The neurological manifestations of Fabry disease include both peripheral nervous system and CNS involvement, with globotriaosylceramide accumulation found in Schwann cells and dorsal root ganglia together with deposits in CNS neurones. The main involvement of the CNS is attributable to cerebrovasculopathy, with an increased incidence of stroke. The abnormal neuronal accumulation of glycosphingolipid appears to have little clinical effect on the natural history of Fabry disease, with the possible exception of some reported mild cognitive abnormalities. The pathogenesis of Fabry vasculopathy remains poorly understood, but probably relates, in part, to abnormal functional control of the vessels, secondary to endothelial dysfunction as a consequence of α-galactosidase A deficiency. Obstructive vasculopathy, either primarily due to accumulation of glycolipid or secondary to consequent inflammation and confounding vascular risk factors, may develop in response to abnormal endothelial and vessel wall function, similar in some respects to that observed with accumulation of cholesterol-laden lipids during atherosclerosis. Involvement of the peripheral nervous system affects mainly small Aδ and C fibres, and is probably causally related to the altered autonomic function and neuropathic pain found in Fabry disease. Other related neurological problems include hypohidrosis and other abnormalities associated with nervous system dysfunction.

Vasculopathy and stroke

The initial feature related to a blood vessel abnormality to be recognized in Fabry disease was angiokeratoma [1]. Although stroke was not mentioned in the original description of Fabry disease, this complication has been known for some time [2, 3]. In the CNS, vascular involvement has been well documented in the vertebrobasilar system and carotid circulation, but is thought to be more common in the vertebrobasilar or posterior circulation [4–7]. As a result, many neurological deficits may occur in a patient with Fabry disease. These include hemiparesis, vertigo/dizziness, diplopia, dysarthria, nystagmus, nausea/vomiting, headaches, hemiataxia and dysmetria, cerebellar gait ataxia and, very rarely, cerebral haemorrhage [4]. Psychiatric behaviour and dementia have also been attributed to cerebral vasculopathy [8, 9]. Recent findings show that about 2–4% of patients with stroke in the general population aged 18–55 years have Fabry disease [10].

The cerebral vasculopathy of Fabry disease can be conveniently categorized into large-and small-vessel disease [4, 5]. Large-vessel stroke is usually caused by occlusion or thrombosis of large intracranial vessels (Figure 1), although embolic strokes may also occur. As with typical vascular occlusions, stroke in Fabry disease is best seen by cranial magnetic resonance imaging (MRI) [11, 12]. Cerebral angiography is the 'gold standard' technique for demonstrating vessel obstruction. Magnetic resonance angiography, a non-invasive technique, has also been utilized (Figure 2) [13]. However, the false-positive rate for detection of intracranial stenosis is about 30% (M Chimowitz, personal communication). Another indicator of the susceptibility to large intracranial vessel disease is the frequently associated finding of dolichoectasia or the elongation and dilation of the affected vessel. This usually involves the basilar artery [4], although the carotid artery may also be affected (Figure 3).

Figure 1

Magnetic resonance image of a lesion caused by a large intracranial vessel occlusion in a patient with Fabry disease. (a) Left cerebellar hemisphere stroke caused by a vertebral artery occlusion (fluid-attenuated inversion recovery magnetic resonance (more...)

Figure 2

Magnetic resonance angiogram, showing occlusion of the left vertebral artery in a patient with Fabry disease.

Figure 3

Dolichoectasia: magnetic resonance angiogram, showing dilation of the carotid arteries and, to a lesser extent, the basilar artery.

Patients with Fabry disease present more commonly with small-vessel disease, either as a cause of symptomatic stroke or as clinically silent lesions found on neuroimaging, although radiological–pathological correlation studies remain to be carried out. These presumed small-vessel lesions are best seen on T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI (Figure 4). The lesions predominate in the white matter, mostly in the posterior periventricular and centrum semiovale region and are more prevalent with increasing age [5, 7, 14].

Figure 4

(a) Serial axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance image, demonstrating the posterior and periventricular predominance of Fabry leukoencephalopathy. (b) Serial axial FLAIR images of a patient with severe Fabry leukoencephalopathy, (more...)

