Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study.

BACKGROUND: Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. METHODS: In this multicentre retrospective cohort study, clinical event rate, left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), antibody formation and globotriaosylsphingosine (lysoGb3) levels were compared between patients with FD treated with agalsidase alfa and beta at their registered dose after correction for phenotype and sex. RESULTS: 387 patients (192 women) were included, 248 patients received agalsidase alfa. Mean age at start of enzyme replacement therapy was 46 (±15) years. Propensity score matched analysis revealed a similar event rate for both enzymes (HR 0.96, P=0.87). The decrease in plasma lysoGb3 was more robust following treatment with agalsidase beta, specifically in men with classical FD (ß: -18 nmol/L, P<0.001), persisting in the presence of antibodies. The risk to develop antibodies was higher for patients treated with agalsidase beta (OR 2.8, P=0.04). LVMI decreased in a higher proportion following the first year of agalsidase beta treatment (OR 2.27, P=0.03), while eGFR slopes were similar. CONCLUSIONS: Treatment with agalsidase beta at higher dose compared with agalsidase alfa does not result in a difference in clinical events, which occurred especially in those with more advanced disease. A greater biochemical response, also in the presence of antibodies, and better reduction in left ventricular mass was observed with agalsidase beta.

Phenotype, disease severity and pain are major determinants of quality of life in Fabry disease: results from a large multicenter cohort study.

Quality of life (QoL) is decreased in patients with Fabry disease (FD). To improve QoL, it is important to understand the influence of FD related characteristics, symptoms, and complications. In this retrospective cohort study we explored the effect of pain (measured by the Brief Pain Inventory), phenotype, treatment, and FD-related complications on QoL. QoL data of Fabry patients as assessed by the EuroQol five dimension questionnaire (EQ-5D) from two international centers of excellence were collected. The aim of this study was to evaluate the effect of sex, phenotype, age, different states of disease severity, pain, and ERT on EQ-5D utilities. For 286 adult FD patients (mean age 42.5 years, 40% men, 60% classical phenotype) 2240 EQ-5Ds were available. QoL is decreased in men as well as women with FD, especially in older men with a classical phenotype. At age 50, utility was lower in men with classical FD compared to those with non-classical disease (ß = -0.12, 95% CI: -0.23 - 0.01, p = 0.037) with further difference in the years thereafter. Cardiovascular complications, stroke or transient ischemic attacks, multiple FD-related complications and pain were also associated with decreased utilities. Overall, no change in utility was seen in patients on ERT over a mean follow-up of 6.1 years. FD leads to a decreased QoL compared to the general population. Disease complications and pain both negatively influence QoL. Adequate assessment and treatment of pain as well as improved strategies to prevent disease complications are needed to improve QoL in the FD population.

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study.

Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95% confidence interval, 3.17 to 10.00; P<0.001; hazard ratio for women, 2.88, 95% confidence interval, 1.54 to 5.40; P<0.001). Furthermore, men with classical Fabry disease had lower eGFR, higher left ventricular mass, and higher plasma globotriaosylsphingosine concentrations than men with nonclassical Fabry disease or women with either phenotype (P<0.001). In conclusion, before treatment with enzyme replacement therapy, men with classical Fabry disease had a history of more events than men with nonclassical disease or women with either phenotype; women with classical Fabry disease were more likely to develop complications than women with nonclassical disease. These data may support the development of new guidelines for the monitoring and treatment of Fabry disease and studies on the effects of intervention in subgroups of patients.

Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease.

BACKGROUND: The level of plasma globotriaosylsphingosine (lysoGb3) is an indication of disease severity in Fabry disease (FD) and its decrease during enzyme replacement therapy could be a reflection of treatment efficacy. Early treatment of FD may improve clinical outcome, but data to support this hypothesis are scarce. In this study we compared lysoGb3 decrease after ERT initiation in men with classical FD who started ERT before the age of 25 (early-treatment) with those who started later in life (late-treatment). METHODS: Treatment naïve men with classical FD from three centers of excellence in Europe were included. Measurements of lysoGb3 levels by tandem mass spectroscopy and antibodies by an inhibitory assay were performed in a single laboratory. Results were adjusted for lysoGb3 at baseline, first ERT (i.e. agalsidase alfa or beta) and the average ERT dose. RESULTS: 85 patients were included, 21 in the early-treatment and 64 in the late-treatment group. LysoGb3 level at baseline was not different between the two groups (112 vs 114nmol/L, p=0.92). The adjusted odds ratio for reaching a lysoGb3 level<20nmol/L was 7.38 for the early-treatment versus late-treatment group (95% CI: 1.91-34.04, p=0.006). The adjusted lysoGb3 levels one year after ERT initiation was 12.9nmol/L lower in the early-treatment (95% CI: -20.1--5.8, p<0.001) compared to the late-treatment group. CONCLUSION: The current retrospective cohort study shows that initiation of ERT at younger age in men with classical Fabry disease results in a better biochemical response.

