In this study we found a low prevalence of orthostatic intolerance and male sexual dysfunction in a rather large cohort of Fabry patients. The cardiovascular autonomic function tests showed normal cardiovascular autonomic control in almost all of our Fabry patients.
This raises the important question whether autonomic neuropathy plays a prominent role in Fabry symptoms and signs. The disturbances that have been ascribed to autonomic neuropathy in Fabry disease include an- or hypohydrosis, decreased tears and saliva formation, abnormal cerebrovascular reactivity, cardiac rhythm disturbances as well as gastrointestinal complaints [4–6]. However, unlike the findings in other diseases that cause autonomic neuropathy  and in patients with proven autonomic failure , orthostatic intolerance and male sexual dysfunction are less frequent and less severe manifestations in our Fabry patients. Furthermore, the low resting heart rate as found in our study patients is unusual in patients with an autonomic neuropathy.
Defective sweating has long been thought to originate from autonomic neuropathy. However, skin biopsies did not reveal a decrease in nerve fibre density of sweat gland innervation, but revealed storage of lipids in sweat glands. Also, the non-length dependent distribution of the an- or hypohydrosis and the rapid effect of single enzyme infusions, suggested a sweat gland dysfunction rather than an autonomic neuropathy . In line with defective sweating, end-organ failure might also account for the abnormal peripheral blood flow that has been found in several studies [19, 20]. A study on vascular hyperreactivity in Fabry disease supports this hypothesis; absence of a difference in plasma epinephrine or norepinephrine levels between patients and controls suggested that the altered vessel response in Fabry disease may be attributed to vasogenic and not to neurogenic factors . This is further supported by almost normal cardiovascular autonomic function, as has been confirmed in the current study as well as in previous studies [6, 12]. Studies on heart rate variability (HRV) in pediatric Fabry patients revealed significantly different results between boys and both girls and controls, with significant improvement of heart rate variability in boys upon ERT [10, 11]. However, it is likely that cardiac pathology (i.e. left ventricular hypertrophy and/or conduction system pathology) has influenced the abnormalities observed in these patients. In the current study, only 6 out of 36 Fabry patients showed an abnormal HRV on one test. As four of these six patients were known with LVH or cardiomyopathy, our findings could be partly explained by the underlying cardiac pathology.
Altogether, our results indicate that symptoms and signs compatible with autonomic dysfunction in Fabry patients are probably not due to autonomic neuropathy. More likely, these symptoms and signs are caused by end-organ failure which has been suggested before by others [22, 23] and is supported by findings from previous studies [7, 21]. An exceptional kind of autonomic neuropathy can, however, not be totally excluded.
It is surprising that, in spite of evidence of small fibre neuropathy in Fabry disease [1, 2], and autonomic functions being carried by these small nerve fibres, we did not find symptoms and signs that are generally found in patients with autonomic neuropathy due to other diseases. Diabetic neuropathy and other small fibre neuropathies (i.e. amyloidosis, leprosy and HIV) lead to equal damage of C and Aδ fibres or to more severe damage of C fibres than Aδ fibres [24–27]. In contrast, Fabry disease causes more severe impairment of Aδ fibres compared to C fibres, as shown by quantitative sensory testing [1, 12]. Preganglionic autonomic fibres consist of small myelinated B fibres and postganglionic autonomic fibres are small unmyelinated C fibres . The relatively selective damage to 'non-autonomic' small myelinated Aδ fibres in Fabry disease could therefore underlie the found preservation of autonomic function in Fabry disease. One other disease, hereditary sensory and autonomic neuropathy (HSAN) type 5, is known to cause selective loss of small myelinated nerve fibres. Autonomic function is usually spared in HSAN type 5; none of the reported patients had orthostatic hypotension, although anhydrosis has been reported in some . Apparently, damage to C-fibres is required for the development of overt autonomic neuropathy.
In contrast to orthostatic intolerance and male sexual dysfunction, gastrointestinal complaints are frequently reported in Fabry disease. These complaints have been attributed to dysfunction of enteric neurons . Data obtained from 342 Fabry patients enrolled in the Fabry Outcome Survey (FOS), revealed that 60.8% of children and 49.8% of adults experienced gastrointestinal complaints. The most frequently reported gastrointestinal symptoms were abdominal pain and diarrhoea . In this light, the high numbers of patients without gastrointestinal disturbances in the current cohort are unexpected. This difference between the FOS data and our results may be due to an overestimation in the FOS as these findings were based on self-reports by patients, and not on a validated questionnaire.
Furthermore, an unexpectedly low number of Fabry patients reported secretomotor problems. This may be attributed to a shortcoming in the questionnaire we used: the ASP assesses changes in sweating in the past five years, whereas Fabry patients usually suffer from sweat problems from childhood on.
Another limitation of the current study is that we included mainly mild to moderately affected patients. As we found a trend towards a correlation between the MSSI sum score and the ASP sum score and relatively high MSSI sum scores in 4 out of 6 patients with an abnormal heart rate variability test result, we cannot exclude that autonomic neuropathy is more prevalent in severely affected patients. Besides, the cross-sectional character of the study precludes definite conclusions on the long term effect of enzyme replacement therapy in individual patients. However, our results suggest that patients with relatively severe disease are more often on ERT and that the severity of autonomic dysfunction is not influenced by ERT. A final limitation is that we have restricted the function tests to those evaluating cardiovascular autonomic function. However, abnormalities in the autonomic control of other organ systems such as peripheral vascular reactivity is thought to reflect end-organ pathology and not real autonomic neuropathy as discussed above.