Mild phenotype in an adult male with X-linked adrenoleukodystrophy - case report.

X-linked adrenoleukodystrophy may present with a deceptively mild phenotype, even in adult males. Tight collaboration between clinicians, geneticists, biochemists, and other specialists is increasingly required for clarification of diagnosis in cases with atypical presentation.

Small and large fiber neuropathy in those with type 1 and type 2 diabetes: a 5-year follow-up study.

The purpose of this study was to evaluate progression of diabetic polyneuropathy and differences in the spectrum and evolution of large- and small-fiber involvement in patients with diabetes type 1 and 2 over 5 years. Fifty-nine patients (35 type 1 and 24 type 2) were included. Nerve conduction studies (NCS), quantitative sensory testing, skin biopsy for quantification of intraepidermal nerve fiber density (IENFD), symptom scoring and clinical evaluations were performed. Z-scores were calculated to adjust for the physiologic effects of age and height/gender. Neuropathic symptoms were not significantly more frequent in type 2 than in type 1 diabetic patients at follow-up (54% vs. 37%). The overall mean NCS Z-score remained within the normal range, but there was a small significant decline after 5 years in both groups: type 1 (p = 0.004) and type 2 (p = 0.02). Mean IENFD Z-scores changed from normal to abnormal in both groups, but only significantly in those with type 2 diabetes (reduction from 7.9 ± 4.8 to 4.3 ± 2.8 fibers/mm, p = 0.006). Cold perception threshold became more abnormal only in those with type 2 diabetes (p = 0.049). There was a minimal progression of large fiber neuropathy in both groups. Reduction of small fibers predominated and progressed more rapidly in those with type 2 diabetes.

Small nerve fiber involvement is frequent in X-linked adrenoleukodystrophy.

OBJECTIVE: To investigate the presence of small nerve fiber dysfunction in subjects with X-linked adrenoleukodystrophy. METHODS: Cross-sectional study in which 11 Norwegian subjects (3 males, 8 females) with X-linked adrenoleukodystrophy, phenotypes ranging from asymptomatic to wheelchair-bound with adrenomyeloneuropathy, were investigated with neurophysiologic studies including EMG, nerve conduction velocities, quantitative sensory testing, tests of autonomic function, and skin biopsy for intraepidermal nerve fiber density measurements. RESULTS: We found small nerve fiber dysfunction in 10 of 11 subjects, increasing with age and more pronounced in males. Low intraepidermal nerve fiber densities were found in 5 of 11 subjects, indicating a loss of thin unmyelinated nerve fibers peripherally. Five of 11 subjects showed small nerve fiber dysfunction despite normal nerve fiber densities, suggesting possible involvement of the spinothalamic tracts. Two subjects showed moderate abnormalities in autonomic function tests. CONCLUSIONS: Evidence of small nerve fiber dysfunction was widespread in this cohort of subjects with X-linked adrenoleukodystrophy, with findings indicating loss of peripheral small nerve fibers and possibly also fibers of the spinothalamic tracts. The results support the theory of primary axonal degeneration in adrenomyeloneuropathy. Evidence of nervous system involvement was found in all heterozygotes, with severity increasing with age. Clinicians caring for these patients should be alert to signs of small nerve fiber involvement.

Diagnostic laboratory testing for Charcot Marie Tooth disease (CMT): the spectrum of gene defects in Norwegian patients with CMT and its implications for future genetic test strategies.

