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ABSTRACT: X-linked myotubular myopathy due to mutations in the MTM1 gene is classically characterized by a severe neonatal phenotype and a typical muscle biopsy presenting globular and centrally located nuclei in muscle myofibers. Recently, four patients with mild late-onset form have been described, a male with a hemizygous mutation and three females with heterozygous mutations in the MTM1 gene. The muscle biopsies were performed at 13-35 years of age and a new histological marker, the necklace fibers, was described. Here, we report two siblings with the pathogenic c.664 C>T mutation in the MTM1 gene, presenting a severe muscle weakness and respiratory impairment requiring ventilatory support since the first months of life until death, at the age of 36 months and 5 months. In the older brother the muscle biopsy, performed at the age of 30 months, showed almost 100% of necklace fibers, which were not present in the younger one submitted to muscle biopsy at 5 months of age. Our findings confirm the necklace fibers can be a histopathological finding of MTM1 myopathies, even in the severe neonatal form, and suggest that the necklace fibers appear or increase in number over time.
Neuromuscular Disorders 01/2012; 22(6):541-5. · 2.80 Impact Factor
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ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of SMN gene (SMN1) and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene. One of these drugs is the valproic acid (VPA), a histone deacetylase inhibitor.
Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC), the Hammersmith Functional Motor Scale (HFMS), and the Barthel Index.
After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period.
Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease.
ClinicalTrials.gov: NCT01033331.
BMC Neurology 03/2011; 11:36. · 2.17 Impact Factor
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ABSTRACT: The purpose of this study was to evaluate the quality of life (QoL) of patients with Duchenne muscular dystrophy (DMD) in different stages of the disease, by means of the Life Satisfaction Index for Adolescents (LSI-A). The practicality of this scale was also verified. The LSI-A was applied four times to 95 patients with DMD who were undergoing steroid therapy, at three-month intervals. The patients were divided into four groups according to age. The results from the four applications and the inter and intra-examiner concordance were treated statistically. Comparing the different age groups, patients with DMD did not lose QoL, even with disease progression. We concluded that, in spite of the progressive course of the disease, the QoL in patients with DMD does not get worse. The use of a scale that embraces a great diversity of circumstances in patients' lives, without considering clinical aspects excessively, is a good alternative for assessing the QoL of these patients.
Arquivos de neuro-psiquiatria 02/2011; 69(1):19-22. · 0.55 Impact Factor
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ABSTRACT: To compare muscle strength (MS) and motor function in patients with Duchenne muscular dystrophy (DMD) receiving steroids for different times against the natural evolution of DMD described by Scott et al.
90 patients with DMD (aged 5- 12 years), receiving steroids for one to seven years, were evaluated by Medical Research Council Scale (MRC) and Hammersmith motor ability score. The relation between MS and motor abilities measurement from our data and Scott's ones were ascertained statistically.
The relation between patient's age and Hammersmith scores revealed decrease of 0.76 point per year for age against decrease of 2.23 points on Scott's study. The relation between MRC scale and patient's age showed decrease of 0.80 point per year of age against decrease of 3.65 points on Scott's study.
In patients with DMD aged five to 12 years the progression of the disease is delayed by steroids and the motor function is less reduced than muscular strength.
Arquivos de neuro-psiquiatria 10/2010; 68(5):683-8. · 0.55 Impact Factor
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ABSTRACT: Neuraminidase 1 (NEU1) regulates the catabolism of sialoglycoconjugates in lysosomes. Congenital NEU1 deficiency in children is the basis of sialidosis, a severe neurosomatic disorder in which patients experience a broad spectrum of clinical manifestations varying in the age of onset and severity. Osteoskeletal deformities and muscle hypotonia have been described in patients with sialidosis. Here we present the first comprehensive analysis of the skeletal muscle pathology associated with loss of Neu1 function in mice. In this animal model, skeletal muscles showed an expansion of the epimysial and perimysial spaces, associated with proliferation of fibroblast-like cells and abnormal deposition of collagens. Muscle fibers located adjacent to the expanded connective tissue underwent extensive invagination of their sarcolemma, which resulted in the infiltration of the fibers by fibroblast-like cells and extracellular matrix, and in their progressive cytosolic fragmentation. Both the expanded connective tissue and the juxtaposed infiltrated muscle fibers were strongly positive for lysosomal markers and displayed increased proteolytic activity of lysosomal cathepsins and metalloproteinases. These combined features could lead to abnormal remodeling of the extracellular matrix that could be responsible for sarcolemmal invagination and progressive muscle fiber degeneration, ultimately resulting in an overt atrophic phenotype. This unique pattern of muscle damage, which has never been described in any myopathy, might explain the neuromuscular manifestations reported in patients with the type II severe form of sialidosis. More broadly, these findings point to a potential role of NEU1 in cell proliferation and extracellular matrix remodeling.
