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Pain, either nociceptive or neuropathic (NP), is a common symptom in Charcot-Marie-Tooth (CMT) disease.We investigated small fibers involvement and its correlation with pain in different CMT subtypes through a systematic clinical and neurophysiological study. We enrolled 50 patients: 19 with duplication of PMP22 (CMT1A), 11 with mutation of MPZ (CMT1B, CMT2I/J, or CMTDID), 12 with mutation of GJB1 (CMTX1), and 8 with mutation of MFN2 (CMT2A and CMT2A2B). Pain was rated with the 11-point Numerical Rating Scale and characterized through Neuropathic Pain Symptoms Inventory. Laser-evoked potentials (LEPs) were recorded after right foot and hand stimulation and N2-P2 complex amplitude and latency were compared with those of 41 controls.Overall pain prevalence was 36%. NP was present in 14.6% of patients, with a length-dependent distribution in 85.7% of cases, and it was significantly more frequent in CMT1A (p 0.001). Aδ fibers involvement greatly varies between CMT subtypes, reflecting differences in molecular pathology and pathophysiologic mechanisms. Prolonged N2 latency from foot stimulation was noted in 11 CMT1A patients, 5 of which report NP. MPZ-CMTs displayed different neurophysiological phenotypes and a very low prevalence of NP. LEPs were normal in all but one CMTX1 patients, although lower limbs N2-P2 amplitude was significantly reduced in males (p = 0.043). MFN2-CMTs were NP free and LEPs recordings were all normal. NP strictly correlated with LEPs alterations (p = 0.017).NP prevalence varies among CMTs subtypes and is mainly related to Aδ fibers impairment.Neuropathic pain is a frequent finding in Charcot-Marie Tooth disease and is related to Aδ fibers impairment. Patients at higher risk are those belonging to certain genetic subtypes (i.e. CMT1A and CMT2J) or with laser-evoked potentials abnormalities. While managing this disease, clinicians should be aware of this symptom in order to offer best treatment options to their patients.

Fatigue, a disabling symptom in many neuromuscular disorders, has been reported also in Charcot-Marie-Tooth disease (CMT). The presence of fatigue and its correlations in CMT was investigated.The Modified Fatigue Impact Scale (MFIS) was administered to CMT patients from the Italian Registry and a control group. An MFIS score38 indicated abnormal fatigue. The correlation with disease severity and clinical characteristics, the Hospital Anxiety and Depression Scale and Epworth Sleepiness Scale scores, and drug use was analysed.Data were collected from 251 CMT patients (136 women) and 57 controls. MFIS total (mean ± standard deviation 32 ± 18.3, median 33), physical (18.9 ± 9.7, 20) and psychosocial (2.9 ± 2.4, 3) scores in CMT patients were significantly higher than controls. Abnormal fatigue occurred in 36% of the patients who, compared to patients with normal scores, had more severe disease (median CMT Examination Score 9 vs. 7), more frequent use of foot orthotics (22% vs. 11%), need of support for walking (21% vs. 8%), hand disability (70% vs. 52%) and positive sensory symptoms (56% vs. 36%). Patients with abnormal fatigue had significantly increased frequency of anxiety/depression/general distress (Hospital Anxiety and Depression Scale), somnolence (Epworth Sleepiness Scale), obesity (body mass index ≥ 30) and use of anxiolytic/antidepressant or anti-inflammatory/analgesic drugs.Fatigue is a relevant symptom in CMT as 36% of our series had scores indicating abnormal fatigue. It correlated with disease severity but also with anxiety, depression, sleepiness and obesity, indicating different components in the generation of fatigue. CMT patients' management must include treatment of fatigue and of its different generators, including general distress, sleepiness and obesity.

Background There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT. Methods We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls. HADS-A and HADS-D scores ≥ 11 defined the presence of anxiety/depression and HADS total score (HADS-T) ≥ 22 of general distress. We analysed correlation with disease severity and clinical characteristics, use of anxiolytics/antidepressants and analgesic/anti-inflammatory drugs. Results We collected data from 252 CMT patients (137 females) and 56 controls. CMT patient scores for anxiety (mean ± standard deviation, 6.7 ± 4.8), depression (4.5 ± 4.0), and general distress (11.5 ± 8.1) did not differ from controls and the Italian population. However, compared to controls, the percentages of subjects with depression (10% vs 2%) and general distress (14% vs 4%) were significantly higher in CMT patients. We found no association between HADS scores and disease duration or CMT type. Patients with general distress showed more severe disease and higher rate of positive sensory symptoms. Depressed patients also had more severe disease. Nineteen percent of CMT patients took antidepressants/anxiolytics (12% daily) and 70% analgesic/anti-inflammatory drugs. Patients with anxiety, depression, and distress reported higher consumption of anxiolytics/antidepressants. About 50% of patients with depression and/or general distress did not receive any specific pharmacological treatment. Conclusions An appreciable proportion of CMT patients shows general distress and depression. Both correlated with disease severity and consumption of antidepressants/anxiolytics, suggesting that the disease itself is contributing to general distress and depression.

Minifascicular neuropathy (MN) is a rare, autosomal recessive disease with prominent structural changes of peripheral nerves. So far, it has been observed in females with a 46,XY karyotype and mutations of the Desert Hedgehog (DHH) gene, thus linking MN to gonadal dysgenesis (GD) and disorders of sex development (DSD). However, a 46,XX proband with normal female sex and gender development underwent clinical evaluations, nerve conduction studies and genetic screening for a severe motor-sensory neuropathy with a pathological phenotype that hinted at MN. Indeed, sural nerve biopsy revealed a profound disturbance of perineurium development with a thin and loose structure. High-resolution ultrasound (HRUS) also disclosed diffuse changes of nerve echotexture that visibly correlated with the pathological features. After extensive genetic testing, a novel homozygous DHH null mutation (p.Ser185*) was identified in the proband and in her sister, who was affected by a similar motor-sensory neuropathy, but was eventually found to be a 46,XY patient according to a late diagnosis of DSD with complete GD. DHH should therefore be considered as a possible cause of rare non-syndromic hereditary motor-sensory neuropathies, regardless of DSD. Furthermore, HRUS could effectively smooth the complex diagnostic workup as it demonstrated a high predictive power to detect MN, providing the same detailed correlations to the pathologic features of the nerve biopsy and Dhh-/- mice in both sisters. Hence, HRUS may assume a pivotal role in guiding molecular analysis in individuals with or without DSD.