BACKGROUND: Current genetic test algorithms for Charcot Marie Tooth (CMT) disease are based on family details and comprehensive clinical and neurophysiological data gathered under ideal conditions for clinical assessment. However, in a diagnostic laboratory setting relying on external test requisitions and patient samples, such conditions are not always met. Our objective was therefore to perform a retrospective evaluation of the data given in laboratory request forms and to assess their quality and applicability with regard to the recommended algorithms for CMT diagnostics. As we are the main test centre for CMT in Norway our results also provide an overview of the spectrum of gene defects in the Norwegian CMT population. METHODS: Genetic testing was performed according to polyneuropathy type; demyelinating/mixed: PMP22 duplication, MPZ, EGR2, LITAF, NEFL, PMP22, GJB1, axonal: MFN2, MPZ, NEFL, and GJB1. RESULTS: Diagnostic testing of index patients was requested in 435 of the 549 cases. Seventy-two (16.6%) positive molecular genetic findings were made. The majority (94.6%) of mutation positive cases showed disease onset before 50 years of age. PMP22 (duplication), MPZ, GJB1 and MFN2 mutations constituted 95.8% of the positive findings. Within the nerve conduction study groups, mutation detection rates were; demyelinating 33.8%; mixed 29.0%; axonal 8.8%; unspecified 16.5%. CONCLUSION: We suggest a simplified algorithm intended for referral centres, dealing with DNA/blood samples, which involves the assessment of age at onset and neurophysiological data followed by testing of four genes; PMP22 (duplication), MPZ, GJB1 and MFN2. Patients negative for mutations in those four genes should be subjected to evaluation at an interdisciplinary inherited neuropathy clinic with the capacity for extended molecular genetic analysis by next generation sequencing.

Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial.

BACKGROUND: High vitamin D levels may reduce the risk of relapses and disease progression in multiple sclerosis. METHODS: This 96-week randomised controlled trial was designed to assess the effect of vitamin D(3) supplementation on bone mineral density in persons with multiple sclerosis. Supplementation with 20,000 IU vitamin D(3) weekly raised median serum 25-hydroxy vitamin D (25[OH]D) to 121 nmol/L. The modified intention to treat analysis included 35 persons in the vitamin D(3) group and 33 in the placebo group. Participants were age 21 to 50 years and fully ambulatory (median Expanded Disability Status Scale (EDSS) 2.5). We studied the effect of supplementing vitamin D(3) on the exploratory outcomes annualised relapse rate (ARR), EDSS, multiple sclerosis functional composite (MSFC) components, grip strength, and fatigue. RESULTS: After 96 weeks, there was no significant difference between groups in ARR (absolute difference 0.10, 95% CI -0.07 to 0.27; p = 0.25), EDSS (absolute difference -0.01, 95% CI -0.35 to 0.35; p = 0.97), MSFC components, grip strength, or fatigue. CONCLUSION: Supplementation with 20,000 IU vitamin D(3) weekly did not result in beneficial effects on the measured multiple sclerosis-related outcomes. This study was not powered to address clinical outcomes, but none of the results were suggestive of an effect in this unselected population of fully ambulatory persons with multiple sclerosis.

Peripheral Nerve Society Guideline on processing and evaluation of nerve biopsies.

Nerve biopsy is often the final step in the diagnostic work-up of neuropathies of unknown origin. The aim of this guideline was to prepare an evidence-based guideline on the methods for performing and evaluating nerve biopsy. The panel performed a search of MEDLINE, hand search of bibliographies of the references retrieved, review of the evidence, and reached agreement by consensus. There were not enough formal studies of diagnostic test accuracy to allow evidence-based recommendations of levels A-C for most questions. The panel summarized the class IV evidence and reached agreement by consensus on the following recommendations: (1) Nerve biopsy should not be performed before adequate clinical, electrophysiological, and laboratory investigation and only be performed with appropriate informed consent. (2) An interactive working relationship with the relevant disciplines involved and the provision of sufficient clinical information is encouraged. (3) Biopsies should be processed and read by professionals with adequate training and experience. (4) Optimal analysis of nerve biopsy is best performed by laboratories that have the facilities and expertise to prepare and evaluate frozen and fixed sections (cryostat, paraffin, and epoxy sections). (5) Immunohistochemistry, teased fiber analysis, electron microscopy, and morphometry may help clarify the diagnosis in some conditions and should be considered as additional studies.

Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study.

The diagnostic reliability of skin biopsy in small fiber neuropathy depends on the availability of normative reference values. We performed a multicenter study to assess the normative values of intraepidermal nerve fiber (IENF) density at distal leg stratified by age deciles. Eight skin biopsy laboratories from Europe, USA, and Asia submitted eligible data. Inclusion criteria of raw data were healthy subjects 18 years or older; known age and gender; 3-mm skin biopsy performed 10-cm above the lateral malleolus; bright-field immunohistochemistry protocol, and quantification of linear IENF density in three 50-µm sections according to published guidelines. Data on height and weight were recorded, and body mass index (BMI) was calculated in subjects with both available data. Normative IENF density reference values were calculated through quantile regression analysis; influence of height, weight, or BMI was determined by regression analyses. IENF densities from 550 participants (285 women, 265 men) were pooled. We found a significant age-dependent decrease of IENF density in both genders (women p < 0.001; men p = 0.002). Height, weight, or BMI did not influence the calculated 5th percentile IENF normative densities in both genders. Our study provides IENF density normative reference values at the distal leg to be used in clinical practice.

