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Cortés-Saladelafont, E.; Fernández-Martín, J.; Ortolano, S. Fabry Disease and Central Nervous System Involvement. Encyclopedia. Available online: https://encyclopedia.pub/entry/42346 (accessed on 20 December 2025).
Cortés-Saladelafont E, Fernández-Martín J, Ortolano S. Fabry Disease and Central Nervous System Involvement. Encyclopedia. Available at: https://encyclopedia.pub/entry/42346. Accessed December 20, 2025.
Cortés-Saladelafont, Elisenda, Julián Fernández-Martín, Saida Ortolano. "Fabry Disease and Central Nervous System Involvement" Encyclopedia, https://encyclopedia.pub/entry/42346 (accessed December 20, 2025).
Cortés-Saladelafont, E., Fernández-Martín, J., & Ortolano, S. (2023, March 20). Fabry Disease and Central Nervous System Involvement. In Encyclopedia. https://encyclopedia.pub/entry/42346
Cortés-Saladelafont, Elisenda, et al. "Fabry Disease and Central Nervous System Involvement." Encyclopedia. Web. 20 March, 2023.
Fabry Disease and Central Nervous System Involvement
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24065246

Fabry disease (FD; MIM: 301500) is a lysosomal storage disorder (LSD) with an X-linked inheritance secondary to mutations in the GLA gene (NCBI: NC_000023.11; Xq22), which results in the absent or decreased activity of lysosomal hydrolase α-galactosidase A (AGA, α-GalA; BRENDA: EC3.2.1.22). The consequent accumulation of its primary substrate globotriaosylceramide (Gb3) and its derivatives (mainly globotriaosylsphingosine (lyso-Gb3)) results in injury to multiple organs and systemic dysfunction, with endothelial vascular involvement being the main pathological alteration in the disease. Although FD is among the most prevalent lysosomal disorders, with up to 2.5 cases per 100,000 males, little is known or has been reported regarding the involvement of the central nervous system (CNS) beyond cerebrovascular disease. This is particularly striking since there are studies available relating FD to certain neuropsychological profiles, Parkinson’s disease (PD), the accumulation of Lewy bodies, and movement or psychiatric disorders.

Fabry disease synapse neurotransmitter neurotransmission lysosome metabolism

1. Introduction

Fabry disease (FD; MIM: 301500) is a lysosomal storage disorder (LSD) with an X-linked inheritance secondary to mutations in the GLA gene (NCBI: NC_000023.11; Xq22), which results in the absent or decreased activity of lysosomal hydrolase α-galactosidase A (AGA, α-GalA; BRENDA: EC3.2.1.22). The consequent accumulation of its primary substrate globotriaosylceramide (Gb3) and its derivatives (mainly globotriaosylsphingosine (lyso-Gb3)) results in injury to multiple organs and systemic dysfunction, with endothelial vascular involvement being the main pathological alteration in the disease [1]. Due to the X-linked mode of inheritance, men are generally more severely affected and disease manifestations occur earlier compared with women, for whom progression of the disease to organ failure generally occurs later in life, and in whom symptom severity tends to be milder and more variable than in males [2][3]. The same occurs for children and adolescences, since clinical manifestations appear earlier in boys than in girls [4]. Nevertheless, since the X chromosome is randomly inactivated in the cells of female patients, a severe phenotype can also be expressed in women [5]. In addition, a distinction is made between classical and non-classical disease phenotypes [2].
Although FD is among the most prevalent lysosomal disorders, with up to 2.5 cases per 100,000 males [6], little is known or has been reported regarding the involvement of the central nervous system (CNS) beyond cerebrovascular disease. This is particularly striking since there are studies available relating FD to certain neuropsychological profiles, Parkinson’s disease (PD), the accumulation of Lewy bodies, and movement or psychiatric disorders.