Charcot-Marie-Tooth disease type 1 (CMT1) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have distinct clinical and neurophysiological features that result from dysmyelination in CMT1 and macrophage-mediated segmental demyelination in CIDP. CMT1 may occur in genetically isolated cases with atypical presentations that converge phenotypically with CIDP; in rare cases, however, CMT1 may be complicated by superimposed CIDP. We report the case of a patient harboring a de novo heterozygous null mutation of the myelin protein zero (MPZ) gene and affected by subclinical CMT1B who became symptomatic due to superimposed CIDP. Peripheral nerve high-resolution ultrasound (HRUS) aided in establishing the coexistence of CMT1B and CIDP; the diagnosis was further supported by favorable clinical, neurophysiological, and ultrasound responses to immunoglobulin therapy.

Background Diagnostic delay of hereditary transthyretin amyloidosis (ATTRv, v for variant) prevents timely treatment and, therefore, concurs to the mortality of the disease. The aim of the present study was to explore with nerve ultrasound (US) possible red flags for early diagnosis in ATTRv patients with carpal tunnel syndrome (CTS) and/or polyneuropathy and in pre-symptomatic carriers. Methods Patients and pre-symptomatic carriers with a TTR gene mutation were enrolled from seven Italian centers. Severity of CTS was assessed with neurophysiology and clinical evaluation. Median nerve cross-section area (CSA) was measured with US in ATTRv carriers with CTS (TTR-CTS). One thousand one hundred ninety-six idiopathic CTS were used as controls. Nerve US was also performed in several nerve trunks (median, ulnar, radial, brachial plexi, tibial, peroneal, sciatic, sural) in ATTRv patients with polyneuropathy and in pre-symptomatic carriers. Results Sixty-two subjects (34 men, 28 women, mean age 59.8 years ± 12) with TTR gene mutation were recruited. With regard to CTS, while in idiopathic CTS there was a direct correlation between CTS severity and median nerve CSA (r = 0.55, p r = − 0.473). ATTRv patients with polyneuropathy showed larger CSA than pre-symptomatic carriers in several nerve sites, more pronounced at brachial plexi (p Conclusions The present study identifies nerve morphological US patterns that may help in the early diagnosis (morpho-functional dissociation of median nerve in CTS) and monitoring of pre-symptomatic TTR carriers (larger nerve CSA at proximal nerve sites, especially at brachial plexi).

Axonal polyneuropathy is the main feature of hereditary transthyretin amyloidosis (ATTRv). Nerve morphological abnormalities have been reported, but longitudinal changes have never been assessed. We performed a prospective widespread nerve ultrasound evaluation and nerve cross-sectional area (CSA) was compared with baseline data in both ATTRv patients and pre-symptomatic carriers. Thirty-eight subjects were evaluated (mean follow-up 17.1 months), among them 21 had polyneuropathy while 17 were pre-symptomatic carriers. CSA significantly increased at brachial plexus in both groups (p = 0.008 and p = 0.012) pointing to progressive brachial plexus enlargement as a longitudinal biomarker of both disease progression and disease occurrence in pre-symptomatic carriers.

To describe clinical features, disease course, treatment response, and sural nerve biopsy findings in a patient with chronic sensory ataxic neuropathy, Binet stage A chronic lymphocytic leukemia, and monoclonal IgMλ paraprotein against ganglioside GD1b. During 9 months of hospitalization at two neurologic centers, the patient underwent serial neurologic examinations, neurophysiologic studies, imaging investigations, extensive laboratory work-up, bone marrow, and sural nerve biopsies. The patient had a severe progressive sensory neuropathy accompanied by motor involvement, dysautonomia, and marked bulbar weakness with preserved ocular movements. Conduction studies were characterized by prolonged F-wave minimal latencies, prolonged distal latencies, reduction of compound motor action potentials, and absence of sensory nerve action potentials. Sural nerve biopsy showed endoneurial edema, axonal degeneration, and regeneration, in the absence of cellular inflammation, macrophagic activation, and B-lymphocyte infiltration; no IgM or complement deposition was detected. Myelinated fibers showed redundant/abnormally thickened myelin, myelin vacuolation, and frank intramyelinic edema with condensed axoplasm. Ultrastructural features included axo-glial detachment, disruption of membrane integrity, and myelin uncompaction. This study shows that monospecific anti-GD1b IgM paraprotein is associated with non-inflammatory nerve damage. We suggest that the loss of myelin and axonal integrity reflects antibody-induced disruption of membrane lipid rafts.

The QTc interval is the electrocardiographic manifestation of ventricular depolarization and repolarization. This marker is often prolonged in acute and chronic neurological conditions. The cause of the cerebrogenic QT prolongation remains unclear. The aim of the study was to analyze the relation between QTc interval and the degree of cognitive impairment and structural brain imaging changes in patients with dementia and mild cognitive impairment (MCI). To this aim, 269 patients were screened, of whom 61 met one or more exclusion criteria. The remaining 208 patients (56 control subjects, 44 patients with MCI, and 108 with dementia) were recruited. Eighty-five patients using drugs causing prolongation of QT interval were further excluded. The QT interval was measured manually in all 12 leads by a single blinded observer, assuming the longest QT value adjusted for heart rate by using the Bazett's formula. All patients underwent a structural brain imaging and the following measures were obtained: the bicaudate ratio and the periventricular hyperintensity and deep white matter hyperintensity using the modified Fazekas scale. Prolonged QTc interval was prevalent in 1) patients with dementia, especially in those with moderate-severe degree; 2) subjects with impairment of praxis and attention, low functional status, and behavioral symptoms; 3) patients with global and temporal atrophy and with higher scores on the Fazekas or leukoaraiosis scales. Degenerative and vascular processes might play a main role in QTc interval prolongation because of the damage to brain areas involved in the control of the autonomic cardiac nervous system.

