Search

Background: We aimed to investigate the clinical features of a large cohort of patients with myelin protein zero ( MPZ )-related neuropathy, focusing on the five main mutation clusters across Italy., Methods: We retrospectively gathered a minimal data set of clinical information in a series of patients with these frequent mutations recruited among Italian Charcot-Marie-Tooth (CMT) registry centres, including disease onset/severity (CMTES-CMT Examination Score), motor/sensory symptoms and use of orthotics/aids., Results: We collected data from 186 patients: 60 had the p.Ser78Leu variant ('classical' CMT1B; from Eastern Sicily), 42 the p.Pro70Ser (CMT2I; mainly from Lombardy), 38 the p.Thr124Met (CMT2J; from Veneto), 25 the p.Ser44Phe (CMT2I; from Sardinia) and 21 the p.Asp104ThrfsX13 (mild CMT1B; from Apulia) mutation. Disease severity (CMTES) was higher (p<0.001) in late-onset axonal forms (p.Thr124Met=9.2±6.6; p.Ser44Phe=7.8±5.7; p.Pro70Ser=7.6±4.8) compared with p.Ser78Leu (6.1±3.5) patients. Disease progression (ΔCMTES/year) was faster in the p.Pro70Ser cohort (0.8±1.0), followed by p.Ser44Phe (0.7±0.4), p.Thr124Met (0.4±0.5) and p.Ser78Leu (0.2±0.4) patients. Disease severity (CMTES=1.2±1.5), progression (ΔCMTES/year=0.1±0.4) and motor involvement were almost negligible in p.Asp104ThrfsX13 patients, who, however, frequently (78%, p<0.001) complained of neuropathic pain. In the other four clusters, walking difficulties were reported by 69-85% of patients, while orthotic and walking aids use ranged between 40-62% and 16-28%, respectively., Conclusions: This is the largest MPZ (and late-onset CMT2) cohort ever collected, reporting clinical features and disease progression of 186 patients from five different clusters across Italy. Our findings corroborate the importance of differentiating between 'classical' childhood-onset demyelinating, late-onset axonal and mild MPZ -related neuropathy, characterised by different pathomechanisms, in view of different therapeutic targets., Competing Interests: Competing interests: GMF acknowledges donations from Pfizer to support research activities of his Research Unit, financial support from Akcea, Kedrion, Pfizer for participation in national and international meetings and from Akcea, Alnylam and Pharnext for participation in Advisory Boards; MG acknowledges donations from Sanofi Genzyme to support research activities of her Research Unit, financial support from Alnylam and Sanofi Genzyme for participation in national and international Meetings, participation in Advisory Board of Pfizer, speaker honorarium from Sanofi Genzyme; AM acknowledges financial support from Pfizer, Alnylam and Akcea for participation in national and international meetings, participation in Advisory Board of Pfizer, Alnylam and Akcea; DP acknowledges participation in Advisory Board of Inflectis, Alnylam, Akcea, Arvinas, Augustine Tx, DTx; ST is supported by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) - A multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). AB, LG, TC, PS, MR, SM, YMF, EM, FT, AG, GO, MF, EC, LC, PM, FB, SM, FT, SCP, AS, FM, CP report no disclosure., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP., Methods: This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed., Results: Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m 2 ; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged., Conclusions: Patisiran largely stabilised disease in patients with ATTRv amyloidosis., (© 2024. The Author(s).)

Background and Purpose: Data are reported from the Italian CMT Registry., Methods: The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot-Marie-Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted., Results: Overall, 1012 patients had registered (535 females) and 711 had received a genetic diagnosis. Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The PMP22 duplication was the most frequent mutation (45.2%), followed by variants in GJB1 and MPZ (both ~10%) and MFN2 (3.3%) genes. A relatively high mutation rate in some "rare" genes (HSPB1 1.6%, NEFL 1.5%, SH3TC2 1.5%) and the presence of multiple mutation clusters across Italy was observed. CMT4A was the most disabling type, followed by CMT4C and CMT1E. Disease progression rate differed depending on the CMT subtype. Foot deformities and walking difficulties were the main features. Shoe inserts and orthotic aids were used by almost one-half of all patients. Scoliosis was present in 20% of patients, especially in CMT4C. Recessive forms had more frequently walking delay, walking support need and wheelchair use. Hip dysplasia occurred in early-onset CMT., Conclusions: The Italian CMT Registry has proven to be a powerful data source to collect information about epidemiology and genetic distribution, clinical features and disease progression of CMT in Italy and is a useful tool for recruiting patients in forthcoming clinical trials., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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., (© 2022. The Author(s).)