Polyneuropathy in type 1 and type 2 diabetes: comparison of nerve conduction studies, thermal perception thresholds and intraepidermal nerve fibre densities.

BACKGROUND: To evaluate possible differences in distal polyneuropathy (PN) characteristics and degree of abnormalities for various small and large fibre parameters in diabetes type 1 (DM1) and type 2 (DM2). METHODS: Sixty-six DM1 and 57 DM2 patients with or without PN symptoms were included. Nerve conduction studies (NCS), quantitative sensory testing (QST) and quantification of intraepidermal nerve fibres (IENFs) were performed. Z-scores were calculated from reference materials. RESULTS: In both groups, 42% had abnormal NCS classification, 42% (DM1) and 39% (DM2) abnormal QST, as well as 40% (DM1) and 32% (DM2) abnormal IENF density. Seventy percent (DM1) and 65% (DM2) had one of the three tests abnormal (differences not significant). Correlations were found between most Z-score parameters and disease duration and HbA1c in DM1, but fewer in DM2. In multivariate analysis, some NCS and QST Z-scores were more abnormal in DM2. Symptom scoring correlated better with NCS and QST parameters in DM1. CONCLUSIONS: The differences could be referred to disease duration, glycaemic control and possibly patient age. The various parameters from NCS, QST and IENF analysis contribute differently in the assessment of polyneuropathy.

Peripheral neuropathy in primary sjogren syndrome: a population-based study.

BACKGROUND: Neurological manifestations appear to be frequently involved in patients with primary Sjögren syndrome (PSS). OBJECTIVE: To investigate the involvement of the peripheral nervous system, including small-diameter nerve fibers, in an unselected cohort of patients who fulfilled the new international criteria for PSS. DESIGN: Cross-sectional study. SETTING: Stavanger University Hospital. Patients Sixty-two patients with PSS (mean +/- SD age, 57.1 +/- 14.6 years). INTERVENTIONS: Clinical neurologic examinations, conventional nerve conduction studies, and skin punch biopsies. MAIN OUTCOME MEASURES: Signs of large-diameter and small-diameter peripheral nerve fiber neuropathy as determined by clinical examination, nerve conduction studies, and densities of intraepidermal nerve fibers in skin punch biopsy specimens. RESULTS: Seventeen patients (27%) were diagnosed as having neuropathy after clinical examination. The results of nerve conduction studies were abnormal in 34 patients (55%): 19 patients (31%) had motor neuropathy, 8 (13%) had sensory neuropathy, and 7 (11%) had sensorimotor neuropathy. Two patients had intraepidermal nerve fiber densities less than 3.4 fibers per millimeter, fitting the morphologic criteria for small-diameter nerve fiber neuropathy. CONCLUSIONS: Peripheral neuropathy occurs in a large proportion of patients with PSS, in most cases as a subclinical demyelinating neuropathy. Small-diameter nerve fiber neuropathy is not a frequent finding in these patients.

Intraepidermal nerve fiber densities in chronic inflammatory autoimmune diseases.

