SHORT REPORT ABSTRACT: To investigate the pathophysiology of neuropathy in Fabry
disease, multiple nerve excitability properties of median motor axons in 20
patients with this disorder but without hyperkalemia were compared with 35
age-matched normal controls. In the patients, depolarizing threshold elect-
rotonus was reduced (P
0.0001) and superexcitability was reduced (P

0.001), but late subexcitability was normal. These findings indicate that the
axons were mildly depolarized, probably due to ischemia, and are consistent
with the hypothesis that poor nerve perfusion in Fabry disease contributes to
axonal damage.
Muscle Nerve 32: 548–551, 2005
EVIDENCE FOR MOTOR AXON DEPOLARIZATION
IN FABRY DISEASE
STELLA V. TAN, MD,
1
PHILIP J. LEE, DM,
2
RICHARD J. L. WALTERS, MD,
1
ATUL MEHTA, MD,
3
and HUGH BOSTOCK, PhD
4
1
Department of Clinical Neurophysiology, National Hospital for Neurology
and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom
2
Department of Metabolic Medicine, National Hospital for Neurology
and Neurosurgery, London, United Kingdom
3
Department of Haematology, Royal Free Hospital, London, United Kingdom
4
Sobell Department of Motor Neuroscience and Movement Disorders,
Institute of Neurology, University College London, London, United Kingdom
Accepted 4 May 2005
Fabry disease is the second most prevalent lysoso-
mal storage disorder of humans after Gaucher
disease, and has an incidence of about 1:117,000–
1:476,000 live births.
7
It is an X-linked disorder
caused by mutation of the gene encoding the ly-
sosomal hydrolase
-galactosidase A.
1,9
Pathology
arises from the progressive accumulation of cer-
amide trihexoside and related
-d-galactosyl con-
jugates in various cells and tissues, particularly in
vascular endothelium and smooth muscle cells,
resulting in a microvasculopathy. Lipid deposits
also occur in renal epithelium, myocardium, skin,
and cornea, and in the central, peripheral, and
autonomic nervous systems.
2,3,8
The disease results
in a small-fiber neuropathy manifest by episodes of
severe painful acroparaesthesias starting in child-
hood and adolescence. The pathogenesis of the
neuropathy is poorly understood. The ceramide
trihexoside and related glycolipids may cause dam-
age directly, by intracellular accumulation in ax-
ons or sensory neurons, or indirectly by accumu-
lation in endothelial cells causing ischemic injury.
In this preliminary study, we have used nerve
excitability testing to seek changes in axonal mem-
brane properties that might provide new light on the
pathophysiology of the neuropathy in Fabry disease.
Motor axons were studied, although they are rela-
tively unaffected in Fabry disease, since the most
affected small fibers cannot be tested noninvasively,
and motor nerve excitability parameters can be mea-
sured more quickly and reliably than those in large
sensory fibers. A microvasculopathy affecting the in-
traneural milieu would be expected to affect all types
of nerve fiber.
METHODS
We studied 20 patients who had either enzymatically
confirmed Fabry disease (
-galactosidase activity lev-
els of
1.5 nmol per hour per millilitre in plasma or

4 nmol per hour per milligram in leukocytes), or
genetically confirmed disease. Other patients with
Fabry disease were excluded because they were on
dialysis or were hyperkalemic (5.0 mmol/L; one
patient), but those with mild renal impairment not
resulting in an elevation in serum potassium and not
requiring treatment were included (serum creati-
nine
200 mol/L). Patients were also excluded if
Key words: electrotonus; Fabry disease; ischemia; nerve excitability; neu-
ropathy
Correspondence to: S. V. Tan; e-mail: veronica.tan@gstt.nhs.uk.
© 2005 Wiley Periodicals, Inc.
Published online 7 July 2005 in Wiley InterScience (www.interscience.wiley.
com). DOI 10.1002/mus.20390
548 Nerve Excitability in Fabry Disease MUSCLE & NERVE October 2005

