Clinical Neurophysiology 119 (2008) 1365–1372 www.elsevier.com/locate/clinph
Neuropathic symptoms and findings in women with Fabry disease q Satu M. Laaksonena,*, Matias Ro¨ytta¨b, Satu K. Ja¨a¨skela¨inena, Ilkka Kantolac, Maila Penttinend, Bjo¨rn Falcka a
Department of Clinical Neurophysiology, Turku University Hospital, Kiinamyllynkatu 4-8, 20520 Turku, Finland b Department of Pathology, Turku University Hospital, Turku, Finland c Department of Medicine, Turku University Hospital, Turku, Finland d Department of Pediatrics, Clinical Genetics Unit, Turku University Hospital, Turku, Finland Accepted 3 February 2008 Available online 1 April 2008
Abstract Objective: To examine the neurologic and neurophysiologic findings and neurologic symptoms in 12 women with Fabry disease and to study the relationship between the subjective symptoms and the findings on the various tests done. Methods: Neurography, vibratory and thermal quantitative sensory testing (QST), skin biopsy for measuring intraepidermal nerve fiber density (IENFD). Heart rate variability (HRV) and sympathetic skin response (SSR) tests for detecting autonomic dysfunction, pain-, depression- and somatic symptom questionnaires and clinical examination. Results: Only two women had no persistent symptoms or signs of polyneuropathy, 10 had symptoms of small fiber neuropathy. Neurological examination was normal in most patients. Five patients had decreased IENFD or thermal hypoesthesia in QST. In QST, Ad-fiber function for innocuous cold was more often impaired than C-fiber function. Conventional nerve conduction studies were mostly normal. Carpal tunnel syndrome (CTS) incidence was increased, 25% had symptomatic CTS. Conclusions: Heterozygous women carrying the gene for Fabry disease have symptoms and findings of small-fiber polyneuropathy more often than has previously been considered. The prevalence of CTS is also increased. Significance: While the clinical diagnosis of small-fiber neuropathy is difficult, the diagnostic yield can be increased using a combination of thermal QST and IENFD measurements. Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Fabry-disease; Small-fiber polyneuropathy; Pain; Intra-epidermal nerve fiber density; QST
1. Introduction Fabry disease is an X-linked lysosomal storage disease, caused by the mutations in the GLA gene coding for the lysosomal enzyme alfa-galactosidase in chromosome Xq22.1 (Eng and Desnick, 1994; Ashley et al., 2001). As a result of the enzyme deficiency, neutral glycosphingolipids accumulate in most visceral tissues (Brady and Schiffmann, 2000; Kaye et al., 1988). Typically, the first neuropathic symptoms, recurrent episodes of severe pain in the extremities during fever, occur during childhood q *
The study was supported by EVO funds of Turku University Hospital. Corresponding author. Tel.: +358 23131936; fax: +358 23133922. E-mail address: satu.laaksonen@utu.fi (S.M. Laaksonen).
or adolescence (MacDermot and MacDermot, 2001). Pain has been reported to first occur as early as 3 years of age in boys, and 6 years of age in girls (Ries et al., 2003). Later on, the most debilitating symptoms are pain and tingling paresthesias in the hands and feet, lasting from minutes to several days (Dutsch et al., 2002; Schiffmann et al., 2003). Because the disease is an X-linked recessive, it has been postulated that only men are affected. In the majority of X-linked disorders, heterozygous women are asymptomatic. In Fabry disease, however, recent studies have shown that heterozygous women have characteristic signs of the disease, and many of them are severely affected (Maier et al., 2006; Mehta et al., 2004; Moller et al., 2006; MacDermot et al., 2001; Moller and Jensen, 2007). The penetrance of the gene mutation is close to 100%, an uncommon feature for women
1388-2457/$34.00 Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2008.02.004
