Neuropathy In Fabry Disease Research Articles

Small fibre neuropathy in Fabry disease: a human-derived neuronal in vitro disease model and pilot data.

Acral burning pain triggered by fever, thermal hyposensitivity and skin denervation are hallmarks of small fibre neuropathy in Fabry disease, a life-threatening X-linked lysosomal storage disorder. Variants in the gene encoding alpha-galactosidase A may lead to impaired enzyme activity with cellular accumulation of globotriaosylceramide. To study the underlying pathomechanism of Fabry-associated small fibre neuropathy, we generated a neuronal in vitro disease model using patient-derived induced pluripotent stem cells from three Fabry patients and one healthy control. We further generated an isogenic control line via gene editing. We subjected induced pluripotent stem cells to targeted peripheral neuronal differentiation and observed intra-lysosomal globotriaosylceramide accumulations in somas and neurites of Fabry sensory neurons using super-resolution microscopy. At functional level, patch-clamp analysis revealed a hyperpolarizing shift of voltage-gated sodium channel steady-state inactivation kinetics in isogenic control neurons compared with healthy control neurons (P < 0.001). Moreover, we demonstrate a drastic increase in Fabry sensory neuron calcium levels at 39°C mimicking clinical fever (P < 0.001). This pathophysiological phenotype was accompanied by thinning of neurite calibres in sensory neurons differentiated from induced pluripotent stem cells derived from Fabry patients compared with healthy control cells (P < 0.001). Linear-nonlinear cascade models fit to spiking responses revealed that Fabry cell lines exhibit altered single neuron encoding properties relative to control. We further observed mitochondrial aggregation at sphingolipid accumulations within Fabry sensory neurites utilizing a click chemistry approach together with mitochondrial dysmorphism compared with healthy control cells. We pioneer pilot insights into the cellular mechanisms contributing to pain, thermal hyposensitivity and denervation in Fabry small fibre neuropathy and pave the way for further mechanistic in vitro studies in Fabry disease and the development of novel treatment approaches.

Generation of GLA-knockout human embryonic stem cell lines to model peripheral neuropathy in Fabry disease

Fabry disease is an X-linked glycolipid storage disorder caused by mutations in the GLA gene which result in a deficiency in the lysosomal enzyme alpha galactosidase A (AGA). As a result, the glycolipid substrate Gb3 accumulates in critical tissues and organs producing a progressive debilitating disease. In Fabry disease up to 80% of patients experience life-long neuropathic pain that is difficult to treat and greatly affects their quality of life. The molecular mechanisms by which deficiency of AGA leads to neuropathic pain are not well understood, due in part to a lack of in vitro models that can be used to study the underlying pathology at the cellular level. Using CRISPR-Cas9 gene editing, we generated two clones with mutations in the GLA gene from a human embryonic stem cell line. Our clonal cell lines maintained normal stem cell morphology and markers for pluripotency, and showed the phenotypic characteristics of Fabry disease including absent AGA activity and intracellular accumulation of Gb3. Mutations in the predicted locations in exon 1 of the GLA gene were confirmed. Using established techniques for dual-SMAD inhibition/WNT activation, we were able to show that our AGA-deficient clones, as well as wild-type controls, could be differentiated to peripheral-type sensory neurons that express pain receptors. This genetically and physiologically relevant human model system offers a new and promising tool for investigating the cellular mechanisms of peripheral neuropathy in Fabry disease and may assist in the development of new therapeutic strategies to help lessen the burden of this disease.

