Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum.

PURPOSE: FLVCR1 encodes a solute carrier (SLC) protein implicated in heme, choline, and ethanolamine transport. While Flvcr1-/- mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa. METHODS: We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants. RESULTS: We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (Z-score -2.5 to -10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits including macrocytic anemia and skeletal malformations with Flvcr1-/- mice and DBA. FLVCR1 variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing. CONCLUSION: These data demonstrate a broad FLVCR1-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.

Validity and reliability of the Persian version of Recce stigma scale in people with multiple sclerosis and its impact on quality of life.

BACKGROUND: There is often a fear of social stigma experienced by people with multiple sclerosis (pwMS), which negatively impacts the quality of their lives (QoL). Currently, no Persian-validated questionnaire is available to assess this issue in pwMS. This study aimed to assess the validaty and reliability of the Persian version of Reece Stigma Scale Multiple Sclerosis (RSS-MS) questionnaire for pwMS. METHOD: This cross-sectional was conducted between January and February 2023 in Isfahan, Iran. The demographic and clinical information and the RSS-MS and Multiple Sclerosis Impact Scale-29 (MSIS-29) questionnaires were recorded from pwMS. The content validity index (CVI) and content validity ratio (CVR) have been used to evaluate validity. To identify the factors supporting the MS-related stigma, an exploratory factor analysis (EFA) was conducted. RESULTS: The present study recruited 194 pwMS. Based on factor analysis, only two factors had eigenvalues ≥ 1.0 and exhibited high internal consistency. The Cronbach's α coefficient for internal consistency of the RSS-MS scale was 0.822. More evidence for the construct validity suggested that having higher levels of stigma is significantly correlated with psychological (r = 0.468, p-value < 0.001) and physical dimensions (r = 0.585, p-value < 0.001) of MSIS-29. Expanded Disability Status Scale, disease duration, and treatment duration did not show a significant correlation with stigma (p-value > 0.05). CONCLUSION: This study indicated that the modified version of the RSS-MS scale in the Persian language showed acceptable validity and reliability for evaluating the stigma among Persian pwMS. Furthermore, this study emphasizes the cruciality of monitoring and addressing stigma among pwMS, as it can potentially enhance medical, psychological, physical, and QoL outcomes.

Minimal important differences and self-identifying treatment response in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION/AIM: The use of outcome measures is recommended for chronic inflammatory demyelinating polyneuropathy (CIDP). Implications of minimal important differences (MID) to ascertain responder status are unknown. The reliability of patient-reported treatment-response in relation to clinically relevant change is also unknown. METHODS: We retrospectively studied 72 subjects with "definite" or "probable" CIDP evaluated at pre-specified time-intervals pre- and post-treatment. We derived MID and the minimum detectable change with 95% confidence intervals (MDC95 ) for four scales. Scale sensitivities were determined with applicable MID-defined cutoffs (aMIDc), to detect subjects with self-identifying treatment response through a single question. RESULTS: The use of MID was not valid for the Medical Research Council Sum Score, as MDC95 > MID. The aMIDc for the Overall Neuropathy Limitation Score (ONLS) was 1 (sensitivity: 84.7%). The aMIDc for the centile Inflammatory Rasch-built Overall Disability Scale (cI-RODS) was 8 (sensitivity: 62.3%). The aMIDc for grip strength was 4 kg (sensitivity: 79.1%). MID-defined amelioration of any one scale among ONLS, cI-RODS, or grip strength, significantly improved sensitivity to detect treatment-responders compared with the ONLS alone (McNemar test: P = .008, odds ratio: 3.36 [95% confidence interval: 1.44-7.86]). Patient-reported improvement was highly reliable in relation to MID-defined amelioration on any one scale. DISCUSSION: In subjects with CIDP, MID-defined amelioration of any one of three commonly used outcome measures offers optimum relevance and sensitivity to detect self-identifying treatment-responders. Patient reliability to single-question ascertainment of response is high in relation to MID-defined clinical relevance. These findings support use of multiple outcome measures in CIDP monitoring and justify enhanced patient involvement in the process.

Comparative value and determinants of suitability of outcome measures in treated chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: The comparative value and suitability of outcome measures are uncertain in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We studied 35 patients with CIDP using the Overall Neuropathy Limitation Scale (ONLS), the inflammatory Rasch-built Overall Disability Scale (I-RODS), and the Medical Research Council Sum Score (MRCSS). RESULTS: Significant associations were determined between initial deficit and ONLS score (P = .002) and MRCSS improvement (P = .001) but not I-RODS score. A strong inverse correlation was observed between disease duration and I-RODS score(P = .002) but not ONLS/MRCSS improvement. A strong association was observed between age ≤ 40 years and I-RODS score (P = .001) but not ONLS/MRCSS improvement. When minimum important differences were used, ONLS and I-RODS sensitivities were comparable (P = .19). DISCUSSION: Overall Neuropathy Limitation Scale and I-RODS are equally sensitive in identifying change. Ease of administration, better ability to detect improvement in severe disease, and greater amplitude responses throughout the disease and in older patients favor the ONLS. The I-RODS appears more useful in early disease/younger patients.