The mechanism by which α-galactosidase A deficiency and glycolipid accumulation causes this vasculopathy is not completely understood. We have hypothesized that Fabry vasculopathy is associated with abnormalities of blood components, blood flow and the vessel wall (Virchow's triad), leading to vascular dysfunction. The finding of increased soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, P-selectin and plasminogen activator inhibitor and decreased thrombomodulin combined with increased monocyte CD11b expression confirms a prothrombotic state in Fabry disease [15]. Dysfunction of the cerebrovascular circulation has been shown in a number of studies using imaging end-points, such as cerebral perfusion (ml/100 g tissue/minute), cerebral blood flow velocity (cm/second) and cerebrovascular reactivity [5–7, 13, 16–20]. These studies found significant cerebral hyperperfusion in patients with Fabry disease compared with controls, predominantly in the posterior cerebral circulation. Hyperperfusion does not exist systemically, as indicated by normal cardiac output found in patients with Fabry disease compared with controls [16]. Interestingly, using post-ischaemic perfusion measurements, another group has shown a decreased hyperaemia in the forearm but an exaggerated hyperperfusion in the skin [21]. This finding suggests heterogeneity in the response to glycolipid storage of different vascular beds. We have subsequently demonstrated that cerebral hyperperfusion is a vascular phenomenon and not caused by neuronal overactivity [5].

Cerebral hyperperfusion is also associated with calcifications (end-organ damage) in the cerebral white matter and in the pulvinar or posterior thalamic regions (Figures 5 and 6) [6, 22]. There are also indications of abnormalities of cerebrovascular autoregulation and vasoreactivity [17, 23]. One can conclude from the above findings that Fabry disease has all the features of a classic vasculopathy, in that there are abnormalities related to blood components, abnormalities related to blood flow and abnormalities related to the vessel wall, as shown by the disturbances in vasoreactivity and autoregulation.

Figure 5

Selected axial computed tomography scans, demonstrating dystrophic calcification of the subcortical arcuate fibres, globus pallidus, pulvinar and cerebellar corticomedullary junction in a severely affected patient with Fabry disease. Reproduced with permission (more...)

Figure 6

Direct axial arterial spin tagging magnetic resonance images, demonstrating a relative increase in cerebral blood flow in the thalamus and posterior circulation at the anterior and posterior commissure plane in a patient (a) without and (b) with pulvinar (more...)

We have also demonstrated an increased endothelium-dependent vascular reactivity to acetylcholine in the forearm vascular bed. This was still present after infusion of a competitive inhibitor of arginine, indicating an alteration in the function of non-nitric oxide pathways [20]. These findings, and the presence of dolichoectasia, led us to test the hypothesis that the vascular dysfunction in Fabry disease is due to increased release of reactive oxygen species, leading to increased oxidative stress and peroxynitrite formation, potentially resulting in persistent vasodilation [16]. Support for this hypothesis was indicated by the increased staining for 3-nitrotyrosine in dermal and cerebral blood vessels and in the increased nitrotyrosine and myeloperoxidase levels in the blood of patients with Fabry disease compared with controls [16, 19]. Using arterial spin tagging and MRI, we found an altered reactivity of the cerebral vasculature to ascorbate infusion, coupled with low blood levels of ascorbate, in patients with Fabry disease [19]. The decreased response to ascorbate may be caused by excessive release of reactive oxygen species. The reason for excessive production of reactive oxygen species in Fabry disease is unclear, but may be related to glycolipid accumulation altering endothelial caveolar function and mechano-transduction of arterial wall shear stress [24]. Excess O₂•^~ could react with nitric oxide (NO) to form peroxynitrite (ONOO⁻) or dismutate to form H₂O₂, the putative endothelial-dependent hyperpolarizing factor. Both O₂•^~ and ONOO⁻ cause dilation of the cerebral vasculature, suggesting that excess reactive oxygen species could not only lead to continued vasodilation but also to increased vulnerability to other vascular dysfunction, such as superimposed atherosclerosis [25]. Elevated levels of myeloperoxidase in the blood may also be related to the recent observation that atherosclerosis is accelerated in patients with Fabry disease. Indeed, we increasingly observe premature fixed coronary artery and cerebral artery disease in patients with Fabry disease [26]. Five of 26 patients (20%) who participated in our original pivotal trial developed complications of atherosclerosis in their 40s [26]. Our findings in patients with Fabry disease (authors' unpublished data) were recently confirmed by another group in an animal model, who found that α-galactosidase A deficiency accelerates atherosclerosis in mice deficient in apolipoprotein E [27]. These authors also found increased staining for 3-nitrotyrosine in aortic lesions and increased inducible NO synthase expression in vessel wall macrophages.

