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1.
Neurology ; 68(20): 1658-67, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17502546

RESUMO

OBJECTIVE: To investigate the clinical and electrophysiologic phenotype of Charcot-Marie-Tooth disease (CMT) Type 2 in a large number of affected families. METHODS: We excluded CMT Type 1, hereditary neuropathy with liability to pressure palsies, and CMT due to Cx32 gene mutations by DNA analysis. We performed genetic analysis of the presently known CMT Type 2 genes. RESULTS: Sixty-one persons from 18 families were affected. Ninety percent of patients were able to walk with or without the help of aids. Proximal leg muscle weakness was present in 13%. Asymmetrical features were present in 15%. Normal or brisk knee reflexes were present in 36%. Extensor plantar responses without associated spasticity occurred in 10 patients from eight families. Only three causative mutations were identified in the MFN2, BSCL2, and RAB7 genes. No mutations were found in the NEFL, HSPB1, HSPB8, GARS, DNM2, and GDAP1 genes. CONCLUSIONS: At group level, the clinical phenotype of Charcot-Marie-Tooth disease (CMT) Type 2 is uniform, with symmetric, distal weakness, atrophy and sensory disturbances, more pronounced in the legs than in the arms, notwithstanding the genetic heterogeneity. Brisk reflexes, extensor plantar responses, and asymmetrical muscle involvement can be considered part of the CMT Type 2 phenotype. The causative gene mutation was found in only 17% of the families we studied.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Subunidades gama da Proteína de Ligação ao GTP/genética , Heterogeneidade Genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Proteínas do Tecido Nervoso/genética , Condução Nervosa , Proteínas rab de Ligação ao GTP/genética , Potenciais de Ação , Adolescente , Adulto , Idade de Início , Idoso , Axônios/fisiologia , Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Doenças Desmielinizantes , Eletromiografia , Feminino , GTP Fosfo-Hidrolases , Subunidades gama da Proteína de Ligação ao GTP/fisiologia , Genótipo , Humanos , Hipestesia/etiologia , Lactente , Masculino , Proteínas de Membrana/fisiologia , Pessoa de Meia-Idade , Proteínas Mitocondriais/fisiologia , Debilidade Muscular/etiologia , Atrofia Muscular/etiologia , Mutação , Proteínas do Tecido Nervoso/fisiologia , Países Baixos/epidemiologia , Exame Neurológico , Nervos Periféricos/fisiopatologia , Fenótipo , Reflexo Anormal , Estudos Retrospectivos , Índice de Gravidade de Doença , Caminhada , Proteínas rab de Ligação ao GTP/fisiologia , proteínas de unión al GTP Rab7
2.
J Neurol Neurosurg Psychiatry ; 77(4): 534-7, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16543539

RESUMO

A late onset axonal Charcot-Marie-Tooth phenotype is described, resulting from a novel mutation in the myelin protein zero (MPZ) gene. Comparative computer modelling of the three dimensional structure of the MPZ protein predicts that this mutation does not cause a significant structural change. The primary axonal disease process in these patients points to a function of MPZ in maintenance of the myelinated axons, apart from securing stability of the myelin layer.


Assuntos
Axônios/patologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína P0 da Mielina/genética , Fosfoproteínas/genética , Adulto , Idade de Início , Idoso , Biópsia , Doença de Charcot-Marie-Tooth/epidemiologia , Estudos de Coortes , Conexinas/genética , Análise Mutacional de DNA , Doenças Desmielinizantes/patologia , Feminino , Humanos , Masculino , Nervo Mediano/fisiopatologia , Pessoa de Meia-Idade , Proteínas da Mielina/genética , Condução Nervosa/fisiologia , Linhagem , Fenótipo , Mutação Puntual , Polimorfismo Conformacional de Fita Simples , Nervo Sural/patologia , Nervo Sural/fisiopatologia , Nervo Ulnar/fisiopatologia , Proteína beta-1 de Junções Comunicantes
4.
Otol Neurotol ; 26(3): 405-14, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15891642