Biochimica et Biophysica Acta 04/2010; 1802(7-8):659-72. · 4.66 Impact Factor
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ABSTRACT: Muscle contractile proteins are expressed as a series of developmental isoforms that are in constant dynamic remodeling during embryogenesis, but how obsolete molecules are recognized and removed is not known. Ozz is a developmentally regulated protein that functions as the adaptor component of a RING-type ubiquitin ligase complex specific to striated muscle. Ozz(-/-) mutants exhibit defects in myofibrillogenesis and myofiber differentiation. Here we show that Ozz targets the rod portion of embryonic myosin heavy chain and preferentially recognizes the sarcomeric rather than the soluble pool of myosin. We present evidence that Ozz binding to the embryonic myosin isoform within sarcomeric thick filaments marks it for ubiquitination and proteolytic degradation, allowing its replacement with neonatal or adult isoforms. This unique function positions Ozz within a system that facilitates sarcomeric myosin remodeling during muscle maturation and regeneration. Our findings identify Ozz-E3 as the ubiquitin ligase complex that interacts with and regulates myosin within its fully assembled cytoskeletal structure.
PLoS ONE 01/2010; 5(3):e9866. · 4.09 Impact Factor
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Arquivos de neuro-psiquiatria 04/2009; 67(1):102-4. · 0.55 Impact Factor
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ABSTRACT: Obstructive sleep apnea syndrome (OSAS) is an upper airway obstruction that occurs during the sleep. One of the suggested mechanisms involved in this process is a neuromuscular abnormality of the palatal muscles. Whether children with OSAS develop into OSAS adults, or children and adult OSAS are two distinct disorders occurring at different ages are questions to be answered. Here, we made the histological analysis of palatophryngeal muscle in 34 oral-breathing children of both genders, aged 5-12 years old, with hypertrophic tonsils and adenoids. According to the polysomnographic study the participants were divided into children without sleeping disorders (group I) and children with primary snoring (group II) or apnea (group III). The main histological findings were fiber size variability in 70% cases from groups II and III and in 71% from group I; perimysial connective tissue infiltration in 48% children from groups II and III and in 71% from group I; intracytoplasmatic mitochondrial proliferation in 63% cases from groups II and III and in 57% cases from group I. Muscle necrosis was only observed in one case, in association with subglandular inflammation. Others findings observed in all groups included fibers with internal architecture alteration, such as moth-eaten and lobulated fibers, type 2 fiber predominance, and small areas of fiber type grouping. The presence of similar histological findings in the palatopharyngeal muscle in children with primary snoring or apnea but also in children without sleeping disorders indicate that such changes could be a normal histological feature of this muscle rather than a neurogenic or myopathic pathology.
International Journal of Pediatric Otorhinolaryngology 03/2007; 71(2):283-90. · 1.17 Impact Factor
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ABSTRACT: In eukaryotic cells, phosphoinositides are lipid second messengers important for many cellular processes and have been found dysregulated in several human diseases. X-linked myotubular (centronuclear) myopathy is a severe congenital myopathy caused by mutations in a phosphatidylinositol 3-phosphate (PtdIns3P) phosphatase called myotubularin, and mutations in dominant centronuclear myopathy (CNM) cases were identified in the dynamin 2 gene. The genes mutated in autosomal recessive cases of CNMs have not been found. We have identified a novel phosphoinositide phosphatase (hJUMPY) conserved through evolution, which dephosphorylates the same substrates as myotubularin, PtdIns3P and PtdIns(3,5)P(2), in vitro and ex vivo. We found, in sporadic cases of CNMs, two missense variants that affect the enzymatic function. One of these appeared de novo in a patient also carrying a de novo mutation in the dynamin 2 gene. The other missense (R336Q) found in another patient changes the catalytic arginine residue of the core phosphatase signature present in protein tyrosine/dual-specificity phosphatases and in phosphoinositide phosphatases and drastically reduces the enzymatic activity both in vitro and in transfected cells. The inheritance of the phenotype with regard to this variant is still unclear and could be either recessive with an undetected second allele or digenic. We propose that impairment of hJUMPY function is implicated in some cases of autosomal CNM and that hJUMPY cooperates with myotubularin to regulate the level of phosphoinositides in skeletal muscle.