As not all patients with Fabry disease develop cerebral lesions, we were interested in identifying potential genetic modifiers of this process. In a prospective observational study, we evaluated 57 consecutive Fabry hemizygous male patients for brain FLAIR MRI lesions. We found that the -174G/C polymorphism of interleukin 6, the G894T polymorphism of endothelial NO synthase, the factor V G1691A mutation as well as the G79A and the A-13G polymorphisms of protein Z, but not the prothrombin G20210A variant or the methylenetetrahydrofolate reductase C677T, were significantly associated with cerebral lesions. These data suggest a relationship between a number of prothrombotic gene polymorphisms and the presumptive ischaemic small-vessel cerebral lesions in Fabry disease. This indicates that endogenous proteins may modulate cerebral vasculopathy in Fabry disease and will potentially allow the prospective identification of patients who are most at risk of developing these complications. Such complications are likely to be associated with a concomitant increase in oxidative stress and accelerated atherosclerosis, especially in genotypically susceptible individuals.

Peripheral neuropathy and hypohidrosis

The peripheral neuropathy in Fabry disease manifests as neuropathic pain, reduced cold and warm sensation and, possibly, gastrointestinal disturbances. Patients with Fabry disease begin having pain towards the end of the first decade of life or during puberty [28, 29]. Children as young as 6 years of age have complained of pain, often associated with febrile illnesses, with reduced heat and exercise tolerance [30]. The patients describe the pain as burning, often associated with a deep aching sensation, or paraesthesiae. Some patients also have joint pain. Most of the 60–80% of patients with Fabry disease who develop neuropathic pain do so by the age of 20 years. Female heterozygotes may also develop neuropathic pain, with the same range of age at onset and clinical characteristics [31, 32]. In general, neuropathic pain in Fabry disease can be continuous or consist of episodic attacks brought about by changes in body or ambient temperature, as well as other stressful situations.

The neuropathy of Fabry disease is associated with significantly increased cold and warm detection thresholds in the hands and feet [33, 34]. They are measured using a well-established biophysical quantitative sensory testing technique [35]. In addition, this neuropathy is associated with severe loss of intra-epidermal innervation at the ankle and, to a lesser extent, at the distal thigh [36]. Patients also have a reduced tolerance to exposure of their limbs to a cold challenge [37]. The findings described below indicate that Fabry disease is associated with a length-dependent peripheral neuropathy affecting predominantly the small myelinated (Aδ) fibres and unmyelinated (C) fibres. The mechanism of this neuropathy is unknown. In general, ischaemia of nerves caused by glycolipid accumulation in the vasa nervorum or an intrinsic nerve dysfunction have been suggested as potential causal mechanisms [33, 37, 38].

In patients with Fabry disease who have normal renal function, the only nerve conduction abnormality is an increased incidence of median nerve entrapment at the wrist (carpal tunnel syndrome). Although usually in the normal range, nerve conduction parameters are significantly impaired compared with controls [34]. One group found nerve conduction of sympathetic skin responses to be generally preserved but of a lower amplitude [34]. The vibration threshold is usually normal in the feet, but some patients show an elevated threshold affecting the hands only, probably due to median nerve entrapment at the wrist [33]. However, another group found that vibration thresholds were significantly impaired in the distal forearm and hands [34]. Pathological examination of peripheral nerves (such as the sural nerve) typically shows a normal number of large myelinated fibres, but there is significant loss of unmyelinated fibres (Figure 7) [36, 39–42]. Groups of denervated Schwann cells can also be found. Glycolipid deposits are seen in the perineurium, as well as in the endothelial cells (Figure 7). The lipid deposits in sensory ganglia have been associated with the peripheral neuropathy itself as well as the neuropathic pain of Fabry disease [38, 40, 43, 44]. This abnormality is also seen in heterozygous females [44].

Figure 7

Electron micrographs of sural nerve biopsy specimens from patients with Fabry disease. (a) Field of unmyelinated fibres with numerous denervated Schwann cells. A cluster of denervated Schwann cells appears at the left (arrows). (b) Several denervated (more...)