RESUMO

OBJECTIVE: To characterize and distinguish the types of sensorineural hearing impairment (SNHI) that occur in hereditary motor and sensory neuropathy Type 1a (HMSN-1a) and hereditary neuropathy with liability to pressure palsies (HNPP), which are caused by deletion or frameshift mutation. STUDY DESIGN: Prospective study. SETTING: Ambulatory patients in a university hospital. PATIENTS: Twelve patients with HMSN-1a due to a duplication of the PMP22 gene on chromosome 17p11.2, 16 patients with HNPP due to the common PMP22 deletion (HNPP del), and 11 HNPP patients with a frame shift mutation (heterozygous PMP22 G-insertion) (HNPP mut), all confirmed by molecular genetic analysis. INTERVENTIONS: Pure-tone audiograms and speech audiograms were obtained. MAIN OUTCOME MEASURES: Results of cross-sectional analysis comprising linear regression of hearing threshold on age. RESULTS: Pure-tone audiograms showed mild to moderate SNHI, predominant at the low and the high frequencies. SNHI showed significant progression by approximately 0.4 dB per year at 0.25 to 4 kHz and up to 1 to 2 dB per year at 4 to 8 kHz. Patients with HMSN-1a had substantial, presumably congenital, SNHI but did not show significant progression beyond presbyacusis. Patients with HNPP showed postnatal onset at age 11 years with progression of SNHI in excess of presbyacusis by 0.4 dB per year. All three types of neuropathy showed normal speech recognition. CONCLUSIONS: All three types of neuropathy showed SNHI with normal speech recognition. HMSN-1a showed stable SNHI without progression beyond presbyacusis. HNPP showed progression beyond presbyacusis with postnatal onset. The differences in SNHI may be explained by the differences in PMP22 expression. The progressive SNHI in HNPP might be explained by the liability for exogenous factors associated with this disorder.


Assuntos
Mutação da Fase de Leitura , Deleção de Genes , Duplicação Gênica , Perda Auditiva Neurossensorial/genética , Proteínas da Mielina/genética , Adulto , Idoso , Envelhecimento , Audiometria de Tons Puros , Audiometria da Fala , Limiar Auditivo , Doença de Charcot-Marie-Tooth/genética , Estudos Transversais , Progressão da Doença , Audição , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Presbiacusia/fisiopatologia , Estudos Prospectivos
5.
J Neurol Neurosurg Psychiatry ; 76(3): 445-7, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15716548

RESUMO

We report the findings in five muscle and three sural nerve biopsies, and in one postmortem plexus specimen, from six patients with hereditary neuralgic amyotrophy (HNA). We found that the sensory nerves are definitely involved in HNA despite the mainly motor symptoms, and that lesions in nerves and muscles are more widespread throughout the peripheral nervous system than clinically presumed, but, simultaneously, very focally affect isolated fascicles within individual nerves.


Assuntos
Neuropatias do Plexo Braquial/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Músculo Esquelético/patologia , Nervo Sural/patologia , Adulto , Idoso , Biópsia , Criança , DNA/análise , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
Neurology ; 59(12): 1865-72, 2002 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-12499475

RESUMO

BACKGROUND: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot-Marie-Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis. METHODS: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1. RESULTS: A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C). CONCLUSIONS: Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.


Assuntos
Axônios/patologia , Doença de Charcot-Marie-Tooth/genética , Doenças Desmielinizantes/genética , Genes Recessivos/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Idade de Início , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Pré-Escolar , Cromossomos Humanos Par 8/genética , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Eletrofisiologia , Família , Feminino , Ligação Genética/genética , Testes Genéticos , Humanos , Lactente , Masculino , Condução Nervosa/fisiologia , Linhagem , Nervo Sural/patologia , Turquia
8.
Neuromuscul Disord ; 12(7-8): 651-5, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12207933

RESUMO

Hereditary neuropathy with liability to pressure palsies is associated with a deficiency in the Peripheral Myelin Protein 22 (PMP22). Most hereditary neuropathy with liability to pressure palsies cases are caused by a deletion of a 1.5 Mb region on chromosome 17p11.2-12 encompassing the PMP22 gene. We describe a hereditary neuropathy with liability to pressure palsies family that lacks the common deletion, but carries a small deletion spanning the 3' region of the PMP22 gene, causing only a partial deletion of one copy of the gene.


Assuntos
Neuropatia Hereditária Motora e Sensorial/genética , Proteínas da Mielina/genética , Paralisia/genética , Adulto , Southern Blotting , Humanos , Masculino , Pressão
9.
J Anat ; 200(4): 377-90, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12090404