Generation of an in vitro model for peripheral neuropathy in Fabry disease using CRISPR-Cas9 in the nociceptive dorsal root ganglion cell line 50B11

Fabry disease is a glycosphingolipid storage disorder that is caused by a genetic deficiency of the lysosomal enzyme alpha-galactosidase A (AGA, EC 3.2.1.22). As a result, the glycolipid substrate, globotriaosylceramide (Gb3) accumulates in various cell types throughout the body producing a multisystem disease that affects the vascular, cardiac, renal, and nervous systems. A hallmark of this disorder is neuropathic pain that occurs in up to 80% of Fabry patients and has been characterized as a small fiber neuropathy. The molecular mechanism by which changes in AGA activity produce neuropathic pain is not clear, in part due to a lack of relevant model systems. Using 50B11 cells, an immortalized dorsal root ganglion neuron with nociceptive characteristics derived from rat, we used CRISPR-Cas9 gene editing of the galactosidase alpha (GLA) gene for AGA to create two stable knock-out clones that have the phenotypic characteristics of Fabry cells. The cell lines show severely reduced lysosomal AGA activity in homogenates as well as impaired degradation of Gb3 in cultured cells. This phenotype is stable over long-term culture. Similar to the unedited 50B11 cell line, the clones differentiate in response to forskolin and extend neurites. Flow cytometry experiments demonstrate that the gene-edited cells express TRPV1 pain receptor at increased levels compared to control, suggesting a possible mechanism for increased pain sensitization in Fabry patients. Our 50B11 cell lines show phenotypic characteristics of Fabry disease and grow well under standard cell culture conditions. These cell lines can provide a convenient model system to help elucidate the molecular mechanism of pain in Fabry patients.

Ion channels and pain in Fabry disease.

Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A (α-Gal A) activity which results in progressive accumulation of globotriaosylceramide (Gb3) and related metabolites. One prominent feature of Fabry disease is neuropathic pain. Accumulation of Gb3 has been documented in dorsal root ganglia (DRG) as well as other neurons, and has lately been associated with the mechanism of pain though the pathophysiology is still unclear. Small fiber (SF) neuropathy in FD differs from other entities in several aspects related to the perception of pain, alteration of fibers as well as drug therapies used in the practice with patients, with therapies far from satisfying. In order to develop better treatments, more information on the underlying mechanisms of pain is needed. Research in neuropathy has gained momentum from the development of preclinical models where different aspects of pain can be modelled and further analyzed. This review aims at describing the different in vitro and FD animal models that have been used so far, as well as some of the insights gained from their use. We focus especially in recent findings associated with ion channel alterations -that apart from the vascular alterations-, could provide targets for improved therapies in pain.

Causally treatable, hereditary neuropathies in Fabry's disease, transthyretin-related familial amyloidosis, and Pompe's disease.

Most acquired neuropathies are treatable, whereas genetic neuropathies respond to treatment in Fabry's disease (FD), transthyretin-related familial amyloidosis (TTR-FA), and Pompe's disease (PD). This review summarizes and discusses recent findings and future perspectives concerning etiology, pathophysiology, clinical presentation, diagnosis, treatment, and outcome of neuropathy in FD, TTR-FA, and PD. Literature review. Neuropathy in FD concerns particularly small, unmyelinated, or myelinated sensory fibers (small fiber neuropathy [SFN]) and autonomic fibers, manifesting as acroparesthesias, Fabry's crises, or autonomous disturbances. FD neuropathy benefits from agalsidase alpha (0.2mg/kg every second week intravenously) or from beta (1.0mg/kg every second week intravenously). Neuropathy in TTR-FA is axonal and affects large and small sensory, motor, and autonomous fibers. Neuropathy in TTR-FA profits from liver transplantation and the TTR kinetic stabilizer tafamidis (20mg/d). Neuropathy in PD particularly occurs in late-onset PD and manifests as mononeuropathy, polyneuropathy, or SFN. PD neuropathy presumably responds to alglucosidase-alpha (20mg/kg every second week intravenously). Neuropathy in FD, TTR-FA, and PD is predominantly a SFN and can be the dominant feature in FD and TTR-FA. SFN in FD, TTR-FA, and PD needs to be recognized and benefits from enzyme replacement treatment or TT-kinetic stabilizers.

