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1.
Artigo em Inglês | MEDLINE | ID: mdl-38839277

RESUMO

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.

2.
Eur J Neurol ; 30(12): 3834-3841, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37531261

RESUMO

BACKGROUND AND PURPOSE: Biallelic mutation/expansion of the gene RFC1 has been described in association with a spectrum of manifestations ranging from isolated sensory neuro(no)pathy to a complex presentation as cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Our aim was to define the frequency and characteristics of small fiber neuropathy (SFN) in RFC1 disease at different stages. METHODS: RFC1 cases were screened for SFN using the Neuropathic Pain Symptom Inventory and Composite Autonomic Symptom Score 31 questionnaires. Clinical data were retrospectively collected. If available, lower limb skin biopsy samples were evaluated for somatic epidermal and autonomic subepidermal structure innervation and compared to healthy controls (HCs). RESULTS: Forty patients, median age at onset 54 years (interquartile range [IQR] 49-61) and disease duration 10 years (IQR 6-16), were enrolled. Mild-to-moderate positive symptoms (median Neuropathic Pain Symptom Inventory score 12.1/50, IQR 5.5-22.3) and relevant autonomic disturbances (median Composite Autonomic Symptom Score 31 37.0/100, IQR 17.7-44.3) were frequently reported and showed scarce correlation with disease duration. A non-length-dependent impairment in nociception was evident in both clinical and paraclinical investigations. An extreme somatic denervation was observed in all patients at both proximal (fibers/mm, RFC1 cases 0.0 vs. HCs 20.5, p < 0.0001) and distal sites (fibers/mm, RFC1 cases 0.0 vs. HCs 13.1, p < 0.0001); instead only a slight decrease was observed in cholinergic and adrenergic innervation of autonomic structures. CONCLUSIONS: RFC1 disease is characterized by a severe and widespread somatic SFN. Skin denervation may potentially represent the earliest feature and drive towards the suspicion of this disorder.


Assuntos
Vestibulopatia Bilateral , Ataxia Cerebelar , Neuralgia , Neuropatia de Pequenas Fibras , Humanos , Pessoa de Meia-Idade , Ataxia Cerebelar/genética , Vestibulopatia Bilateral/complicações , Estudos Retrospectivos , Fibras Nervosas
3.
Eur J Neurol ; 30(8): 2461-2470, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37170966

RESUMO

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.


Assuntos
Doença de Charcot-Marie-Tooth , Feminino , Humanos , Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/diagnóstico , Mutação , Progressão da Doença , Itália/epidemiologia
5.
Brain Sci ; 11(12)2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34942918

RESUMO

(1) Background: Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited chronic motor and sensory polyneuropathy. Over 100 CMT causative genes have been identified. Previous reports found PMP22, GJB1, MPZ, and MFN2 as the most frequently involved genes. Other genes, such as BSCL2, MORC2, HINT1, LITAF, GARS, and autosomal dominant GDAP1 are responsible for only a minority of CMT cases. (2) Methods: we present here our records of CMT patients harboring a mutation in one of these rare genes (BSCL2, MORC2, HINT1, LITAF, GARS, autosomal dominant GDAP1). We studied 17 patients from 8 unrelated families. All subjects underwent neurologic evaluation and genetic testing by next-generation sequencing on an Ion Torrent PGM (Thermo Fischer) with a 44-gene custom panel. (3) Results: the following variants were found: BSCL2 c.263A > G p.Asn88Ser (eight subjects), MORC2 c.1503A > T p.Gln501His (one subject), HINT1 c.110G > C p.Arg37Pro (one subject), LITAF c.404C > G p.Pro135Arg (two subjects), GARS c.1660G > A p.Asp554Asn (three subjects), GDAP1 c.374G > A p.Arg125Gln (two subjects). (4) Expanding the spectrum of CMT phenotypes is of high relevance, especially for less common variants that have a higher risk of remaining undiagnosed. The necessity of reaching a genetic definition for most patients is great, potentially making them eligible for future experimentations.

6.
J Neurol ; 268(11): 4280-4290, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33884451

RESUMO

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 < 0.001) or sensorimotor (3/138, 2%, P < 0.001) neuropathy. The mutation was associated with sensory ataxia (τb = 0.254, P < 0.001), autonomic disturbances (35% vs 8%, Prevalence Odds Ratio-POR 6.73 CI 95% 2.79-16.2, P < 0.001), retained deep tendon reflexes (score 18.0/24 vs 11.5/24, R = 0.275, P < 0.001). On pathology, we observed absent/scant regenerative changes (τb = - 0.362, P < 0.001), concomitant involvement of large (100% and 99%, n.s.), small myelinated (97% vs 81%, POR 7.74 CI 95% 1.03-58.4, P = 0.02) and unmyelinated nerve fibers (85% vs 41%, POR 8.52 CI 95% 3.17-22.9, P < 0.001). Cerebellar or vestibular involvement was similarly rare in the two groups. 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.