2. The Framework of LSDs and Fabry Disease

Approximately two-thirds of patients suffering from LSDs are expected to exhibit some kind of neurological involvement, with a very different range of symptoms and a wide clinical spectrum [6][7]. All these characteristics and the neurological phenotypes have been more deeply explored and described for some other LSDs than FD. This is supported by the fact that the main clinical phenotype of FD differs widely from mucopolysaccharidosis III type C or Niemann–Pick type C disease, for example, in which neurodegeneration and dementia are the most prominent symptoms. In general, neurological manifestations of FD include small fiber neuropathy, associated with pain and reduced temperature sensation, and premature cerebrovascular events, attributed to complex vasculopathy secondary to progressive glycosphingolipid accumulation in vessels and to cardiac involvement [8]. Neurodegeneration and neuroinflammation manifesting with microgliosis and astrocytosis are described as the most common hallmarks of brain pathology in neurological LSD, and FD is not considered among them. With FD, the accumulation of Gb3/lyso-Gb3 could induce an inflammatory response and increase oxidative stress and apoptosis in different cell types with prominent endothelial damage (such as cardiomyocytes or podocytes) [1]. Moreover, substrate accumulation has increasingly been shown to involve cellular structures beyond the lysosome, and its downstream effects (fibrosis, inflammation, generation of reactive oxygen species, etc.) also seem to play key roles in pathogenesis [9].

3. Clinical Manifestations Related to CNS Involvement in FD

The classic neurological manifestations of FD are considered to be small fiber neuropathy associated with pain, along with reduced temperature sensation and heat intolerance, and premature cerebrovascular disease [10][11]. Both are attributed to progressive glycosphingolipid accumulation in vessels and to cardiac involvement, which leads to secondary complex vasculopathy. Ischemic stroke and transient ischemic attacks may occur, and white matter lesions are commonly seen on MRI, even in asymptomatic patients [12]. Autonomic nervous system disease may manifest with gastrointestinal symptoms similar to irritable bowel syndrome and hypohidrosis [13]. 

3.1. The Pain in Fabry Disease

The peripheral neuropathy in Fabry disease manifests as neuropathic pain and is one of the main hallmarks of the disease. It is characterized by reduced cold and warm sensation, gastrointestinal disturbances, burning pain with a globe and socking distribution, and sudden pain crises [11]. The pain is mainly localized in the hands and feet and encompasses fingers, palms and soles [14]. It can manifest as early as 2 or 3 years of age, is reported in both boys and girls, and is often associated with febrile illnesses, with reduced heat and exercise tolerance. It is a debilitating condition that negatively interferes in quality of life in these patients [15].
As a brief summary, the four main mechanisms linked to peripheral neuropathic pain in Fabry disease would be as follows: Glycolipid and Gb3 deposits in the perineurium, the endothelial cells (vasa nervorum), the dorsal root ganglion, and the Schwann cells, as well as dysfunctional ion channels in the nerves [14][16]. Focusing on the central mechanisms of neuropathic pain, it is important to distinguish (1) the central component, mainly due to direct injuries or sequela to the central nervous system (mostly identified in patients with multiple sclerosis, strokes, etc.), from (2) the central sensitization, which refers to a situation in which chronic nociceptive afferent input from a peripheral pain generator causes reversible changes in central nociceptive pathways [17]. The latter has been reported in Fabry disease; several studies report hypersensitivity to mechanical stimuli [14], and a central disinhibition pain mechanism due to a reduced A-delta fiber input (reduced protective sensitive afferent stimuli, not properly mediated by these A-delta fibers, leading to a constant C-fiber unmyelinated-input that mediates pain) [16]. When talking about this central mechanism, it has to be noted that basic central networks are involved including mechanisms of reward and antireward via the medial thalamic pathway.