Human Molecular Genetics 12/2006; 15(21):3098-106. · 7.64 Impact Factor
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ABSTRACT: Congenital muscular dystrophy (CMD) composes a group of disorders characterized by hypotonia and muscular weakness noticed in the first year of life. The Ullrich's form is characterized by proximal joint contractures and distal hiperextensibility. About 40% of these patients present mutations in one of the genes that codify the sub-units of the collagen VI protein (COL6), producing total or partial deficiency of the protein expression. We analyzed, through immunohistochemistry, the expression of COL6 in muscle fragments of 50 patients with CMD; 20 of them presented merosin expression deficiency. We identified 4 cases with total COL6 deficiency (8% of the total), representing 13% of the cases with normal merosin expression. The histological findings of patients with deficiency of COL6 were indistinguishable from other forms of CMD, but milder than that abnormalities observed in merosin deficient patients. In three COL6 deficient patients were observed hypotonia and weakness in the neonatal period, delayed of motor milestones, muscular retractions of knees and elbows, distal joint hiperextensibility and congenital hip dislocation (two patients). One patient lost the ability to walk; and one died due to respiratory problems. The analysis of COL6 expression, as well as merosin expression, in the muscle tissue from CMD patients, can be important for identification and phenotypic characterization of different CMD subtypes.
Arquivos de Neuro-Psiquiatria 07/2005; 63(2B):514-8. · 0.72 Impact Factor
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ABSTRACT: Congenital muscular dystrophy (CMD) is a heterogeneous group of disorders characterized by early onset of hypotonia and weakness. Almost 50% of the cases are caused by primary deficiency of a protein named merosin (MD), and present a homogenous phenotype with a severe motor and respiratory involvement. Eleven children with clinical and histological diagnosis of CMD-MD, aged of 3 to 15 years, were studied using the manual muscle testing (Medical Research Council), goniometric analysis, motor ability and day life activities (Barthel index) scales, with the objective to characterize the main motor function limitations. The muscular groups most affected were cervical flexors, paravertebral and proximal portions of limbs. The muscular groups of upper limbs were as affected as the lower limbs, and the extensors were more affected than the flexors groups. All children had severe muscular retractions on the hip, knee and elbow. Other frequent deformities were scoliosis and equinus-varum feet. No children presented the motor ability to walk, stand up and crawl; and all of them were classified as dependents or semi-dependents in the day life activities scale. Our findings confirm the severe and diffuse involvement of skeletal muscle in CMD-MD patients, producing serious motor limitations and deformities.
Arquivos de Neuro-Psiquiatria 07/2005; 63(2A):298-306. · 0.72 Impact Factor
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American Journal of Medical Genetics Part A 05/2005; 134(3):338-40. · 2.39 Impact Factor
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ABSTRACT: Congenital muscular dystrophies (CMD) are characterized by neonatal hypotonia and/or artrogriposis associated with a dystrophic muscle biopsy. The CMD1A form is caused by a deficiency of the alpha2 chain of laminin 2 (LAMA2 gene at 6q2), a protein present in the basal lamina of muscle fibers, in Schwann cells, epidermis, and in fetal trophoblastic tissue. This allows its study for prenatal diagnosis in the chorionic villous (CV), which was performed in a family with one deceased affected CMD1A child. Immunohistochemical analysis of the CV using antibodies against the C- and N-terminal domains of the alpha2-laminin protein showed a normal positive labeling for both antibodies in the "at-risk" CV, which did not differ from the normal control CV. The integrity of the CV membrane was confirmed through the analysis with antibodies against alpha1, beta1, and gamma1 laminins. DNA study using markers flanking the 6q2 region showed that the affected patient and the "at-risk" fetus did not share the same haplotype. Therefore, the fetus was considered normal through both methodologies, which was confirmed after the birth of a clinically normal male baby. As the LAMA2 gene is very large and the spectrum of mutations causing disease is wide, the analysis of the protein in muscle biopsy has been largely used for the diagnosis. Besides, the possibility to detect it in the chorionic villous, mainly using positive markers, also offers a powerful tool for prenatal diagnosis.
