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1.
Eur J Neurol ; 29(7): 2056-2065, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35286755

RESUMO

BACKGROUND AND PURPOSE: Mutations in DNAJB2 are associated with autosomal recessive hereditary motor neuropathies/ Charcot-Marie-Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms. METHODS: Patients with DNAJB2 mutations were characterized clinically, electrophysiologically and by means of skin biopsy. mRNA and protein levels were studied in lymphoblastoid cells (LCLs) from patients and controls. RESULTS: Three affected siblings were found to carry a homozygous DNAJB2 null mutation segregating with the disease. The disease manifested in the second to third decade of life. Clinical examination showed severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles. Sensation was reduced in the lower limbs. All patients had severe hearing loss and the proband also had Parkinson's disease (PD). Nerve conduction studies showed an axonal motor and sensory length-dependent polyneuropathy. DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy. Interestingly, we detected phospho-alpha-synuclein deposits in the proband, as already seen in PD patients, and demonstrated TDP-43 accumulation in patients' skin. CONCLUSIONS: Our results broaden the clinical spectrum of DNAJB2-related neuropathies and provide evidence that DNAJB2 mutations should be taken into account as another causative gene of CMT2 with hearing loss and parkinsonism. The mutation likely acts through a loss-of-function mechanism, leading to toxic protein aggregation such as TDP-43. The associated parkinsonism resembles the classic PD form with the addition of abnormal accumulation of phospho-alpha-synuclein.


Assuntos
Doença de Charcot-Marie-Tooth , Proteínas de Choque Térmico HSP40 , Chaperonas Moleculares , Doença de Charcot-Marie-Tooth/genética , Proteínas de Ligação a DNA/genética , Proteínas de Choque Térmico HSP40/genética , Homozigoto , Humanos , Chaperonas Moleculares/genética , Mutação/genética , Fenótipo , RNA Mensageiro , alfa-Sinucleína
2.
Eur J Neurol ; 28(3): 934-944, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33190326

RESUMO

BACKGROUND AND PURPOSE: Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood. METHODS: We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near-normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy-targeted next generation sequencing panel. RESULTS: We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early-onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early-onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early-onset diseases with central hypomyelination/dysmyelination. CONCLUSIONS: A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease-causing genes, including genes associated with severe early-onset HLDs, and genes causing peroxisome biogenesis disorders.


Assuntos
Doenças Desmielinizantes , Leucoencefalopatias , Adulto , Feminino , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imageamento por Ressonância Magnética , Proteínas Associadas aos Microtúbulos , Mutação
3.
J Peripher Nerv Syst ; 25(4): 429-432, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32815244

RESUMO

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of distal symmetric polyneuropathies due to progressive and length-dependent degeneration of peripheral nerves. Cranial nerve involvement has been described in association with various CMT-genes mutations, such as GDAP1, TRPV4, MFN2, MTMR2 and EGR2. Compound heterozygous mutations in the TRIM2 gene, encoding an E3 ubiquitin ligase, were previously identified in two patients with early-onset axonal CMT (CMT2). One of them also had bilateral vocal cord paralysis. The aim of this study is to further delineate the phenotypic and molecular genetic features of TRIM2-related CMT. We studied clinical, genetic and neurophysiological aspects of two unrelated CMT2 patients. Genetic analysis was performed by next generation sequencing of a multigene CMT panel. Patients presented with congenital hypotonia and bilateral clubfoot, delayed motor milestones, and severely progressive axonal neuropathy. Interestingly, along with vocal cord paralysis, they exhibited clinical features secondary to the involvement of several other cranial nerves, such as facial weakness, dysphagia, dyspnoea and acoustic impairment. Genetic analysis revealed two novel TRIM2 mutations in each patient. Our results expand the genotypic and phenotypic spectrum of TRIM2 deficiency showing that cranial nerves involvement is a core feature in this CMT2-subtype. Its finding should prompt physicians to suspect TRIM2 neuropathy. Conversely, patients carrying TRIM2 variants should be carefully evaluated for the presence of cranial nerve dysfunction in order to prevent and manage its impact on auditory and respiratory function and nutrition.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Doença de Charcot-Marie-Tooth/patologia , Feminino , Humanos , Masculino , Fenótipo
4.
Neuropediatrics ; 51(3): 173-177, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31784971