BACKGROUND: Some patients with systemic lupus erythematosus have selective loss of small-diameter nerve fibers, while larger nerve fibers are unaffected. OBJECTIVE: To determine intraepidermal nerve fiber densities in patients with different chronic inflammatory autoimmune diseases. DESIGN: Cross-sectional study. SETTING: Stavanger University Hospital, Stavanger, and Haukeland University Hospital, Haukeland, Norway. PATIENTS: Sixty patients with systemic lupus erythematosus (SLE) (mean +/- SD age, 43.2 +/- 13.5 years), 61 patients with primary Sjögren syndrome (age, 57.1 +/- 14.7 years), and 52 patients with rheumatoid arthritis (age, 57.4 +/- 12.3 years) were compared with 106 healthy subjects (age, 49.0 +/- 19.6 years). INTERVENTIONS: Skin biopsy specimens. MAIN OUTCOME MEASURES: To evaluate small-diameter nerve fiber loss, intraepidermal nerve fiber densities were measured in skin punch biopsy specimens obtained from the distal part of the leg. RESULTS: The mean +/- SD densities were 7.5 +/- 3.8 fibers/mm in patients with SLE, 9.2 +/- 3.8 fibers/mm in primary Sjögren syndrome, and 10.9 +/- 5.4 fibers/mm in rheumatoid arthritis vs 12.4 +/- 4.6 fibers/mm in healthy subjects. Densities were significantly less in patients with SLE vs patients with rheumatoid arthritis and vs healthy subjects (P<.001 for both), as well as in patients with primary Sjögren syndrome vs healthy subjects (P<.001). Eight patients (13%) with SLE, 2 patients (3%) with primary Sjögren syndrome, and 2 patients (4%) with rheumatoid arthritis had densities below the lower reference limit of 3.4 fibers/mm, consistent with small-diameter nerve fiber neuropathy. CONCLUSION: The degree of loss of small-diameter nerve fibers differs among patients with these chronic inflammatory autoimmune diseases, likely reflecting differences in pathogenesis and organ affinity of the individual disease entities.

Small-diameter nerve fiber neuropathy in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an inflammatory, autoimmune, multiorgan disease often involving the central and peripheral nervous systems. OBJECTIVE: To determine whether there is a selective small-diameter nerve fiber neuropathy in patients with SLE. DESIGN: Cross-sectional study. SETTING: Stavanger University Hospital, Stavanger, Norway. Patients Sixty patients with SLE, aged 43.2 +/- 13.5 years (mean +/- SD). INTERVENTIONS: Skin biopsies, nerve conduction studies, and clinical neurologic examinations. MAIN OUTCOME MEASURES: Density of intraepidermal small-diameter nerve fibers in skin biopsy specimens and large-diameter nerve fiber function as determined by nerve conduction studies and clinical examinations. RESULTS: The mean density of intraepidermal small-diameter nerve fibers in patients with SLE was 7.5 +/- 3.8/mm. Eight patients (13%) had densities below reference values, consistent with small-diameter nerve fiber neuropathy, and results of nerve conduction studies were normal in 6 of them. Eleven patients (18%) had abnormal results of nerve conduction studies, reflecting large-diameter nerve fiber neuropathy, and 4 patients (7%) were classified by an experienced neurologist as having polyneuropathy after the clinical examination. CONCLUSIONS: An abnormal reduction in intraepidermal small-diameter nerve fiber densities is evident in some patients despite normal function of their larger nerve fibers. This adds further support to the theory that a pure small-diameter nerve fiber neuropathy may occur in SLE.

Fatigue in patients with lupus is not associated with disturbances in cerebral blood flow as detected by SPECT.

OBJECTIVES: Fatigue is a common complaint in patients with systemic lupus erythematosus (SLE). We investigated whether focal or general disturbances of cerebral blood flow (CBF), as assessed by SPECT, were associated with the presence of fatigue in an unselected group of SLE patients. METHODS: Fifty-six patients were included. Mean age was 47.5 years (+/-12.7), mean disease duration 14.7 years (+/-8.9), and disease activity measured by SLE disease activity index (SLEDAI) was 5.7 (+/-5.4). Fatigue was assessed by the Fatigue Severity Scale (FSS) and CBF by Tc-99m-hexamethyl propylamine oxime (HMPAO)-SPECT. The images were read and processed quantitatively by a computer program using the primary visual cortex as reference region and > 15% CBF deviation as definition of abnormality. RESULTS: The mean FSS score was 4.6 (+/-1.8). SPECT revealed focal CBF disturbances in 17 patients (30.4 %). Generalized symmetrical CBF reductions were present in 32 patients (57.1 %). There were no significant associations between CBF disturbances in any region of the brain and the degree of fatigue. CONCLUSIONS: Fatigue in SLE patients is not related to focal or general CBF disturbances. Therefore, factors that do not influence blood flow seem responsible for the fatigue phenomenon.