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who are heterozygous for an X-linked recessive trait (Maier et al., 2006). Many women present with the full spectrum of the disease manifestations, but with a later onset of symptoms, a slower rate of progression, and a higher phenotypic variability than men (Mehta et al., 2004). Life expectancy is reduced in both men and women, by about 30 years in men and 20 years in women, due to renal, cerebral and cardiac complications (MacDermot and MacDermot, 2001; Maier et al., 2006; Mehta et al., 2004; Fellgiebel et al., 2006). The neuropathic symptoms in Fabry disease together with the neuropathologic and neurophysiologic signs have not been studied earlier. Earlier studies of the peripheral nervous system in Fabry disease have shown that large myelinated axons are spared in the early stages of the disease, but small-fiber function mediated by unmyelinated C fibers and small myelinated Ad fibers is affected in most patients (Dutsch et al., 2002; Luciano et al., 2002; Low et al., 2007). Our goal was to study neuropathic symptoms, neurophysiologic findings including thermal quantitative sensory thresholds (QST) and intraepidermal nerve fiber-density (IENFD) in skin biopsy in women with Fabry disease before enzyme replacement therapy was started. We studied the diagnostic yield of different neurophysiologic and IENFD tests in the diagnosis of smallfiber neuropathy in Fabry gene carriers, and we were also interested in the relationship between the subjective symptoms and the findings on the different diagnostic tests. 2. Patients The study group consisted of 12 women with Fabry disease aged 17–63 years, (mean 45.5, SD 15.1 years). The diagnosis was confirmed by mutation analysis in nine (Table 2b) and by skin biopsy in one, while two were obligate carriers. The patients gave their informed consent before participating in the study. The study was approved by the Ethical Committee of Turku University Hospital district. Eleven of the patients agreed to have a skin biopsy; one patient did not give her consent for a biopsy, but gave consent for the other tests. Serum creatinine was normal in all patients and the renal function was also considered normal. No-one had diabetes or any other systemic disease that could lead to peripheral neuropathy. 3. Methods Subjective symptoms and pain questionnaire. Subjective symptoms and clinical findings were evaluated using a questionnaire covering sensory and autonomic symptoms. The questionnaire is a modified version of the ‘‘Neuropathy Symptom Score” (NSS) (Dyck, 1993). The section on subjective sensory symptoms had 10 questions about positive and negative polyneuropathy-related symptoms. Four of the questions in the questionnaire concerned the type of pain. The autonomic symptoms questionnaire had eight questions. If patient had a symptom, one point was given. Items of the questionnaire are shown in detail in Table 1.
A separate pain questionnaire that evaluated the severity, type and distribution of pain was used. This questionnaire had questions from the ‘‘graded chronic pain status” (Von Korff et al., 1990; Dworkin and LeResche, 1992; Smith et al., 1997) and the ‘‘symptom checklist -90R” (SCL-90R) questionnaire (Derogatis et al., 1973). In this questionnaire, a numerical rating from 0–10 points was used. The patient also indicated whether the pain was intermittent or continuous. The questionnaire had questions about pain now, worst pain and average pain within the last 6 months. It included a ‘‘social disability score” within the last 6 months by a numerical rating from 0 to 10. The questionnaire had separate questions to evaluate depressive symptoms and a section for non-specific somatic symptoms like ‘‘feeling unwell, diffuse symptoms in the stomach”. One to four points were given for each positive answer, regarding the severity of the symptom asked about. The points were added and divided with the number of questions in the questionnaire. Depressive symptoms were graded as severe, if the patient scored >1.105 points, moderate 0.535–1.105 points, and normal <0.535 points. The somatic symptom score was graded normal (<0.5 points) moderate (0.5–1) and severe (>1 point). 3.1. Clinical examination The neuropathy disability score was the same as that used in our previous study (Laaksonen et al., 2005), this score is adapted from Dyck’s score (Dyck, 1993). The neuropathy disability score included clinical findings: (1) the strength of the limb and trunk muscles on the MRC-scale, (2) biceps brachi, triceps, patellar and Achilles tendon reflexes, (3) clinical sensory examination; touch-pressure was tested with long-fiber cotton wool, pin-prick with straight pins: the tests were done on the dorsal surface at the base of the nail of the terminal phalanx of the index finger and great toe, and (4) joint position, measured by moving the terminal phalanx of the index finger and great toe.
