Enzyme replacement therapy and intraepidermal innervation density in Fabry disease

We prospectively evaluated the effect of enzyme replacement therapy (ERT) on the intraepidermal nerve fiber density (IENFD) and thermal threshold in patients with Fabry disease, an X-linked disorder associated with a painful small-fiber neuropathy and decreased linear IENFD in a length-dependent pattern. Twenty-five hemizygous male patients with Fabry disease were enrolled in a 6-month, randomized, placebo-controlled ERT trial of 0.2 mg/kg of alpha-galactosidase A (agalsidase-alfa) every 2 weeks followed by an additional 12 months of open-label ERT for both populations. IENFD and thermal threshold were measured in the distal thigh at baseline, 6 months, and 18 months from initiation of the trial. We found no significant difference in IENFD between the treatment groups at 6 months. After an additional year of ERT, there was a significant reduction in IENFD in the patient group as a whole, attributable to the declining glomerular filtration rate. Thermal thresholds remained unchanged. We conclude that epidermal nerve fiber regeneration, as measured in the distal thigh, does not occur in this patient population after 12-18 months of ERT.     

Detection of small-fiber neuropathy by sudomotor testing

The symptoms of burning sensation affecting the feet, thought to be due to a distal small-fiber neuropathy (DSFN) affecting somatic unmyelinated fibers, are usually accompanied by vasomotor or sudomotor changes suggestive of involvement of autonomic fibers. We therefore examined the relationship between pattern of anhidrosis and DSFN and its etiology, comparing patients with "pure" DSFN (with normal nerve conduction) to those with clinical DSFN (minor conduction abnormalities). We reviewed 125 cases with a clinical phenotype of DSFN. These patients had distal burning discomfort, variable sensory deficits, and intact motor function. All had undergone assessment with thermoregulatory sweat test (TST), autonomic reflex screen (ARS), and nerve conduction studies and electromyography (NCS/EMG). TST showed a distal pattern of anhidrosis in 74%. The quantitative sudomotor axon reflex test (QSART) was abnormal in 74%, with 80% of those having a length-dependent pattern of anhidrosis/hypohidrosis. In total, 93% of patients had a distal pattern of abnormality on QSART or TST. The Composite Autonomic Severity Score (CASS) was used to quantify the severity and distribution of autonomic deficits: 98% had CASS abnormality (sudomotor, 98%; adrenergic, 43%; cardiovagal, 35%). EMG was normal or showed unrelated abnormalities in 75%. The most common etiologies of DSFN were idiopathic (73%), presumed hereditary (18%), and diabetes (10%). Sudomotor examination is thus a highly sensitive detection tool in DSFN. Autonomic involvement is mainly distal, and additionally may involve adrenergic and the long cardiovagal fibers.     

Measures of small-fiber neuropathy in HIV infection

Introduction

Noninvasive methods are needed to detect distal sensory polyneuropathy in HIV-infected persons on antiretroviral therapy (ART).

Methods

Quantitative sudomotor axon reflex test (QSART) and Utah Early Neuropathy Scale (UENS), small-fiber sensitive measures, were assessed in subjects with and without clinical neuropathy. Pain was assessed by visual analog scale (VAS).

Results

Twenty-two subjects had symptoms and signs of neuropathy, 19 had neither, and all were receiving ART. Median sweat volume (μL) was lower at all testing sites in those with neuropathy compared to those without (p < 0.01 for all). UENS and VAS (mm) were higher in neuropathy subjects (p < 0.05 for each). Lower sweat volume at all sites correlated with higher pin UENS subscore, total UENS, and VAS (p < 0.05 for all). In multivariable analyses adjusting for age, CD4⁺ T cells, sex, and use of “d-drug” ART, QSART and UENS remained associated (p = 0.003).

Conclusion

QSART and UENS have not been previously studied in this patient population and may identify small-fiber neuropathy in HIV-infected, ART-treated persons.     