Discontinuation of enzyme replacement therapy in Fabry disease in the Dutch cohort.

Fabry disease (FD) is a progressive, multi-organ, lysosomal storage disease. Enzyme replacement therapy (ERT) is available for the treatment of the disease. While the reasons to initiate ERT have been frequently discussed, discontinuation of ERT is rarely reported. In this paper we describe our experiences with stopping ERT in FD. From 1999 through 2015, twenty-one patients discontinued ERT. These patients were generally older and more severely affected in comparison those who continued ERT. The reason to discontinue ERT switched from death or terminal illness in the first years towards treatment failure in more recent years. Three cases are described in more detail. We conclude that discontinuation of ERT should or may be considered in subgroups of FD patients although further studies on the effectiveness of ERT in subgroups of patients and the course of the disease after discontinuation of ERT are needed.

Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease.

BACKGROUND: Fabry disease (FD), a lysosomal storage disorder caused by α-galactosidase A (GLA) gene variants, has a heterogeneous phenotype. GLA variants can lead to classical FD, an attenuated non-classical phenotype, or no disease at all. This study investigates the value of plasma globotriaosylsphingosine (lysoGb3) to distinguish between these groups. This is of particular importance in the diagnosis of individuals with a GLA variant and an uncertain diagnosis of FD, lacking characteristic features of classical FD. METHODS: Subjects with GLA variants were grouped as classical, non-classical, uncertain or no FD, using strict phenotypical, biochemical and histological criteria. Plasma lysoGb3 was assessed by LC/MS/MS (normal ≤ 0.6 nmol/L). RESULTS: 154 subjects were grouped into classical (38 males (M), 66 females (F)), non-classical (13 M, 14 F), uncertain (5M, 9 F) or no FD (6M, 3F). All subjects with a classical phenotype had elevated lysoGb3 values (M: range 45-150, F: 1.5-41.5). LysoGb3 values in patients with a non-classical phenotype (M: 1.3-35.7, F: 0.5-2.0) were different from healthy controls (M: p<0.01, F: p<0.05), but females overlapped with controls. In the no-FD group, lysoGb3 was normal. CONCLUSIONS: LysoGb3 is a reliable diagnostic tool to discern classical FD from subjects without FD. This study suggests that the same applies to patients with a non-classical phenotype. LysoGb3 values of female patients overlap with controls. Consequently, in uncertain cases, increased lysoGb3 values are very suggestive for FD, but normal values cannot exclude FD. Confirmation in larger cohorts and data on the specificity of small lysoGb3 increases are necessary.

Chronic kidney disease and an uncertain diagnosis of Fabry disease: approach to a correct diagnosis.

BACKGROUND AND OBJECTIVES: Screening for Fabry disease (FD), an X-linked lysosomal storage disorder, reveals a significant number of individuals with a genetic variant of unknown significance without classical FD manifestations; these variants in the α-galactosidase A gene often result in a high residual leukocyte α-galactosidase A and it is unclear whether these individuals suffer from FD. Therefore, a structured diagnostic approach is warranted. We present a diagnostic algorithm on how to approach adults with chronic kidney disease and an uncertain diagnosis of FD nephropathy. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A modified Delphi procedure was conducted to reach consensus among 11 FD experts. A systematic review was performed to identify possible criteria that could confirm or exclude FD nephropathy. RESULTS: The gold standard for FD nephropathy was defined as characteristic storage on electron microscopy (EM) in a kidney biopsy in the absence of medication that may induce similar storage. The suggested criteria to confirm FD nephropathy are as follows: 'renal cysts', 'Maltese cross sign', 'immunohistochemical staining of Gb3 in urine' and 'high urinary Gb3'; and to exclude FD nephropathy: 'absence of renal cysts', 'small kidneys' and 'high protein excretion' were rejected because of low or uncertain specificity. Urinary Gb3 may be increased in other kidney diseases and there was no agreement on this criterion, although a third of the panel indicated that it is sufficient to diagnose FD nephropathy. The 'Maltese cross sign' and 'high urinary Gb3' were selected as red flags to suggest the possibility of FD nephropathy, but are not sufficient for a definite diagnosis of FD nephropathy. CONCLUSIONS: In adults with chronic kidney disease, an α-galactosidase A gene variant and an uncertain diagnosis of FD, a kidney biopsy with EM analysis should be performed to confirm or reject the diagnosis of FD nephropathy. Other criteria currently cannot substitute for a biopsy in these cases.