Table 1 Questions asked in sensory and autonomic questionnaires Sensory symptoms
Autonomic symptoms
Decreased feeling of the surface features, size, shape or texture when touching Decreased recognition of hot from cold Decreased feeling of pain, cuts or other injuries Continuous ‘‘dead feeling” like novocaine without prickling Continuous ‘‘prickling” or ‘‘tingling” feeling Unusual sensitivity or tenderness Sharp needle-like pain Burning discomfort Deep aching pain Other pain
Feeling faint, only on sitting or standing Repeated nausea Persistent diarrhea, especially at night Loss of bladder control, not due to gynecologic/prostate problems Loss of rectal control Impotence Dryness of eyes Dryness of mouth
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3.2. Neurography Motor nerve conduction velocities (CV), M-wave amplitudes (AMPL), and latency of the peroneal, tibial, ulnar and median nerves were measured. F-wave minimal latency was recorded with 20 supramaximal stimuli. Sensory nerve conduction velocity and sensory nerve action potentials were recorded antidromically from radial, median and sural nerves with surface electrodes. The exact details of the methods for each nerve have been described elsewhere (Falck et al., 1994; Sta˚lberg and Falck, 1993). The temperature of the hand had to be at least 29 °C and of the foot 27 °C. If they were cooler, they were warmed. The measurements were done using Medtronic Keypoint EMG equipment (Skovlunde, Denmark) and the appropriate analysis programs. All neurophysiologic and psychophysical tests were done on the non-dominant side. The severity of neurography findings in the patients with carpal tunnel syndrome (CTS) was scored according to the classification of Padua et al. (Padua et al., 1997). 3.3. Vibratory detection threshold (VDT) VDT was measured over the middle of the 1st metatarsal bone on the dorsal side of the foot with a 100 Hz vibratory device (Vibrameter type II, Somedic AB, Solna, Sweden). The method has been described in detail elsewhere (Laaksonen et al., 2002). 3.4. Thermal thresholds The cold (CDT) and warm (WDT) detection thresholds were measured from the foot and hand with Thermotest equipment (Somedic AB, Solna, Sweden). The thermode consisted of Peltier elements that either cooled or warmed up linearly depending on the direction of the applied electric current that was changed by a patient operated switch. The exact details of the test are described elsewhere (Forssell et al., 2002). The thermode, size 25 55 mm, was placed (1) over the extensor digitorum brevis muscle, and (2) over the thenar eminence. The measurement was repeated with cooling and warming five times; after deleting the highest and the lowest value, the mean of the remaining three values was calculated to be used as the cold or warm detection threshold. 3.5. Sympathetic skin response (SSR) SSR was recorded from the hand and foot. The recording electrodes were placed on the palm of the hand and the sole of the foot, while the reference electrodes were placed on the dorsal side. The stimuli were deep inhalation, electrical stimulation of the median or peroneal nerve, loud noise (technician clapped her hands together once), and light touch to hand skin. The tests were done using standard techniques with Keypoint EMG software (Skovlunde,
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Denmark). If no responses were recorded from two or more tests, the test result was considered abnormal. 3.6. Heart rate variability (HRV) The autonomic nerves of the heart were tested with a 20min HRV test at rest, Breathing was not controlled because the study lasted 20 min. The study was done after 20 min resting in a supine position with Keypoint-EMG software (Skovlunde, Denmark). The frequency domain measures for total power (TP), high frequency (HP), low frequency (LP), and LF/HF were measured and the results were compared with the reference values of our laboratory for normality. The HRV test was done as the first test of each examination. 3.7. Intraepidermal nerve-fiber density (IENFD) Punch biopsies of the skin were taken with a 3-mm disposable circular punch after a local infiltration with 5% lidocaine; no suture was needed. Biopsy specimens were obtained 10 cm above the lateral malleolus from the nondominant side and fixed with Zamboni’s fixative. Ten micrometer-thick sections (Koskinen et al., 2005) were stained with a polyclonal panaxonal marker PGP 9.5. The light microscopic examination of the nerve fibers was done under the Olympus BX51 microscope and the number of intraepidermal nerve fibers were morfometrically analysed by using Olympus Soft Imaging system (Cell*) using Olympus Colourview IIIu microscope. The intraepidermal nerve fiber counts were done by two independent observers (S.L. and M.R.). Only fibers clearly penetrating into epidermis were counted. Unmyelinated fibers were considered as separate if (1) the distance between the two different perpendicular sections of the immunoreactive nerve exceeded 5 times the diameter of an axon, or (2) there were clearly two individual parallel fibers. Nerves in the underlying dermis and sweat glands served as internal positive controls. The density of nerve fibers/mm was calculated. 3.8. Reference values The reference values of our laboratory were used in the assessment of each test. Many of the neurophysiologic parameters depend on several independent variables, especially age and height. Therefore, linear regression models for age and/or height were used (Falck et al., 1991). Reference values are expressed as Z scores unless stated otherwise. The Z-score indicates the distance of the measured value from the expected value of the subject in standard deviations. For nerve conduction velocity and response AMPLs, Z scores < 2 were designated as abnormal; for F-wave latencies, F-wave dispersion, thermal thresholds and VDT, Z scores > +2 were considered abnormal. As an example, Z-score = 2 for nerve conduction velocities has a 2, 23% probability of being normal. Reference values for IENFD of our own laboratory were used.