Background A biallelic intronic AAGGG repeat expansion in the Replication Factor C subunit 1 (RFC1) gene has been recently associated with Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome, a disorder often presenting as a slowly evolving sensory neuropathy at the onset. “Chronic Idiopathic Axonal Polyneuropathy” (CIAP) is a common indolent axonal neuropathy of adulthood which remains without an identifiable cause despite thorough investigations. Methods We screened 234 probands diagnosed with CIAP for a pathogenic biallelic RFC1 AAGGG repeat expansion. Patients were selected from 594 consecutive patients with neuropathy referred to our tertiary-care center for a sural nerve biopsy over 10 years. Results The RFC1 AAGGG repeat expansion was common in patients with pure sensory neuropathy (21/40, 53%) and less frequent in cases with predominantly sensory (10/56, 18%, P P τb = 0.254, P P R = 0.275, P τb = − 0.362, P P = 0.02) and unmyelinated nerve fibers (85% vs 41%, POR 8.52 CI 95% 3.17–22.9, P Conclusions This study highlights the frequent occurrence of the RFC1 AAGGG repeat expansion in patients diagnosed with CIAP and characterizes the clinical and pathological features of the related neuro(no)pathy.

Despite the introduction of non-invasive techniques in the study of peripheral neuropathies, sural nerve biopsy remains the gold standard for the diagnosis of several neuropathies, including vasculitic neuropathy and neurolymphomatosis. Besides its diagnostic role, sural nerve biopsy has helped to shed light on the pathogenic mechanisms of different neuropathies. In the present review, we discuss how pathological findings helped understand the mechanisms of polyneuropathies complicating hematological diseases.

Hereditary neuropathies may result from mutations in genes expressed by Schwann cells or neurons that affect selectively the peripheral nervous system (PNS) or may represent a minor or major component of complex inherited diseases that involve also the central nervous system and/or other organs and tissues. The chapter is constantly expanding and reworking, thanks to advances of molecular genetics; next-generation sequencing is identifying a plethora of new genes and is revolutionizing the diagnostic approach. In the past, diagnostic sural nerve biopsies paved the way to the discovery and elucidation of major genes and molecular pathways associated to most frequent hereditary motor-sensory neuropathies. Nowadays, a sural nerve biopsy may prove useful in selected cases for the differential diagnosis of an acquired neuropathy when clinical examination, nerve conduction studies, and molecular tests are not sufficiently informative. Skin biopsy has emerged as a minimally invasive window on the PNS, which may provide biomarkers of progression and clues to the physiopathology and molecular pathology of inherited neuropathies. The aim of our review is to illustrate the pathological features of more frequent and paradigmatic hereditary neuropathies and to highlight their correlations with the roles of the involved genes and functional consequences of related molecular defects.

A 58-year-old male with B-cell chronic lymphocytic leukemia presented with fever, chest pain, and acute-onset neurological deficits suggestive of multiple strokes (A). Brain autopsy revealed softening areas in the brain parenchyma (B, C) corresponding to extensive necrosis (D) caused by neuroinvasion by Aspergillus hyphae (E, F) necrosis (D) caused by neuroinvasion by Aspergillus hyphae (E, F).

In patients with suspected dementia with Lewy bodies, the detection of the disease-associated α-synuclein in easily accessible tissues amenable to be collected using minimally invasive procedures remains a major diagnostic challenge. This approach has the potential to take advantage of modern molecular assays for the diagnosis of α–synucleinopathy and, in turn, to optimize the recruitment and selection of patients in clinical trials, using drugs directed at counteracting α-synuclein aggregation. In this study, we explored the diagnostic accuracy of α-synuclein real-time quaking-induced conversion assay by testing olfactory mucosa and CSF in patients with a clinical diagnosis of probable (n = 32) or prodromal (n = 5) dementia with Lewy bodies or mixed degenerative dementia (dementia with Lewy bodies/Alzheimer’s disease) (n = 6). Thirty-eight patients with non-α-synuclein-related neurodegenerative and non-neurodegenerative disorders, including Alzheimer’s disease (n = 10), sporadic Creutzfeldt–Jakob disease (n = 10), progressive supranuclear palsy (n = 8), corticobasal syndrome (n = 1), fronto-temporal dementia (n = 3) and other neurological conditions (n = 6) were also included, as controls. All 81 patients underwent olfactory swabbing while CSF was obtained in 48 participants. At the initial blinded screening of olfactory mucosa samples, 38 out of 81 resulted positive while CSF was positive in 19 samples out of 48 analysed. After unblinding of the results, 27 positive olfactory mucosa were assigned to patients with probable dementia with Lewy bodies, five with prodromal dementia with Lewy bodies and three to patients with mixed dementia, as opposed to three out 38 controls. Corresponding results of CSF testing disclosed 10 out 10 positive samples in patients with probable dementia with Lewy bodies and six out of six with mixed dementia, in addition to three out of 32 for controls. The accuracy among results of real-time quaking-induced conversion assays and clinical diagnoses was 86.4% in the case of olfactory mucosa and 93.8% for CSF. For the first time, we showed that α-synuclein real-time quaking-induced conversion assay detects α-synuclein aggregates in olfactory mucosa of patients with dementia with Lewy bodies and with mixed dementia. Additionally, we provided preliminary evidence that the combined testing of olfactory mucosa and CSF raised the concordance with clinical diagnosis potentially to 100%. Our results suggest that nasal swabbing might be considered as a first-line screening procedure in patients with a diagnosis of suspected dementia with Lewy bodies followed by CSF analysis, as a confirmatory test, when the result in the olfactory mucosa is incongruent with the initial clinical diagnosis., Perra et al. detected α-synuclein aggregates in olfactory mucosa and CSF samples of patients with dementia with Lewy bodies, using real-time quaking-induced conversion assay. Positivity in unpaired olfactory mucosa and CSF samples was significantly concordant with the clinical diagnosis and nearly 100% in participants in whom paired samples were tested., Graphical Abstract Graphical Abstract