RESUMO

Charcot-Marie-Tooth disease type 1A is a dominantly inherited demyelinating disorder of the peripheral nervous system. It is most frequently caused by overexpression of peripheral myelin protein 22 (PMP22), but is also caused by point mutations in the PMP22 gene. We describe a new transgenic mouse model (My41) carrying the mouse, rather than the human, pmp22 gene. The My41 strain has a severe phenotype consisting of unstable gait and weakness of the hind limbs that becomes obvious during the first 3 weeks of life. My41 mice have a shortened life span and breed poorly. Pathologically, My41 mice have a demyelinating peripheral neuropathy in which 75% of axons do not have a measurable amount of myelin. We compare the peripheral nerve pathology seen in My41 mice, which carry the mouse pmp22 gene, with previously described transgenic mice over-expressing the human PMP22 protein and Trembler-J (TrJ) mice which have a P16L substitution. We also look at the differences between CMT1A duplication patients, patients with the P16L mutation and their appropriate mouse models.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Camundongos Transgênicos , Modelos Animais , Proteínas da Mielina/genética , Animais , Doença de Charcot-Marie-Tooth/patologia , Expressão Gênica , Humanos , Camundongos , Bainha de Mielina/fisiologia , Fibras Nervosas/patologia
10.
Neuromuscul Disord ; 12(3): 281-5, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11801400

RESUMO

Charcot-Marie-Tooth disease caused by mutations of the myelin protein zero gene demonstrates considerable phenotypical variability. We describe a 45-year-old female with a peripheral neuropathy with demyelinating and axonal features, pes cavus and pupillary light-near dissociation. She was heterozygous for two mutations in the myelin protein zero gene (His81Tyr and Val113Phe), both present on the same allele. Our patient shows a less severe phenotype than previously described patients with a His81Arg mutation. Multiple mutations in the myelin protein zero gene, as well as Charcot-Marie-Tooth with pupillary abnormalities have previously been described in rare instances. However, concurrent occurrence of both phenomena is a novel finding.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Proteína P0 da Mielina/genética , Distúrbios Pupilares/genética , Adulto , Substituição de Aminoácidos , Doença de Charcot-Marie-Tooth/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína P0 da Mielina/química , Condução Nervosa , Fenótipo , Estrutura Terciária de Proteína , Distúrbios Pupilares/etiologia , Reflexo Pupilar
11.
Neuromuscul Disord ; 11(8): 753-6, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11595518

RESUMO

We describe a family carrying the Thr148Met mutation in the P0 gene. Contrary to other neuropathies caused by myelin gene defects, no demyeliantion could be found in our biopsies. Based on follow up examinations, extensive morphometry and immunohistochemical analysis we suggest that the mild hypomyelination documented in our family secondarily causes axonal degeneration and axonal loss of large and small fibers which predominates the clinical picture.


Assuntos
Axônios/patologia , Axônios/fisiologia , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/fisiopatologia , Proteína P0 da Mielina/genética , Adulto , Substituição de Aminoácidos , Biópsia , Contagem de Células , Doença de Charcot-Marie-Tooth/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Proteína P0 da Mielina/biossíntese , Bainha de Mielina/patologia , Glicoproteína Associada a Mielina/biossíntese , Condução Nervosa , Nervo Sural/metabolismo , Nervo Sural/patologia , Nervo Sural/ultraestrutura
12.
Neurology ; 56(12): 1766-8, 2001 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-11425952

RESUMO

The authors report a patient with neurofibromatosis type 2 (NF2) presenting with an axonal mononeuropathy multiplex. Sural nerve biopsy showed small scattered groups of Schwann cells transformed into irregular branching cells with abnormal cell-cell contacts. The authors hypothesize that defective Schwann cell function, due to inactivation of the NF2 gene product merlin, leads to changes in morphology, cell-cell contact, and growth, and finally to degeneration of axons.


Assuntos
Neurofibromatose 2/patologia , Doenças do Sistema Nervoso Periférico/patologia , Axônios/patologia , Axônios/ultraestrutura , Feminino , Humanos , Microscopia Eletrônica , Pessoa de Meia-Idade , Células de Schwann/ultraestrutura , Nervo Sural/patologia
13.
J Neurophysiol ; 83(5): 2980-6, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10805693