Small fibers in Fabry disease: baseline and follow-up data under enzyme replacement therapy

Fabry disease (FD) is an X-linked lysosomal storage disorder which may lead to impaired peripheral nerve function, mostly affecting small nerve fibers, and to neuropathic pain. Characteristics of the neuropathy associated with FD and the covariates for its development and temporal course have not been described in a large cohort. We studied small fiber function and morphology in 120 Fabry patients at baseline and in subgroups of these until 4-year follow-up. Baseline neurological (89/120) and electrophysiological (106/120) examination was mostly normal. Quantitative sensory testing revealed impaired cold detection thresholds in 84% of men and 39% of women. Lower leg intraepidermal nerve fiber density (IENFD) was reduced to 46% in Fabry patients compared to controls and to 12.5% in men with impaired renal function. Patients with abnormal IENFD more often had pain. Group means for IENFD did not improve under enzyme replacement therapy (ERT), but IENFD in the back increased under ERT in 4/15 patients with good renal function and clinical improvement. Cutaneous cytokine gene expression did not differ from controls. We conclude that ERT may improve proximal skin innervation in patients with good renal function, but does not protect small fiber function in men with impaired renal function.     

Sweat testing to evaluate autonomic function

Sudomotor dysfunction is common in many subtypes of neuropathy but is one of the earliest detectable neurophysiologic abnormalities in distal small fiber neuropathy. Clinical assessments of sudomotor function include thermoregulatory sweat testing (TST), quantitative sudomotor axon reflex testing (QSART), silicone impressions, the sympathetic skin response (SSR), the acetylcholine sweat-spot test and quantitative direct and indirect axon reflex testing (QDIRT). These testing techniques, when used in combination, can detect and localize pre- and postganglionic lesions, can provide early diagnosis of sudomotor dysfunction and can monitor disease progression or disease recovery. In this article, we describe many of the common clinical tests available for evaluation of sudomotor function with focus on the testing methodology and limitations while providing concrete examples of test results.     

Autonomic skin responses in females with Fabry disease

Fabry disease is a genetic lysosomal disorder with dysfunction of the lysosomal enzyme α-galactosidase A causing accumulation of glycolipids in multiple organs including the nervous system and with neuropathy as a prominent manifestation. Neurological symptoms include pain and autonomic dysfunction. This study examined peripheral autonomic nerve function in 19 female patients with Fabry disease and 19 sex and age-matched controls by measuring (1) sweat production following acetylcholine challenge; (2) the sympathetically mediated vasoconstrictor responses to inspiratory gasp, stress, and the cold pressor test; and (3) cutaneous blood flow following capsaicin. The vasoconstrictor response to inspiratory gasp was increased in Fabry patients compared to controls (p = 0.03), while the response to cold and mental stress did not change. Female patients with Fabry disease had a reduced sweat response to iontophoresis of acetylcholine (p = 0.04) and a smaller capsaicin-induced flare compared to controls. These findings suggest that female patients both have an impaired C-fiber function and local abnormalities in blood vessels and sweat glands.     

Comparison of SSR and QSART in early diabetic neuropathy--the value of length-dependent pattern in QSART

We evaluated postganglionic sympathetic function using the sympathetic skin response (SSR) and quantitative sudomotor axon reflex test (QSART) on the feet of 31 patients with early diabetic neuropathy and 20 age-matched normal controls. The amplitude of SSR and the sweat volume of QSART were significantly decreased in the diabetic patients. We evaluated the sensitivity of the tests in detecting autonomic failure. Out of 31 patients, 14 (45%) had abnormal SSR (14 absent; 17 present), while 16 of 31 patients (52%) had abnormal QSART (1 absent; 5 absolutely reduced and 10 showed a length-dependent pattern of reduction). More important than differences in sensitivity is the specificity of QSART, which specifically evaluates the postganglionic axon (instead of polysynaptic pathways in SSR) and provides quantitative data on the severity and pattern of autonomic deficit. In normal controls under 65 years of age, there was a significant correlation between the amplitude of SSR and the sweat volume of QSART. However, there was no significant relationship between these in diabetic patients. These results suggest that QSART can evaluate early diabetic neuropathy more precisely than SSR.     

Small-fiber neuropathy

Small-fiber neuropathy is a common disorder. It is often "idiopathic" and typically presents with painful feet in patients over the age of 60. Autoimmune mechanisms are often suspected, but rarely identified. Known causes of small-fiber neuropathy include diabetes mellitus, amyloidosis, toxins, and inherited sensory and autonomic neuropathies. Occasionally, small-fiber neuropathy is diffuse or multifocal. Depending on the type of small-fiber neuropathy, autonomic dysfunction can be significant or subclinical. Diagnosis is made on the basis of the clinical features, normal nerve conduction studies, and abnormal specialized tests of small-fiber function. These specialized studies include assessment of epidermal nerve fiber density as well as sudomotor, quantitative sensory, and cardiovagal testing. The sensitivities of these tests range from 59-88%. Each has certain advantages and disadvantages, and the tests may be complementary. Unless an underlying disease is identified, treatment is usually directed toward alleviation of neuropathic pain.     

Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome

BACKGROUND: Classic Fabry disease, an X-linked recessive lysosomal storage disease due to the deficient activity of alpha-galactosidase A, typically presents in early childhood with acroparesthesias, angiokeratomas, hypohidrosis, and corneal dystrophy. The neuropathic pain presumably results from glycosphingolipid accumulation in the vascular endothelium and in small-caliber nerve fibers, and is treatable by enzyme replacement therapy. Later-onset variants with residual alpha-galactosidase A activity lack vascular endothelial involvement and classic symptoms, which lead to the development of cardiac and/or renal disease after the fourth decade of life. OBJECTIVE: To expand the later-onset Fabry phenotype to include cramp-fasciculation syndrome without small-fiber neuropathy. METHODS: A 34-year-old man who presented with chronic exercise-induced pain, fasciculations, and cramps of the feet and legs, and his similarly affected mother, were evaluated. Clinical, biochemical, and molecular studies were performed. RESULTS: Clinical evaluation suggested the diagnosis of Fabry disease, which was confirmed by reduced plasma and leukocyte alpha-galactosidase A activities (8.8% and 13.4% of normal, respectively) due to a missense A143T mutation. His mother was heterozygous for the A143T mutation. CONCLUSION: The presentation of cramps and fasciculations without apparent small-fiber neuropathy expands the phenotype of later-onset Fabry disease.     

Evaluation of cutaneous autonomic innervation in idiopathic sensory small-fiber neuropathy

To evaluate the loss of autonomic nerve fibers in patients with clinical pure small-fiber sensory neuropathy, we performed skin punch biopsies in 17 and 15 age- and sex-matched controls. Biopsies were taken 10 cm above the lateral malleolus, and 5-mum sections were stained with hematoxylin and eosin and the panaxonal marker protein gene product (PGP) 9.5. Positively stained fibers, represented as dots, innervating the erector pili muscles, arterioles, and sweat glands (SG) were counted. The ratios between the number of nerve fibers and nuclei of each structure were calculated. The autonomic innervation was significantly reduced in the patients' group compared with controls in all the examined autonomic-innervated structures: SG (0.27 +/- 0.15 vs. 0.66 +/- 0.37, p = 0.001), arterioles (0.38 +/- 0.32 vs. 0.86 +/- 0.45, p=0.002), and the erector pili muscle (0.58 +/- 0.27 vs. 1.23 +/- 0.87, p = 0.036). Our results suggest that autonomic involvement occurs in patients with sensory small-fiber neuropathy and that punch skin biopsy using thin sections is a simple and convenient method to detect these dermal autonomic small-fiber abnormalities.     

Sudomotor function in familial dysautonomia

BACKGROUND: Patients with familial dysautonomia (FD) manifest episodic hyperhidrosis despite the reduction of sudomotor fibres and sweat glands associated with this autonomic neuropathy. We assessed peripheral sudomotor nerve fibre and sweat gland function to determine if this symptom was due to peripheral denervation hypersensitivity. METHODS: In 14 FD patients and 11 healthy controls, direct and axon reflex mediated sweat responses were determined by measuring transepidermal water loss (TEWL) after application of acetylcholine via a microdialysis membrane, a novel method to evaluate sudomotor function in neuropathy patients. Results were compared with data from conventional quantitative sudomotor axon reflex testing (QSART). Using microdialysis, interstitial fluid was analysed for plasma proteins to evaluate protein extravasation induced by acetylcholine as an additional parameter of C-fibre function. RESULTS: Although reduced axon reflex sweating was expected in FD patients, neither direct or axon reflex mediated sweat responses, nor acetylcholine induced protein extravasation differed between control and patient groups. However, the baseline resting sweat rate was higher in FD patients than controls (p<0.05). TEWL and QSART test results correlated (r = 0.64, p = 0.01), proving the reliability of TEWL methodology in evaluating sudomotor function. CONCLUSION: The finding of normal direct and axon reflex mediated sweat output in FD patients supports our hypothesis that, in a disorder with severe sympathetic nerve fibre reduction, sudomotor fibres, but not the sweat gland itself, exhibit chemical hypersensitivity. This might explain excessive episodic hyperhidrosis in situations with increased central sympathetic outflow.     