Background Hereditary transthyretin amyloidosis (hATTR), alias ATTR variant (ATTRv) is a severe and disabling disease causing sensory and motor neuropathy, autonomic dysfunction, and cardiomyopathy. The progressive decline of patient’s functional autonomy negatively affects the patient’s quality of life and requires increasing involvement of relatives in the patient’s daily life. Family caregiving may become particularly demanding when the patient is no longer able to move independently. This study is focused on the psychosocial aspects of ATTRv from the patient and relative perspectives. In particular, it explored: the practical and psychological burdens experienced by symptomatic patients with ATTRv and their key relatives and the professional and social network support they may rely on; whether burden varied in relation to patients’ and relatives’ socio-demographic variables, patients’ clinical variables, and perceived professional and social network support; and, any difference in burden and support between patients and their matched relatives. Methods The study was carried out on symptomatic patients included in the ATTRv Italian national registry and living with at least one adult relative not suffering from severe illness and being free from ATTRv symptoms. Patients and relatives’ assessments were performed using validated self-reported tools. Results Overall, 141 patients and 69 relatives were evaluated. Constraints of leisure activities, feelings of loss and worries for the future were the consequences of ATTRv most frequently reported by patients and relatives. Both in patients and their relatives, the burden increased with the duration of symptoms and the level of help in daily activities needed by the patient. In the 69 matched patient-relative pairs, the practical burden was significantly higher among the patients than among their relatives, while the psychological burden was similar in the two groups. Moreover, compared to their relatives, patients with ATTRv reported higher levels of professional and social network support. Conclusions These results show that ATTRv is a disease affecting quality of life of both patients and their families. Supporting interventions should be guaranteed to patients, to facilitate their adaptation to the disease, and to their families, to cope as best as possible with the difficulties that this pathology may involve.

The second most common form of Charcot-Marie-Tooth disease (CMT) follows an X-linked dominant inheritance pattern (CMTX1), referring to mutations in the gap junction protein beta 1 gene (GJB1) that affect connexin 32 protein (Cx32) and its ability to form gap junctions in the myelin sheath of peripheral nerves. Despite the advances of next-generation sequencing (NGS), attention has only recently also focused on noncoding regions. We describe two unrelated families with a c.-17+1G>T transversion in the 5′ untranslated region (UTR) of GJB1 that cosegregates with typical features of CMTX1. As suggested by in silico analysis, the mutation affects the regulatory sequence that controls the proper splicing of the intron in the corresponding mRNA. The retention of the intron is also associated with reduced levels of the transcript and the loss of immunofluorescent staining for Cx32 in the nerve biopsy, thus supporting the hypothesis of mRNA instability as a pathogenic mechanism in these families. Therefore, our report corroborates the role of 5′ UTR of GJB1 in the pathogenesis of CMTX1 and emphasizes the need to include this region in routine GJB1 screening, as well as in NGS panels.

Pathological evidence of amyloid on nerve biopsy has been the gold standard for diagnosis in hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) for a long time. In this article, we reviewed the pathological findings of a large series of sural nerve biopsies from a cohort of hATTR-PN patients, collected by different Italian referral centers. Patients and Methods: We reviewed clinical and pathological data from hATTR-PN patients, diagnosed and followed in five Italian referral centers for peripheral neuropathies. Diagnosis was formulated after a positive genetic test for transthyretin (TTR) mutations. Sural nerve biopsy was performed according to standard protocols. Results: Sixty-nine sural nerve biopsies from hATTR-PN patients were examined. Congo red positive deposits were found in 73% of cases. Only the Phe64Leu mutation failed to show amyloid deposits in a high percentage of biopsies (54%), as already described. Unusual pathological findings, such as myelin abnormalities or inflammatory infiltrates, were detected in occasional cases. Conclusions: Even if no longer indicated to confirm hATTR-PN clinical suspicion, nerve biopsy remains, in expert hands, a rapid and inexpensive tool to detect amyloid deposition. In Italy, clinicians should be aware that a negative biopsy does not exclude hATTR-PN, particularly for Phe64Leu, one of the most frequent mutations in this country.