RESUMO

Heterozygous deletions of the gene PMP22 are associated to hereditary neuropathy with liability to pressure palsies (HNPP), a demyelinating neuromuscular disease causing variable transitory focal muscles weakness. Deletions involving both copies of PMP22 cause more severe phenotypes, with early-onset neuropathy and impairment in motor development. We report a patient with a severe early-onset demyelinating neuropathy, caused by two different inherited deletions of PMP22, whose parents had an HNPP. The patient showed neurological signs and delay in motor development but normal intellective abilities. A motor and sensitive conduction study showed severe signs of demyelination, suggestive for Dejerine Sottas Syndrome (DSS). The patient's father had a typical HNPP caused by a heterozygous 17p11.2 deletion, encompassing PMP22. The patient's mother reported no neuropathic symptoms, but in a nerve conduction studies, parents and several relatives showed signs of sensory-motor deficit with focal slowing of conduction at common sites of entrapment. Quantitative analysis of PMP22, performed in our patient by multiplex ligation-dependent probe amplification, revealed a compound heterozygous status with the same deletion of the father and a deletion of PMP22 exon 5, after proved to be inherited from the mother. Therefore, when we face an early-onset, severe form of neuropathy, we have to consider rare forms of hereditary neuropathy caused by homozygous or compound heterozygous mutations in PMP22, even if parents are asymptomatic; an exhaustive family history and an electrodiagnostic study are essential to guide genetic tests and to make a diagnosis.


Assuntos
Artrogripose , Neuropatia Hereditária Motora e Sensorial , Proteínas da Mielina/genética , Artrogripose/diagnóstico , Artrogripose/genética , Artrogripose/fisiopatologia , Pré-Escolar , Feminino , Deleção de Genes , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Neuropatia Hereditária Motora e Sensorial/genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Condução Nervosa/fisiologia , Linhagem
5.
J Peripher Nerv Syst ; 22(1): 47-50, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27982524

RESUMO

Charcot-Marie-Tooth disease type 4D (CMT4D), also known as hereditary motor and sensory neuropathy Lom type (HMSNL), is an autosomal recessive, early onset, severe demyelinating neuropathy with hearing loss, caused by N-Myc downstream-regulated gene 1 (NDRG1) mutations. CMT4D is rare with only three known mutations, one of which (p.Arg148Ter) is found in patients of Romani ancestry and accounts for the vast majority of cases. We report a 38-year-old Italian female with motor development delay, progressive neuropathy, and sensorineural deafness. Magnetic resonance imaging showed slight atrophy of cerebellum, medulla oblongata, and upper cervical spinal cord. She had a novel homozygous NDRG1 frameshift mutation (c.739delC; p.His247ThrfsTer74). The identification of this NDRG1 mutation confirms that CMT4D is not a private Romani disease and should be considered in the differential diagnosis of recessive demyelinating CMT.


Assuntos
Proteínas de Ciclo Celular/genética , Doença de Charcot-Marie-Tooth/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Doença de Refsum/genética , Adulto , Cerebelo/diagnóstico por imagem , Doença de Charcot-Marie-Tooth/diagnóstico por imagem , Análise Mutacional de DNA , Feminino , Humanos , Imageamento por Ressonância Magnética , Bulbo/diagnóstico por imagem , Doença de Refsum/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem
6.
J Peripher Nerv Syst ; 22(1): 59-63, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27982499

RESUMO

We report the first Italian family affected by hereditary gelsolin amyloidosis (HGA), a rare autosomal dominant disease characterized by adult-onset slowly progressive cranial neuropathy, lattice corneal dystrophy, and cutis laxa. The index case was a 39-year-old male with a 9-year history of progressive bilateral facial nerve palsy. His mother had two episodes of acute facial palsy, and his maternal aunt and grandfather were also affected. Electrophysiological studies confirmed bilateral facial nerve involvement, without signs of peripheral polyneuropathy, and ophthalmological examination showed bilateral lattice corneal dystrophy, in both the index case and his mother. Gelsolin-gene sequencing revealed the heterozygous c.640G>A mutation (p.Asp187Asn) in the proband, his mother and aunt and also in three apparently asymptomatic relatives. The majority of HGA patients come from Finland, although several cases have been reported from other countries. HGA should be considered in the differential diagnosis of progressive or recurrent bilateral facial neuropathy.