Diagnostic Molecular Pathology 10/2004; 13(3):167-71. · 2.26 Impact Factor
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ABSTRACT: Congenital muscular dystrophies (CMD) are characterized by neonatal hypotonia and/or artrogriposis associated with a dystrophic muscle biopsy. The CMD1A form is caused by a deficiency of the α2 chain of laminin 2 (LAMA2 gene at 6q2), a protein present in the basal lamina of muscle fibers, in Schwann cells, epidermis, and in fetal trophoblastic tissue. This allows its study for prenatal diagnosis in the chorionic villous (CV), which was performed in a family with one deceased affected CMD1A child. Immunohistochemical analysis of the CV using antibodies against the C- and N-terminal domains of the α2-laminin protein showed a normal positive labeling for both antibodies in the “at-risk” CV, which did not differ from the normal control CV. The integrity of the CV membrane was confirmed through the analysis with antibodies against α1, β1, and γ1 laminins. DNA study using markers flanking the 6q2 region showed that the affected patient and the “at-risk” fetus did not share the same haplotype. Therefore, the fetus was considered normal through both methodologies, which was confirmed after the birth of a clinically normal male baby. As the LAMA2 gene is very large and the spectrum of mutations causing disease is wide, the analysis of the protein in muscle biopsy has been largely used for the diagnosis. Besides, the possibility to detect it in the chorionic villous, mainly using positive markers, also offers a powerful tool for prenatal diagnosis.
Diagnostic Molecular Pathology 08/2004; 13(3):167-171. · 2.26 Impact Factor
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ABSTRACT: Skin biopsy has become an attractive technique to evaluate the terminal regions of small nerve fibers. There is extensive innervation of the skin by both sensory and autonomic fibers as demonstrated by staining for the pan-axonal marker PGP 9,5. The normal pattern is fundamental before any study, since three different techniques described in the literature with different results. Skin biopsy specimens of 3-mm in diameter were obtained from the distal leg of 30 healthy controls. Median intraepidermal nerve fiber density was 5.3/mm. Skin biopsy may be a useful tool for assessing the topographic extent and degree of nerve fiber damage in sensory neuropathies and may be particularly useful in experimental treatment trials for peripheral neuropathies since, in contrast to standard nerve biopsy, the test can be repeated.
Arquivos de Neuro-Psiquiatria 07/2004; 62(2A):271-5. · 0.72 Impact Factor
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ABSTRACT: Progressive muscular atrophy (PMA), an infrequent type of motor neuron disease (MND), is a predominantly lower motor neuron degeneration, causing muscle wasting and weakness with loss of weight and fasciculations. The diagnosis is based on rigid criteria, considering clinical aspects and eletroneuromyography findings. Blood tests and radiological investigation are necessary to look for other diagnosis mimicking PMA. We herein present 11 patients with PMA (5.9% of all our MND patients), 9 men and 2 women, which onset of symptoms occurred mainly under de age of 50, with a mean of 45.5 years. Cramp was the most frequent symptom preceding muscular weakness. Muscle pain, fatigue and fasciculations were also cited as starting symptoms. Asymmetric weakness of the arms was the most frequent pattern of onset of the disease. Bulbar muscular weakness developed in all patients during the course of the disease. Predisposing factors and distinctive clinical outcome was not observed in any of the patients. Ophthalmoparesis and sphincter dysfunction were seen in two patients who had a prolonged time in artificial respiratory assistance. Immunosuppressive therapy was ineffective in all patients. Progressive course was seen in all cases and the mean survival time was 44 months.
Arquivos de Neuro-Psiquiatria 04/2004; 62(1):119-26. · 0.72 Impact Factor
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ABSTRACT: A atrofia muscular progressiva (AMP) é um tipo raro de doença do neurônio motor (DNM) com acometimento exclusivo do neurônio motor inferior (NMI) e com características clínicas bem definidas. A eletroneuromiografia é o principal exame subsidiário para a realização do diagnóstico, com demonstração de alterações neurogênicas generalizadas, agudas e crônicas. Outras doenças que mimetizam comprometimento do NMI devem ser excluídas através de investigação laboratorial ampla. Neste estudo são apresentados 11 casos de AMP (5,9% de todos os nossos casos de DNM), sendo 9 homens e 2 mulheres. O início dos sintomas ocorreu preferencialmente abaixo dos 50 anos, com média de idade de 45,5 anos. A cãibra foi o sintoma que mais comumente precedeu a fraqueza muscular. Outras queixas preliminares foram dor, fadiga muscular e fasciculações. O padrão mais freqüente de inauguração dos sintomas foi fraqueza muscular assimétrica, preferencialmente nos membros superiores. Com a evolução da doença, todos os pacientes apresentaram comprometimento bulbar. Não foi identificado nenhum fator predisponente para a doença, nem tampouco as evoluções foram distintas entre os casos. Oftalmoparesia e acometimento dos esfíncteres, sinais pouco comuns nas DNMs, foram observados em dois pacientes que se mantiveram por longo tempo em respiração artificial. As terapêuticas imunossupressoras / imunomodulatórias utilizadas (ciclofosfamida, gamaglobulina hiperimune, plasmaferese) não tiveram resultado favorável. A doença teve caráter progressivo em todos os casos. Todos os pacientes faleceram, com tempo médio de sobrevida de 44 meses.
