104 research outputs found
Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT
OBJECTIVE: To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene (GJB1).
METHODS: Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3′ untranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected.
RESULTS: Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5′UTR. A novel mutation, c.*15C>T, was detected in the 3′ UTR of GJB1 in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3′UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population.
CONCLUSIONS: Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions
Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1)
OBJECTIVE: To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships. METHODS: Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers. RESULTS: We evaluated 87 males who had a mean age of 41 years (range 10-78 years) and 73 females who had a mean age of 46 years (range 15-84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity. CONCLUSIONS: In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1. CLINICALTRIALSGOV IDENTIFIER: NCT01193075
Adherence and Reactogenicity to Vaccines against SARS-COV-2 in 285 Patients with Neuropathy: A Multicentric Study
Background: The safety of the new vaccines against SARS-CoV-2 have already been shown, although data on patients with polyneuropathy are still lacking. The aim of this study is to evaluate the adherence to SARS-CoV-2 vaccination, as well as the reactogenicity to those vaccines in patients affected by neuropathy. Methods: A multicentric and web-based cross-sectional survey was conducted among patients affected by neuropathy from part of South Italy. Results: Out of 285 responders, n = 268 were included in the final analysis and n = 258 of them (96.3%) were fully vaccinated. Adherence to vaccination was higher in patients with hereditary neuropathies compared to others, while it was lower in patients with anti-MAG neuropathy (all p < 0.05). The overall prevalence of adverse events (AEs) was 61.2% and its occurrence was not associated with neuropathy type. Being female and of younger age were factors associated with higher risk of AEs, while having an inflammatory neuropathy and steroids assumption were associated with a lower risk (all p < 0.05). Younger age, having had an AE, and COVID-19 before vaccination were factors associated with symptoms worsening after vaccination (all p < 0.05). (4) Conclusions: Patients with neuropathy showed a high level of adherence to COVID-19 vaccination. Safety of vaccines in patients with neuropathies was comparable to the general population and it was more favorable in those with inflammatory neuropathy
Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation
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 diculties, 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>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
A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders
To date, 3 AIFM1 (apoptosis inducing factor mitochondrial 1, located on Xq26.1) mutations have been reported: 2 missense changes (c.923G>A/p.Gly308Glu; c.1478A>T/p.Glu493Val) and a 3-basepair deletion (c.601delAGA/p.Arg201del). Two mutations have been described in early-onset severe mitochondrial encephalomyopathy related to impaired oxidative phosphorylation.(1,2) A third mutation is associated with Cowchock syndrome, or Charcot-Marie-Tooth X4 (CMTX4), a slowly progressive disorder characterized by axonal neuropathy, hearing loss, and mental retardation.(3,4</SUP
Miller Fisher syndrome: an updated narrative review
IntroductionMiller Fisher syndrome (MFS) is considered a rare variant of Guillain-Barré syndrome (GBS), a group of acute-onset immune-mediated neuropathies characterized by the classic triad of ataxia, areflexia, and ophthalmoparesis. The present review aimed to provide a detailed and updated profile of all aspects of the syndrome through a collection of published articles on the subject, ranging from the initial description to recent developments related to COVID-19.MethodsWe searched PubMed, Scopus, EMBASE, and Web of Science databases and gray literature, including references from the identified studies, review studies, and conference abstracts on this topic. We used all MeSH terms pertaining to “Miller Fisher syndrome,” “Miller Fisher,” “Fisher syndrome,” and “anti-GQ1b antibody.”ResultsAn extensive bibliography was researched and summarized in the review from an initial profile of MFS since its description to the recent accounts of diagnosis in COVID-19 patients. MFS is an immune-mediated disease with onset most frequently following infection. Anti-ganglioside GQ1b antibodies, detected in ~85% of patients, play a role in the pathogenesis of the syndrome. There are usually no abnormalities in MFS through routine neuroimaging. In rare cases, neuroimaging shows nerve root enhancement and signs of the involvement of the central nervous system. The most consistent electrophysiological findings in MFS are reduced sensory nerve action potentials and absent H reflexes. Although MFS is generally self-limited and has excellent prognosis, rare recurrent forms have been documented.ConclusionThis article gives an updated narrative review of MFS with special emphasis on clinical characteristics, neurophysiology, treatment, and prognosis of MFS patients
CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis
BACKGROUND: The international Inherited Neuropathy
Consortium (INC) was created with the goal of obtaining
much needed natural history data for patients with
Charcot-Marie-Tooth (CMT) disease. We analysed clinical
and genetic data from patients in the INC to determine
the distribution of CMT subtypes and the clinical
impairment associated with them.