Small fiber neuropathy in unexpected clinical settings: a review.

Small fiber neuropathy (SFN) is being recognized with increasing frequency in neuromuscular practice due to improved diagnostic techniques. Although there are some common etiologies, up to one-third of cases are considered idiopathic. In recent years, several disorders have unexpectedly been reported in association with SFN, on clinical grounds and complementary investigations, including quantitative sensory testing, intraepidermal nerve fiber density and confocal corneal microscopy. Knowledge of these disorders is important in clinical practice as increased awareness enables prompt diagnosis of SFN in these settings and early optimal therapeutic management of affected patients. Furthermore, these new developments may lead to a better understanding of the pathophysiologic mechanisms underlying SFN in these different disorders as well as, in some cases, an expanded spectrum of affected organs and systems. This article reviews these reported associations, their possible pathophysiologic bases, and the potential resulting management implications.

The Effect of Functional Stretching Exercises on Neural and Mechanical Properties of the Spastic Medial Gastrocnemius Muscle in Patients with Chronic Stroke: A Randomized Controlled Trial.

BACKGROUND: Following spasticity, neural and mechanical changes of the paretic muscle often occur, which affect the muscle function. The aim of this study was to investigate the effect of functional stretching exercises on neural and mechanical properties of the spastic muscle in patients with stroke. MATERIALS AND METHODS: This study was a single-blinded, randomized control trial. Forty five patients with stroke (experimental group: n = 30; control group: n = 15) participated in this study. Subjects in the experimental group participated in a functional stretching program 3 times a week for 4 weeks. Subjects in both groups were evaluated before the training, at the end of training, and then during a 2-month follow-up. Neural properties, including H-reflex latency and Hmax/Mmax ratio, were acquired. Mechanical properties, including fascicle length, pennation angle, and muscle thickness in the spastic medial gastrocnemius muscle, were evaluated. Repeated measure analysis of variance was used in the analysis. RESULTS: Time by group interaction in the pennation angle (P = .006), and in muscle thickness (P = .030) was significant. The results indicated that the H-reflex latency (P = .006), pennation angle (P < .001), and muscle thickness (P = .001) were altered after stretching training program and these changes were at significant level after 2-month follow-up. CONCLUSION: The results indicated that the use of functional stretching exercises can cause significant differences in neural and mechanical properties of spastic medial gastrocnemius muscle in patients with chronic stroke.

The effects of intradermal botulinum toxin type a injections on pain symptoms of patients with diabetic neuropathy.

BACKGROUND: Considering the dramatic increasing rate of diabetes and consequently its related complications, most importantly diabetic peripheral neuropathy (DPN), challenges regarding proper treatment of DPN and its effect on the quality-of-life and care of diabetic patients, the aim of this current study is to evaluate the effect of intradermal botulinum toxin type A (BTX-A) injections on pain symptoms of patients with diabetic neuropathic pain. MATERIALS AND METHODS: In this randomized double-blind placebo-controlled clinical trial study, diabetic patients aged <70 years with neuropathic pain in both feet were enrolled. Diabetic neuropathy (DN) in selected patients was diagnosed using DN4 questionnaire and nerve conduction velocity examinations. They randomized in two intervention (BTX-A injection/100 unit, N = 20) and placebo groups (normal saline injection, N = 20). The outcome of injection on diabetic neuropathic pain was assessed using neuropathy pain scale (NPS) and visual analog scale (VAS) score and compared in two studied groups. RESULTS: There was no significant difference in DN4, NPS and VAS scales of studied population after intervention in the placebo group. Intradermal injection of BTX-A reduced NPS scores for all items except cold sensation (P = 0.05). It reduced DN4 scores for electric shocks, burning, pins and needles and brushing (P < 0.05). According to VAS scale 30% and 0% of patients in intervention and placebo groups have no pain after intervention (P = 0.01). CONCLUSION: Intradermal injection of BTX-A is a well-tolerated agent that has a significant effect on DPN pain.

A comparison of the ultrasonographic median nerve cross-sectional area at the wrist and the wrist-to-forearm ratio in carpal tunnel syndrome.