Arquivos de Neuro-Psiquiatria. 01/2004;
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ABSTRACT: O recente método de avaliação das fibras nervosas intraepidérmicas com o PGP 9,5 vem se mostrando de grande utilidade no diagnóstico das neuropatias sensitivas de fibras finas, autonômicas e neuropatias periféricas subclínicas. Devido à variação da técnica relatada na literatura é de fundamental importância uma padronização normal. Estudamos 15 homens e 15 mulheres com média de idade de 34,5 anos. Em todos os voluntários foi realizada biopsia de pele na porção distal da perna. A média da densidade linear das fibras nervosas intraepidérmicas foi 5,3/mm com mediana de 6,0 e desvio padrão de 1,94. Essa técnica possui um grande número de vantagens em relação à biopsia de nervo convencional, é simples, pouco invasiva, reproduzível e pode ser repetida no mesmo paciente para avaliar progressão da neuropatia e possíveis respostas terapêuticas.
Arquivos de Neuro-Psiquiatria. 01/2004;
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ABSTRACT: To describe the early and late postoperative data from SMA patients with surgical procedure.
Clinical data and radiographic imaging from 14 SMA patients with surgical treatment of scoliosis were reviewed, and all were reassessed clinically with new spinal radiographs and a questionnaire. The mean follow-up were 22 months. The mean preoperative Cobb angle was 78.4 . All patients presented pelvic obliquity (mean 25.5 ) and 11 had cifosis. The mean age at time of surgery was 12 years and 3 months. All patients were treated with posterior spinal fusion with Luque-Galveston instrumentation in 12 and Cotrel-Dubousset instrumentation in 2.
The average curve correction at the immediate postoperative was 64.3% for scoliosis and 36.4% for cifosis, with the pelvic obliquity correction of the 70.9%. The complications were liquoric fistula and infection earlier in one case, and lately wire looseness of T1 in 2 patients. It was detected mean lost of the correction at the final assessment of the 0.26 of the scoliosis and the 1.28 of the pelvic obliquity. Relatives and the patients related good improvement regarding to esthetic aspects, posture balance, body care, as well as respiratory problems.
The spinal fusion for scoliosis in SMA patients has a satisfactory impact for esthetic, quality of life and respiratory function, with minimal lost of corrected deformities and few complications.
Arquivos de Neuro-Psiquiatria 10/2003; 61(3A):631-8. · 0.72 Impact Factor
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ABSTRACT: Nemaline myopathy is a structural congenital myopathy associated with the presence of rodlike structures inside the muscle fibers and type I predominance. It may be caused by mutations in at least five genes: slow alpha-tropomyosin 3 (chromosome 1q22-23), nebulin (chromosome 2q21.1-q22), actin (chromosome 1q42), tropomyosin 2 (chromosome 9p13), and troponin T1 (chromosome 19q13.4). The effect of these mutations in the expression of the protein and the mechanism of rod formation is still under investigation. We analyzed the possibility of progressive alterations with time and/or disease evolution, such as transformation of type I to type II fiber and rod pattern and distribution in muscle fibers from patients with nemaline myopathy, through a morphometric and immunohistochemical analysis of different muscle protein isoforms. A tendency of diffuse rods to be organized in the subsarcolemmal region was observed in two patients who were submitted to subsequent biopsies after 10 and 13 years. Additionally, we observed the expression of type II protein isoforms in type I fibers and a higher proportion of type II fibers in the younger patient of a pair of affected sibs, giving further support to the hypothesis of progressive conversion of type II to type I fibers in nemaline myopathy.
Journal of Child Neurology 04/2003; 18(3):235-40. · 1.75 Impact Factor