Cutaneous silent periods in patients with Fabry disease

We assessed the cutaneous silent period (CSP) in 24 patients with Fabry disease with small-fiber sensory neuropathy and 12 normal subjects to test the hypothesis that small-diameter afferents are responsible for producing the CSP. Sensory nerve conduction studies and quantitative sensory testing for cold and vibration detection thresholds were also measured. Overall, Fabry patients had impaired thermal, but not vibration, detection thresholds, with greatest impairment in the feet. In the upper extremity, CSP latencies, duration, and suppression of electromyographic activity (EMG) did not differ. In the lower extremity, patients had reduced suppression of EMG during the CSP compared to normal controls. CSP durations exhibited a bimodal distribution in patients, including a subset of seven patients with durations shorter than all controls. This subset had profound loss of thermal sensation in the feet, but this was also true of some patients who had normal CSPs. Patients with shortened CSPs had modestly elevated vibration thresholds and reduced sensory potentials in comparison to patients with normal CSPs. Reduced CSPs in Fabry patients are associated with, but not entirely explained by, the severity of small-fiber neuropathy as measured by quantitative sensory testing. The possibility that large-diameter fibers provide a minor contribution to producing the CSP should be considered.     

Corneal confocal microscopy: A novel noninvasive means to diagnose neuropathy in patients with fabry disease

Neuropathy is a cause of significant disability in patients with Fabry disease, yet its diagnosis is difficult. In this study we compared the novel noninvasive techniques of corneal confocal microscopy (CCM) to quantify small‐fiber pathology, and non‐contact corneal aesthesiometry (NCCA) to quantify loss of corneal sensation, with established tests of neuropathy in patients with Fabry disease. Ten heterozygous females with Fabry disease not on enzyme replacement therapy (ERT), 6 heterozygous females, 6 hemizygous males on ERT, and 14 age‐matched, healthy volunteers underwent detailed quantification of neuropathic symptoms, neurological deficits, neurophysiology, quantitative sensory testing (QST), NCCA, and CCM. All patients with Fabry disease had significant neuropathic symptoms and an elevated Mainz score. Peroneal nerve amplitude was reduced in all patients and vibration perception threshold was elevated in both male and female patients on ERT. Cold sensation (CS) threshold was significantly reduced in both male and female patients on ERT (P < 0.02), but warm sensation (WS) and heat‐induced pain (HIP) were only significantly increased in males on ERT (P < 0.01). However, corneal sensation assessed with NCCA was significantly reduced in female (P < 0.02) and male (P < 0.04) patients on ERT compared with control subjects. According to CCM, corneal nerve fiber and branch density was significantly reduced in female (P < 0.03) and male (P < 0.02) patients on ERT compared with control subjects. Furthermore, the severity of neuropathic symptoms and the neurological component of the Mainz Severity Score Index correlated significantly with QST and CCM. This study shows that CCM and NCCA provide a novel means to detect early nerve fiber damage and dysfunction, respectively, in patients with Fabry disease. Muscle Nerve, 2009     

Fabry disease: impaired autonomic function

Previous reports of extensive lipid accumulation within neurons of the autonomic nervous system in Fabry disease suggest an anatomicopathologic basis for the peculiar pain, diminished sweating, and gastrointestinal symptoms experienced in this disorder. To further assess autonomic function in Fabry disease, noninvasive clinical tests were performed on 10 patients. Diminished sweating was found in each; the loss was approximately uniform proximally and distally, suggesting sweat gland dysfunction rather than autonomic neuropathy. Impaired pupillary constriction with pilocarpine, and reduced saliva and tear formation were found in half the patients. Disordered intestinal mobility was demonstrated in the oldest patients. In all cases, the cutaneous flare response to scratch and intradermal histamine was diminished, and pruritus was not experienced. Signs of autonomic dysfunction are present in Fabry disease and correlate with the known lipid deposition in autonomic neurons.     

Acute steroid responsive small‐fiber sensory neuropathy: a new entity?

Small-fiber neuropathy is often idiopathic and commonly follows a chronic course. Treatment is often effective in treating the core symptom of pain, but it has no effect on the pathologic process. We describe four patients with acute small-fiber neuropathy who responded dramatically to steroid therapy. All patients had acute onset neuropathic pain, normal nerve conduction studies, and evidence of small-fiber dysfunction in quantitative sensory testing and skin biopsy. Symptoms were distal and symmetrical in three patients and generalized in one patient. In two cases, the neuropathy presented as an erythromelalgia-like syndrome. Marked clinical improvement occurred 1-2 weeks after oral prednisone therapy was initiated. Three patients remained symptom free, and one patient experienced recurrence of neuropathy after prednisone was tapered.     