Objective: Single cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19., Methods: GBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered., Results: Incidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002)., Conclusions: This study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: To develop recommendations for vaccination for coronavirus-19 (COVID-19) in patients with inflammatory neuropathies., Methods: Key questions were formulated in order to perform a literature review on the safety and efficacy of vaccines in patients with inflammatory neuropathies. Based on the best evidence and expert opinion, a list of recommendations was formulated to inform decision on vaccination for COVID-19 in patients with inflammatory neuropathies and increase adherence to vaccination programmes., Results: Recommendations addressing safety and efficacy of vaccination in patients with inflammatory neuropathies were formulated. No data are currently available on the safety and efficacy of COVID-19 vaccines in patients with inflammatory neuropathies or other immune-mediated conditions. There is only sparse data on the safety of previous available vaccines in patients with inflammatory neuropathies, but studies on other autoimmune disorders indicate that these are safe and mostly efficacious. Patients with inflammatory neuropathies might be at increased risk for severe illness from COVID-19., Interpretation: Patients with inflammatory neuropathies should be encouraged to adhere to the vaccination campaign for COVID-19. These recommendations provide guidance on the management of vaccinations for COVID-19 in patients with inflammatory neuropathies. More research is needed regarding the safety and efficacy of vaccination in patients with inflammatory neuropathies and other immune conditions., (© 2021 Peripheral Nerve Society.)

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.

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 < 0.01), in the subgroup of TTR-CTS subjects (16 subjects, 5 with bilateral CTS) CSA did not significantly correlate with CTS severity (r = - 0.473). ATTRv patients with polyneuropathy showed larger CSA than pre-symptomatic carriers in several nerve sites, more pronounced at brachial plexi (p < 0.001)., 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).

Objective: To collect information on frequency of pregnancy and delivery complications in Charcot-Marie-Tooth (CMT) disease and on CMT course during pregnancy., Methods: Through 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., Results: We 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., Conclusions: We 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., (© 2020 American Academy of Neurology.)

Hereditary transthyretin amyloidosis (ATTRv, v for variant) is a late-onset, autosomal dominant disease caused by progressive extracellular deposition of transthyretin amyloid fibrils, leading to organ damage and death. For other late-onset fatal diseases, as Huntington's disease, protocols for pre-symptomatic genetic testing (PST) are available since decades. For ATTRv, limited experience has been reported to date, mostly gathered before the availability of approved therapies. We aimed at developing recommendations for a safe and feasible PST protocol in ATTRv in the era of emerging treatments, taking also into account Italian patients' characteristics and healthcare system rules. After an initial survey on ongoing approaches to PST for ATTRv in Italy, two roundtable meetings were attended by 24 experts from 16 Italian centers involved in the diagnosis and care of this disease. Minimal requirements for PST offer and potential critical issues were highlighted. By November 2019, 457 families affected by ATTRv with 209 molecularly confirmed pre-symptomatic carriers were counted. The median age at PST was 41.3 years of age, regardless of the specific mutation. Half of the Italian centers had a multidisciplinary team, including a neurologist, an internist, a cardiologist, a medical geneticist and a psychologist, although in most cases not all the specialists were available in the same center. A variable number of visits was performed at each site. Experts agreed that PST should be offered only in the context of genetic counselling to at risk individuals aged 18 or older. Advertised commercial options for DNA testing should be avoided. The protocol should consist of several steps, including a preliminary clinical examination, a pre-test information session, an interval time, the genetic test and a post-test session with the disclosure of the test results, in the context of an experienced multidisciplinary team. Recommendations for best timing were also defined. Protocols for PST in the context of ATTRv can be refined to offer at risk individuals the best chance for early diagnosis and timely treatment start, while respecting autonomous decisions and promoting safe psychological adjustment to the genetic result.

Introduction: ATTRv amyloidosis is worldwide spread with endemic foci in Portugal and Sweden, Japan, Brazil, Maiorca, and Cyprus. A national Registry was developed to characterise the epidemiology and genotype-phenotype correlation of ATTRv amyloidosis in Italy and to allow a better planning of diagnostic and therapeutic services., Methods: Fifteen Italian referral centres for amyloidosis spread all over the country have contributed to the Registry., Results: Four-hundred-forty-seven subjects were enrolled, 187 asymptomatic carriers and 260 affected patients. Thirty-one different mutations were recorded. The seven most represented genetic variants were significantly different in terms of age at onset, clinical features and geographical distribution. National prevalence is 4.33/million with higher values in Southern Italy. Overall symptoms of polyneuropathy were present at disease onset in about half of the patients, symptoms of cardiomyopathy in a quarter of patients, the rest referring carpal tunnel syndrome, dysautonomia or lumbar spinal stenosis. 52.6% of patients were in FAP stage 1, 20.4% in stage 2 and 13.5% in stage 3, while 13.5% patients had no neuropathy, presenting only cardiological symptoms., Conclusions: We presented an epidemiological study based on collaboration among referral centres for ATTRv amyloidosis spread in all the Italian territory, using web-based Registry. It provided a detailed map of the regional distribution of the disease. The increased awareness of the disease among general practitioners and medical specialists has contributed to reduce the diagnostic delay and the rate of misdiagnosis. The Registry will allow to collect also future information about clinical and instrumental follow-up.