3.2. Parkinson’s Disease (PD)

The prevalence of LSD mutations in PD patients strengthens the idea that lysosomal dysfunction is a key player in PD pathogenesis [9]. A sequencing analysis of 54 genes in PD patients that are causative of different LSDs were analyzed (including the GLA gene), and a total of 54% of the PD patients were shown to have at least one variant in one of those genes [18]. Moreover, studies have shown a direct relationship between decreased or loss-of-function activity of lysosomal glucocerebrosidase (accumulated in Gaucher disease) and effects on the processing and clearance of α-synuclein that facilitates its aggregation. In addition, impaired autophagy and lysosomal function were bi-directionally detected in many LSDs, including FD, and in PD, suggesting a possible link between these disorders [19][20][21]. AGA activity was also tested in PD patients and showed similar results, in that these patients presented lower activity of this enzyme than controls [22]. It is also of importance to mention that despite not being able to prove a neurodegenerative pattern in FD [8], motor abnormalities involving slower gait, reduced hand speed, and poorer fine manual dexterity have been identified and shown to be independent of cerebrovascular symptoms.

3.3. Neurodegeneration

A study with a large cohort of FD patients (110 patients: 60 heterozygous females, 50 hemizygous males) found that FD was associated with impaired motor function and various nonmotor symptoms, but that it did not lead to a pattern of extrapyramidal symptoms, significant cognitive problems, or other symptoms commonly preceding neurodegenerative diseases (PD or dementia with Lewy bodies) [8]. Nevertheless, the authors concluded that they could not rule out neurodegeneration in FD, since the study was focused only on detecting the clinical prodromes that normally precede other neurodegenerative disorders, for example, Gaucher disease. The authors stated that FD might lead to a focused brainstem pathology, resulting in a distinct clinical phenotype with mild motor impairment and nonmotor symptoms (i.e., depression, pain, daytime sleepiness, and hearing loss) but not associated with the cardinal clinical prodromes of neurodegenerative diseases. In contrast, in a report from one severely affected FD patient with a prominent hypokinetic phenotype, severe neuronal loss in the substantia nigra pars compacta and Lewy pathology was found [23]. Therefore, it might be concluded that larger cohorts of patients, with matching pathology findings and clinical manifestations, are also needed to analyze if a GLA deficit may contribute to the more severe phenotype in CNS when associated with other genetic or epigenetic factors.

3.4. Psychiatric Manifestations and Cognitive Functioning

Psychological and psychiatric manifestations, in particular, depression, have been reported to be common in FD. These patients also score significantly worse than general population samples and patients with other chronic diseases (including Gaucher disease, another LSD) on measures of depression, anxiety and health-related quality of life perception [24]. In a recent study from a Dutch cohort, patients scored significantly worse in terms of subjective cognitive status [25]. In the previously mentioned study from Löhle et al., reporting the prospective results from a large cohort of FD patients, they were able to reproduce what other studies had previously reported: A high prevalence of depression (up to 46%), pain and daytime sleepiness (up to 50–60%) in FD patients [26].
There is an interesting study reporting on four individuals from two generations from the same family, three of whom exhibited mainly neuropsychological symptoms as their prominent clinical presentation [27]. The family presented mild neurological symptoms along with neuropsychiatric symptoms, such as depression and schizophrenia, which could not be confirmed as primary or secondary manifestations of FD. Nevertheless, the authors lacked an alternative diagnosis and reported reduced α-galactosidase activity, together with increased levels of lyso-Gb3 in urine and plasma, and a pathogenic mutation in the GLA gene. The study does not report whether a whole genome analysis was carried out, which could rule out the contribution of alternative genes to this phenotype.
Additional psychiatric manifestations in patients with FD have been documented, albeit rarely, including acute psychotic symptoms, and personality and behavioral changes [24][28]. Another study focused on delineating a psychiatric and cognitive phenotype in FD in terms of psychiatric and cognitive functioning that was not only related to the difficulty these patients have coping with a chronic long-term disease [29].
The literature from some years ago suggested that there may be preservation of general intellectual functioning, memory, naming, perceptual functioning and global cognitive functioning in the absence of severe cerebrovascular events such as stroke or dementia [24]. In this same systematic literature review, they also pointed to evidence of impairment in executive functioning, information processing speed and attention. The more recent literature supports the principle of executive dysfunction in adult FD patients, with symptoms of attention-deficit/hyperactivity (ADHD), manifesting as difficulties with cognitive functioning, particularly in the realms of attention and concentration [30].
Cognitive impairment has been reported to be present in FD patients [24], and although a recent short-term follow-up study found no major changes in cognitive functioning, they studied the cohort of patients for only 1 year [31].
With regard to psychological impacts on pediatric patients, a study indicated that children with FD experience a poorer quality of life than their healthy counterparts [32]. Their results consistently identified adolescents with FD as being more heavily impacted than younger children, although not to the same degree as adults with FD.
A study in a Dutch cohort of 154 FD patients was not able to confirm the relationship between a history of stroke and depressive symptoms or between white matter lesions and depressive symptoms [32]. This further strengthens the hypothesis that brain abnormalities are not the main cause of depressive symptoms in patients with FD, and further studies are needed to elucidate the molecular and biochemical basis at a cellular level to understand the link between neuronal dysfunction and clinical manifestations.
Finally, focusing on sleep disturbances in FD, there are published data reporting a high prevalence of sleep-disordered breathing and abnormal periodic limb movements. A study showed that although the presence of abnormal periodic limb movements alone might have a minimal impact on sleep disturbance, they were associated with depression and analgesic requirements [33]. This supports the idea that exploring quality of sleep might also help FD patients and lessen the impact of FD with regard to psychological states.