Assuntos
Vestibulopatia Bilateral , Ataxia Cerebelar , Polineuropatias , Adulto , Ataxia , Humanos , Polineuropatias/diagnóstico , Polineuropatias/genética , Proteína de Replicação C
7.
J Peripher Nerv Syst ; 25(1): 19-26, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31919945

RESUMO

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.


Assuntos
Erros de Diagnóstico , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Adulto , Idoso , Feminino , Neuropatia Hereditária Motora e Sensorial/líquido cefalorraquidiano , Neuropatia Hereditária Motora e Sensorial/tratamento farmacológico , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Fatores Imunológicos/farmacologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/líquido cefalorraquidiano , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Guias de Prática Clínica como Assunto , Ultrassonografia
8.
Neurol Sci ; 41(5): 1239-1243, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31902012

RESUMO

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.


Assuntos
Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Feminino , Testes Genéticos , Humanos , Itália/epidemiologia , Masculino , Mutação , Estudos Retrospectivos , Centros de Atenção Terciária
10.
Muscle Nerve ; 60(6): 744-748, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31469427

RESUMO

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 (ß: -0.19) and fibular compound muscle action potential amplitude (-1.50) significantly influenced CMTNS2 and that median forearm CSA significantly influenced CMTNS2 (ß: 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.


Assuntos
Doença de Charcot-Marie-Tooth/fisiopatologia , Nervo Mediano/fisiopatologia , Condução Nervosa/fisiologia , Nervo Fibular/fisiopatologia , Nervo Ulnar/fisiopatologia , Adulto , Doença de Charcot-Marie-Tooth/diagnóstico por imagem , Doença de Charcot-Marie-Tooth/patologia , Feminino , Humanos , Masculino , Nervo Mediano/diagnóstico por imagem , Nervo Mediano/patologia , Pessoa de Meia-Idade , Tamanho do Órgão , Nervo Fibular/diagnóstico por imagem , Nervo Fibular/patologia , Índice de Gravidade de Doença , Nervo Ulnar/diagnóstico por imagem , Nervo Ulnar/patologia , Ultrassonografia
11.
J Neurol Neurosurg Psychiatry ; 90(10): 1171-1179, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31167812

RESUMO

BACKGROUND: Inherited peripheral neuropathies (IPNs) represent a broad group of genetically and clinically heterogeneous disorders, including axonal Charcot-Marie-Tooth type 2 (CMT2) and hereditary motor neuropathy (HMN). Approximately 60%-70% of cases with HMN/CMT2 still remain without a genetic diagnosis. Interestingly, mutations in HMN/CMT2 genes may also be responsible for motor neuron disorders or other neuromuscular diseases, suggesting a broad phenotypic spectrum of clinically and genetically related conditions. Thus, it is of paramount importance to identify novel causative variants in HMN/CMT2 patients to better predict clinical outcome and progression. METHODS: We designed a collaborative study for the identification of variants responsible for HMN/CMT2. We collected 15 HMN/CMT2 families with evidence for autosomal recessive inheritance, who had tested negative for mutations in 94 known IPN genes, who underwent whole-exome sequencing (WES) analyses. Candidate genes identified by WES were sequenced in an additional cohort of 167 familial or sporadic HMN/CMT2 patients using next-generation sequencing (NGS) panel analysis. RESULTS: Bioinformatic analyses led to the identification of novel or very rare variants in genes, which have not been previously associated with HMN/CMT2 (ARHGEF28, KBTBD13, AGRN and GNE); in genes previously associated with HMN/CMT2 but in combination with different clinical phenotypes (VRK1 and PNKP), and in the SIGMAR1 gene, which has been linked to HMN/CMT2 in only a few cases. These findings were further validated by Sanger sequencing, segregation analyses and functional studies. CONCLUSIONS: These results demonstrate the broad spectrum of clinical phenotypes that can be associated with a specific disease gene, as well as the complexity of the pathogenesis of neuromuscular disorders.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Atrofia Muscular Espinal/genética , Adulto , Idoso , Agrina/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Biologia Computacional , Enzimas Reparadoras do DNA/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos/genética , Proteínas Musculares/genética , Atrofia Muscular Espinal/fisiopatologia , Linhagem , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Proteínas Serina-Treonina Quinases/genética , Receptores sigma/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Sequenciamento do Exoma , Receptor Sigma-1
12.
Clin Neurophysiol ; 129(11): 2259-2267, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30216910

RESUMO

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.


