Congenital muscular dystrophy caused by beta1,3-Nacetylgalactosaminyltransferase 2 gene mutation:Two case reports

BACKGROUND Mutations in the beta1,3-N-acetylgalactosaminyltransferase 2(B3GALNT2)gene can lead to impaired glycosylation ofα-dystroglycan,which,in turn,causes congenital muscular dystrophy(CMD).The clinical phenotypes of CMD are broad,and there are only a few reports of CMD worldwide.CASE SUMMARY This report describes the cases of two children with CMD caused by B3GALNT2 gene mutation.The main manifestations of the two cases were abnormal walking posture,language development delay,and abnormal development of the white matter.Case 2 also had unreported symptoms of meningocele and giant arachnoid cyst.Both cases had compound heterozygous mutations of the B3GALNT2 gene,each containing a truncated mutation and a missense mutation,and three of the four loci had not been reported.Nineteen patients with CMD caused by B3GALNT2 gene mutation were found in the literature.Summary and analysis of the characteristics of CMD caused by B3GALNT2 gene mutation showed that 100%of the cases had nervous system involvement.Head magnetic resonance imaging often showed abnormal manifestations,and more than half of the children had eye and muscle involvement;some of the gene-related symptoms were self-healing.CONCLUSION B3GALNT2 gene can be used as one of the candidate genes for screening CMD,cognitive development retardation,epilepsy,and multiple brain developmental malformations in infants.

Homozygous deletion, c. 1114-1116del, in exon 8 of the CRPPA gene causes congenital muscular dystrophy in Chinese family: A case report

BACKGROUND Congenital muscular dystrophy(CMD)is a clinically and genetically heterogeneous group of inherited muscle disorders.Mutations in the CRPPA gene(encoding CDPLribitol pyrophosphorylase A)are recognized as causative factors of dystroglycanopathies,a subtype of CMD with defects in glycosylation.CASE SUMMARY The present study examined a Chinese family,whose proband presented mainly with muscle weakness in both lower limbs but without brain and eye symptoms.In this family,a homozygous deletion,c.1114-1116del(p.V372del),was identified in exon 8 of CRPPA in the proband,while a heterozygous deletion was identified in the proband’s father and mother,who lacked symptoms.A mild dystroglycanopathy of CMD was diagnosed.CONCLUSION The findings of this study expanded the clinical and mutational spectrum of patients with CMD associated with CRPPA mutations.

Clinical manifestations and prenatal diagnosis of Ullrich congenital muscular dystrophy: A case report

BACKGROUND Ullrich congenital muscular dystrophy(UCMD)is one of the collagen-VI-related myopathies caused by mutations of COL6A1,COL6A2,and COL6A3 genes.Affected individuals are characterized by muscle weakness,proximal joint contracture,distal joint hyperlaxity,and progressive respiratory failure.There is currently no cure for UCMD.Here,we report the clinical manifestations and prenatal diagnosis of compound heterozygous mutations of the COL6A2 gene in a Chinese family with UCMD.CASE SUMMARY A 3-year-old boy,his 4-year-old brother,their parents,and a 20-wk-old fetus in the mother’s womb were included in the study.The brothers had the typical manifestations of the early-severe subtype:A delayed motor milestone(never walking independently),torticollis,scoliosis,proximal joint contracture,distal joint hyperextension,right hip joint dislocation,and calcaneal protuberance.Both brothers were found by whole-exome sequencing and Sanger sequencing to carry two mutations of the COL6A2 gene(c.1353_c.1354insC,p.Arg453Profs-Ter42/c.2105G>A,p.Trp702Ter).The absence of collagen VI staining in the younger brother’s muscle was identified accurately.Genetic counseling and prenatal diagnosis were crucial for the family,as the autosomal recessive genetic disease affected a quarter of the patient’s siblings.The fetus of the mother’s third child underwent prenatal diagnosis and carried the same two mutations of COL6A2,confirmed in the amniotic fluid by multiplex ligation-dependent probe amplification and short tandem repeats.After a painful psychological struggle,the parents finally decided to terminate the pregnancy.CONCLUSION We report a Chinese family suffering from UCMD.By clarifying the COL6A2 mutations in the probands,the parents had the opportunity to opt for voluntary interruption of the third UCMD pregnancy.

Lama1 upregulation prolongs the lifespan of the dy^(H)/dy^(H) mouse model of LAMA2-related congenital muscular dystrophy

LAMA2-related congenital muscular dystrophy(LAMA2-CMD),characterized by laminin-α2 deficiency,is debilitating and ultimately fatal.To date,no effective therapy has been clinically available.Laminin-a1,which shares significant similarities with laminin-a2,has been proven as a viable compensatory modifier.To evaluate its clinical applicability,we establish a Lama2 exon-3-deletion mouse model(dy^(H)/dy^(H)).The dy^(H)/dy^(H) mice exhibit early lethality and typical LAMA2-CMD phenotypes,allowing the evaluation of various endpoints.In dy^(H)/dy^(H) mice treated with synergistic activation mediator-based CRISPRa-mediated Lama1 upregulation,a nearly doubled median survival is observed,as well as improvements in weight and grip.Significant therapeutical effects are revealed by MRl,serum biochemical indices,and muscle pathology studies.Treating LAMA2-CMD with LAMA1 upregulation is feasible,and early intervention can alleviate symptoms and extend lifespan.Additionally,we reveal the limitations of LAMA1 upregulation,including high-dose mortality and non-sustained expression,which require further optimization in future studies.