Small Fiber Neuropathy in Fabry Disease: a Review of Pathophysiology and Treatment

Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of glycolipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fib...

α-Galactosidase A Knockout Mice: Progressive Organ Pathology Resembles the Type 2 Later-Onset Phenotype of Fabry Disease

Fabry disease is an X-linked lysosomal storage disease caused by deficient activity of α-galactosidase A and the resultant systemic accumulation of globotrioasylceramide (GL-3) and related glycolipids. α-Galactosidase A gene knockout (Gla KO) mice have no α-galactosidase A activity and progressively accumulate GL-3 in tissues and fluids, similarly to FD patients. The nature and temporal effects of the progressive substrate accumulation on tissue histology in these mice have not previously been characterized. Here, we report the pathology of young to old (3 to 17 months old) Gla KO mice and compare these changes with those in strain-matched control animals. Gla KO mice accumulated GL-3 in various tissues and fluids with age. Lysosomal GL-3 inclusions increased with age in multiple cell types, including renal epithelial, intestinal, and vascular smooth muscle cells, and neurons in trigeminal and dorsal root ganglia, as detected by light and electron microscopy. However, unlike the case for male FD patients with the type 1 classic phenotype, GL-3 inclusions were not detected in vascular endothelial cells or cardiomyocytes. The histological changes in Gla KO mice better resemble the type 2 later-onset phenotype observed in patients with residual α-galactosidase A activity. GL-3 accumulation in the small intestine and sensory ganglia of Gla KO mice provides a model for study of enteropathy and neuropathy in Fabry disease.

Neurological Complications of Anderson-Fabry Disease

Characteristic clinical manifestations of AFD such as acroparesthesias, angiokeratoma, corneal opacity, hypo/ and anhidrosis, gastrointestinal symptoms, renal and cardiac dysfunctions can occur in male and female patients, although heterozygous females with AFD usually seem to be less severely affected. The most prominent CNS manifestations consist of cerebrovascular events such as transient ischaemic attacks (TIAs) and (recurrent) strokes. For the most part, CNS complications in AFD have been attributed to cerebral vasculopathy, including anatomical abnormalities. The natural history of Fabry patients includes transitory cerebral ischaemia and strokes, even in very young persons of both genders. The mechanism is partly due to vascular endothelial accumulation of Gb-3. White matter lesions (WML) on occur MRI. Both males and females can be safely treated with enzyme replacement; and thus screening for Fabry disease of young stroke populations should be considered. There are, however, no hard data of treatment effect on mortality and morbidity. Stroke in Anderson-Fabry disease study of 721 patients with cryptogenic stroke, aged 18-55 years, showed a high prevalence of Fabry disease in this group: 5% (21/432) of men and 3% (7/289) of women. Combining results of both sexes showed that 4% of young patients with stroke of previously unknown cause had Fabry disease, corresponding to about 1-2% of the general population of young stroke patients. Cerebral micro- and macro-vasculopathy have been described in Fabry disease. Neuronal globotriaosylceramide accumulation in selective cortical and brain stem areas including the hippocampus has been reported by autopsy studies in FD, but clinical surrogates as well as the clinical relevance of these findings have not been investigated so far. Another Neurologic hallmark of Fabry disease (FD) includes small fiber neuropathy as well as cerebral micro- and macroangiopathy with premature stroke. Cranial MRI shows progressive white matter lesions (WML) at an early age, increased signal intensity in the pulvinar, and tortuosity and dilatation of the larger vessels. Conventional MRI shows a progressive load of white matter lesions (WMLs) due to cerebral vasculopathy in the course of FD. Another study has been conducted to quantify brain structural changes in clinically affected male and female patients with FD. 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. Children as young as 6 years of age have complained of pain often associated with febrile illnesses with reduced heat and exercise tolerance. The patients describe the pain as burning that is often associated with deep ache or paresthesiae. Some patients also have joint pain. A high proportion of patients with Fabry disease is at increased risk of developing neuropsychiatric symptoms, such as depression and neuropsychological deficits. Due to both somatic and psychological impairment, health-related quality of life (QoL) is considerably reduced in patients with Fabry disease. Targeted screening for Fabry disease among young individuals with stroke seems to disclose unrecognized cases and may therefore very well be recommended as routine in the future. Furthermore, ischemic stroke is related to inflammation and arterial stiffness and no study had addressed this relationship in patients with AF disease and cerebrovascular disease, so this topic could represent a possible future research line.