Assuntos
Plexo Braquial/diagnóstico por imagem , Doença de Charcot-Marie-Tooth/diagnóstico por imagem , Ultrassonografia/métodos , Adolescente , Adulto , Idoso , Plexo Braquial/fisiopatologia , Doença de Charcot-Marie-Tooth/classificação , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Sensibilidade e Especificidade , Ultrassonografia/normas
13.
Clin Neurophysiol ; 129(1): 21-32, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29136549

RESUMO

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.


Assuntos
Doença de Charcot-Marie-Tooth/fisiopatologia , Proteína P0 da Mielina/deficiência , Adulto , Idoso , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios Motores/fisiologia , Proteína P0 da Mielina/genética , Proteína P0 da Mielina/metabolismo , Nervo Sural/diagnóstico por imagem , Nervo Sural/metabolismo , Nervo Sural/fisiopatologia , Ultrassonografia
14.
Seizure ; 42: 1-6, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27632409

RESUMO

PURPOSE: A small case series with a neurodegenerative disorder involving central nervous system and related to Seipin mutations was recently reported. Herein we describe clinical and EEG features of three patients presenting with Progressive Myoclonus Epilepsy (PME) and Congenital Generalized Lipodystrophy type 2 (CGL2) related to novel Seipin mutations. METHODS: The EEG-clinical picture was evaluated at epilepsy onset and in the follow-up period. The molecular analysis of BSCL2, Laforin and Malin genes was performed to patients and/or their parents by Denaturing High Performance Liquid Chromatography and automated nucleotide sequencing. Skin specimens collected from a patient were processed for histochemical and ultrastructural analysis. RESULTS: The CGL2-PME syndrome co-segregated with two different BSCL2 genotypes: the homozygosity for c.782_783dupG involving exon 8 (two cases), or the compound heterozygosity for c.782_783dupG/c.828_829delAA (one case). Periodic-Acid Schiff positive osmiophilic material in the cytoplasm of fibrocytes and eccrine-gland cells were found in skin specimens. The lack of Lafora's bodies in skin specimens and the molecular analysis excluding mutations in Laforin and Malin genes ruled out Lafora disease. CONCLUSION: The spectrum of CGL2 associated to BSCL2 gene mutations may include PMEs. Selected mutations in BSCL2 gene seem to be related to PMEs in patients with CGL2 phenotype.


Assuntos
Encéfalo/fisiopatologia , Subunidades gama da Proteína de Ligação ao GTP/genética , Lipodistrofia Generalizada Congênita/genética , Lipodistrofia Generalizada Congênita/fisiopatologia , Epilepsias Mioclônicas Progressivas/genética , Epilepsias Mioclônicas Progressivas/fisiopatologia , Encéfalo/diagnóstico por imagem , Proteínas de Transporte/genética , Criança , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Lipodistrofia Generalizada Congênita/diagnóstico , Lipodistrofia Generalizada Congênita/patologia , Masculino , Epilepsias Mioclônicas Progressivas/diagnóstico , Epilepsias Mioclônicas Progressivas/patologia , Proteínas Tirosina Fosfatases não Receptoras/genética , Pele/metabolismo , Pele/patologia , Ubiquitina-Proteína Ligases
16.
Clin Neurol Neurosurg ; 144: 67-71, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26989944

RESUMO

OBJECTIVES: CMT is a group of heterogeneous motor and sensory neuropathies divided into demyelinating (CMT1) and axonal forms (CMT2). Distal Hereditary Motor Neuropathy (dHMN) is a motor neuropathy/neuronopathy which resembles CMT. Final genetic diagnosis is poor in CMT2 and in dHMN when compared with CMT1. Our aim is to report clinical, neurophysiological and genetic findings in a cohort of patients with axonal inherited neuropathies. PATIENTS AND METHODS: We report clinical, neurophysiological and genetic findings from 45 patients with CMT2 or dHMN, coming from 39 unrelated families, observed in our Institute of Neurology over a 20-year period. RESULTS: Clinical and electrophysiological examinations showed that 38 patients had CMT2 and 7 patients presented dHMN. Extensive genetic evaluation showed 6 mutations in MFN2, 4 mutations in HSPB1, 2 mutations in BSCL2, 3 mutations in GJB1, 1 mutation in MPZ. CONCLUSION: Since next-generation sequencing will not be easily accessible, epidemiological data and clinical "phenotyping" remain the best strategy for clinicians to reach a correct genetic diagnosis in CMT2 and dHMN patients.