METHODS: We analysed data from 1652 patients
evaluated at 13 INC centres. The distribution of CMT
subtypes and pathogenic genetic mutations were
determined. The disease burden of all the mutations was
assessed by the CMT Neuropathy Score (CMTNS) and
CMT Examination Score (CMTES).
RESULTS: 997 of the 1652 patients (60.4%) received
a genetic diagnosis. The most common CMT subtypes
were CMT1A/PMP22 duplication, CMT1X/GJB1
mutation, CMT2A/MFN2 mutation, CMT1B/MPZ
mutation, and hereditary neuropathy with liability to
pressure palsy/PMP22 deletion. These five subtypes of
CMT accounted for 89.2% of all genetically confirmed
mutations. Mean CMTNS for some but not all subtypes
were similar to those previously reported.
CONCLUSIONS: Our findings confirm that large numbers
of patients with a representative variety of CMT subtypes
have been enrolled and that the frequency of achieving
a molecular diagnosis and distribution of the CMT
subtypes reflects those previously reported. Measures of
severity are similar, though not identical, to results from
smaller series. This study confirms that it is possible to
assess patients in a uniform way between international
centres, which is critical for the planned natural history
study and future clinical trials. These data will provide a
representative baseline for longitudinal studies of CMT.
CLINICAL TRIAL REGISTRATION ID NUMBER: NCT0119307
Monitoring effectiveness and safety of Tafamidis in transthyretin amyloidosis in Italy: a longitudinal multicenter study in a non-endemic area
open24noTafamidis 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.openCortese, A.; Vita, G.; Luigetti, M.; Russo, M.; Bisogni, G.; Sabatelli, M.; Manganelli, F.; Santoro, L.; Cavallaro, T.; Fabrizi, G.M.; Schenone, A.; Grandis, M.; Gemelli, C.; Mauro, A.; Pradotto, L.G.; Gentile, L.; Stancanelli, C.; Lozza, A.; Perlini, S.; Piscosquito, G.; Calabrese, D.; Mazzeo, A.; Obici, L.; Pareyson, DCortese, Andrea; Vita, G.; Luigetti, M.; Russo, M.; Bisogni, G.; Sabatelli, M.; Manganelli, F.; Santoro, L.; Cavallaro, T.; Fabrizi, G. M.; Schenone, A.; Grandis, M.; Gemelli, C.; Mauro, A.; Pradotto, L. G.; Gentile, L.; Stancanelli, C.; Lozza, A.; Perlini, Stefano; Piscosquito, G.; Calabrese, D.; Mazzeo, A.; Obici, L.; Pareyson, D
Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1).
OBJECTIVE: To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships. METHODS: Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers. RESULTS: We evaluated 87 males who had a mean age of 41 years (range 10-78 years) and 73 females who had a mean age of 46 years (range 15-84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity. CONCLUSIONS: In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1. CLINICALTRIALSGOV IDENTIFIER: NCT01193075
Case report: Asp194Ala variant in MFN2 is associated with ALS-FTD in an Italian family
Background:MFN2 gene encodes the protein Mitofusin 2, involved in essential mitochondrial functions such as fusion, trafficking, turnover, and cellular interactions. We describe a family carrying a novel MFN2 mutation associated with ALS-frontotemporal dementia (FTD) clinical phenotype in the mother and Charcot-Marie-Tooth disease type 2A (CMT2A) in her son.Case presentation: The mother, a 67-year-old woman, referred to us for a three year-history of mood disturbance and gait impairment, and a more recent hypophonia, dysarthria, dysphagia, and diffuse muscle wasting. Family history was positive for psychiatric disorders and gait disturbances. Brain 18F-FDG PET showed severe hypometabolism in the fronto-temporal brain cortex bilaterally. Electrodiagnostic studies (EDX) showed severe motor axonopathy in the bulbar, cervical and lumbosacral districts. Her 41-year-old son had a history of mood depression and sensory disturbances in the limbs, along with mild muscle wasting, weakness, and reduced reflexes. Nerve conduction studies revealed a moderate sensory-motor polyneuropathy, while brain MRI was normal. Whole exome sequencing of the patients’ DNA identified the novel MFN2 (NM_014874.4) variant c.581A>C p.(Asp194Ala).Conclusion: Our findings provide evidence of heterogenous clinical manifestations in family members sharing the same MFN2 molecular defect. Additionally, we present the first documented case of ASL-FTD associated with an MFN2 mutation, thereby expanding the range of MFN-related disorders. Further research involving larger cohorts of patients will be needed to better understand the role of MFN2 as a contributing gene in the development of ALS-FTD
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