BACKGROUND: Electrophysiologic (EDX) study is the most valuable method in grading the severity of carpal tunnel syndrome (CTS), but it is invasive and painful. We evaluated the efficacy of ultrasound for this purpose. MATERIALS AND METHODS: Eighty-one wrists of 52 consecutive patients with clinical evidences of CTS, confirmed and graded by EDX as mild, moderate, and severe, were examined by ultrasonography. Cross-sectional area (CSA) of the median nerve was measured at the distal wrist (CSA-D), and proximal forearm (CSA-P), and wrist-to-forearm ratio (WFR) was calculated for each hand. RESULTS: The mean CSA-D was 0.12 cm(2) ± 0.03, 0.15 cm(2) ± 0.03 and 0.19 cm(2) ± 0.06 and the mean WFR was 2.77 ± 1.14, 3.07 ± 1.07 and 4.07 ± 1.61 in mild, moderate and severe groups respectively. WFR showed significant differences between the severe and none severe CTS groups (P < 0.001), but there was no significant difference between mild and moderate CTS groups (P < 0.381). CSA-D showed a significant difference between all groups (P < 0.0001). In the Receiver Operating Characteristic curve analysis, the optimal cut-off value of the CSA-D and WFR for detecting severe CTS were 0.15 (area under the curve 0.784, 95% confidence interval (CI): 0.662-0.898, P < 0.001, sensitivity of 68.2% and specificity of 70.9%) and 3 (area under the curve 0.714, 95% CI: 0.585-0.84, P = 0.001, sensitivity of 68.2% and specificity of 64.8%) respectively. All values were superior in CSA-D. CONCLUSION: Ultrasonography, can be complementary but not conclusive to the classification of CTS severities. CSA-D and WFR both increased in proportion to CTS severity, but neither parameter exhibited excellent performance in grading the severities.

Association between cerebrospinal fluid chitotriosidase level and amyotrophic lateral sclerosis: a systematic review.

INTRODUCTION: One of the fatal and debilitating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS). Increasing age is one of the risk factors of ALS. Considering that the elderly population in the world is increasing, it is very important to identify useful and effective diagnostic and treatment methods. The purpose of this systematic review is to determine the relationship between chitotriosidase (CHIT1) level and ALS disorder. CONTENT: Keywords "Amyotrophic Lateral Sclerosis", "Gehrig* Disease", "Charcot Disease", "Guam Disease", ALS, CHIT1 and chitotriosidase were searched in PubMed, Scopus, Web of Science and Science Direct databases without time limit on September 2023. Hundred twenty studies were obtained by searching, and finally, 14 studies were included in this study using the inclusion and exclusion criteria. In all 14 selected studies, the level of biomarker CHIT1 in the CSF of ALS patients was significantly higher than that of healthy control and disease control groups. But, in 8 studies that included 3 groups, no significant difference was observed between the CHIT1 levels in the two control groups. Six studies have reported the amount of CHIT1 level quantitatively. Among these 6 studies, in 5 studies CHIT1 level in disease control was higher than healthy control (not significant) and in only one study CHIT1 level was higher in healthy control compared to disease control (not significant). SUMMARY AND OUTLOOK: In all 14 studies, a multifold increase in CHIT1 levels has been observed in patients compared to healthy and disease control groups. Therefore, based on the findings of the studies, this study confirms the relationship between CHIT1 increase and ALS disorder.

Small fiber neuropathy in irritable bowel syndrome.

Aim: In this study, we intend to evaluate the occurrence of small fiber neuropathy in patients with irritable bowel syndrome (IBS). Background: Small fiber neuropathy (SFN) is a sensory neuropathy that results from the degeneration of small Aδ and unmyelinated C fibers. SFN manifests positive symptoms, such as tingling, burning, prickling, and aching, and negative symptoms, including numbness, tightness, and coldness. The SFN coexistence with other comorbidities (e.g., fibromyalgia, inflammatory bowel disease, celiac disease) has been reported in previous studies. Methods: We conducted a cross-sectional study to assess the coexistence of SFN and IBS. Forty-two IBS patients and forty-three healthy individuals were asked to complete the Michigan Neuropathy Screening Instrument (MNSI) questionnaire. Results greater than three (>3) were considered positive. Participants with positive MNSI questionnaire results were examined for any neuropathy signs according to the Utah Early Neuropathy Scale (UENS) examination. The participants with positive results for the questionnaire and examination were checked for the sural and the superficial peroneal nerve conduction study (NCS). Normal NCS represented intact large fibers and the diagnosis of SFN. Results: Ten participants, 7 (16.7 %) in the IBS group and 3 (6.9 %) in the healthy group, had positive results for the questionnaire. Four participants were positive for the examination, with normal NCS, and were classified as SFN-positive. All four SFN diagnoses were from the IBS group. No one in the healthy group was diagnosed with SFN. We could find a significant statistical difference (p<0.05) between the IBS and healthy groups regarding the prevalence of SFN diagnosis. Conclusion: The co-occurrence of SFN and IBS suggests the possibility of a generalized neuropathy syndrome characterized by widespread neuronal impairment. Thus, any peripheral neuropathy symptom in IBS patients (and potentially other chronic pain disorders) should be evaluated for SFN since timely diagnosis and proper treatment result in a better quality of life for the patients.