Assuntos
Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Neuropatia Hereditária Motora e Sensorial/epidemiologia , Neuropatia Hereditária Motora e Sensorial/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Charcot-Marie-Tooth/diagnóstico , Criança , Estudos de Coortes , Feminino , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
17.
Neurol Sci ; 36(6): 1003-6, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25547330

RESUMO

Mutations in the small heat-shock protein HSP27 gene are associated with distal hereditary motor neuropathy and with the axonal form of Charcot-Marie-Tooth disease type 2. We present the clinical and electrophysiological data on a multigenerational family with the p.Arg136Leu HSP27 mutation. Atypical features such as deafness and pyramidal signs were present in our cases adding new data to the large spectrum of HSP27-related phenotype.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Proteínas de Choque Térmico HSP27/genética , Adulto , Idoso , Feminino , Proteínas de Choque Térmico , Humanos , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares , Mutação , Linhagem , Fenótipo
18.
J Alzheimers Dis ; 41(3): 709-14, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24718101

RESUMO

PSEN1 gene mutations represent the first cause of familiar early-onset Alzheimer's disease (EOAD). More than 190 mutations in PSEN1 have been reported to date. The clinical phenotype is mainly characterized by cognitive decline but movement disorders have been rarely described. We report a novel PSEN1 mutation (p.Thr147Pro) responsible for a sporadic early-onset dementia with prominent cerebellar symptoms, resembling a spinocerebellar syndrome. Neuroradiological and cerebrospinal fluid biomarkers examinations were performed on the patient, showing typical findings of EOAD and suggesting the pathogenicity of the novel mutation. Our study widens the number of unusual phenotypes related to PSEN1 mutations.


Assuntos
Doença de Alzheimer/genética , Ataxia Cerebelar/genética , Mutação/genética , Presenilina-1/genética , Adulto , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Ataxia Cerebelar/complicações , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Análise Mutacional de DNA , Donepezila , Feminino , Fluordesoxiglucose F18 , Humanos , Indanos/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Piperidinas/uso terapêutico , Tomografia por Emissão de Pósitrons , Adulto Jovem
19.
J Peripher Nerv Syst ; 17(4): 414-7, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23279344

RESUMO

Genetic germinal and somatic mosaicisms of dominant Charcot-Marie-Tooth disease (CMT) mutations are rarely reported and/or recognized. We describe a novel heterozygous p.Trp39Cys missense mutation in the extracellular domain of the peripheral myelin protein 22 (PMP22) associated with an early-onset demyelinating CMT type 1 E (CMT1E) in two siblings born from asymptomatic non-consanguineous parents. The 29-year-old mother, harboring approximately 20% of the mutant PMP22 allele in blood, had minor signs of distal polyneuropathy (pes cavus, decreased ankle jerk reflexes and vibration sense in legs) and slight reduction of sural nerve action potentials (SNAPs). Authors suggest that mutations of CMT-related genes which originate in post-zygotic stages may be associated with mild phenotypes of peripheral neuropathy.


Assuntos
Mosaicismo , Proteínas da Mielina/genética , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologia , Substituição de Aminoácidos , Doença de Charcot-Marie-Tooth/genética , Criança , Análise Mutacional de DNA , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Eletrodiagnóstico , Éxons/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Mutação de Sentido Incorreto/fisiologia , Exame Neurológico , Linhagem , Fenótipo
20.
J Peripher Nerv Syst ; 16(2): 119-29, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21692911

RESUMO

Autosomal-dominant transthyretin (TTR)-related amyloidosis usually manifests in the second to fourth decade with a length-dependent axonal neuropathy with prominent involvement of the small fibers and multi-organ systemic failure. We retrospectively analyzed seventeen probands, including thirteen apparently isolated cases, carrying eight mutations of TTR gene (age of onset = 60.4 ± 13.5 years). Thirteen patients were initially un/misdiagnosed; interval from onset to definite diagnosis was 3.3 ± 2.3 years. Inaugural syndromes were a length-dependent motor-sensory neuropathy in seven cases, a sensory neuropathy in four, an isolated carpal tunnel syndrome in three, a pure dysautonomia in two, and a painful neuropathy in one. Atypical presentations included demyelinating nerve conduction changes with increased cerebrospinal fluid proteins resembling chronic inflammatory demyelinating polyradiculoneuropathy and a predominantly motor involvement resembling a motor neuron disorder. Misleading findings also included amyloid-negative abdominal fat aspirate/biopsy, biclonal gammopathy, and hepatitis C virus (HCV) seropositivity. Sural nerve biopsy detected amyloid deposits in thirteen of fifteen patients, including one case with a previous negative biopsy. TTR-immunohistochemistry was necessary to complete the diagnosis of primary amyloidosis light chain in a patient with biclonal gammopathy. A recurrent p.Phe64Leu mutation manifested in the seventh decade with painful motor-sensory polyneuropathy, dysautonomia, bulbar palsies, and fasciculations. TTR should be tested in a wide clinical spectrum of cryptogenetic, progressive, and motor-sensory neuropathies even manifesting with a very late onset.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Pré-Albumina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/fisiopatologia , Biópsia , Análise Mutacional de DNA , Diagnóstico Diferencial , Eletrofisiologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/diagnóstico , Mutação , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Estudos Retrospectivos
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