BACKGROUND: Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on disease-modifying pharmacological treatment for TTR-related and other FAPs, encompassing amyloid kinetic stabilisers, amyloid matrix solvents, and amyloid precursor inhibitors. OBJECTIVES: To assess and compare the efficacy, acceptability, and tolerability of disease-modifying pharmacological agents for familial amyloid polyneuropathies (FAPs). SEARCH METHODS: On 18 November 2019, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We reviewed reference lists of articles and textbooks on peripheral neuropathies. We also contacted experts in the field. We searched clinical trials registries and manufacturers' websites. SELECTION CRITERIA: We included randomised clinical trials (RCTs) or quasi-RCTs investigating any disease-modifying pharmacological agent in adults with FAPs. Disability due to FAP progression was the primary outcome. Secondary outcomes were severity of peripheral neuropathy, change in modified body mass index (mBMI), quality of life, severity of depression, mortality, and adverse events during the trial. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: The review included four RCTs involving 655 people with TTR-FAP. The manufacturers of the drugs under investigation funded three of the studies. The trials investigated different drugs versus placebo and we did not conduct a meta-analysis. One RCT compared tafamidis with placebo in early-stage TTR-FAP (128 randomised participants). The trial did not explore our predetermined disability outcome measures. After 18 months, tafamidis might reduce progression of peripheral neuropathy slightly more than placebo (Neuropathy Impairment Score (NIS) in the lower limbs; mean difference (MD) -3.21 points, 95% confidential interval (CI) -5.63 to -0.79; P = 0.009; low-certainty evidence). However, tafamidis might lead to little or no difference in the change of quality of life between groups (Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score; MD -4.50 points, 95% CI -11.27 to 2.27; P = 0.19; very low-certainty evidence). No clear between-group difference was found in the numbers of participants who died (risk ratio (RR) 0.65, 95% CI 0.11 to 3.74; P = 0.63; very low-certainty evidence), who dropped out due to adverse events (RR 1.29, 95% CI 0.30 to 5.54; P = 0.73; very low-certainty evidence), or who experienced at least one severe adverse event during the trial (RR 1.16, 95% CI 0.37 to 3.62; P = 0.79; very low-certainty evidence). One RCT compared diflunisal with placebo (130 randomised participants). At month 24, diflunisal might reduce progression of disability (Kumamoto Score; MD -4.90 points, 95% CI -7.89 to -1.91; P = 0.002; low-certainty evidence) and peripheral neuropathy (NIS plus 7 nerve tests; MD -18.10 points, 95% CI -26.03 to -10.17; P < 0.001; low-certainty evidence) more than placebo. After 24 months, changes from baseline in the quality of life measured by the 36-Item Short-Form Health Survey score showed no clear difference between groups for the physical component (MD 6.10 points, 95% CI 2.56 to 9.64; P = 0.001; very low-certainty evidence) and the mental component (MD 4.40 points, 95% CI -0.19 to 8.99; P = 0.063; very low-certainty evidence). There was no clear between-group difference in the number of people who died (RR 0.46, 95% CI 0.15 to 1.41; P = 0.17; very low-certainty evidence), in the number of dropouts due to adverse events (RR 2.06, 95% CI 0.39 to 10.87; P = 0.39; very low-certainty evidence), and in the number of people who experienced at least one severe adverse event (RR 0.77, 95% CI 0.18 to 3.32; P = 0.73; very low-certainty evidence) during the trial. One RCT compared patisiran with placebo (225 randomised participants). After 18 months, patisiran reduced both progression of disability (Rasch-built Overall Disability Scale; least-squares MD 8.90 points, 95% CI 7.00 to 10.80; P < 0.001; moderate-certainty evidence) and peripheral neuropathy (modified NIS plus 7 nerve tests - Alnylam version; least-squares MD -33.99 points, 95% CI -39.86 to -28.13; P < 0.001; moderate-certainty evidence) more than placebo. At month 18, the change in quality of life between groups favoured patisiran (Norfolk QOL-DN total score; least-squares MD -21.10 points, 95% CI -27.20 to -15.00; P < 0.001; low-certainty evidence). There was little or no between-group difference in the number of participants who died (RR 0.61, 95% CI 0.21 to 1.74; P = 0.35; low-certainty evidence), dropped out due to adverse events (RR 0.33, 95% CI 0.13 to 0.82; P = 0.017; low-certainty evidence), or experienced at least one severe adverse event (RR 0.91, 95% CI 0.64 to 1.28; P = 0.58; low-certainty evidence) during the trial. One RCT compared inotersen with placebo (172 randomised participants). The trial did not explore our predetermined disability outcome measures. From baseline to week 66, inotersen reduced progression of peripheral neuropathy more than placebo (modified NIS plus 7 nerve tests - Ionis version; MD -19.73 points, 95% CI -26.50 to -12.96; P < 0.001; moderate-certainty evidence). At week 65, the change in quality of life between groups favoured inotersen (Norfolk QOL-DN total score; MD -10.85 points, 95% CI -17.25 to -4.45; P < 0.001; low-certainty evidence). Inotersen may slightly increase mortality (RR 5.94, 95% CI 0.33 to 105.60; P = 0.22; low-certainty evidence) and occurrence of severe adverse events (RR 1.48, 95% CI 0.85 to 2.57; P = 0.16; low-certainty evidence) compared to placebo. More dropouts due to adverse events were observed in the inotersen than in the placebo group (RR 8.57, 95% CI 1.16 to 63.07; P = 0.035; low-certainty evidence). There were no studies addressing apolipoprotein AI-FAP, gelsolin-FAP, and beta-2-microglobulin-FAP. AUTHORS' CONCLUSIONS: Evidence on the pharmacological treatment of FAPs from RCTs is limited to TTR-FAP. No studies directly compare disease-modifying pharmacological treatments for TTR-FAP. Results from placebo-controlled trials indicate that tafamidis, diflunisal, patisiran, and inotersen may be beneficial in TTR-FAP, but further investigations are needed. Since direct comparative studies for TTR-FAP will be hampered by sample size and costs required to demonstrate superiority of one drug over another, long-term non-randomised open-label studies monitoring their efficacy and safety are needed.

The Tropomyosin-receptor kinase fused gene (TFG) encodes TFG which is expressed in spinal motor neurons, dorsal root ganglia and cranial nerve nuclei, and plays a role in the dynamics of the endoplasmic reticulum. Two dominant missense TFG mutations have previously been reported in limited geographical areas (Far East, Iran, China) in association with hereditary motor sensory neuropathy with proximal involvement (HMSN-P) of the four limbs, or with Charcot-Marie-Tooth disease type 2 (CMT2). The 60-year-old female proband belonging to a three-generation Italian family presented with an atypical neuropathy characterized by diffuse painful cramps and prominent motor-sensory impairment of the distal upper limbs. Her sural nerve biopsy showed chronic axonal neuropathy without active degeneration or regeneration. Targeted next-generation sequencing of a panel with 98 genes associated with inherited peripheral neuropathies/neuromuscular disorders identified three candidate genes: TFG, DHTKD1 and DCTN2. In the family, the disease co-segregated with the TFG p.(Gly269Val) variant. TFG should be considered in genetic testing of patients with heterogeneous inherited neuropathy, independently of their ethnic origin.