RESUMO

During human gait, transmission of cutaneous reflexes from the foot is controlled specifically according to the phase of the step cycle. These reflex responses can be evoked by nonnociceptive stimuli, and therefore it is thought that the large-myelinated and low-threshold Abeta afferent fibers mediate these reflexes. At present, this hypothesis is not yet verified. To test whether Abeta fibers are involved the reflex responses were studied in patients with a sensory polyneuropathy who suffer from a predominant loss of large-myelinated Abeta fibers. The sural nerve of both patients and healthy control subjects was stimulated electrically at a nonnociceptive intensity during the early and late swing phases while they walked on a treadmill. The responses were studied by recording electromyographic (EMG) activity of the biceps femoris (BF) and tibialis anterior (TA) of the stimulated leg. In both phases, large facilitatory responses were observed in the BF of the healthy subjects. These facilitations were reduced significantly in the BF of the patients, indicating that Abeta fibers mediate these reflexes. In TA similar results were obtained. The absolute response magnitude across the two phases was significantly smaller for the patients than for the healthy subjects. The TA responses for the healthy subjects were on average facilitatory during early swing and suppressive during end swing. Both facilitations and suppressions were considerably smaller for the patients, indicating that both types of responses are mediated by Abeta fibers. It is concluded that low-threshold Abeta sensory fibers mediate these reflexes during human gait. The low threshold and the precise phase-dependent control of these responses suggest that these responses are important in the regulation of gait. The loss of such reflex activity may be related to the gait impairments of these patients.


Assuntos
Fibras Nervosas Mielinizadas/fisiologia , Polineuropatias/fisiopatologia , Reflexo/fisiologia , Pele/inervação , Caminhada/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estimulação Elétrica , Eletromiografia , Teste de Esforço , Feminino , Marcha/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiologia , Neurônios Aferentes/fisiologia , Tempo de Reação/fisiologia , Limiar Sensorial/fisiologia , Nervo Sural/fisiologia
14.
Brain ; 123 ( Pt 5): 1001-6, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10775544

RESUMO

The hereditary demyelinating neuropathy Charcot-Marie-Tooth type 1A is caused by duplication or by point mutations of the PMP22 gene. Histopathological differences in these genotypes suggest distinct disease mechanisms. In the present investigation we demonstrate a pathologically altered cellular distribution of PMP22 in sural nerve biopsies of patients with PMP22 point mutations. In these patients, in contrast to findings in patients with PMP22 duplication, PMP22 partially accumulates in the Schwann cells instead of being inserted in the myelin sheath. These findings may explain the different histopathology and may suggest different mechanisms of pathogenesis in these genotypes.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Proteínas da Mielina/genética , Nervo Sural/patologia , Adolescente , Adulto , Substituição de Aminoácidos , Biópsia , Criança , Pré-Escolar , Duplicação Gênica , Humanos , Imuno-Histoquímica , Proteínas da Mielina/análise , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/ultraestrutura , Mutação Puntual , Células de Schwann/patologia
17.
Muscle Nerve ; 21(11): 1419-27, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9771665

RESUMO

This study examined major histocompatibility complex (MHC) class II expression and macrophage infiltration in sural nerve biopsies from patients with genetically proven Charcot-Marie-Tooth (CMT) 1A and 1B and hereditary neuropathy with liability to pressure palsies (HNPP) by immunocytochemistry. In both young and older patients with duplication of the PMP22 gene, MHC class II expression was consistently up-regulated and not closely related to the extent of macrophage infiltration. On the other hand, MHC class II expression was more variable in CMT1A and CMT1B caused by point mutations and in HNPP. The extent of nerve pathology as assessed by teased fiber preparations or electron microscopy was not predictive for the degree of MHC class II expression in CMT1/HNPP. We conclude that MHC class II up-regulation is a common feature in hereditary neuropathies. As shown for the animal model of globoid cell dystrophy, it is conceivable that increased expression of MHC class II molecules in CMT1 and HNPP accelerates nerve pathology.


Assuntos
Doença de Charcot-Marie-Tooth/imunologia , Antígenos de Histocompatibilidade Classe II/análise , Macrófagos/imunologia , Adolescente , Adulto , Biomarcadores , Biópsia , Doença de Charcot-Marie-Tooth/genética , Criança , Pré-Escolar , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Microscopia Eletrônica , Pessoa de Meia-Idade , Fibras Nervosas/imunologia , Fibras Nervosas/patologia , Fibras Nervosas/ultraestrutura , Mutação Puntual , Nervo Sural/imunologia , Nervo Sural/patologia , Linfócitos T/imunologia
18.
Brain ; 121 ( Pt 8): 1451-8, 1998 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9712007

RESUMO

In six families with hereditary neuropathy with liability to pressure palsies (HNPP) the 17p11.2 deletion was absent, but single strand conformation-analysis and subsequent sequencing demonstrated a heterozygous G-insertion in a stretch of six Gs at nt 276281 of the PMP22 gene, resulting in a frame shift after Gly94. Haplotype comparison of the six families revealed common ancestry. We compared the phenotype of 23 patients from these six families with the phenotype of 63 patients of 17 families with the common deletion. The patients with the G-insertion showed the clinical, electrophysiological and morphological characteristics of common HNPP, but in addition they had significantly more neuropathic features, mimicking hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1). To explain this distinct phenotype we suggest that, by translation of the mutated gene, a markedly changed polypeptide is formed without the normal cytoplasmic C-terminal of the native protein, resulting in a loss of function similar to that with the common deletion, but exerting an extra disturbance of Schwann cell functions, probably by hampering normal myelin formation or maintenance.


