Limb-girdle muscular dystrophy in Brazilian children: clinical, histological and molecular characterization

Abstract

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic muscular dystrophies, involving 16 autosomal recessive subtypes and eight autosomal dominant subtypes. Autosomal recessive dystrophy is far more common than autosomal dominant dystrophy, particularly in children. The clinical course in this group is characterized by progressive proximal weakness, initially in pelvic and after in shoulder-girdle musculature, varying from very mild to severe degree. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunolabeling studies, and DNA analysis is the gold standard to establish the specific form of muscular dystrophy. Objectives: The aim of this study was to characterize the clinical, histological and molecular aspects in children with LGMD who attend a big public neuromuscular centre in our country to determine the frequency of different forms. Method: Thirty seven patients were classified as LGMD and included in this analysis. The study period extended from 2009-2012. The female to male ratio was 3:1. The age of onset ranged from two to 13 years, mean 7,5 years. Onset in the first decade was seen in 90%. Results: The initial clinical signs included: frequent falls (22 cases), difficulty in climbing stairs (13 cases), walk on tip toes (2 cases), difficulty in rising from the floor (2 cases) and difficulty on walking (1 case). The serum CK levels were high in all cases. Among the 37 patients, 15 (40,5%) were classified as sarcoglycanopathies (LGMD2C-F), five (13,5%) as dysferlinopathy (LGMD2B), five (13,5%) as calpainopathy (LGMD2A). Mutations in LMNA gene (LGMD1B), FKRP gene (LGMDI) and caveolin gene (LGMD 1C) were identified in two (5,5%), two (5,5%) and one patient (2,5%), respectively. In seven of 37 cases (19%) it was impossible to determine specific diagnosis. Calf hypertrophy, scapular winging and scoliosis were the most characteristic signs in sarcoglycanopathies. In LGMD2I calf hypertrophy is also observed. Atrophy of posterior compartment of thighs is frequent in children with LGMD2B and could suggest the diagnosis. In LGMD2A winging of scapulae and contractures in Achilles tendons were important findings. Muscle biopsy showed a dystrophic pattern in all cases, more intense in sarcoglycanopathies and LGMD2I. Differently from adult's patients, inflammation changes in dysferlinopaties were uncommon. Lobuled fibers were characteristic changes in calpainopathies in children. Conclusions: A definitive diagnosis among various subtypes of LGMD in children is challenging. Our series was a large study on LGMD in Brazilian children and showed high frequency of sarcoglycanopathies followed by LGMD2A, LGMD2B, LGMD2I, LGMD1B and LGMD1C.

Clinicogenetic lessons from 370 patients with autosomal recessive limb‐girdle muscular dystrophy

“…Our epidemiological profile is similar to recent large samples studies from Italy and the United States; however, it partially differed from previous Brazilian reports more focused on the pediatric population. A previous single‐center study in São Paulo reported that sarcoglycanopathies were diagnosed in 40.5% of a series of 37 children with LGMD2/LGMD‐R . A single‐center study from southern Brazil evaluated 56 patients with LGMD only with immunohistochemistry and reported sarcoglycanopathies (32%) as the most common diagnosis, followed by LGMD2B/LGMD‐R2‐dysferlin‐related (14.3%) and LGMD2A/LGMD‐R1‐calpain3‐related (8.9%) .…”

“…LGMD2/LGMD‐R are the most common group of these disorders, but relative frequencies among LGMD2/LGMD‐R subtypes vary from region to region . There is a lack of epidemiological data about LGMD in Latin America, with only few single‐center studies reporting sarcoglycanopathies as the most frequent subtypes in Brazil …”

“…[8][9][10][11] There is a lack of epidemiological data about LGMD in Latin America, with only few single-center studies reporting sarcoglycanopathies as the most frequent subtypes in Brazil. [12][13][14] The differential diagnosis among LGMD subtypes relies upon muscle immunohistochemistry (IHC) and genetic diagnosis. 1,2 However, considering the growing number of subtypes and its clinical overlap, the lack of specific tests to identify protein defects for most recently described subtypes, and the costs and laboriousness of conventional Sanger sequencing diagnosis for genetically heterogeneous disorders; target or unbiased next-generation sequencing (NGS) is becoming widely used as both confirmatory and first-tier approaches for LGMD diagnosis.…”

Автосомно-Рецесивна Кінцівково-Поясна М’язова Дистрофія Типу 2А: Огляд Літератури Та Клінічні Спостереження

“…Також поступово виникли труднощі з утриманням важких предметів в руках та рук над головою (рис. [1][2][3].…”

“…Ключові слова: кінцівково-поясна м'язова дистрофія; ген CAPN3; прийом Говерса; проксимальна м'язова слабкість Вступ Кінцівково-поясна м'язова дистрофія (LGMD)це неоднорідна група генетично обумовлених нервовом'язових захворювань, що характеризуються прогресуючою слабкістю і атрофіями м'язів тазового та плечового поясів, а також значно варіабельним перебігом захворювання [1]. Найчастіше при даних формах м'язових дистрофій уражуються м'язи плечей, верхніх кінцівок, тазового пояса та стегон [2,3].…”