Hearing loss in adult patients with Fabry disease treated with enzyme replacement therapy.

INTRODUCTION: Data on prevalence, natural history, and effect of enzyme replacement therapy (ERT) on hearing loss (HL) in Fabry disease (FD) are scarce. METHODS: This is a retrospective study with cross-sectional and longitudinal analyses. Low and high-frequency HL in the Dutch FD cohort was studied in four groups: classical and non-classical FD patients with or without ERT. To study effects of ERT, longitudinal data, corrected for age and gender according to ISO-1999 guidelines, were analyzed with mixed models. RESULTS: In the cross-sectional analysis, 107 FD patients (41 males), median age 47.6 years (18.8-80.6) were analyzed. At baseline, i.e., before start of ERT, HL was present in 18 patients (16.8 %), of whom four had bilateral sensorineural HL. HL was more often present in patients with the classical phenotype than non-classical patients (p < 0.01). Likewise, males had more often HL than females. Compared to the general population, FD patients show a median HL of 8.2 dB at low frequencies (p < 0.01) and 29.5 dB at ultra-high frequencies (p < 0.01). Longitudinal analyses (n = 91) revealed that ERT treated patients show a similar rate of decline, not significantly different from healthy controls. CONCLUSION: Adult FD patients, especially classical affected males, show impaired hearing. Longitudinal analyses during ERT in these patients demonstrates a decline of HL similar to healthy controls, but HL present before initiation of therapy cannot be reversed. Whether early therapy can prevent hearing loss is unknown.

Malignancies and monoclonal gammopathy in Gaucher disease; a systematic review of the literature.

Gaucher disease is an autosomal, recessively inherited, lysosomal storage disease, which has been associated with gammopathies and malignancies. This report represents the results of a systematic review of the literature on the prevalence of monoclonal gammopathies and malignancies in Gaucher disease. A PubMed search identified 365 studies, of which 80 reported on concomitant Gaucher disease and malignancies and/or gammopathies (15 cohort/cross sectional studies, and 65 case reports/series). Based on these studies, we conclude that compared to the general population, Gaucher patients have an increased risk of cancer in general [pooled relative risk of 1·70 (95% confidence interval 1·27-2·31)], and multiple myeloma and haematological malignancies in particular (estimated risk between 25·0 and 51·1 and 3·5 and 12·7, respectively). In addition, an increased risk has been reported for hepatocellular carcinoma and renal cell carcinoma. Several factors have been hypothesized to play a role in the pathophysiology. These include: splenectomy, immune dysregulation, endoplasmic reticulum stress, genetic modifiers, altered iron metabolism and insulin resistance.

Fabry disease: a rare cause of neuropathic pain.

Fabry disease is characterized by burning or shooting pains in hands and feet, which have a severe impact on the quality of life of patients. It is therefore of importance that Fabry patients receive adequate diagnosis, counseling, treatment and follow up. This review describes neuropathic pain in classical Fabry disease with the aim to help clinicians to recognize Fabry patients among patients presenting with chronic extremity pain. The diagnostic dilemmas in patients with neuropathic pain and a non-classical disease course are discussed, together with the available diagnostic modalities, pain medication options and the effect of enzyme replacement therapy on small fiber neuropathy.

Small fiber neuropathy in Fabry disease.

Previous studies have explicitly shown that small nerve fibers are affected in Fabry disease which is assumed to cause the severe neuropathic pain that patients may have from childhood on. Neuropathic pain and small fiber neuropathy characteristics have therefore been considered as appropriate study endpoints in studies on the efficacy of enzyme replacement therapy. However, the relationship between small fiber neuropathy characteristics and pain, as well as the course of small fiber neuropathy in Fabry disease is still uncertain. In this article a comprehensive overview of the existing literature on small nerve fiber function and structure and the relationship with pain, age and disease severity is presented supplemented with data from the Dutch Fabry cohort, with the aim to identify consensus as well as controversies and to propose a hypothesis on the evolution of neuropathy in Fabry disease.

The cognitive profile of type 1 Gaucher disease patients.