Assuntos
Neuropatia Hereditária Motora e Sensorial/genética , Adolescente , Adulto , Idoso , Criança , Elementos de DNA Transponíveis , Eletrofisiologia , Feminino , Mutação da Fase de Leitura , Deleção de Genes , Neuropatia Hereditária Motora e Sensorial/patologia , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas da Mielina/genética , Nervos Periféricos/patologia , Nervos Periféricos/fisiopatologia , Fenótipo
19.
J Neurosci ; 18(2): 731-40, 1998 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-9425015

RESUMO

Nonconservative point mutations of the peripheral myelin protein 22 (PMP22) are associated with Charcot-Marie-Tooth type 1A disease, the most common inherited peripheral neuropathy in humans, and with the Trembler J (TrJ) and Trembler (Tr) alleles in mice. We investigated the intracellular transport of wild-type PMP22 and its TrJ and Tr mutant forms in Schwann cells and in a non-neuronal cell line. In contrast to wild type, mutant proteins were not inserted into the plasma membrane and accumulated in the endoplasmic reticulum and Golgi compartments. Coexpression of each mutant with wild-type PMP22 confirmed the different intracellular distribution of the mutant forms, indicating that neither the TrJ nor Tr protein has a dominant-negative effect on the cellular distribution of wild-type PMP22. Accumulation of PMP22 immunoreactivity in the cell body of myelinating Schwann cells was also observed in nerve biopsies obtained from CMT1A patients carrying the TrJ point mutation. We propose that impaired trafficking of mutated PMP22 affects Schwann cell physiology leading to myelin instability and loss.


Assuntos
Doença de Charcot-Marie-Tooth/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Mutação , Proteínas da Mielina/genética , Animais , Compartimento Celular , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Retículo Endoplasmático/patologia , Complexo de Golgi/patologia , Células HeLa , Humanos , Camundongos , Proteínas da Mielina/metabolismo , Células de Schwann/patologia , Transfecção
20.
Acta Neuropathol ; 94(4): 310-5, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9341930

RESUMO

Charcot-Marie-Tooth disease type 1A (CMT1A) is a common hereditary demyelinating neuropathy caused by a duplication of the gene for the myelin protein PMP22, resulting in overexpression of PMP22 in young patients. Although genetically well defined, the pathogenesis of the hereditary demyelinating neuropathy CMT1A is still unclear. Homology of PMP22 cDNA to the growth arrest-specific gene gas3 and experiments in vitro showing decreased proliferation in PMP22-overexpressing Schwann cells suggest a role of PMP22 in Schwann cell differentiation. Furthermore, overexpression of PMP22 in fibroblasts induces programmed cell death. In this report we applied morphometrical methods using electron micrographs and immunohistochemistry to further characterise Schwann cells in CMT1A nerve biopsy samples from CMT1A patients. We show that the total number of PMP22-expressing Schwann cells, i.e. Schwann cells that are in a 1:1 relationship with axons, was not reduced in sural nerve biopsy samples from six young CMT1A patients. We excluded non-specific secondary Schwann cell proliferation. Thus, in young CMT1A patients with increased PMP22 overexpression there seems to be no evidence for altered initial Schwann cell proliferation in achieving a 1:1 relationship to axons prior to the process of de- and remyelination. Further, using electron microscopy we found no evidence for apoptosis of Schwann cells in CMT1A. However, we provide additional support for an abnormal Schwann cell phenotype in CMT1A by showing the expression of neural cell adhesion molecule immunoreactivity in onion bulbs. Thus, the role of PMP22 in cell growth and differentiation does not lead to an altered number of myelinating Schwann cells but to altered Schwann cell differentiation in CMT1A.


Assuntos
Doença de Charcot-Marie-Tooth/metabolismo , Proteínas da Mielina/metabolismo , Bainha de Mielina/patologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Células de Schwann/metabolismo , Diferenciação Celular , Doença de Charcot-Marie-Tooth/patologia , Criança , Pré-Escolar , Humanos , Imuno-Histoquímica , Microscopia Eletrônica , Células de Schwann/patologia , Nervo Sural/patologia
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