ObjectiveTo collect information on frequency of pregnancy and delivery complications in Charcot-Marie-Tooth (CMT) disease and on CMT course during pregnancy.MethodsThrough an ad hoc online questionnaire, we investigated pregnancy and neuropathy course in women with CMT adhering to the Italian CMT Registry. Data were compared to those of controls (recruited among friends and unaffected relatives) and the Italian (or other reference) population.ResultsWe collected data on 193 pregnancies from 86 women with CMT (age 20–73 years) with 157 deliveries (81.4%) after a mean of 38.6 gestational weeks. In women with CMT, there were no differences compared to controls (59 pregnancies and 46 deliveries from 24 controls) and the reference population for miscarriages (11.4%) and planned (21.0%) and emergency (14.0%) cesarean sections. We found a significantly higher frequency of placenta previa (1.6% vs 0.4%), abnormal fetal presentations (8.4% vs 4.5%), and preterm deliveries (20.3% vs 6.9%; most in week 34–36 of gestation) compared to reference populations. Excluding twins, newborn weight did not differ from the reference population. Postpartum bleeding rate in patients with CMT (2.1%) was similar to that of the general population (2.4%). CMT status worsened during 18 of 193 pregnancies (9.3%) with no recovery in 16 of them and with similar figures in the CMT1A and non-CMT1A subtypes.ConclusionsWe observed higher rates of placenta previa, abnormal presentations, and preterm deliveries in CMT, but pregnancy outcome and newborn weight and health were similar to those of the reference populations. Worsening of CMT is not infrequent and occurs not only in CMT1A. Pregnant women with CMT should be monitored with particular care.

The diagnosis of peripheral neuropathies can be challenging with consequent difficulties in patients' management. The aim of this study was to explore the current diagnostic role of sural nerve biopsy and to compare pathological findings with serum neurofilament light chain levels (NfL) as biomarkers of axonal damage. We collected demographic, clinical, and paraclinical data of patients referred over 1 year to the Neurology Unit, University of Verona, Italy, to perform nerve biopsy for diagnostic purposes, and we analyzed NfL levels in available paired sera using a high sensitive technique (Quanterix, Simoa). Eighty-two patients were identified (37.8% females, median age 65.5 years). Neuropathy onset was frequently insidious (68.3%) with a slowly progressive course (76.8%). Lower limbs were usually involved (81.7%), with a predominance of sensory over motor symptoms (74.4% vs 42.7%). The most common neuropathological findings were a demyelinating pattern (76.8%), clusters of regenerations (58.5%), and unmyelinated fibers involvement on ultrastructural evaluation (52.4%). A definite pathological diagnosis was achieved in 29 cases, and in 20.7% of patients, the referral clinical diagnosis was modified. Coexistent hematological conditions and hepatitis were diagnostic confounding factors (p = 0.012 and 0.034, respectively). In the analyzed paired sera (n = 37), an inverse despite not significant relationship between NfL values and fiber density was observed (Spearman's rho - 0.312, p = 0.056). In addition, we noted increased serum NfL values of patients with active axonal degeneration. Nerve biopsy remains a useful diagnostic investigation to achieve a correct diagnosis and guide patients' management in selected cases of peripheral neuropathy. Serum NfL is an accessible and potential valuable marker of axonal damage in these conditions.

The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A&gt, G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family.

Neurolymphomatosis, the infiltration of the peripheral nervous system from lymphoid cells, represents an uncommon manifestation of lymphomas. We describe the challenging diagnostic work-up in a patient with neurolymphomatosis. A 58-year-old woman with previous breast diffuse large B-cell lymphoma treated with chemo- and radiation-therapy, presented with dysesthesias, neuropathic pain at left abdomen and thigh, and weakness at left lower limb 9 years after disease remission. Neurophysiology revealed left T10-L4 radiculo-plexopathy with no abnormalities at cerebrospinal fluid (CSF), nerve ultrasound, and 18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). MR-neurography disclosed left rectus abdominis muscle atrophy, neurogenic edema, and denervation. Radiation-induced damage, paraneoplastic, infectious radiculo-plexopathies, and atypical chronic inflammatory demyelinating polyradiculoneuropathy were ruled out. Neurolymphomatosis was suspected, and the patient treated with rituximab with improvement. Despite treatment, the radiculo-plexopathy eventually extended to the right side and sacral roots. Later in the disease course, sural nerve biopsy confirmed the diagnosis. Maintenance therapy was continued, until cutaneous localizations occurred, requiring salvage therapy and autologous stem cell transplant. Although rare, neurolymphomatosis should be considered in all patients with lymphomas and unexplained peripheral nervous system involvement. Hematological, CSF, and neuroimaging findings may be unremarkable, and a high index of suspicion required in order to achieve the diagnosis.

Metachromatic leukodystrophy (MLD; OMIM #250100) is a panethnic, autosomal recessive disease characterized by intralysosomal accumulation of sulfatides, mainly in oligodendrocytes and Schwann cells. MLD classically presents in childhood, and results from mutations in ARSA gene,1 encoding arylsulfatase A (ARSA), a lysosomal enzyme responsible for sulfatide degradation.

We herein report an unusual case of a 40-year-old woman presenting to the emergency department with acute-onset tetraparesis due to inhalation of chemical solvents containing n-hexane. The clinical picture, a mild albumin-cytologic dissociation and the demyelinating features on nerve conduction study initially mimicked the presentation of Guillain-Barré syndrome (GBS), but the patient failed to respond to intravenous immunoglobulin treatment and plasma exchange. Diagnosis of hexane-induced neuropathy was then confirmed by means of sural nerve biopsy, showing axonal enlargement with secondary retraction and thinning of the myelin sheath.