Assuntos
Amiloidose Familiar/complicações , Amiloidose Familiar/genética , Paralisia Facial/etiologia , Gelsolina/genética , Mutação/genética , Adulto , Progressão da Doença , Saúde da Família , Humanos , Masculino
7.
J Peripher Nerv Syst ; 21(3): 142-9, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27231023

RESUMO

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive (AR) demyelinating neuropathy associated to SH3TC2 mutations, characterized by early onset, spine deformities, and cranial nerve involvement. We screened 43 CMT4 patients (36 index cases) with AR inheritance, demyelinating nerve conductions, and negative testing for PMP22 duplication, GJB1 and MPZ mutations, for SH3TC2 mutations. Twelve patients (11 index cases) had CMT4C as they carried homozygous or compound heterozygous mutations in SH3TC2. We found six mutations: three nonsense (p.R1109*, p.R954*, p.Q892*), one splice site (c.805+2T>C), one synonymous variant (p.K93K) predicting altered splicing, and one frameshift (p.F491Lfs*32) mutation. The splice site and the frameshift mutations are novel. Mean onset age was 7 years (range: 1-14). Neuropathy was moderate-to-severe. Scoliosis was present in 11 patients (severe in 4), and cranial nerve deficits in 9 (hearing loss in 7). Scoliosis and cranial nerve involvement are frequent features of this CMT4 subtype, and their presence should prompt the clinician to look for SH3TC2 gene mutations. In our series of undiagnosed CMT4 patients, SH3TC2 mutation frequency is 30%, confirming that CMT4C may be the most common AR-CMT type.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Doenças Desmielinizantes/genética , Mutação/genética , Proteínas/genética , Adolescente , Adulto , Idoso , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/patologia , Doenças Desmielinizantes/complicações , Doenças Desmielinizantes/patologia , Fenômenos Eletrofisiológicos/fisiologia , Feminino , Testes Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
8.
J Peripher Nerv Syst ; 20(4): 380-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26306937

RESUMO

Mitofusin-2 (MFN2) mutations are the most common cause of autosomal dominant axonal Charcot-Marie-Tooth disease (CMT, type 2A), sometimes complicated by additional features such as optic atrophy (CMT6) and upper motor neuron involvement (CMT5). Several pathogenic mutations are reported, mainly acting in a dominant fashion, although few sequence variants behaved as recessive or semidominant in rare homozygous or compound heterozygous patients. We describe a 49-year-old woman with CMT5 associated with compound heterozygosity for two MFN2 variants, one already reported missense mutation (c.748C>T, p.R250W) and a novel nonsense sequence change (c.1426C>T, p.R476*). Her mother, carrying the p.R250W variant, had very late-onset minimal axonal neuropathy, whilst the father harboring the nonsense sequence change had neither clinical nor electrophysiological neuropathy. The missense mutation is likely pathogenic according to in silico analyses and a previous report, while the nonsense variant is predicted to behave as a null allele. The p.R250W variant behaves as semidominant by causing only a mild, almost subclinical, neuropathy when heterozygous; the nonsense mutation in the father was phenotypically silent, suggesting that haploinsufficiency for MFN2 is not disease causative, but was deleterious in the daughter who had only one active mutated MFN2 allele.


