Miopatías relacionadas a colágeno VI: cuando sospecharlas, cómo identificarlas: aporte de la resonancia magnética muscular / Collagen VI related myopathies: when to suspect, how to identify: the contribution of muscle magnetic resonance

Resumen: Las miopatías secundarias a mutaciones en el colágeno VI (M-COLVI) son las más frecuentes en el hemisferio norte, afectando población adulta y pediátrica. No existen datos de su prevalencia en Latinoamérica. Se caracterizan por presentar una gran variabilidad clínica, desde fenotipos severos, como la distrofia muscular congénita de Ullrich (DMCU), a intermedios y leves como la Miopatía de Bethlem (MB). Su inicio también es variable y se extiende desde el período de recién nacido hasta la vida adulta. Dada la presencia de hiperlaxitud articular, el diagnóstico diferencial se debe realizar con diversas enfermedades del tejido conectivo. El algoritmo diagnóstico clásico en muchos pacientes ha sido insuficiente para orientar el estudio genético de forma adecuada, y a partir de esto la resonancia magnética muscular ha emergido como una herramienta de gran utilidad para una mejor aproxima ción diagnóstica de ésta y otras patologías musculares. Esta revisión tiene como objetivo examinar las formas de presentación, características clínicas, estudio diagnóstico específico, diagnóstico dife rencial y manejo de una de las patologías musculares herediatarias más frecuentes, con énfasis en el aporte de la resonancia magnética muscular.

Abstract: Myopathies secondary to collagen VI mutations (COLVI-M) are the most frequent in the northern hemisphere, affecting the adult and pediatric population. There are no data on its prevalence in Latin America. They are characterized by a great clinical variability, from severe phenotypes, such as Ullrich congenital muscular dystrophy (UCMD), to intermediate and mild ones such as Bethlem myopathy (BM). Its onset is also variable and extends from the neonatal period to adulthood. Given the presence of joint hypermobility, the differential diagnosis should be made with various connective tissue diseases. The classical diagnostic algorithm in many patients has been insufficient to guide the genetic study in an adequate way, and from this the muscular magnetic resonance imaging has emerged as a very useful tool for a better diagnostic approach of this and other muscular pathologies. This ob jective of this review is to study the forms of presentation, clinical characteristics, specific diagnostic study, differential diagnosis and management of one of the most frequent hereditary muscular patho logies, with emphasis on the contribution of muscle magnetic resonance imaging.

Distrofia muscular congênita de Ullrich moderadamente progressiva / Moderately progressive Ullrich congenital muscular dystrophy

OBJETIVOS: Descrever características clínicas e genéticas da distrofia muscular congênita de Ullrich (DMCU), e relatar o caso de um paciente diagnosticado com DMCU após uma exaustiva investigação, que incluiu análise imuno-histoquímica e genômica do colágeno tipo VI. DESCRIÇÃO: Este estudo baseou-se na avaliação clínica e imuno-histoquímica do tecido muscular e na análise genômica dos fibroblastos dérmicos de um menino de 7 anos e meio, e do DNA dos seus pais. São discutidos aspectos clínicos e o diagnóstico diferencial com outras doenças. COMENTÁRIOS: O melhor conhecimento das distrofias musculares congênitas aumentará o número de diagnósticos corretos e abrirá novos horizontes para o tratamento dessas doenças. A avaliação genética dos pacientes com DMCU tem implicações relevantes para o prognóstico e o aconselhamento genético da família. É aconselhável divulgar essa doença na comunidade pediátrica, devido ao início precoce das manifestações clínicas e o fato de ser frequentemente mal diagnosticada ou não ser diagnosticada.

OBJECTIVES: To describe genetic and clinical features of Ullrich congenital muscular dystrophy (UCMD), and to report the case of a patient diagnosed with UCMD after an exhaustive investigation, which included collagen VI immunohistochemical and genomic analyses. DESCRIPTIONS: This study was based on clinical, immunohistochemical assessment of muscle tissue and genomic analysis of dermal fibroblasts of a 7 1/2-year old boy and of the DNA of his parents. Clinical aspects and differential diagnosis with other disorders are discussed. COMMENTS: A better knowledge of congenital muscular dystrophies will improve the number of correct diagnoses and open new horizons for the treatment of such diseases. Genetic evaluation of UCMD patients has relevant implications for prognosis and genetic counseling of the family. The divulgation of this disorder in the pediatric community is advisable, because of the early onset of clinical manifestations and the fact that it is frequently misdiagnosed or not diagnosed at all.