Small fibre neuropathy in Fabry disease

Fabry disease is an X-linked inherited lysosomal storage disorder associated with glycosphingolipid accumulation in organs and vascular endothelium [1]. Neuropathic pain is common in Fabry disease and is associated with small fibre neuropathy [2, 3]. The diagnosis of small fibre neuropathy is based on symptoms like paresthesias, dysesthesias and pain and clinical signs with abnormal pin prick sensation, quantitative sensory testing (QST) and skin biopsy [4]. Corneal confocal microscopy examination of patients with diabetes mellitus as well as Fabry disease has demonstrated a reduction in sub-basal nerve density, also reflecting small fibre neuropathy [5–7]. In the present study we have compared these tests in patients with Fabry disease. Fifteen patients (five males with mean age of 16.2 years and 10 females with mean age of 33.8 years) with Fabry disease, all verified by mutation analysis, were recruited from the Bergen Fabry cohort at Haukeland University Hospital, Bergen, Norway (2004–2009). Blood levels of alpha-galactosidase varied from 2.2 to 37.8 lkat/kg protein (N: 17.7–26.4). All patients had episodes of neuropathic pain aggravated by heat. Eleven sexand age-matched healthy individuals served as controls for the assessment of small fibre affection. The disease severity scoring system (DS3) was used to measure the general neurological, cardiovascular and renal symptoms and signs in the Fabry patients [8]. Age was positively correlated with the DS3 total score (r = 0.68, p = 0.005; Pearson’s test), while it was negatively associated with the DS3 peripheral nervous system (PNS) score (r = -0.52, p = 0.045; Pearson’s test). Males had higher DS3 PNS score than females (p = 0.043; t test), but there was no sex association with DS3 total score (p = 0.73; t test). The alpha-galactosidase levels were not associated with the DS3 PNS score (r = 0.40, p = 0.135; Pearson’s test). Routine clinical and neurological examination, nerve conduction studies, electromyography, and QST (vibrametry and thermotests) were performed. A slit scanning confocal microscope (Confoscan 3, Nidek Technologies, Vigonza, Italy) was used to measure the sub-basal cornea nerve fibre length (CNFL) (mm/mm) in the central cornea of one eye of each subject. Skin-punch biopsy from the A. K. Bertelsen J. Aarseth C. A. Vedeler (&) Department of Neurology, Haukeland University Hospital, Bergen, Norway e-mail: christian.vedeler@helse-bergen.no

Upregulation of inward rectifying currents and Fabry disease neuropathy

Peripheral neuropathy and neuropathic pain are common clinical manifestations of Fabry disease (FD). Although the mechanisms underlying the development of sensory neuropathy remain to be fully elucidated, a chronic ischemic process was proposed. Consequently, this study utilized axonal excitability techniques to gain further insights into the pathophysiological mechanisms underlying the development of FD neuropathy. Median motor and sensory axonal excitability studies were undertaken in 13 FD patients and results were compared to 19 healthy subjects. A "fanning-in" of threshold electrotonus, suggestive of membrane depolarization, was evident only in motor axons in FD patients. In contrast, the sensory axons exhibited a lower threshold in FD (p < 0.05) and a significantly increased hyperpolarizing current/threshold (I/V) gradient (FD 0.48 ± 0.03; controls, 0.31 ± 0.02, p < 0.001), which correlated with clinical scores of disease severity (Rho = 0.65, p < 0.05), neuropathy (Rho = 0.54, p < 0.05) and neuropathic pain (Rho = 0.56, p < 0.05). These findings indicate that upregulation of I(h) , rather than ischemia, may underlie the sensory symptoms and possibly development of neuropathy in FD. Modulation of sensory I(h) may prove therapeutically useful in Fabry disease.