BACKGROUND: The absence of neurological symptoms and signs is traditionally considered mandatory for a diagnosis of type 1 Gaucher disease (GD1), but in recent years many reports have emerged on neurological manifestations in GD1 patients. Nevertheless, it has been unclear whether cognitive deficits are part of the disease as well. METHODS: Cognitive function was assessed in a large cohort of GD1 patients with the use of the CDR system, a set of computerised cognitive tests. Testing was performed at baseline and every 6 months thereafter during a two-year study period. RESULTS: Our patient cohort (84 patients, median age 40 years, median time from diagnosis 15 years) showed mild deficits relative to healthy age-matched subjects on the composite scores: power of attention (Z-score (mean ± SD) -0.9 ± 1.37) and speed of memory (Z-score (mean ± SD) -1.39 ± 1.49). No decline in cognitive function was seen during the two-year period. Age correlated with the composite scores variability of attention and quality of working memory. Moreover, severely affected patients (Zimran severity score (SSI) ≥ 15) scored more poorly compared to mildly affected patients (SSI ≤ 5) on the composite measure power of attention, reflecting the ability to concentrate. CONCLUSIONS: GD1 patients exhibit mild deficits in power of attention and speed of memory, reflecting a decreased ability to focus attention and process information, together with a slowing in the speed of retrieval of items from memory. The clinical relevance of these findings is uncertain.

Peripheral neuropathy in adult type 1 Gaucher disease: a 2-year prospective observational study.

Type 1 Gaucher disease is currently categorized as non-neuronopathic, although recent studies suggest peripheral neurological manifestations. We report prevalence and incidence data for peripheral neuropathy and associated conditions from a multinational, prospective, longitudinal, observational cohort study in patients with type 1 Gaucher disease, either untreated or receiving enzyme replacement therapy. The primary outcome parameters were the prevalence and incidence of polyneuropathy, evaluated by standardized assessments of neurological symptoms and signs, and electrophysiological studies. All diagnoses of polyneuropathy were adjudicated centrally. Secondary outcome parameters included the prevalence and incidence of mononeuropathy, other neurological or electrophysiological abnormalities not fulfilling the criteria for a mono- or polyneuropathy and general type 1 Gaucher disease symptoms. Furthermore, a literature search was performed to identify all studies reporting on prevalence and incidence of polyneuropathy in the general population. One hundred and three patients were enrolled [median (range) age: 42 (18-75) years; disease duration: 15 (0-56) years; 52% female]; 14 (13.6%) were untreated and 89 (86.4%) were on enzyme replacement therapy. At baseline, 11 patients [10.7%; 95% confidence interval (CI): 5.9-18.3] were diagnosed with sensory motor axonal polyneuropathy. Two (1.9%; 95% CI: 0.1-7.2) had a mononeuropathy of the ulnar nerve. The 2-year follow-up period revealed another six cases of polyneuropathy (2.9 per 100 person-years; 95% CI: 1.2-6.3). Patients with polyneuropathy were older than those without (P<0.001). Conditions possibly associated with polyneuropathy were identified in four patients only, being monoclonal gammopathy, vitamin B(1) deficiency, folic acid deficiency, type 2 diabetes mellitus, renal insufficiency, alcohol abuse and exposure to toxins related to profession. The 11 cases of polyneuropathy found at baseline were confirmed during follow-up. According to the literature, the prevalence of polyneuropathy in the general population was estimated between 0.09 and 1.3% and the incidence was estimated between 0.0046 and 0.015 per 100 person-years. Thus, we conclude that the prevalence and incidence of polyneuropathy in patients with type 1 Gaucher disease is increased compared with the general population.

Poikilothermia in a 38-year-old Fabry patient.

A Fabry patient with poikilothermia is described. Laboratory investigations, neuro-imaging and autonomic function tests did not disclose a cause. Assessment of intra-epidermal nerve fibre density and quantitative sensory testing revealed small fibre neuropathy with a highly impaired cold sensation. We speculate that the poikilothermia is either caused by a vascular lesion in the hypothalamus not visible on MRI or by small fibre neuropathy leading to disturbed body temperature perception and therefore impaired thermoregulation.

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

BACKGROUND: Fabry 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. METHODS: Forty-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. RESULTS: The 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. CONCLUSIONS: Male 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.

Oncologic orphan drugs approved in the EU - do clinical trial data correspond with real-world effectiveness?

