Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Abstract

-The congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem), CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscleeye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D), and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.Key WorDs: congenital muscular dystrophy, MDC1A, collagen VI related disorders, glycosylation of alphadystroglycan, Fukuyama DMC, muscle-eye-brain (MeB) disease, Walker-Warburg syndrome, rigid spine syndrome. distrofia muscular congênita. parte ii: revisão da patogênese e perspectivas terapêuticas resumo -As distrofias musculares congênitas (DMCs) são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. são caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. o quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. os aspectos clínicos e diagnósticos dos principais subtipos de DMC foram apresentados no número anterior deste periódico, como primeira parte desta revisão. Nesta segunda parte apresentaremos os principais mecanismos patogênicos e as perspectivas terapêuticas dos subtipos mais comuns de DMC: DMC tipo 1A com deficiência de merosina, DMCs relacionadas com alterações do colágeno VI (Ullrich e Bethlem), e DMCs com anormalidades de glicosilação da alfa-distroglicana (DMC Fukuyama, DMC "Muscle-eye-brain" ou MeB, síndrome de Walker Warburg, DMC tipo 1C, DMC tipo 1D). A DMC com espinha rígida, mais rara e não relacionada com alterações do complexo distrofina-glicoproteínas associadas-matriz extracelular também será abordada quanto aos mesmos aspectos patogênicos e terapêuticos.PAlAVrAs-ChAVes: distrofia muscular congênita, merosina, colágeno VI, glicosila...

Dystroglycan controls signaling of multiple hormones through modulation of STAT5 activity

“…Notably, a close relationship between DG and integrin signaling has been observed in the brain where, similarly to our observations in the mammary gland, there is a convergence of phenotypes observed among the conditional knockouts of DG, 1 integrin, FAK and ILK, where each exhibits defects of cortical organization (Beggs et al, 2003;Graus-Porta et al, 2001;Moore et al, 2002;Niewmierzycka et al, 2005;Satz et al, 2008). Similar CNS abnormalities are observed in mouse models of congenital muscular dystrophies originating from defects in laminin-2, 71 integrin or DG function (Lee et al, 2005;Levedakou et al, 2005;Miyagoe et al, 1997;Satz et al, 2008), and are reflected in human congenital muscular dystrophy patients with defects of laminin-2 and DG (Reed, 2009). Correspondingly, mice expressing hypomorphic Stat5 alleles demonstrate defects of cell proliferation and neural migration in the CNS (Hennighausen and Robinson, 2008;Markham et al, 2007), portending that loss of STAT5 activity can underlie CNS defects of congenital muscular dystrophies.…”

CNS findings in congenital muscular dystrophy 1A (with laminin alpha-2-deficiency)

“…The clinical outcome concerning cognition and speech does not correlate to the changes in white matter detected by MRI [1,2]. Cortical abnormalities indicate an elevated risk for epilepsy and developmental delay [9].…”

“…Biopsies of affected muscle tissue show dystrophic changes. However, cardiac muscle involvement is rare [1,2].…”

“…The alpha-2 subunit of laminin is also expressed in the basal lamina of the Schwann cell-axon unit and a deficiency can cause congenital muscular dystrophy associated with peripheral motor neuropathy [5]. Patients develop marked muscle weakness and atrophy, diffuse joint contractures, an inability to achieve independent ambulation, facial dysmorphism and significant elevations of creatine kinase (CK) levels in blood serum [1,2]. A partial deficiency of LAMA2 protein can result in various phenotypes.…”

Anaesthesia Management and Use of Sugammadex in a Patient with Ullrich’s Disease

“…cleroatonic muscular dystrophy also known as Ullrich's Disease is an autosomal recessive congenital muscular dystrophy that is characterized with generalized muscle weakness, multiple contractures in the axial joints and hyper-laxity in the distal joints with increased creatine phosphokinase levels (1). A defect in the collagen IV that is an extracellular matrix protein is held responsible (2).…”