Phenotypic Characterization of Ligamentum Flavum Cells from Patients with Ossification of Ligamentum Flavum

PURPOSE: The objective of this study was to determine the phenotypic characterization of ligamentum flavum cells from patients with ossification of the ligamentum flavum (OLF). MATERIALS AND METHODS: Ligamentum flavum tissues were harvested from OLF and non-OLF patients during surgery. OLF and non-OLF cells were isolated from explant cultures. Cultured cells were analyzed using immunofluorescence staining and reverse transcription-polymerase chain reaction. RESULTS: OLF cells exhibited various appearances compared with the typical fibroblast-like morphology of non-OLF cells. Expressions of collagen type I and collagen type III were observed in OLF and non-OLF cells. OLF cells uniquely expressed osteocalcin, which is a marker for osteoblasts, and collagen type II which is a marker for chondrocytes, whereas they were negative in non-OLF cells. CONCLUSION: These findings indicate that OLF cells have phenotypic characterization of osteoblasts and chondrocytes which could play a role in the pathophysiology of OLF.

Identification of COL6A1 as a differentially expressed gene in human astrocytomas

Diffuse infiltrating gliomas are the most common tumors of the central nervous system. Gliomas are classified by the WHO according to their histopathological and clinical characteristics into four classes: grade I (pilocytic astrocytoma), grade II (diffuse astrocytoma), grade III (anaplastic astrocytoma), and grade IV (glioblastoma multiforme). Several genes have already been correlated with astrocytomas, but many others are yet to be uncovered. By analyzing the public SAGE data from 21 patients, comprising low malignant grade astrocytomas and glioblastomas, we found COL6A1 to be differentially expressed, confirming this finding by real time RT-PCR in 66 surgical samples. To the best of our knowledge, COL6A1 has never been described in gliomas. The expression of this gene has significantly different means when normal glia is compared with low-grade astrocytomas (grades I and II) and high-grade astrocytomas (grades III and IV), with a tendency to be greater in higher grade samples, thus rendering it a powerful tumor marker.

Ullrich congenital muscular dystrophy and Bethlem myopathy: clinical and genetic heterogeneity

Ullrich congenital muscular dystrophy (UCMD), due to mutations in the collagen VI genes, is an autosomal recessive form of CMD, commonly associated with distal joints hyperlaxity and severe course. A mild or moderate involvement can be occasionally observed. OBJECTIVE: To evaluate the clinical picture of CMD patients with Ullrich phenotype who presented decreased or absent collagen VI immunoreactivity on muscular biopsy. RESULTS: Among 60 patients with CMD, two had no expression of collagen V and their clinical involvement was essentially different: the first (3 years of follow-up) has mild motor difficulty; the second (8 years of follow-up) never acquired walking and depends on ventilatory support. A molecular study, performed by Pan et al. at the Thomas Jefferson University, demonstrated in the first a known mutation of Bethlem myopathy in COL6A1 and in the second the first dominantly acting mutation in UCMD and the first in COL6A1, previously associated only to Bethlem myopathy, with benign course and dominant inheritance. CONCLUSION: Bethlem myopathy should be considered in the differential diagnosis of UCMD, even in patients without fingers contractures; overlap between Ullrich and Bethlem phenotypes can be supposed.

A distrofia muscular congênita (DMC) com hiperextensibilidade articular distal (fenótipo Ullrich) associa-se a mutações nos genes do colágeno VI e corresponde a um grave quadro congênito de herança autossômica recessiva e curso progressivo, ocasionalmente mostrando menor gravidade. OBJETIVO: Avaliar o quadro clínico dos pacientes com DMC tipo Ullrich que apresentam imunoexpressão baixa ou ausente do colágeno VI na biópsia muscular. RESULTADOS: Entre 60 pacientes com DMC, dois mostravam imunomarcação negativa do colágeno VI. Mostravam-se clinicamente essencialmente diferentes: o primeiro, com 8 anos de idade e três de seguimento mostra leve dificuldade motora; o segundo, com 14 anos de idade e 8 de seguimento, não deambula e apresenta insuficiência respiratória. O estudo molecular, realizado na Thomas Jefferson University por Pan et al., revelou no primeiro, no gene COL6A1, mutação típica da miopatia de Bethlem, que tem curso benigno e herança autossômica dominante; e no segundo a primeira mutação de efeito dominante e do gene COL6A1, previamente associado apenas à miopatia de Bethlem. CONCLUSÃO: A miopatia de Bethlem deve constar no diagnóstico diferencial da DMC tipo Ullrich, mesmo na ausência das típicas contraturas dos dedos; pode existir sobreposição dos fenótipos Ullrich e Bethlem.