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3.9. Statistics Pearson and Spearman correlation coefficients were used to evaluate the relationship between clinical, QST, neurophysiologic and neuropathologic variables. One-sample T-test was used to determine if the neurophysiologic, neuropathologic and quantitative sensory test results differed at group level from the reference populations. P values <0.05 were considered significant. 4. Results The main results are summarized in Tables 2a and 2b. 4.1. Subjective symptoms Pain in the extremities, continuous or discontinuous, was reported by 10 patients; the youngest patient did not report any pain. Burning pain in the extremities during fever and/or hot conditions was present in 8 of 12 patients. Deep pain in the extremities was the most often reported type of continuous pain; present in 4 of 12 patients. Other symptoms were unspecific (Table 2a). Symptoms related to CTS were excluded from the analysis of symptoms due to Fabry disease. One patient did not answer the questions about pain now, worst pain, average pain and pain affecting social life. The pain affected patients’ social life in all five patients with continuous pain. In four of them the effect to social life was severe. These patients also had high sub-scores on the question that referred to current pain. Average pain experienced by the patients within 6 months was from 2–7/10, two of the youngest patients did not report any pain during last 6 months, the second youngest patient had had pain earlier only during fever (Table 2a). 4.2. Symptoms of depression and unspecific somatic symptoms Nine of 12 patients filled in the questionnaire screening depressive and unspecific somatisation symptoms. Two patients had scores indicating severe depressive symptoms. They also had elevated scores for unspecific somatic symptoms. In addition, they had neuropathic pain on the pain questionnaire, together with moderately decreased IENFD. Three patients had scores indicating moderate depressive symptoms. The same patients also had scores indicating unspecific somatic symptoms. Of the patients who answered, 50% had normal scores indicating no depression; one of them had moderately elevated scores on unspecific somatic symptoms (Table 2a). 4.3. Clinical findings Clinical neurological examination, done to ten patients, was mostly normal. In the foot, only one patient did not feel the pin prick (patient 9). Ankle reflex was diminished
but not absent in patient 10. The tendon reflexes and muscle strength were normal in all the other patients. 4.4. Neurography We found slowing of the median nerve sensory conduction velocity at the wrist in three patients, indicating median nerve entrapment at the wrist. All of them had subjective symptoms compatible with CTS. One patient (patient 6) had severe CTS with no other neurologic symptoms, but slight abnormalities in sensory sural neurography; Z-score of sural nerve amplitude was 2.3. Her median nerve sensory responses from the fingers were absent, and the median nerve motor distal latency from the wrist to the thenar muscles was markedly increased (9.1 ms, Z-score 15.5). Moderate CTS was seen in patient 5 with increased median nerve motor distal latency, and sensory CV of the median nerve at the wrist was slow. This patient also had mild peripheral neuropathy (> two abnormalities in neurophysiologic tests, and sensory symptoms; abnormal sensory radial (Z 2.2), sural amplitude (Z 3.7) and motor tibial amplitude (Z 2.3). The third patient had mild CTS with mild sensory median nerve conduction velocity (Z 2.6), and normal median nerve motor distal latency. The IENFD was close to the lower limit of normal (Z 1.6), but other tests were normal. One (patient 11) had slightly decreased sural nerve sensory amplitude (Z 2.3), while neurography was otherwise normal. Her legs were markedly swollen, which probably caused the reduced sural nerve response amplitude. In the other patients, neurography was normal. 4.5. Thermal and vibration sensation thresholds Four patients (33%) had abnormal CDT in the foot. Two of them were also the oldest patients in the study group with longest disease duration. One patient did not feel cold at all in the foot, but CDT was normal in her hand. Two of these patients also had abnormal WDT in the foot. VDTs were normal in all patients (Table 2b). 4.6. Sympathetic skin response (SSR) Eleven out of 12 patients had normal SSR responses from both upper and lower extremities. One patient (number 12) did not have recordable responses in the foot, but showed normal response from the hand. She also had autonomic symptoms; feeling faint, dryness of eyes and mouth. 4.7. Heart rate variability test (HRV) HRV frequency domain measures were measured in eight patients. One patient had atrial fibrillation and the HRV tests were not performed, and in three patients, the program was not available at the time the studies were done. The HRV variables in the frequency and time domains were normal in all patients studied.