S15.4 Small-fiber neuropathy in Fabry disease and diabetes different patterns of loss of afferent functions?

S15.4 Small-fiber neuropathy in Fabry disease and diabetes different patterns of loss of afferent functions?

Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel

BackgroundFabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen.MethodsAn international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain.ResultsWe describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e.g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients.ConclusionsOur recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.

Autonomic neuropathy in Fabry disease: a prospective study using the Autonomic Symptom Profile and cardiovascular autonomic function tests

BackgroundFabry patients have symptoms and signs compatible with autonomic dysfunction. These symptoms and signs are considered to be due to impairment of the peripheral nervous system, but findings indicative of autonomic neuropathy in other diseases, such as orthostatic intolerance and male sexual dysfunction, are infrequently reported in Fabry disease. The aim of our study was to investigate autonomic symptoms and cardiovascular autonomic function in a large cohort of male and female Fabry patients.MethodsForty-eight Fabry patients (15 male, 30 treated with enzyme replacement therapy) and 48 sex- and age-matched controls completed a questionnaire on autonomic symptoms (the Autonomic Symptom Profile). Thirty-six Fabry patients underwent cardiovascular function tests.ResultsThe Autonomic Symptom Profile revealed a significantly higher sum score in Fabry patients than in healthy control subjects (22 versus 12), but a relatively low score compared to patients with proven autonomic neuropathy. Fabry patients scored worse than healthy controls in the orthostatic intolerance domain. Scores in the male sexual dysfunction domain were comparable between healthy controls and male Fabry patients. The cardiovascular autonomic function tests revealed only mild abnormalities in seven patients. None of these seven patients showed more than one abnormal test result. Enzyme replacement therapy was not associated with less severe disease, lower ASP scores or less frequent abnormal cardiovascular function test results.ConclusionsMale sexual function and autonomic control of the cardiovascular system are nearly normal in Fabry patients, which cast doubt on the general accepted assumption that autonomic neuropathy is the main cause of symptoms and signs compatible with autonomic dysfunction in Fabry disease. Possibly, end-organ damage plays a key role in the development of symptoms and signs in Fabry patients. An exceptional kind of autonomic neuropathy is another but less likely explanation.

Subclinical optic neuropathy in Fabry disease

Background: Fabry disease is a rare X-linked lysosomal storage disorder, caused by the deficiency of α-galactosidase A. Ophthalmic features comprise a cornea verticillata, conjunctival aneurysms, tortuous conjunctival and/or retinal vessels, and anterior and posterior subcapsular cataracts. The issue of a possible subclinical optic neuropathy in Fabry disease has been raised recently. In this pilot study, we looked for signs of optic neuropathy in our cohort of Fabry patients.Methods: Thirty-one Fabry patients (15 male, 16 female, mean age 34 years) underwent an ophthalmological investigation consisting of assessment of best corrected visual acuity, slit lamp investigation, testing of pupillary reaction, funduscopy, applanation tonometry, and automated perimetry (Humphrey 30-2). Twenty-nine patients received enzyme replacement therapy with agalsidase alpha (Replagal).Results: Twenty-five of thirty-one patients showed the typical cornea verticillata, tortuous vessels were seen in 17. Two patients exhibited the pathognomonic posterior subcapsular spoke-like (‘Fabry’) cataract. Intraocular pressure (IOP) was ≤ 20 mm Hg in all patients (mean IOP, range 10–20 mm Hg), and all had normal appearing discs on direct funduscopy. Ten out of 31 patients revealed pathological visual fields exhibiting relative central scotomas in automated 30° static perimetry.Conclusions: In the absence of any other plausible explanation responsible for the field defects detected, we found subclinical optic neuropathy in 10/31 patients suffering from Fabry disease. This figure is in line with a previous report and raises the question whether perimetry should become a part of the ophthalmological examination in Fabry patients. Remarkably, our patients did not complain about any visual impairment. Further investigations are needed to more precisely define this complication of Fabry disease.