Assuntos
Doença de Charcot-Marie-Tooth/genética , GTP Fosfo-Hidrolases/genética , Proteínas Mitocondriais/genética , Mutação , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
9.
Brain ; 137(Pt 7): 1907-20, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24833714

RESUMO

Hereditary spastic paraplegias are a heterogeneous group of neurodegenerative disorders, clinically classified in pure and complex forms. Genetically, more than 70 different forms of spastic paraplegias have been characterized. A subgroup of complicate recessive forms has been distinguished for the presence of thin corpus callosum and white matter lesions at brain imaging. This group includes several genetic entities, but most of the cases are caused by mutations in the KIAA1840 (SPG11) and ZFYVE26 genes (SPG15). We studied a cohort of 61 consecutive patients with complicated spastic paraplegias, presenting at least one of the following features: mental retardation, thin corpus callosum and/or white matter lesions. DNA samples were screened for mutations in the SPG11/KIAA1840, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG48/AP5Z1 and SPG54/DDHD2 genes by direct sequencing. Sequence variants were found in 30 of 61 cases: 16 patients carried SPG11/KIAA1840 gene variants (26.2%), nine patients carried SPG15/ZFYVE26 variants (14.8%), three patients SPG35/FA2H (5%), and two patients carried SPG48/AP5Z1 gene variants (3%). Mean age at onset was similar in patients with SPG11 and with SPG15 (range 11-36), and the phenotype was mostly indistinguishable. Extrapyramidal signs were observed only in patients with SPG15, and epilepsy in three subjects with SPG11. Motor axonal neuropathy was found in 60% of cases with SPG11 and 70% of cases with SPG15. Subjects with SPG35 had intellectual impairment, spastic paraplegia, thin corpus callosum, white matter hyperintensities, and cerebellar atrophy. Two families had a late-onset presentation, and none had signs of brain iron accumulation. The patients with SPG48 were a 5-year-old child, homozygous for a missense SPG48/AP5Z1 variant, and a 51-year-old female, carrying two different nonsense variants. Both patients had intellectual deficits, thin corpus callosum and white matter lesions. None of the cases in our cohort carried mutations in the SPG21/ACP33 and SPG54/DDH2H genes. Our study confirms that the phenotype of patients with SPG11 and with SPG15 is homogeneous, whereas cases with SPG35 and with SPG48 cases present overlapping features, and a broader clinical spectrum. The large group of non-diagnosed subjects (51%) suggests further genetic heterogeneity. The observation of common clinical features in association with defects in different causative genes, suggest a general vulnerability of the corticospinal tract axons to a wide spectrum of cellular alterations.


Assuntos
Variação Genética/genética , Fenótipo , Proteínas/genética , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/fisiopatologia , Adolescente , Adulto , Encéfalo/patologia , Proteínas de Transporte/genética , Criança , Pré-Escolar , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista/genética , Proteínas/classificação , Índice de Gravidade de Doença , Adulto Jovem
10.
J Peripher Nerv Syst ; 19(2): 183-6, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24863494

RESUMO

X-linked Charcot-Marie-Tooth type 1 (CMTX1) is the second most common type of CMT and is caused by mutations in the Gap-Junction Beta-1 gene (GJB1), encoding connexin 32 which is expressed in Schwann cells as well as in oligodendrocytes. More than 400 GJB1 mutations have been described to date. Many mutation-carrier males have subclinical central nervous system (CNS) involvement, a few show mild CNS clinical signs, whereas only rarely overt though transient CNS dysfunction occurs. We report a 29-year-old man with CMTX1 who, at 16 years, showed short-lived CNS symptoms with transitory white matter abnormalities on cerebral magnetic resonance imaging (MRI) as first clinical presentation of a novel GJB1 mutation (p.Gln99_His100insGln). He had three consecutive episodes of right hemiparesis, together with sensory loss in the paretic limbs and expressive aphasia, all lasting a few hours, over a 2-day period, with concurrent white matter hyperintensity on MRI. These "stroke-like" episodes occurred just after arriving at sea level, after travelling from home at 700 m of altitude. Only a few years later did symptoms of peripheral neuropathy appear. In conclusion, CMTX1 should be included in the differential diagnosis of diseases characterized by transient CNS symptoms and white matter abnormalities on MRI.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Conexinas/genética , Mutação/genética , Acidente Vascular Cerebral/fisiopatologia , Adulto , Encéfalo/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Proteína beta-1 de Junções Comunicantes
11.
J Peripher Nerv Syst ; 18(2): 185-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23781967