4. MRI Abnormalities (Other Than Cerebrovascular Disease) in FD

While computed tomography (CT) application is limited to only acute cerebrovascular events, conventional MRI is the “gold standard” imaging technique to evaluate brain alterations in FD. The major conventional imaging findings in FD are (1) white matter hyperintensities (due to small vessel microangiopathy), which are the most common neuroradiological findings and present in up to 80% of patients; (2) stroke; (3) vertebrobasilar diameter abnormalities, which are a common, although inconstant, neuroradiological feature; and (4) the pulvinar sign, which was originally thought to be a common and pathognomonic sign of FD, but is no longer considered as such due to its low incidence and specificity [34][35].
Although it is the first-choice imaging technique, brain MRI fails in terms of diagnostic accuracy and thus has a poor sensitivity and specificity [34]. Brain lesions in FD are rather diffuse and do not have any specific anatomical localization [36]. Nevertheless, some new MRI techniques such as diffusion tensor imaging (DTI) have evidenced a good correlation with cognition (processing speed) and clinical disease severity [36]; they confirmed widespread areas of microstructural white matter disruption beyond the white matter hyperintensities seen on conventional MRI.
In the next sections, an analysis of the main findings with advanced neuroimaging techniques is discussed, with a focus on the possible link between them and the pathophysiology of the disease beyond its cerebrovascular involvement. There is also a brief comment on the neuroradiological findings in pediatric FD patients.

4.1. Reduced Intracranial Volume and Thalamic and Hippocampal Atrophy

The presence of cerebral atrophy (with losses in grey matter (GM) and white matter (WM)) in the absence of a severe cerebrovascular disease has been previously reported as a possible neuroradiological feature of FD, although there are some reported technical limitations in brain tissue volume studies [34][37]. Moreover, some focal differences in GM volume have been investigated, but no significant differences were found. Despite these previous findings, atrophy in specific brain regions, specifically the thalamus and the hippocampus, has been reported in FD patients compared to healthy controls and corrected for cerebrovascular events [34]. In addition, a global reduction in intracranial volume has been observed, suggesting the presence of abnormal neural development [38]. Clinical correlations with all these abnormalities have not been addressed, and additional studies are needed to investigate, for example, the role of the thalamus in pain perception, hippocampal atrophy in cognitive and memory complaints, or decreased global intracranial volume in abnormal brain development.