BACKGROUND: Evaluation of evidence for efficacy of orphan medicinal products (OMPs) for rare malignancies may be hampered by the use of tumor measurements instead of clinical endpoints. This may cause efficacy data to not always match effectiveness in the real-world. We investigated whether an efficacy-effectiveness gap exists for oncologic OMPs and aimed to identify which factors contribute to it. Also, the magnitude of the clinical efficacy of oncologic OMPs was evaluated. METHODS: We included all oncologic OMPs authorized in the European Union from 2000 to 2017. Pivotal studies were evaluated by means of the European Society for Medical Oncology - Magnitude of Clinical Benefit Scale (ESMO-MCBS). To estimate real-world effectiveness, a literature search was performed to identify post-marketing studies, of which data on overall survival (OS) were extracted. OS of the new OMP was compared with OS data of standard of care. An OS gain of ≥3 months compared to pre-marketing data was considered clinically relevant. RESULTS: Twenty OMPs were included, of which 5 were authorized based on OS as a primary endpoint. 10 OMPs had post-marketing data available, of which 40% did not show a clinically relevant OS gain in the real world. All OMPs that were studied with OS as primary endpoint in the pivotal study had a clinically relevant OS gain in the real world. Furthermore, all OMPs that had a high ESMO-MCBS score and post-marketing data available, resulted in a clinically relevant OS gain in the real world. CONCLUSIONS: Although the sample size is small, our results indicate an efficacy-effectiveness gap for oncologic OMPs exists. Significant changes in PFS do not always lead to an increased OS. The use of PFS may be justified, but validation of surrogate endpoints is needed.

Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors.

Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR <90 ml/min/1.73m2 to 4 at eGFR <30, compared to patients with an eGFR >90. In addition, men with classical disease and a baseline eGFR <60 ml/min/1.73m2 had a faster yearly decline (-2.0 ml/min/1.73m2) than those with a baseline eGFR of >60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension.

Cornea verticillata supports a diagnosis of Fabry disease in non-classical phenotypes: results from the Dutch cohort and a systematic review.

BACKGROUND: Screening for Fabry disease (FD) increasingly reveals individuals without characteristic features and with a variant of unknown significance in the α-galactosidase A (GLA) gene. Cornea verticillata (CV) assessment, as a characteristic sign of FD, may be a valuable diagnostic tool to assess whether these individuals have a non-classical phenotype or no FD at all. METHODS: We performed a systematic review to estimate the prevalence of CV in FD. Additionally, CV prevalence was assessed in the Dutch FD cohort. Data were stratified by gender and phenotype (classical, non-classical, uncertain, no-FD) using predefined criteria. RESULTS: CV was assessed in 21 cohorts (n=753, 330 men, age 0-85 years). Pooled prevalence was 69% (74% men, 66% women). In six studies, 77 (19 men) individuals with a non-classical or uncertain diagnosis were identified. Individual data were available in 4/6 studies (n=66, 16 men). CV was present in 24% (n=16, 2 men). 101 (35 men) subjects from the Dutch cohort were grouped as classical, of whom 86% (94% men, 82% women including five women who used amiodarone) had CV. Of the 25 (11 men) non-classical patients, 4 (three men) had CV. Subjects in the uncertain and no-FD groups did not have CV. CONCLUSIONS: CV is related to classical or biopsy-proven non-classical FD, with a very high sensitivity in classical men. Thus, presence of CV in an individual with an uncertain diagnosis of FD indicates a pathogenic GLA variant, in the absence of medication that may induce CV; if CV is absent, FD cannot be excluded.

In Patients with an α-Galactosidase A Variant, Small Nerve Fibre Assessment Cannot Confirm a Diagnosis of Fabry Disease.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by an α-galactosidase A enzyme deficiency due to pathogenic variants in the α-galactosidase A gene (GLA). An increasing number of individuals with a GLA variant, but without characteristic FD features, are identified. A definite diagnosis of FD has important consequences for treatment and counselling. OBJECTIVES: We assessed the diagnostic value of quantitative sensory testing (QST) and intraepidermal nerve fibre density (IENFD) for patients with an uncertain FD diagnosis. METHODS: All patients with a GLA variant who initially presented at the Academic Medical Center with an uncertain FD diagnosis were included. A biopsy of an affected organ in a patient or family member showing FD characteristic storage is used as a reference standard for a diagnosis of FD. All patients underwent a comprehensive QST protocol and IENFD assessment which was compared to age and gender-matched healthy controls. Sensitivity and specificity were calculated for a combination of ≥1 abnormal QST modality and an abnormal IENFD. RESULTS: Twenty-six patients participated (nonclassical FD n = 18, 9 males; no FD n = 5, 3 males; uncertain n = 3, 1 male). Of the patients classified as nonclassical FD, 28% had ≥1 abnormal QST modalities, and 83% had an abnormal IENFD. From the patients without FD, 20% had ≥1 abnormal QST modality, and IENFD was abnormal in 25% (1 not available). Sensitivity was 28% and specificity 80%. CONCLUSIONS: In our study cohort, QST and IENFD could not reliably distinguish patients with FD from those without FD.