their skin temperature over the recording site was

29.5°C, as relative refractory period measurements
are sensitive to skin temperature (three patients).
The patient group did not include asymptomatic
heterozygotes. Informed consent was obtained from
all patients. The study was approved by the National
Hospital for Neurology and Neurosurgery and the
Institute of Neurology Joint Research Ethics Com-
mittee.
Excitability studies were performed on median
motor axons at the wrist according to a recently
described protocol designed to test multiple axonal
excitability parameters rapidly in the clinical set-
ting.
5
The measures included threshold electroto-
nus, to measure accommodation to subthreshold
depolarizing and hyperpolarizing currents, strength–
duration time constant, the recovery cycle to a su-
pramaximal stimulus (refractoriness, superexcitabil-
ity, and late subexcitability), and a current–
threshold relationship to assess inward and outward
rectification.
5
Values for these excitability parame-
ters were compared between the patients and a con-
trol group of 35 age- and sex-matched normal sub-
jects who provided informed consent to participate,
using unpaired two-tailed t-tests. Parameters were
normalized by logarithmic transformation when this
was appropriate.
RESULTS
Baseline Data. The patient and control groups were
similar in age [20 patients with Fabry disease, 22–59
years, mean 44.3  11.6 (SD); 35 controls, 29–58
years, mean 41.2  8.9], sex ratio (patients: 4
women, 16 men; controls: 8 women, 27 men), and
skin temperature (patients, 32.1  1.2°C; controls,
32.4  0.8°C). Serum potassium averaged 4.28 
0.22 mM in the patients, slightly lower than expected
for the controls (not measured, but expected aver-
age 4.48).
Excitability Data. The excitability data were broadly
similar between the two groups (Fig. 1A,B), consis-
tent with previous findings that, compared with
small fibers, motor axons are relatively unaffected in
Fabry disease.
8
Nevertheless, there were a few signif-
icant differences, which may provide information
about the nature of the neuropathy.
The most significant abnormality in the patients
was a “fanning-in” of the threshold electrotonus
waveforms, so that the excitability change to a
100-ms depolarizing current, set to 40% of thresh-
old, was significantly less than normal (Fig. 1A,C).
Although only one of the patient electrotonus values
was abnormal, in the sense of being outside the 99%
confidence limits for the control population, there
was a clear tendency for the threshold reductions of
the patients with Fabry disease (39.9  0.8%;
mean  SE) to be lower than those of the controls
(44.6  0.6%; P
0.0001). Similarly, superexcitabil-
ity in the patients (18.5  1.4%) was less (in an
absolute sense) on average than that in the controls
(24.6  0.9%; P
0.001; Fig. 1B,D). These two
parameters were previously found to be the most
sensitive to membrane potential
4
and the changes
indicate membrane depolarization. Changes in
other excitability parameters were consistent with
depolarization, though mostly nonsignificant. Late
subexcitability was not significantly different be-
tween the groups.
No correlation was found between the excitabil-
ity changes and white cell
-galactosidase levels, ther-
mal perception thresholds, or size of the sural sen-
sory action potential. There was no significant
difference between the findings in patients with (13)
or without painful acroparaesthesias, cardiac dys-
function (8), mild renal impairment (3), carpal tun-
nel syndrome (2), or carbamazepine treatment (4).
DISCUSSION
This study documents abnormalities in the excitabil-
ity properties of motor nerve axons in Fabry disease,
and provides clear evidence of axonal membrane
depolarization. The three excitability parameters
previously found to correlate most strongly with
membrane potential (depolarizing threshold elect-
rotonus, resting current–threshold slope, and super-
excitability)
4
all showed significant changes in the
direction of depolarization, and other changes were
consistent with this interpretation. Other nerve ex-
citability studies have shown that late subexcitability
provides information about the mechanism of mem-
brane depolarization, presumably because it de-
pends on extra-axonal potassium concentration as
well as membrane potential: when depolarization is
caused by applied currents there is an increase in
late subexcitability,
4
when it is caused by ischemia
there is little or no change in subexcitability,
4
but
when it is caused by hyperkalemia, there is a reduc-
tion in late subexcitability.
6
In Fabry disease, the
axonal membrane depolarization was accompanied
by normal late subexcitability, suggesting an isch-
emic origin of the depolarization and inconsistent
with hyperkalemia. This would be in keeping with
histological findings of a microvasculopathy in Fabry
disease, caused by glycolipid accumulation in the
endothelial, perithelial cells and smooth muscle cells
Nerve Excitability in Fabry Disease MUSCLE & NERVE October 2005 549