RESUMO

At age 35, a man with a genetic diagnosis of Charcot-Marie-Tooth disease type 1A (CMT1A) but no family history of neuropathy and no clinical symptoms developed rapidly progressive loss of balance, distal limb numbness, loss of manual dexterity, and hand tremor. Five years later, he walked with support and had mild pes cavus, marked sensory ataxia, severe leg and hand weakness, absent deep tendon reflexes (DTRs), severe sensory loss, and hand tremor. He had dramatically reduced motor nerve conduction velocity (MNCV), strikingly prolonged motor distal latencies, absent sensory action potentials and lower limb compound muscle action potentials. CMT1A duplication was reconfirmed but the dramatic change in his clinical course suggested a superimposed acquired neuropathy. An IgM-kappa monoclonal gammopathy of uncertain significance (MGUS) with high titer anti-myelin associated glycoprotein (anti-MAG) activity was found. Nerve biopsy showed severe loss of myelinated fibers with onion bulbs, no evidence of uncompacted myelin, and few IgM deposits. Rituximab was given and he improved. It is very likely that this is a chance association of two rare and slowly progressive neuropathies; rapidly worsening course may have been due to a "double hit". Interestingly, there are reports of possible superimposition of dysimmune neuropathies on hereditary ones, and the influence of the immune system on inherited neuropathies is matter for debate.


Assuntos
Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/fisiopatologia , Polirradiculoneuropatia/complicações , Polirradiculoneuropatia/fisiopatologia , Adulto , Doença de Charcot-Marie-Tooth/patologia , Humanos , Masculino , Glicoproteína Associada a Mielina/imunologia , Polirradiculoneuropatia/patologia
12.
J Neurol ; 270(9): 4219-4234, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37171481

RESUMO

BACKGROUND: Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. METHODS: In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019. RESULTS: We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1H-spectroscopy primarily showed N-acetyl-aspartate reduction; 18fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2. CONCLUSIONS: AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.


Assuntos
Doenças Desmielinizantes , Leucoencefalopatias , Doenças por Armazenamento dos Lisossomos , Doenças Neurodegenerativas , Acidente Vascular Cerebral , Substância Branca , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Fator de Iniciação 2B em Eucariotos/genética , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imageamento por Ressonância Magnética , Mutação/genética , Estudos Observacionais como Assunto , Substância Branca/diagnóstico por imagem
13.
Mov Disord ; 27(9): 1153-7, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22407521

RESUMO

Psychogenic movement disorders are heterogeneous and diagnostically challenging. Despite the growing literature on adult forms, clinical features in children have received relatively little attention. We retrospectively reviewed medical records and video of patients <18 years diagnosed with a psychogenic movement disorder at our institute between 2007 and 2010. We identified 14 patients (6 males and 8 females) with a mean onset age of 11.5 years. Levels of diagnostic confidence were documented (2 patients), clinically established (8 patients), and probable (4 patients). A single movement disorder was present in 10 patients (71%); 4 patients (29%) presented an association of two or more movement disorders. Eleven patients presented other medically unexplained symptoms associated with their movement disorders. Five patients, among 6 with chronic occurrence, performed a polymyographic study showing significant modifications of frequency, amplitude, and distribution of electromyographic activity, related to distracting maneuvers. The present series represents 5% of all movement disorders observed in the considered period and 32% of nonorganic neurological manifestations. The most frequent movement disorders were tremor (36%) and dystonia (29%). We describe two phenotypes not previously reported among psychogenic movement disorders: myoclonus and association of myoclonus with dystonia. We remark on the presence of psychogenic symptoms associated with movement disorders (79%) as being one of the most useful clinical clues as well as on the value of polymyographic study in chronic psychogenic movement disorders, which provide evidence of the inconsistency of movement disorders.