Most of the patients who suffer from neuropathic pain also have a deficiency in eccrine sweat gland function, but a one-to-one relationship between these symptoms has not been established [45]. As a result of eccrine sweat gland dysfunction, children and young adults often complain of poor exercise tolerance, resulting from lack of sweating and severe neuropathic pain [28, 29]. Patients with neuropathic pain also tend to have lower residual enzyme activity, and have mutations that lead to non-conservative amino acid substitution or to stop codons [46]. The sweating deficiency can be demonstrated using a global sweat test, the thermoregulatory sweat test [47–49], or by an iontophoresis method using acetylcholine [45]. One recently developed form of the latter test is the quantitative sudomotor axon reflex test [50], which has shown a marked reduction in sweat output in adults and children with Fabry disease [28, 51].

Involvement of the dorsal root ganglions of the peripheral nervous system and sympathetic nervous system was previously thought to cause anhidrosis or hypohidrosis [38, 52]. Staining of dermal nerve endings for a pan-neuronal protein such as protein gene product 9.5, however, demonstrated no decrease in the density of sweat gland innervation (Figure 8) [53]. Skin biopsies of patients with Fabry disease show the presence of sweat glands containing lipid inclusions, particularly in the myoepithelial cells [54–56]. The lack of nerve or sweat gland loss, normal neurophysiological testing [55], the non-neuropathic distribution of hypohidrosis [45] and the presence of storage material in sweat glands [54] indicate that a dysfunction of the glands, rather then a destructive process, plays a major role in the hypohidrosis of Fabry disease. Acute improvement in sweating 24–48 hours after intravenous administration of α-galactosidase A (agalsidase alfa) also supports the functional impairment of sweat glands in patients with Fabry disease [51]. Some authors have suggested that both the peripheral neuropathy and the hypohidrosis of Fabry disease are caused by an ischaemic process [57, 58]. Although the vascular elements supplying these systems contain storage material [54], the clinical, physiological and pathological characteristics of these disturbances do not support such a mechanism. Furthermore, blood flow to the skin was not found to be reduced in patients compared with controls [21].

Figure 8

Innervation of sweat glands. Representative staining of sweat glands in a punch skin biopsy at a site near the hip with protein gene product 9.5 (PGP 9.5) antibodies (a) in a control individual and (b) in an age-matched patient with Fabry disease. The (more...)

Some of the manifestations of Fabry disease have been attributed to autonomic neuropathy [45]. There is no evidence of a global autonomic abnormality in Fabry disease, with normal plasma adrenaline and noradrenaline as well as preserved skin sympathetic responses [20, 33]. However, there are reports of significant orthostatic hypotension and syncope in patients with Fabry disease [59–61]. Some authors consider the abnormality of vasomotor control in Fabry disease to be an indication of a dysfunction of the autonomic nervous system [23, 62].

Despite these pathological abnormalities, the precise mechanism of neuropathic pain is unknown. It is likely that the increased levels of globotriaosylceramide in extra-lysosomal membranous compartments interfere with the function of critical proteins, such as ion channels. In general, neuropathic pain, whether of peripheral or central origin, is characterized by a neuronal hyperexcitability in damaged areas of the nervous system [63]. In peripheral neuropathic pain, damaged nerve endings exhibit abnormal spontaneous and increased evoked activity, partly due to an increased and novel expression of sodium channels [64]. The peripheral hyperexcitability may also be due to molecular changes at the level of the peripheral nociceptor, in dorsal root ganglia, in the dorsal horn of the spinal cord and in the brain [65]. These changes include abnormal expression and distribution of sodium channels [66], abnormal responses to endogenous pain-producing substances and cytokines (e.g. tumour necrosis factor), and an alteration of calcium influx into cells [65]. The neuronal hyperexcitability and corresponding molecular changes in neuropathic pain have many features in common with the cellular changes in certain forms of epilepsy [67]. This has led to the use of anticonvulsant drugs for the treatment of Fabry neuropathic pain, with some therapeutic efficacy [68, 69]. The mechanisms by which accumulated globotriaosylceramide causes nerve dysfunction, however, is not clear.

Conclusions

Recent years have brought a better understanding of the mechanism of the vasculopathy of Fabry disease. The data described above clearly show that the old dogma that ischaemic cerebral lesions in Fabry disease are due to bulging lipid-laden vascular endothelial cells encroaching upon the vessel lumen is incorrect. Although the exact mechanism is still poorly understood, it is likely to involve an interaction between the accumulating glycolipids and specific cellular proteins, leading to their dysfunction. The pathogenesis of the peripheral neuropathy and the pain that is associated with Fabry disease is even less well understood than that of the vasculopathy. Better awareness of the disease processes should lead to improved management of this disorder.

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