Introduction: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disease. Thanks to the advances of the latest generation sequencing, more than 80 causative genes have been reported to date., Methods: In this retrospective, observational study, we have analyzed clinical, electrophysiological, and genetic data of CMT patients in care at Neuromuscular Center of Messina University Hospital, Messina, Italy, for at least 22 years (from 1994 to 2016). Our center is the only reference center for genetic neuropathies in Sicily and in the southern part of Calabria., Results: We reviewed the clinical records of 566 patients with the aim to evaluate how many patients received a genetic diagnosis and the distribution of the genetic subtypes. About 352/566 (62.19%) received a genetic diagnosis. The most frequent genetic diagnoses were CMT1A/PMP22 duplication (51.13%), followed by HNPP/PMP22 deletion (15.05%), CMT1B/MPZ mutation (10.22%), CMTX/GJB1 mutation (9.37%), and CMT2F/HSPB1 (4%). Other rare mutations included MFN2 mutation (n. 8 pts), BSCL2 mutation (n.8 pts), PMP22 point mutation (n.7 pts), GDAP1 mutation (n.4 pts), GARSmutation (n. 2 pts), TRPV4 mutation (n. 2 pts), LITAF mutation (n.1 pt), and NEFL mutation (n. 1 pt)., Conclusions: Our study provides further data on frequency of CMT genes, subtypes in a wide Mediterranean area and contributes to help clinicians in addressing the genetic testing workup.

Background and Purpose: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy, but therapeutic options have been limited to symptom management. Past pharmacological trials have failed, possibly due to insensitive outcome measures (OMs). The aim of the current study was to evaluate the validity and reliability of the 6-min walk test (6MWT) and StepWatch(™) Activity Monitoring (SAM) with other previously validated OMs in CMT disease., Methods: A prospective multicenter study was performed, consecutively enrolling 168 CMT patients (104 with CMT1A, 27 with CMT1B, 37 with X-linked CMT) from Italian centers specializing in CMT care., Results: Statistical analysis showed that the 6MWT was highly related with all previously used OMs. Some, but not all, SAM parameters were related to commonly used OMs but may provide more information about quality of life., Conclusions: The current study demonstrated the validity and reliability of the 6MWT and SAM as OMs for CMT. Moreover, SAM provides data that correlate better with quality of life measures, making it useful in future rehabilitation trials., (© 2016 EAN.)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of familial vascular dementia, is caused by mutations of the NOTCH3 gene. Approximately two hundred pathogenic mutations have been reported within five exons (exons 3, 4, 6, 11 and 19) which accounted for 78% of known mutations in worldwide series. We reported twenty-one NOTCH3 pathogenic mutations (including five novel ones) identified in 53 index Italian patients. Exons 4 (28%), 7 (21%) and 19 (24%) were the most frequently involved. To dissect genetic heterogeneity, we analyzed five haplotyped tagging single nucleotide polymorphisms (rs1044009, rs4809030, rs10426042, rs10423702 and rs3815188) in 95 patients, 39 unaffected pedigree members and 50 healthy controls. SNPs were analyzed using the Illumina VeraCode Universal Capture Beads technology by Allele Specific Primer Extension (ASPE). We identified ten different haplotypes named H1-H10; H1 was the most common haplotype in patients and controls and it was associated with at least twelve out of the twenty-one mutations. Detected mutations were not associated to specific haplotypes while genotyping was compatible with a possible founder effect for the novel p.S396C mutation which clustered in a restricted geographical area of northeast Italy. The results added on to the genetic heterogeneity of CADASIL and emphasized difficulties in designing algorithms for molecular diagnosis., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Heterozygous mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene have been associated with different clinical phenotypes including Silver syndrome/spastic paraplegia 17, distal hereditary motor neuropathy type V, and Charcot-Marie-Tooth disease type 2 (CMT2) with predominant hand involvement. We studied an Italian family with a CMT2 phenotype with pyramidal signs that had subclinical sensory involvement on sural nerve biopsy. Direct sequencing analysis of the BSCL2 gene in the three affected siblings revealed an S90L mutation. This report confirms the variability of clinical phenotypes associated with a BSCL2 Ser90Leu mutation and describes the first Italian family with this mutation.