Assuntos
Transtornos dos Movimentos/fisiopatologia , Transtornos dos Movimentos/psicologia , Transtornos Somatoformes/fisiopatologia , Transtornos Somatoformes/psicologia , Adolescente , Idade de Início , Criança , Pré-Escolar , Distúrbios Distônicos/etiologia , Distúrbios Distônicos/fisiopatologia , Eletromiografia , Feminino , Humanos , Masculino , Transtornos dos Movimentos/diagnóstico , Mioclonia/etiologia , Mioclonia/fisiopatologia , Testes Neuropsicológicos , Estudos Retrospectivos , Transtornos Somatoformes/diagnóstico , Tremor/etiologia , Tremor/fisiopatologia
16.
Amyotroph Lateral Scler ; 10(5-6): 410-5, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19922132

RESUMO

Preclinical studies demonstrated that erythropoietin is neuroprotective in different models of peripheral and central nervous system diseases. We investigated safety and tolerability of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). We performed a phase II double-blind, randomized, placebo-controlled study. After screening, 23 patients were randomly assigned to rhEPO or placebo arm. Patients were examined during a six-month lead-in period, and then they received fortnightly either 40,000 units of rhEPO or placebo for 24 months. Primary outcomes were adverse events, safety, and death or tracheotomy. Treatment was safe and well tolerated. One patient in the rhEPO arm dropped out for a superficial phlebitis. Median values of haematocrit, haemoglobin, red cells, and reticulocytes were non-significantly higher in rhEPO than placebo arm. Haemoglobin did not increase >1 g/dl between subsequent doses. Anti-rhEPO antibodies were not detected. Survival and slope of ALSFRS-R curves did not significantly differ between treatment groups. RhEPO treatment was safe and well tolerated in ALS patients. Our results suggest that larger studies are warranted to confirm safety of treatment and to investigate different dose schedule and efficacy.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Eritropoetina/uso terapêutico , Placebos/uso terapêutico , Adulto , Idoso , Animais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Proteínas Recombinantes , Taxa de Sobrevida , Resultado do Tratamento
17.
Neurol Sci ; 30(2): 149-51, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19214379

RESUMO

We describe a 60-year-old woman complaining of severe burning feet for 3 months. A neurological examination showed absent Achilles tendon reflexes; nerve conduction study demonstrated mild sensory neuropathy, and skin biopsy revealed a length-dependent loss of intraepidermal nerve fibres. Haematological exams demonstrated a subclinical hypothyroidism and hormone replacement therapy was started. Conversely, symptomatic treatments for neuropathic pain were withdrawn after few days because of side effects. During the following months, thyroid function recovered, and the patient experienced a progressive decrease of neuropathic pain intensity. At 6- and 12-month follow-ups, nerve conduction study and clinical examination were normal, whereas skin biopsy demonstrated a complete reinnervation of the epidermis. Subclinical hypothyroidism is a possible cause of sensory neuropathy and hormone replacement therapy can prompt nerve regeneration.


Assuntos
Estrogênios/farmacologia , Hipotireoidismo/complicações , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/etiologia , Biópsia , Estrogênios/uso terapêutico , Feminino , Pé/inervação , Pé/fisiopatologia , Terapia de Reposição Hormonal , Humanos , Hipotireoidismo/fisiopatologia , Pessoa de Meia-Idade , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologia , Neuralgia/fisiopatologia , Medição da Dor , Doenças do Sistema Nervoso Periférico/fisiopatologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/patologia , Células Receptoras Sensoriais/fisiologia , Testes de Função Tireóidea , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/fisiopatologia , Resultado do Tratamento
18.
Mov Disord ; 23(6): 892-5, 2008 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-18307268

RESUMO

A few patients with mutations in the microtubule-associated protein tau gene (MAPT), affected by frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), may clinically present with a corticobasal syndrome (CBS). We report a case of apparently sporadic CBS bearing a mutation in the MAPT gene so far associated with frontotemporal dementia (FTD) phenotype. The patient is a 41-year-old man with progressive asymmetric signs of cortical and basal ganglia involvement consistent with CBS. Magnetic resonance imaging showed asymmetric cortical atrophy and unusual corticospinal tract hyperintensity in T2-weighted images. Genetic testing revealed a heterozygous G to C mutation at the first base of codon 389 of the MAPT gene, changing glycine to arginine (G389R), in the patient and his unaffected elderly father. In conclusion, the MAPT G389R mutation shows phenotypic variability resulting in both FTD and CBS. The mutation also demonstrates incomplete penetrance. Corticospinal tract degeneration is an exceptional finding.