Table 2a Pain, depressive, somatic symptoms and sensory descriptors Age (years)
Pain now
Worst pain
Average pain
Pain affecting social life
Depressive
Somatic symptoms
Pain descriptors
Sensory descriptors
Autonomic symptoms
1 2 3
18 20 37
0 0 0
0 0 3
0 0 2
0 0 4
*
*
–
0 *
– Burning pain during fever, feet Burning pain during fever hands only
–
0 *
Unusual sensitivity or tenderness legs only
Feeling faint
4 5
41 43
0 0
6 0
2 0
1 0
0 0
0 0
Burning pain during fever hands and feet Burning pain during fever hands and feet
Feeling faint
*
*
7
0 2
1 2
5
8
1
2
9
7
7
2
2
Burning pain during fever hands and feet Sharp needle-like pain legs only, deep pain legs only, burning pain during fever hands and feet Sharp needle-like pain legs only, deep pain legs only Deep pain, hands and feet
Continuous dead feeling without prickling, arms only –
6 7 8
45 46 54
0 *
0 *
0 *
0 *
6
3
6
9
56
9
9
10
60
7
11
63
0
6
3
3
1
2
Sharp pain legs only, burning pain during fever hands and feet
12
63
7
8
6
7
1
2
Deep pain legs and arms only, burning pain during fever hands and feet
Worst pain, average pain and pain affecting patient’s social life within last 6 months. Sensory, points from sensory symptom questionnaire 0–10 points. Depressive and somatic symptoms, 0–10 points. *, Did not answer.
– Feeling faint
Prickling or tingling, legs only Feeling faint, dryness of mouth Continuous dead feeling without prickling, arms only Prickling or tingling, dead feeling, arms and legs
Feeling faint, dryness of eyes and mouth
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Patient nr
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Table 2b Results of small-fiber and CTS tests Patient nro
Age (years)
Confirmation of the disease
CTS
1 2 3 4 5 6 7 8 9 10 11 12
18 20 37 41 43 45 46 54 56 60 63 63
Pro409Ala Leu311Phe Arg227Gln Gln283STOP Obligate carrier Obligate carrier Arg227Gln Gln283STOP Leu311Phe Pro409Ala Biopsy (skin) His46Arg
– – – – moderate severe – – – mild – –
IENFD Z score 0.7 – 0.1 1.9 1.8 2.2 1.3 1.8 1.2 1.6 2.2 3.4
CDT hand Z-score .9 .0 1.2 .8 1.6 1.0 1.2 1.5 .7 1.9 .9 1.9
CDT foot Z-score .2 .1 .8 22.8 1.7 .6 .2 1.5 4.5 .2 4.1 25.1
WDT hand Z-score 1.9 .8 .3 1.1 .9 .3 .4 1.6 .7 1.9 .2 1.4
WDT foot Z-score 0.8 1.1 1.1 .2 2.3 .8 0.9 1.4 2.5 1.2 3.5 1.4
CTS, Carpal tunnel syndrome; IENFD, Z-score of intraepidermal nerve-fiber density; Cold hand, Z-score, cold detection threshold from hand, etc.; WDT, warm detection threshold.