46. An evaluation of peripheral neuropathy in fabry disease

46. An evaluation of peripheral neuropathy in fabry disease

Detection of a Characteristic Painful Neuropathy in Fabry Disease: A Pilot Study

Fabry disease (FD) is an X-linked lipid storage disorder showing a high prevalence and early occurrence of painful neuropathy. Early detection of this likely underdiagnosed disease is an important approach because a causal therapy is available. We used a quantitative sensory testing to determine the detailed somatosensory profile of male Fabry patients and compare this profile with somatosensory profiles of other painful sensory neuropathies (SN). Within this pilot-study, the profile revealed a small-fiber sensory neuropathy selectively affecting C- and A-delta fibers. The comparison with different somatosensory profiles of painful SN, including painful small-fiber sensory neuropathies of other etiologies, showed that the FD profile differs significantly and is characterized by a severe impairment of thermal and preserved vibratory and mechanical discrimination. Thus, somatosensory profiling in male patients with painful extremities may be useful in the detection of FD.

130. Evaluation of peripheral neuropathy in Fabry disease

130. Evaluation of peripheral neuropathy in Fabry disease

Evidence for motor axon depolarization in Fabry disease

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 electrotonus 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.

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 74

It is well known that painful neuropathy of the small fiber type is frequent in Fabry disease, however it has been rarely investigated in childhood. We report an 11‐year‐old boy without known familial history of neuromuscular diseases, who complained of painful symptoms in the lower extremities by age 9. Initially pain was present only in association with fever, but during the last year it was triggered also by mild variations in the environmental temperature, so that the boy, to prevent pain, was forced to stay barefooted for most the time during spring and summer, and to wear at least two or three pairs of socks during winter. Physical and neurological examination was negative, except for several small red spots in the testes. Neurophysiological study was negative, but EMG showed motor unit potentials with possible myopathic pattern. Muscle biopsy was unremarkable, apart from endothelial cells containing electron dense lipid inclusions of regular lamellar structure, which were seen also in skin biopsy within fibroblasts, pericytes and endothelial cells. Intraepidermal nerve fiber density was within normal limits (5.5/mm at distal leg and 8.3/mm at proximal thigh), but prominent axonal swellings (possible predegenerative changes) were frequently seen. Diagnosis of Fabry disease was confirmed by deficiency of alfa‐galactosidase. Symptomatic treatment with gabapentin was started, in addition to enzyme replacement therapy. Symptoms of small fiber neuropathy in Fabry disease may be present in early disease as an onset manifestation, and the occurrence of small fiber neuropathy during childhood strongly suggests a diagnosis of Fabry disease. Painful symptoms may occur before a significant intraepidermal nerve fiber loss is seen, and are probably correlated to predegenerative changes in the small sensory fibers.

Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves.

An ultrastructural examination of intradermal nerve fibers in Fabry disease revealed signs of lipid accumulation and small unmyelinated nerve fiber degeneration. Many axons were swollen, and their internal organelles were lost. In several damaged axons, dense inclusions, probably lipid, were observed. No lipid inclusions were found in Schwann cells, which may indicate that they utilize different metabolic processes or are impervious to ceramide trihexoside. It is hypothesized that Schwann cells and myelin sheaths act as a metabolic barrier protecting the larger myelinated fibers. Lacking this barrier, the smaller unmyelinated fibers are more susceptible to lipid infiltration. This view may explain the small fiber neuropathy in Fabry disease.