Assuntos
Gânglios da Base/patologia , Encefalopatias/genética , Córtex Cerebral/patologia , Demência/genética , Tauopatias/genética , Proteínas tau/genética , Adulto , Substituição de Aminoácidos , Cromossomos Humanos Par 17 , Humanos , Masculino , Doença de Parkinson/genética , Tremor/etiologia , Tremor/genética
19.
Mov Disord ; 23(1): 28-34, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17853490

RESUMO

Myoclonus-dystonia syndrome (MDS) is an inherited movement disorder with clinical and genetic heterogeneity. The epsilon sarcoglycan (SGCE) gene is an important cause of MDS. We report the results of a clinical and genetic study of 20 patients from 11 families. We disclosed six novel and two previously described mutations in nine families. The majority of patients had a phenotype of myoclonus and dystonia in combination, but clinical findings considered atypical, such a very early onset, distal myoclonus, and legs involvement, were detected in a significant proportion of cases. The disease course was variable, from progression to spontaneous remission of the motor symptoms. There were no obvious differences between mutation-positive and -negative cases.


Assuntos
Distonia , Mioclonia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Cromossomos Humanos Par 7/genética , Primers do DNA/genética , DNA Complementar/genética , Progressão da Doença , Distonia/epidemiologia , Distonia/genética , Distonia/fisiopatologia , Eletromiografia , Éxons/genética , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Músculo Esquelético/inervação , Músculo Esquelético/fisiopatologia , Mioclonia/epidemiologia , Mioclonia/genética , Mioclonia/fisiopatologia , Mutação Puntual/genética , Processamento de Proteína/genética , Sarcoglicanas/genética , Síndrome , Extremidade Superior/fisiopatologia
20.
Mov Disord ; 23(14): 2041-8, 2008 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-18759336

RESUMO

Mutations in the epsilon-sarcoglycan (SGCE) gene have been associated with DYT11 myoclonus-dystonia syndrome (MDS). The aim of this study was to characterize myoclonus in 9 patients with DYT11-MDS presenting with predominant myoclonus and mild dystonia by means of neurophysiological techniques. Variously severe multifocal myoclonus occurred in all of the patients, and included short (mean 89.1 +/- 13.3 milliseconds) electromyographic bursts without any electroencephalographic correlate, sometimes presenting a pseudo-rhythmic course. Massive jerks could be evoked by sudden stimuli in 5 patients, showing a "startle-like" muscle spreading and latencies consistent with a brainstem origin. Somatosensory evoked potentials and long-loop reflexes were normal, as was silent period and long-term intracortical inhibition evaluated by means of transcranial magnetic stimulation; however, short-term intracortical inhibition revealed subtle impairment, and event-related synchronization (ERS) in the beta band was delayed. Blink reflex recovery was strongly enhanced. Myoclonus in DYT11-MDS seems to be generated at subcortical level, and possibly involves basal ganglia and brainstem circuitries. Cortical impairment may depend from subcortical dysfunction, but it can also have a role in influencing the myoclonic presentation. The wide distribution of the defective SCGE in DYT11-MDS may justify the involvement of different brain areas.


Assuntos
Distúrbios Distônicos/complicações , Distúrbios Distônicos/genética , Mioclonia/complicações , Mioclonia/genética , Neurofisiologia/métodos , Estimulação Acústica/métodos , Adolescente , Adulto , Criança , Estimulação Elétrica/métodos , Eletroencefalografia/métodos , Eletromiografia/métodos , Potenciais Somatossensoriais Evocados/fisiologia , Feminino , Humanos , Masculino , Mutação , Condução Nervosa/fisiologia , Tempo de Reação/fisiologia , Reflexo/fisiologia , Sarcoglicanas/genética , Estimulação Magnética Transcraniana/métodos , Adulto Jovem
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