4.8. Intraepidermal nerve fiber density (IENFD) IENFD was decreased compared to normal values of our laboratory in three out of 11 patients. Three patients had borderline abnormality and only one patient had clearly normal IENFD (Z = 0.8) (Table 2b). The IENFD was related with age (p = 0.04), older patients having fever intraepidermal nerve fibers compared to young patients. 4.9. Associations between subjective symptoms and findings in neurophysiologic, QST and neuropathologic tests Low Z-scores of IENFD were associated with high pain symptom sub-scores within the last 6 months. Subjective symptoms (pain, sensory or autonomic) were not associated with the CDT or WDT test in either hand or foot. The thermal thresholds did not correlate with IENFD. Age and the findings in QST did not have a significant correlation. Nor did age reach significance with subjective symptoms. However, two of the youngest patients did not score any points on the pain questionnaire. 5. Discussion There are only few studies concerning Fabry disease related peripheral neuropathy in women (Hilz et al., 2000; Moller et al., 2006; Gibas et al., 2006; Deegan et al., 2006; MacDermot et al., 2001). In women, some alpha galactosidase activity is usually present due to the unaffected X-chromosome, skewed X inactivation and mosaicism, thus leading to a milder disease (Mehta et al., 2004; Maier et al., 2006). Peripheral neuropathy in patients with Fabry disease is axon length-dependent and characterized by small-fiber neuropathy (Dutsch et al., 2002; Luciano et al., 2002; Scott et al., 1999; Hilz et al., 2004). Cold perception is more frequently and severely impaired than warm perception (Luci-
ano et al., 2002; Low et al., 2007). Chronic continuous pain in the extremities has also been reported. In a study by Mac Dermot et al. (MacDermot et al., 2001), 70% of 60 female Fabry carriers had experienced neuropathic pain which affected their daily life. In line with this, most of our patients reported continuous or fluctuating neuropathic pain. The cold detection thresholds were impaired in the patients with pain, while unmyelinated C-fiber -mediated warm detection thresholds were often within normal range. Based on our QST findings, there could be a more pronounced loss of Ad-fibers than C-fibers in Fabry disease. The PGP 9.5 antibody is currently the most commonly used marker for IENFD studies, it is a polyclonal panaxonal marker that stains both Ad- and C-fibers. Therefore, decrease in IENFD in the present material cannot be attributed to a loss of specific small-fiber type because different nerve-fiber subclasses were not selectively stained. Icolecitin B4 (IB4) and Substance P are specific antigens for C-fiber neurons in rat and mouse (Ruscheweyh et al., 2007), but they were not available for this study. Heat-pain detection thresholds were not used in this study; these responses have a large variation in healthy control subjects and therefore wide reference limits (Teerijoki-Oksa et al., 2003) and they are diagnostically insensitive. In previous clinical studies from our laboratory, CDT and WDT are more sensitive and diagnostically useful than pain thresholds (Teerijoki-Oksa et al., 2003, 2004). Painful episodes occurring in hot conditions or during fever were described as burning by all our patients experiencing pain. The episodes usually occur less frequently with ageing, but can also become more frequent and more severe (Dutsch et al., 2002; Valeriani et al., 2004). The exact pathophysiology of pain in Fabry disease is not fully understood, although the deposition of glycosphopholipid in the dorsal root ganglia, with subsequent cell death, has been proposed as a possible mechanism (Gadoth and Sandbank, 1983). Small-fiber damage or anterolateral tract
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lesions are considered essential in the development of neuropathic pain after peripheral nerve damage or central nervous system lesions (Cruccu et al., 2004). In the present and previous studies (Luciano et al., 2002), thermal hypoesthesia to cold stimuli in QST indicates damage to the thinly myelinated Ad fibers in Fabry disease. In line with QST findings, Ad-fiber mediated heat pain responses are also decreased in Fabry patients when evaluated with laserevoked-potential (LEP) recordings (Valeriani et al., 2004). This occurs in combination with relative enhancement of C-fiber mediated cortical LEP responses, and results in imbalance between the Ad- and C-fiber system inputs (Valeriani et al., 2004). Small-fiber neuropathy was evident in the present material of women with Fabry disease, showing cold hypoesthesia in CDT and decreased IENFD. IENFD was clearly diminished in 25% of our patients and another 25% had borderline findings. CDTs were abnormal in the foot in a similar proportion of patients, although in partly different subjects, and the WDTs were abnormal only in 17% of the patients. The diagnostic yield in small fiber neuropathy increases by studying both IENFD and