Mutations in small heat-shock protein 27 and small heat-shock protein 22 genes were found in association with Charcot-Marie-Tooth disease type 2 and distal hereditary motor neuropathy. We searched for mutations in small heat-shock protein 27 gene in an Italian family with peripheral neuropathy and intrafamilial phenotypic variability. A novel heterozygous frame-shift mutation c.476&#95;477delCT was found while point mutations in most genes associated with hereditary neuropathies were ruled out. In the proband, who showed a severe early onset peripheral neuropathy, an independent pathogenetic effect on the peripheral nervous system secondary to the tetanus toxoid injection may be supposed. This is the first truncating nonsense mutation in the small heat-shock protein 27 gene identified so far and the clinical, neurophysiologic, and neuropathological findings are discussed.

There is no treatment for Charcot-Marie-Tooth disease 1A (CMT1A), but ascorbic acid (AA) is efficacious in the transgenic mouse model. Thus, a clinical trial of AA in CMT1A is warranted. The CMT-TRIAAL is a phase III randomized, double-blind, placebo-controlled study involving 222 CMT1A adults from eight Italian centers. Eligible for the study are symptomatic adults with genetically confirmed CMT1A. Treatment consists of 2-year oral AA (1500mg/day) or placebo. The primary trial endpoint is an improvement in CMT Neuropathy Score. Secondary efficacy endpoints are changes in distal arm and leg maximum voluntary isometric contraction; 10m timed walking; 9-hole-peg test; overall neuropathy limitations scale; pain and fatigue visual analog scales; health-related quality of life (SF-36); and electrophysiology. Clinical-electrophysiological assessments are performed at baseline and every 6 months thereafter. In consenting patients from three centers, skin biopsy is performed to evaluate PMP22 expression. The study will last 34 months, starting from March 2006.

The gene products involved in mammalian mitochondrial DNA (mtDNA) maintenance and organization remain largely unknown. We report here a novel mitochondrial protein, Twinkle, with structural similarity to phage T7 gene 4 primase/helicase and other hexameric ring helicases. Twinkle colocalizes with mtDNA in mitochondrial nucleoids. Screening of the gene encoding Twinkle in individuals with autosomal dominant progressive external ophthalmoplegia (adPEO), associated with multiple mtDNA deletions, identified 11 different coding-region mutations co-segregating with the disorder in 12 adPEO pedigrees of various ethnic origins. The mutations cluster in a region of the protein proposed to be involved in subunit interactions. The function of Twinkle is inferred to be critical for lifetime maintenance of human mtDNA integrity.

Charcot-Marie-Tooth neuropathy type 1 (CMT1), the most common hereditary neurological disorder in humans, is characterized by clinical and genetic heterogeneity. It is caused mainly by a 1.5 Mb duplication in 17p11.2, but also by mutations in the myelin genes PMP22 (peripheral myelin protein 22), MPZ (myelin protein zero), Cx32 (connexin 32; also called GJB1), and EGR2 (early growth response 2). In this study, we have screened 172 index cases of Italian families in which there was at least one subject with a CMT1 diagnosis for the duplication on 17p11.2 and mutations in these genes. Among 170 informative unrelated patients, the overall duplication frequency was 57.6%. A difference could be observed between the duplication frequency in familial cases (71.6%) and that observed in non-familial cases (36.8%). Among the non-duplicated patients, 12 were mutated in Cx32, four in MPZ, two in PMP22, and none in the EGR2. In the non-duplicated cases, the overall point mutation frequency for these genes was 25.0%. We describe the mutations identified, and consider possible genotype-phenotype correlation., (Copyright 2001 Wiley-Liss, Inc.)

We report on two Italian families with an early-adult onset autosomal dominant disorder, characterized by leukoencephalopathy, migraine, psychiatric disturbances, stroke and dementia. These findings fulfill the diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome. Moreover, to confirm the CADASIL gene location to 19p12, we performed a linkage analysis with four microsatellite markers. The results of the genetic study gave positive but not significant lod scores, indicating only weak evidence of a linkage with 19p12. In one autopsy case, we found extensive ischemic changes due to the selective involvement of the small muscular arteries of the cerebral white matter. The lesions consisted of a thickening of the media with deposition of granular eosinophilic material. Ultrastructural examination of the arterial walls showed graded damage to smooth muscle cells, mostly of the longitudinal layer, and an abnormal proliferation of basal lamina components. Immunocytochemical analysis showed strong reactivity using antibodies to collagen IV and smooth myosin proteins. The results suggest a primary involvement of the smooth muscle cells of small cerebral arteries, with a secondary alteration of basal lamina components and elastic tissue.