Hereditary neuropathies may be misdiagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). A correct diagnosis is crucial for avoiding unnecessary therapies and access genetic counseling. We report on nine patients (seven men, mean age 49.2 ± 16.1) diagnosed with and treated as CIDP, in whom mutations or variants of unknown significance (VUS) in genes associated with hereditary neuropathies were reported. All underwent neurological and neurophysiological examination, eight also cerebrospinal fluid (CSF) analysis. In 4/9, nerve ultrasound and/or MR-neurography were performed. All the patients complained of progressive upper or lower limbs sensory-motor symptoms, with heterogeneous disease duration (1-34 years, mean 8.6 ± 10.8). Neurophysiology showed demyelinating signs in seven patients, mixed findings with predominant axonal damage in two patients. Neuroimaging disclosed diffuse abnormalities at proximal and distal segments. Molecular screening showed PMP22 duplication in two patients, mutations in the MPZ, EGR2, and GJB1 genes were reported in each of the remaining patients. The two patients with mixed neurophysiological findings had p.Val30Met mutation in the transthyretin gene. Two patients had VUS in the MARS and HSPB1 genes. Four patients had partial response to immunomodulant therapies, and CSF and neurophysiological features suggesting an inflammatory condition concomitant with the hereditary neuropathy. Hereditary neuropathy may be misdiagnosed with CIDP. The most common pitfalls are CSF (high protein levels and oligoclonal bands), incorrect interpretation of neurophysiology, and transient benefit from therapies. Neuroimaging may be helpful in cases with atypical presentations or when severe axonal damage complicate the neurophysiological interpretation.

Introduction Nerve cross-sectional area (CSA) is larger than normal in Charcot-Marie-Tooth disease 1A (CMT1A), although to a variable extent. We explored whether CSA is correlated with CMT clinical severity measured with neuropathy score version 2 (CMTNS2) and its examination subscore (CMTES2) in CMT1A. Methods We assessed 56 patients with CMT1A (42 families). They underwent nerve conduction study (NCS) and nerve high-resolution ultrasound (HRUS) of the left median, ulnar, and fibular nerves. Results Univariate analysis showed NCS and HRUS variables to be significantly correlated with CMTNS2 and CMTES2 and with each other. Multivariate analysis showed that ulnar motor nerve conduction velocity (β: -0.19) and fibular compound muscle action potential amplitude (-1.50) significantly influenced CMTNS2 and that median forearm CSA significantly influenced CMTNS2 (β: 5.29) and CMTES2 (4.28). Discussion Nerve size is significantly associated with clinical scores in CMT1A, which suggests that it might represent a potential biomarker of CMT damage and progression.

Charcot-Marie-Tooth (CMT) is the most common inherited neuropathy, yet has no available pharmacological therapy. Past pharmacotherapy trials failed to provide positive results, possibly due to a poor choice of outcome measures. We previously performed a study in which we validated the 6-minute walk test and StepWatch™ Activity Monitor in CMT. The aim of the current study was to determine if these outcome measures are sensitive to change over a 12-month period. In this longitudinal multicenter study, 149 out of 169 initially enrolled patients were re-evaluated after 12 months using the 6-minute walk test, StepWatch™ Activity Monitor and other outcome measures commonly adopted in CMT disease. Statistical analysis showed a worsening of the CMT-Neuropathy Score (p 0.05), strength of distal muscles measured by myometry (p 0.05) and StepWatch™ Activity Monitor outputs (p 0.05). The 10 meter walking test (p 0.05), muscular strength as detected by clinical evaluation (p 0.05), 6-minute walk test (p 0.05), pain (p 0.05) and quality of life (p 0.05) showed no change. In the current study, patients showed clinical worsening over 12 months, confirmed by a reduction of activity as detected by StepWatch™ Activity Monitor. The 6-minute walk test failed to detect change.

Tafamidis is a transthyretin (TTR) stabilizer able to prevent TTR tetramer dissociation. There have been a few encouraging studies on Tafamidis efficacy in early-onset inherited transthyretin amyloidosis (ATTR) due to Val30Met mutation. However, less is known about its efficacy in later disease stages and in non-Val30Met mutations. We performed a multi-center observational study on symptomatic ATTR patients prescribed to receive Tafamidis. We followed up patients according to a standardized protocol including general medical, cardiological and neurological assessments at baseline and every 6 months up to 3 years. Sixty-one (42 males) patients were recruited. Only 28 % of enrolled subjects had the common Val30Met mutation, mean age of onset was remarkably late (59 years) and 18 % was in advanced disease stage at study entry. Tafamidis proved safe and well-tolerated. One-third of patients did not show significant progression along 36 months, independently from mutation type and disease stage. Neurological function worsened particularly in the first 6 months but progression slowed significantly thereafter. Autonomic function remained stable in 33 %, worsened in 56 % and improved in 10 %. Fifteen percent of patients showed cardiac disease progression and 30 % new onset of cardiomyopathy. Overall, Tafamidis was not able to prevent functional progression of the disease in 23 (43 %) subjects, including 16 patients who worsened in their walking ability and 12 patients who reached a higher NYHA score during the follow-up period. A higher mBMI at baseline was associated with better preservation of neurological function. In conclusion, neuropathy and cardiomyopathy progressed in a significant proportion of patients despite treatment. However, worsening of neurological function slowed after the first 6 months and also subjects with more advanced neuropathy, as well as patients with non-Val30Met mutation, benefited from treatment. Body weight preservation is an important favorable prognostic factor.

The peripheral nervous system may be involved at any stage in the course of lymphoproliferative diseases. The different underlying mechanisms include neurotoxicity secondary to chemotherapy, direct nerve infiltration (neurolymphomatosis), infections, immune-mediated, paraneoplastic or metabolic processes and nutritional deficiencies. Accordingly, the clinical features are heterogeneous and depend on the localization of the damage (ganglia, roots, plexi, and peripheral nerves) and on the involved structures (myelin, axon, and cell body). Some clinical findings, such a focal or diffuse involvement, symmetric or asymmetric pattern, presence of pain may point to the correct diagnosis. Besides a thorough medical history and neurological examination, neurophysiological studies, cerebrospinal fluid analysis, nerve biopsy (in selected patients with suspected lymphomatous infiltration) and neuroimaging techniques (magnetic resonance neurography and nerve ultrasound) may be crucial for a proper diagnostic workup.