CDT. The oldest patients in this study group had signs of clinical small-fiber neuropathy. Thermal detection thresholds were more often abnormal in the elderly patients, but the correlation analysis did not reach statistical significance between age and thermal detection thresholds, probably due to the small number of patients. Large-fiber function was normal in most of our patients. Two patients showed very mild axonal polyneuropathy, also affecting Ab-fiber afferents. Their serum creatinine level was normal, and renal function preserved. Uremic neuropathy can occur in end-stage Fabry disease, but in our patients it was an unlikely cause of the neuropathy. Poor nerve perfusion may also contribute to axonal damage (Tan et al., 2005), but in most earlier Fabry studies, large-fiber function has been reported to be preserved (Dutsch et al., 2002; Luciano et al., 2002). Five patients reported autonomic symptoms, but these symptoms did not affect their daily life. One patient showed signs of mild autonomic neuropathy; she had no SSR response in the foot, and she reported autonomic symptoms (feeling faint, dryness of eyes and mouth). Although signs of autonomic dysfunction have been reported in Fabry disease, and they have been shown to correlate with lipid deposition in autonomic neurons (Cable et al., 1982), autonomic neuropathy could not be diagnosed in the other 11 of our patients with the methods we used. Our test battery included a simple HRV test at rest. A more complete set of autonomic nervous system, especially HRV tests with 6/min controlled breathing, tilt test and Valsalva maneuver might have increased the yield of abnormalities. The oldest patients in our study had abnormally high scores on the depressive symptoms subscale. In spite of this, depression was not a major clinical problem in our patients. In the general population, lifetime prevalence for anxiety disorders is 28.8% (Kessler et al.,
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2005). Unspecific somatic symptoms scores were elevated in about half of our patients (42%). The prevalence and co-occurrence of somatoform disorders among the general population has been 35.9% (Toft et al., 2005), so compared to this study, the prevalence of somatic symptoms was not markedly elevated. On the basis of neurophysiological findings and IENFD studies, we believe that the pain symptoms reported by our patients were due to neuropathic pain caused by the disease. The patients with depressive symptoms did not have increased thermal detection thresholds, and they did not report unspecific somatic symptoms. The thermal QST results did not correlate significantly with IENFD. One reason could be the low statistical power of the relatively small study group. On the other hand, thermal QSTs we used do not measure heat or cold pain detection thresholds, only thresholds for warm and cold. Our thermal QST did not evaluate ‘‘pain fiber function” as probably the IENFD additionally did. However, IENFD as a quantitative pathologic test and thermal QST as a psychophysiologic test complement each other in the diagnosis of small-fiber dysfunction, as was evident in our results. In our study group three of 12 (25%) patients had CTS, which is clearly higher than the prevalence in women overall, 2.7% (Atroshi et al., 1999)–7.4% (De Krom et al., 1992). The study group was relatively small; of course there is a risk that a chance could explain the high prevalence of CTS. However, increased prevalence of CTS in patients with Fabry disease has also been reported by Luciano et al. (Luciano et al., 2002). They found that 27% of Fabry patients had CTS. The precise cause of this predisposition is not known; perhaps glycosphingolipids also accumulate in the carpal tunnel and in tendons passing it, thus thickening them and causing CTS. In this study, only women with Fabry disease were evaluated. In other neurophysiologic studies on Fabry disease, the patients have mostly been men. As discussed earlier, the disease is X-linked and manifestations can be milder and occur later in women than in homozygotic men. However, women affected with Fabry disease do have symptoms and neurophysiologic findings compatible with peripheral thin fiber neuropathy, as do men (Gibas et al., 2006; MacDermot et al., 2001), but clinical examination alone is insensitive in detecting small fiber neuropathy in these patients. References Ashley GA, Shabbeer J, Yasuda M, Eng CM, Desnick RJ. Fabry disease: twenty novel alpha-galactosidase A mutations causing the classical phenotype. J Hum Genet 2001;46(4):192–6. Atroshi I, Gummesson C, Johnsson R, Ornstein E, Ranstam J, Rosen I. Prevalence of Carpal tunnel syndrome in a general population. JAMA 1999;281(2):153–8. Brady RO, Schiffmann R. Clinical features of and recent advances in therapy for Fabry disease. JAMA 2000;284(21):2771–5. Cable WJ, Kolodny EH, Adams RD. Fabry disease: impaired autonomic function. Neurology 1982;32(5):498–502.
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