Neuropathy and Fabry disease: pathogenesis and enzyme replacement therapy

The neurological manifestations of Fabry disease include both peripheral and central nervous system involvement caused by a deficiency of alpha-galactosidase A and accumulation of alpha-D-galactosyl moieties, particularly globotriosylceramide accumulation (Gb3). These are found in Schwann cells and dorsal root ganglia together with deposits in central nervous system neurons. Involvement of the peripheral nervous system affect mainly small Adelta and C fibers and are likely causally related to the altered autonomic function and neuropathic pain found in this disorder. Other related abnormalities to be discussed are hypohidrosis and other abnormalities attributed to autonomic nervous system dysfunction. The function of the peripheral nervous system is somewhat improved by ERT with reduction in neuropathic pain and an improvement of the detection threshold for cold and warm sensation in the hand and foot. Improvement in sweating and heat tolerance is also noted following ERT. Despite those positive results, ERT does not normalize the function of the peripheral nervous system.     

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.     

Fabry Disease: A Disorder of Childhood Onset

BackgroundFabry disease, an X-linked disorder of glycosphingolipids, markedly increases the risk of systemic vasculopathy, ischemic stroke, small-fiber peripheral neuropathy, cardiac dysfunction, and chronic kidney disease.MethodsWe performed an extensive PubMed search on the topic of Fabry disease and drew from our cumulative 43 years of experience.ResultsMost of these complications are nonspecific in nature and clinically indistinguishable from similar abnormalities that occur in the context of more common disorders in the general population. This disease is caused by variants of the GLA gene, and its incidence may have been underestimated. However, one must also guard against overdiagnosis of Fabry disease and unjustified enzyme replacement therapy, because some of the gene variants are benign. Specific therapy for Fabry disease has been developed in the last few years, but its clinical effect has been modest. Novel therapeutic agents are being developed. Standard “nonspecific” medical and surgical therapy is necessary and effective in slowing deterioration or compensating for organ failure in patients with Fabry disease.ConclusionsFabry disease is a treatable and modifiable genetic risk factor for a myriad of clinical organ complications. Fabry disease may be frequently overlooked but on occasion overdiagnosed.     

Neuropathic symptoms and findings in women with Fabry disease

ObjectiveTo 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.MethodsNeurography, 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.ResultsOnly 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, Aδ-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.ConclusionsHeterozygous 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.SignificanceWhile the clinical diagnosis of small-fiber neuropathy is difficult, the diagnostic yield can be increased using a combination of thermal QST and IENFD measurements.     

Painful sensory neuropathy: prospective evaluation using skin biopsy

OBJECTIVE: In patients presenting with painful, burning feet with minimal signs of neuropathy, the following questions were addressed: 1) How many of these patients have a peripheral neuropathy? 2) What is the role of skin biopsy in establishing a diagnosis of neuropathy? 3) What conditions are associated with the neuropathy? and 4) What laboratory studies are useful in this patient population? METHODS: A total of 117 consecutive patients referred for evaluation were prospectively studied. All underwent nerve conduction studies (NCS) and a battery of blood tests, including antinerve antibodies. If NCS were normal, a punch biopsy of the skin of the distal leg was performed to ascertain the intraepidermal nerve fiber (IENF) density. In a subset of 32 patients, the sensitivity of skin biopsy was compared to quantitative sudomotor axon test (QSART) and quantitative sensory tests (QST). Results: Three groups emerged. Group 1, with abnormal NCS (n = 60, 34 F/26 M, mean age 60 +/- 14 years), represented 51% of the cohort. The majority had neuropathies of undetermined cause, but 18 (30%) had associated conditions. Group 2, with normal NCS and reduced IENF density (n = 44, 29 F/15 M, mean age 57 +/- 14 years), represented 38% of the cohort. Three in this group had associated conditions. Group 3, with normal NCS and IENF density (n = 13, 6 F/7 M, mean age 53 +/- 13 years), represented 11% of the cohort; most had no diagnoses but two had MS. In a comparative subset analysis, skin biopsy was more sensitive than QSART or QST in diagnosing a neuropathy. CONCLUSIONS: Patients presenting with painful feet are heterogeneous, consisting of both large and small fiber sensory neuropathies. In rare cases, a central cause for pain can be found. Over one-third of patients required a skin biopsy to diagnose a small fiber sensory neuropathy. A limited battery of blood tests facilitated diagnosis, but serum antinerve antibodies were not helpful.