Objective Ulnar/median motor nerve conduction velocity (MNCV) is ≤38 m/s in demyelinating Charcot-Marie-Tooth disease (CMT). Previous nerve high resolution ultrasound (HRUS) studies explored demyelinating CMT assuming it as a homogeneous genetic/pathological entity or focused on CMT1A. Methods To explore the spectrum of nerve HRUS findings in demyelinating CMTs, we recruited patients with CMT1A (N = 44), CMT1B (N = 9), CMTX (N = 8) and CMT4C (N = 4). They underwent nerve conduction study (NCS) and HRUS of the median, ulnar, peroneal nerve, and the brachial plexus. Results Median, ulnar and peroneal MNCV significantly differed across CMT subtypes. Cross sectional area (CSA) was markedly and diffusely enlarged at all sites, except entrapment ones, in CMT1A, while it was slightly enlarged or within normal range in the other CMTs. No significant right-to-left difference was found. Age had limited effect on CSA. CSAs of some CMT1A patients largely overlapped with those of other demyelinating CMTs. A combination of three median CSA measures could separate CMT1A from other demyelinating CMTs. Conclusions Nerve HRUS findings are heterogeneous in demyelinating CMTs. Significance Nerve HRUS may separate CMT1A from other demyelinating CMTs. The large demyelinating CMTs HRUS spectrum may be related to its pathophysiological variability.

Objective Nerve ultrasound (US) data on myelin protein zero (MPZ)-related Charcot-Marie-Tooth disease (CMT) are lacking. To offer a comprehensive perspective on MPZ-related CMTs, we combined nerve US with clinics, electrodiagnosis and histopathology. Methods We recruited 36 patients (12 MPZ mutations), and correlated nerve US to clinical, electrodiagnostic measures, and sural nerve biopsy. Results According to motor nerve conduction velocity (MNCV) criteria, nine patients were categorized as “demyelinating” CMT1B, 17 as “axonal” CMT2I/J, and 10 as dominant “intermediate” CMTDID. Sural nerve biopsy showed hypertrophic de-remyelinating neuropathy with numerous complex onion bulbs in one patient, de-remyelinating neuropathy with scanty/absent onion bulbs in three, axonal neuropathy in two, mixed demyelinating-axonal neuropathy in five. Electrodiagnosis significantly differed in CMT1B vs. CMT2I/J and CMTDID subgroups. CMT1B had slightly enlarged nerve cross sectional area (CSA) especially at proximal upper-limb (UL) sites. CSA was negatively correlated to UL MNCV and not increased at entrapment sites. Major sural nerve pathological patterns were uncorrelated to UL nerve US and MNCV. Conclusions Sural nerve biopsy confirmed the wide pathological spectrum of MPZ-CMT. UL nerve US identified two major patterns corresponding to the CMT1B and CMT2I/J-CMTDID subgroups. Significance Nerve US phenotype of MPZ-CMT diverged from those in other demyelinating peripheral neuropathies and may have diagnostic value.

Background: In humans, Desert Hedgehog (DHH) gene mutations are a very rare cause of 46,XY gonadal dysgenesis (GD), eventually associated with peripheral neuropathy. Patients and Methods: Clinical records of 12 patients with 46,XY GD and unknown genetic background were reviewed and a 46,XY woman with peripheral neuropathy was individuated. Her 46,XX sister affected by similar neuropathy was also investigated. Genomic DNA was extracted and DHH exons sequenced and analyzed. A comparative genomic hybridization array was also performed. Results: In both the 46,XY and 46,XX sisters, a homozygous c.554C>A mutation in exon 2 of the DHH gene was found, determining a premature termination codon (p.Ser 185*). Heterozygous consanguineous carrier parents showed neither reproductive problems nor peripheral neuropathy. In the proband and her sister, a 499-kb duplication in 9p22.1 was also found. Conclusion: A 46,XY European woman with 46,XY GD and a novel homozygous DHH pathogenic variant is reported, confirming that this gene plays a key role in male gonadal development. Her 46,XX sister, harboring the same mutation, showed normal internal and external female phenotype. Thus, DHH seems not to be involved in the ovarian development pathway or its postpubertal function. Homozygous DHH mutations cause a specific peripheral neuropathy in humans with both 46,XY and 46,XX karyotypes.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess and compare the efficacy, acceptability, and tolerability of pharmacologic disease‐modifying agents for familial amyloid neuropathy (FAP).

Distal hereditary motor neuropathies (dHMNs) are clinically and genetically heterogeneous neurological conditions characterized by degeneration of the lower motor neurons. So far, 18 dHMN genes have been identified, however, about 80% of dHMN cases remain without a molecular diagnosis. By a combination of autozygosity mapping, identity-by-descent segment detection and whole-exome sequencing approaches, we identified two novel homozygous mutations in the SIGMAR1 gene (p.E138Q and p.E150K) in two distinct Italian families affected by an autosomal recessive form of HMN. Functional analyses in several neuronal cell lines strongly support the pathogenicity of the mutations and provide insights into the underlying pathomechanisms involving the regulation of ER-mitochondria tethering, Ca2+ homeostasis and autophagy. Indeed, in vitro, both mutations reduce cell viability, the formation of abnormal protein aggregates preventing the correct targeting of sigma-1R protein to the mitochondria-associated ER membrane (MAM) and thus impinging on the global Ca2+ signalling. Our data definitively demonstrate the involvement of SIGMAR1 in motor neuron maintenance and survival by correlating, for the first time in the Caucasian population, mutations in this gene to distal motor dysfunction and highlight the chaperone activity of sigma-1R at the MAM as a critical aspect in dHMN pathology.