Fardeau, M. et al.. Juvenile limb-girdle muscular dystrophy: clinical, histopathological and genetic data from a small community living in the Reunion Island. Brain 119, 295-308

INSERM U153, Paris, France.
Brain (Impact Factor: 9.2). 03/1996; 119 ( Pt 1)(1):295-308. DOI: 10.1093/brain/119.1.295
Source: PubMed


A series of patients affected by a muscular dystrophy, similar to the original description of a juvenile scapulo-humeral form by Erb in 1884 and fitting with the criteria used to define limb-girdle muscular dystrophies, was discovered in a small community living in the southern part of Reunion Island in the Indian Ocean. A detailed clinical analysis was conducted over 5 years on a cohort of 20 patients. This community presented a high degree of consanguinity as it was segregated from the majority of the island population for more than a century. In previous molecular genetic studies, the disease locus has been mapped to chromosome 15p. Mutations were recently identified in a gene located in this region encoding for muscle-specific calcium activated neutral protease (CANP3). Clinical, pathological, genetic and complete identification of the mutations are presented here, establishing, for the first time, precise clinico-genetic correlations in this form of autosomal recessive, juvenile, limb-girdle muscular dystrophy (LGMD).

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    • "Limb girdle muscular dystrophy (LGMD) is a group of progressive muscle diseases, with weakness and wasting affecting predominantly shoulder and pelvic girdle muscles of both males and females with clinical onset, in general, in the first three decades [1] [2] [3] [4]. The initial clinical description of what is now known as an LGMD goes back over 100 years when a German neurologist, Wilhelm Neurich Erb, described a juvenile form of scapulo-humeral form of muscular dystrophy [5]. "
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    ABSTRACT: Calpain 3 is a member of the calpain family of calcium-dependent intracellular proteases. Thirteen years ago it was discovered that mutations in calpain 3 (CAPN3) result in an autosomal recessive and progressive form of limb girdle muscular dystrophy called limb girdle muscular dystrophy type 2A. While calpain 3 mRNA is expressed at high levels in muscle and appears to have some role in developmental processes, muscles of patients and mice lacking calpain 3 still form apparently normal muscle during prenatal development; thus, a functional calpain 3 protease is not mandatory for muscle to form in vivo but it is a pre-requisite for muscle to remain healthy. Despite intensive research in this field, the physiological substrates of the calpain 3 protein (hereafter referred to as CAPN3) and its alternatively spliced isoforms remain elusive. The existence of these multiple isoforms complicates the search for the physiological functions of CAPN3 and its pathophysiological role. In this review, we summarize the genetic and biochemical evidence that point to loss of function of the full-length isoform of CAPN3, also known as p94, as the pathogenic isoform. We also argue that its natural substrates must reside in its proximity within the sarcomere where it is stored in an inactive state anchored to titin. We further propose that CAPN3 has many attributes that make it ideally suited as a sensor of sarcomeric integrity and function, involved in its repair and maintenance. Loss of these CAPN3-mediated activities can explain the "progressive" development of muscular dystrophy.
    Full-text · Article · Nov 2008 · Neuromuscular Disorders
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    • "Limb-girdle muscular dystrophy (LGMD), a kind of progressive muscular dystrophy (PMD), is a group of heterogeneous disorders with variable clinical and genetic features including autosomal dominant and recessive subgroups [12], in which the pelvic and shoulder girdle musculatures are predominantly or primarily involved. This kind of disease is also characterized by increased SCK levels, muscle fiber necrosis, and regeneration [13]. LGMD varies greatly from patient to patient in the age of onset, in disease progression and in the distribution of the affected muscles [14]. "
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    ABSTRACT: Limb-girdle muscular dystrophy (LGMD) is a group of heterogeneous muscular disorders with autosomal dominant and recessive inheritance, in which the pelvic or shoulder girdle musculature is predominantly or primarily involved. Although analysis of the defective proteins has shed some light onto their functions implicated in the etiology of LGMD, our understanding of the molecular mechanisms underlying muscular dystrophy remains incomplete. To give insight into the molecular mechanisms of AR-LGMD, we have examined the differentially expressed gene profiling between the relative normal and pathological skeletal muscles from the same AR-LGMD patient with the differential display RT-PCR approach. The research subjects came from a Chinese AR-LGMD family with three affected sisters. In this report, we have identified 31 known genes and 12 unknown ESTs, which were differentially expressed between the relative normal and dystrophic muscle from the same LGMD patient. The expression of many genes encoding structural proteins of skeletal muscle fibers (such as titin, myosin heavy and light chains, and nebulin) were dramatically down-regulated in dystrophic muscles compared to the relative normal muscles. The genes, reticulocalbin 1, kinectin 1, fatty acid desaturase 1, insulin-like growth factor binding protein 5 (IGFBP5), Nedd4 family interacting protein 1 (NDFIP1), SMARCA2 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2), encoding the proteins involved in signal transduction and gene expression regulation were up-regulated in the dystrophic muscles. The functional analysis of these expression-altered genes in the pathogenesis of LGMD could provide additional information for understanding possible molecular mechanisms of LGMD development.
    Full-text · Article · Feb 2006 · Journal of Translational Medicine
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    • "In contrast to LGMD2I in both dystrophies there is more involvement of the quadriceps muscle than the posterior thigh compartment muscles (B, E). However, in the lower limbs in dystrophinopathy Becker type the most severe changes are observed in both heads of the gastrocnemius muscle (C), which is not seen in alpha-sarcoglycanopathy (F) tern known from LGMD2A (Fardeau et al. 1996; Pollitt et al. 2001). It is noteworthy, however, that calpainopathy differs clinically from LGMD2I in some important features: the rare occurrence of generalised or calf hypertrophy (seen in two thirds of LGMD2I patients) and the absence of cardiac involvement (occurring in about 30 % of LGMD2I patients) (Mercuri et al. 2003; Poppe et al. 2003). "
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    ABSTRACT: Mutations in the fukutin-related protein (FKRP) have recently been demonstrated to cause limb girdle muscular dystrophy type 2I (LGMD2I), one of the most common forms of the autosomal recessive LGMDs in Europe. We performed a systematic clinical and muscle MRI assessment in 6 LGMD2I patients and compared these findings with those of 14 patients with genetically confirmed diagnosis of other forms of autosomal recessive LGMDs or dystrophinopathies. All LGMD2I patients had a characteristic clinical phenotype with predominant weakness of hip flexion and adduction, knee flexion and ankle dorsiflexion. These findings were also mirrored on MRI of the lower extremities which demonstrated marked signal changes in the adductor muscles, the posterior thigh and posterior calf muscles. This characteristic clinical and MRI phenotype was also seen in LGMD2A. However, in LGMD2A there was a selective involvement of the medial gastrocnemius and soleus muscle in the lower legs which was not seen in LGMD2I. The pattern in LGMD2A and LGMD2I were clearly different from the one seen in alpha-sarcoglycanopathy and dystrophinopathy type Becker which showed marked signal abnormalities in the anterior thigh muscles. Our results indicate that muscular MRI is a powerful tool for differentiating LGMD2I from other forms of autosomal recessive LGMDs and dystrophinopathies.
    Full-text · Article · Jun 2005 · Journal of Neurology
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