Genetic and Clinical Advances of Congenital Muscular Dystrophy

Objective： The aim was to update the genetic and clinical advances of congenital muscular dystrophy （CMD）, based on a systematic review of the literature from 1991 to 2017. Data Sources： Articles in English published in PubMed from 1991 to 2017 English were searched. The terms used in the literature searches were CMD. Study Selection： The task force initially identified citations for 98 published articles. Of the 98 articles, 52 studies were selected after further detailed review. Three articles, which were not written in English, were excluded from the study. This study referred to all the important and English literature in full. Results： CMD is a group of early-onset disorders encompassing great clinical and genetic heterogeneity. Patients present with muscle weakness typically from birth to early infancy, delay or arrest of gross motor development, and joint and/or spinal rigidity. The diagnosis of CMD relies on clinical findings, brain and muscle imaging, muscle biopsy histology, muscle and/or skin immunohistochemical staining, and molecular genetic testing. Conclusions： Advances in next-generation sequencing and histopathological techniques have enabled the recognition of distinct CMD subtypes supported by specific gene identification. Genetic counseling and multidisciplinary management of CMD play an important role in help patients and their family. Further elucidation of the significant clinical and genetic heterogeneity, therapeutic targets, and the clinical care for patients remains our challenge for the future.

Novel collagen VI mutations identified in Chinese patients with Ullrich congenital muscular dystrophy

Background:We determined the clinical and molecular genetic characteristics of 8 Chinese patients with Ullrich congenital muscular dystrophy(UCMD).Methods:Clinical data of probands were collected and muscle biopsies of patients were analyzed.Exons of COL6A1,COL6A2 and COL6A3 were analyzed by direct sequencing.Mutations in COL6A1,COL6A2 and COL6A3 were identifi ed in 8 patients.Results:Among these mutations,5 were novel[three in the triple helical domain(THD)and 2 in the second C-terminal(C2)domain].We also identified five known missense or in-frame deletion mutations in THD and C domains.Immunohistochemical studies on muscle biopsies from patients showed reduced level of collagen VI at the muscle basement membrane and mis-localization of the protein in interstitial and perivascular regions.Conclusions:The novel mutations we identified underscore the importance of THD and C2 domains in the assembly and function of collagen VI,thereby providing useful information for the genetic counseling of UCMD patients.

Benign Congenital Muscular Dystrophy with Autosomal Dominant Heredity

Benign congenital muscular dystrophy with autsomal dominant heredity of a pedigree is reported.The grandfather.

Muscle Magnetic Resonance Imaging in Patients with Various Clinical Subtypes of LMNA-Related Muscular Dystrophy

Background： LMNA-related muscular dystrophy can manifest in a wide variety of disorders, including Emery-Dreifuss muscular dystrophy （EDMD）, limb-girdle muscular dystrophy （LGMD）, and LMNA-associated congenital muscular dystrophy （L-CMD）. Muscle magnetic resonance imaging （MRI） has become a useful tool in the diagnostic workup of patients with muscle dystrophies. This study aimed to investigate whether there is a consistent pattern of MRl changes in patients with LMNA mutations in various muscle subtypes. Methods： Twenty-two patients with LMNA-related muscular dystrophies were enrolled in this study. M RI of the thigh and/or calf muscles was performed in them. The muscle MRI features of the three subtypes were compared by the Mann-Whitney U-test. The relationship between the clinical and MRI findings was also investigated by Spearman＇s rank analyses. Results： The present study included five EDMD, nine LGMD, and eight L-CMD patients. The thigh muscle MRI revealed that the fatty infiltration of the adductor magnus, semimembranosus, long and short heads of the biceps femoris, and vasti lnuscles, with relative sparing of the rectus femoris, was the predominant change observed in the EDMD, LGMD, and advanced-stage L-CMD phenotypes, ahhough the involvement of the vasti muscles was not prominent in the early stage of L-CMD. At the level of the call; six patients （one EDMD, four LGMD, and one L-CMD） also showed a similar pattern, in which the soleus and the medial and lateral gastrocnemius muscles were most frequently observed to have fatty infiltration. The fatty infiltration severity demonstrated higher scores associated with disease progression. with a corresponding rate of 1.483 ＋ 0.075 × disease dnration （X） （r = 0.444, P - 0.026）. It was noteworthy that in six L-CMD patients with massive inflammatory cell infiltration in muscle pathology, no remarkable edema-like signals were observed in muscle MRI. Conclusions： EDMD, LGMD and advanced-staged L-CMD subtypes showed similar pattern of muscle MRI changes, while early-staged L-CMD showed somewhat different changes. Muscle MRI of L-CMD with a nluscular dystrophy pattern in MRI provided important clues for differentiating it from childhood inflammatory myopathy. The fatty infiltration score could be used as a reliable biomarker for outcome measure of disease progression.