen, K. Y., Desnick, S. J., et al.: Fabry's disease: Enzymatic diagnosis of hemizygotes and heterozygotes. Alpha-galactosidase activities in plasma serum, leukocytes and urine, J. Lab. Clin. Med. 81:157, 1973. Johnson, D. L., DelMonte, M. A., Cottier, E., et al.: Fabry's disease: Diagnosis of hemizygotes and heterozygotes by alpha-galactosidase A activity in tears, Clin Chim. Acta 63:81, 1975. Schmitt, O. H., and Simonson, E.: The present status of vectorcardiography, Arch. Intern. Med. 96:574, 1955.
American Heart Journal
15. Desnick, R. J., Blieden, L. C., Sharp, H. L., et al.: Cardiac valvular anomalies in Fabry's disease. Clinical morphologic and biochemical studies, Circulation (In press, November, 1976) 16. The Criteria Committee of the New York Heart Association: Nomenclature and criteria for diagnosis of disease of the heart and great vessels, ed. 7, Boston, 1973, Little, Brown & Company. 17. Altman, P. L., and Dittmer, D. S., editors: Respiration and circulation, Bethesda, Md., 1971, Federation of American Societies for Experimental Biology, p. 281. 18. Brohet, C. R., Liedtke, C. E., and Tuna, N.: P wave abnormalities in the orthogonal electrocardiogram: Correlation with ventricular overload in pulmonic and aortic valvular heart disease, J. Electrocardiol. 8:103, 1975. 19. Chou, T. C., and Helm, R. A.: Clinical vectocardiography, New York, 1967, Grune & Stratton, Inc. 20. Ohnishi, A., and Dyck, P. J.: Loss of small peripheral sensory neurons in Fabry's disease, Arch. Neurol. 31:120, 1974. 21. Blieden, L. C., Desnick, R. J., Carter, J. B., et al.: Cardiac involvement in Sandhoff's disease: An inborn error of glycosphingolipid metabolism, Am. J. Cardiol. 34:83, 1974. 22. Hadley, R. N., and Hagstrom, J. W. C.: Cardiac lesions in a patient with familial neurovisceral lipidosis (generalized gangliosidosis), Am. J. Chn. Pathol. 55:237, 1971. 23. Rodriguez-Torres, R., Schneck, L., et al.: Electrocardiographic and biochemical abnormalities in Tay-Sachs disease, Bull. New York Acad. Med. 47:717, 1971. 24. Scholmerich, P.: Myocarditis and weitere Myokardiopathien, in Bergman, G., Frey, W., and Schweiegk, H., editors: Handbuch er Inneren Medizin, Berlin, 1960, Springer Verlag, p. 960. 25. Desnick, R. J., Thorpe, S. R., and Fiddler, M. B.: Towards enzyme therapy for lysosomal storage disease, Phys. Rev. 56:57, 1976.
705