4.2. Motor Cortex and Cerebellar and Nigrostriatal Pathway Involvement

In a recent study using resting-state functional MRI (RS-fMRI), the presence of functional connectivity (FC) alterations in the motor circuits in patients with FD was evaluated [39]. FD patients with a history of stroke were excluded from the study, both male and female patients were included, and the patients were compared to healthy controls. There was significant FC involvement of the bilateral caudate and lenticular nuclei, as well as cerebellar involvement that encompassed portions of lobules 8 and 9 of both the vermis and cerebellar hemispheres. Functions of the basal ganglia and cerebellum have been related to the control of movement, but they also play a central role in processing cognitive and emotional information. These findings could shed some insights into the cerebral implications of FD, both in terms of symptoms related to PD and cognitive involvement.
Regarding basal ganglia involvement, a diffusion tensor imaging study showed the presence of microstructural damage affecting the thalamus [40].
In a study of three different pedigrees of FD patients who also exhibited signs and symptoms of akinetic-rigid PD, an 18F-DOPA-PET scan was performed [21]. There was evidence of reduced presynaptic dopaminergic enhancement in the nigrostriatal regions of these three patients, similar to what might be expected in idiopathic PD. These findings might support the hypothesis that the dopaminergic pathway is affected in FD patients. Moreover, another study revealed reduced nigral volume (suggesting neurodegeneration in this region) that correlated with the increased susceptibility of this region in FD patients [41].

4.3. Neurodegeneration, Neuronal Dysfunction and Hypometabolic Brain Regions

Brain MR spectroscopy (1H-MRS) has been used to investigate possible changes in the N-acetylaspartate/creatine (NAA/Cr) ratio (which might indicate neuronal degeneration and loss and is considered a marker of neuronal dysfunction) [42]. This study revealed diffuse reductions in the NAA/Cr ratio in different brain areas, affecting both cortical and subcortical structures. Nevertheless, these findings were inconsistent, as they were not reproducible in other studies [43].
In a recent review of quantitative susceptibility mapping investigating different neurodegenerative diseases (including one patient with FD), the authors found increased magnetic susceptibility in the putamen, caudate nuclei and substantia nigra in patients compared to controls [44]. Excess iron deposition in particular regions of the brain has been proposed as playing an important role in the pathology of neurodegenerative diseases, and whether this is related to neurodegeneration in FD has yet to be elucidated, since larger cohorts are needed and this is only an anecdotical, yet interesting, finding.
Regarding brain metabolism studied using positron emission tomography [45], hypometabolic areas were found only in regions with infarcts or hemorrhages on MRI scans, and there were no significant global glucose metabolic changes affecting the brains of FD patients [43].

4.4. MRI Changes in Children and Adolescents with FD

Children and adolescents with FD might present with brain MRI abnormalities in the form of white matter lesions (WML), deep grey matter lesions and infratentorial involvement [46]. In this study, they had a sample of 44 patients (20 boys and 24 girls, aged between 7 and 21 years old), and 90.9% were symptomatic of FD (neuropathic pain, cornea verticillata, abdominal pain or proteinuria). None of the patients showed microbleeds or any vascular abnormalities. A total of 7 out of 44 patients (15.9%) presented WML (5 girls and 2 boys), all patients presented the classic phenotype, and 3 patients (42.8%) had been receiving enzyme replacement treatment (ERT) for a mean period of 11 months. This frequency of abnormalities found in FD pediatric patients is higher than expected for the healthy pediatric population, which might have incidental and asymptomatic findings in brain MRI, with a reported frequency of 2.9–5.6%. It is also important to comment on these findings being present in three children who were receiving ERT. Studies regarding white matter hyperintensity progression while on ERT have been inconclusive; some studies reported progression despite treatment [47], and other studies ruled out a possible association between white matter hyperintensity (WMH) progression and ERT [48].

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Subjects: Neurosciences
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Elisenda Cortés-Saladelafont , Julián Fernández-Martín , Saida Ortolano
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Update Date: 20 Mar 2023
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