Spectrum Of Congenital Muscular Dystrophies Research Articles

Analysis of clinical features and FKTN gene variant in a child with congenital muscular dystrophy

To analyze the clinical features and genetic basis for a child featuring elevated creatine kinase (CK). Next-generation sequencing (muscular dystrophy related gene panel) was carried out for the proband. Candidate variants were verified by Sanger sequencing of the child and his parents. The child was found to harbor compound heterozygous variants of the FKTN gene, including a missense c.536G>C (p.R179T) variant from his father and a non-frameshift c.1299_1301delGTG (p.W434del) variant from his mother. Both variants were predicted to be pathogenic. The compound heterozygous variants of the FKTN gene probably underlay the disease in this child. Above finding has expanded the mutation spectrum of congenital muscular dystrophy.

Muscle disorders P-MU002. Mutation spectrum of congenital muscular dystrophies: A case series from India

Introduction . Congenital muscular dystrophies (CMD) are a group of neuromuscular disorders with clinical and genetic heterogeneity with onset at birth or infancy. Little is known about the genetic spectrum of CMD in India. Methods . A retrospective study on genetically confirmed CMDs (2015- 2019). Detailed phenotyping and Next Generation Sequencing (NGS) were done. Results . A total of 19 patients were classified into 5 subgroups based on the protein and gene defect. Ullrich CMD group=three patients, mean age of onset of 1year, M:F=2:1, clinically had motor delay and limb girdle weakness, proximal contractures, distal hypotonia, joint hyperextensibility, prominent calcaneum and velvety palms/soles. Homozygous mutations were found in COL6A2[c.310C>T(p.Gln104Ter), (c.2098G>A(p.Gly700Ser)), COL6A3[c.79C>T(p.Gln27Ter)] gene respectively. Bethlem myopathy=6 patients, mean age of onset=10 years, M:F= 2:4, had limb girdle weakness, prominent calf hypertrophy and contractures. Heterozygous mutations in COL6A1[c.805G>A; p.Gly269Arg], COL6A2{[c.655A>C(p.Met219Leu)], [c.1690G>C (p.Gly564Arg)]}; COL6A3{[c.6309+3A>G 5' splice site], [c.175C>T(p.Arg59Ter)]}; COL12A1[c.2944G>A (p.Gly982Arg)] respectively. Merosin deficient=5 patients, mean age of onset=4 years, M: F=2:3, had motor delay with limb girdle weakness, bifacial weakness, proximal and distal contractures, calf hypertrophy. Neuroimaging showed leukoencephalopathy with cerebellar cysts. Mutations were homozygous in LAMA2 gene in two patients [c.6350A>G] and exon 13 (c. 1823_1824del(p.Tyr608Ter) respectively and compound heterozygous in three [Exon,36- c.5176A>T(p.Lys1726Ter); Exon,56-c.7810C>T(p.Arg2604Ter)], (exon 8c.1176_1177del)p.Cys393TyrfsTer2), exon38(c.5476C>T(p.Arg1826Ter), [Exon,49- c.6955C>T(p.Arg2319Ter), CNVvariation(deletion)- exon,34-37]. Emery-Dreifuss Muscular dystrophy=3, mean age of onset of 10 years, M:F=1:2, had limb girdle pattern of weakness, elongated facies, neck and elbow contractures, kyphoscoliosis, scapular winging. Heterozygous mutations in LMNA gene seen in all 3 [c.115A>C (p.Asn39His)], [c.1357C>T(p.Arg453Trp)] and c.305T>C. CMD dystroglycanopathy with or without mental- retardation=two with onset in infancy, had motor delay, genetically had homozygous mutation in FKRP gene [c.1343C>T(p.Pro448Leu)] and POMT1(c.193G>A(p.Gly65Arg) Conclusion . This study describes a large cohort of genetically confirmed CMDs from a single center in India and demonstrates the genetic heterogeneity.

Genetic variations and clinical spectrum of dystroglycanopathy in a large cohort of Chinese patients.

Dystroglycanopathy is a group of muscular dystrophies with deficient glycosylation of alpha-dystroglycan (α-DG). We recruited patients from 36 tertiary academic hospitals in China. In total, 143 patients with genetically diagnosed dystroglycanopathy were enrolled. Of these, limb girdle muscular dystrophy was the most common initial diagnosis (83 patients) and Walker-Warburg syndrome was the least common (1 patient). In 143 patients, mutations in FKRP gene were the most prevalent (62 patients), followed by POMT2, POMT1 (16), POMGNT1, ISPD (14), FKTN, GMPPB, B3GALNT2, DPM3, and DAG1. Several frequent mutations were identified in FKRP, POMT1, POMGNT1, ISPD, and FKTN genes. Many of these were founder mutations. Patients with FKRP mutations tended to have milder phenotypes, while those with mutations in POMGNT1 genes had more severe phenotypes. Mental retardation was a clinical feature associated with mutations of POMT1 gene. Detailed clinical data of 83 patients followed up in Peking University First Hospital were further analyzed. Our clinical and genetic analysis of a large cohort of Chinese patients with dystroglycanopathy expanded the genotype variation and clinical spectrum of congenital muscular dystrophies.

Cannabinoid receptor‐1 expressing interneurons require postsynaptic dystroglycan for targeting during postnatal brain development

Dystroglycan is a transmembrane glycoprotein highly expressed in muscle and brain that links the extracellular matrix to the actin cytoskeleton through its two subunits, a heavily glycosylated extracellular subunit alpha dystroglycan (a‐DG), and the membrane spanning beta‐dystroglycan (b‐DG). Glycosylation of dystroglycan by at least 18 enzymes is essential for its ability to bind extracellular ligands throughout development. Mutations in genes encoding glycosyltransferases such as B4gat1 and ISPD reduce dystroglycan function and cause a spectrum of congenital muscular dystrophies characterized by muscle weakness, brain malformations, and cognitive deficits. In the brain, dystroglycan is expressed by both glia and excitatory neurons, but its specific function in neurons has remained elusive. Recently, neuronal dystroglycan was discovered to be important for the formation of presynaptic cannabinoid receptor 1 (CB1R) synapses derived from cholecystokinin (CCK) interneurons, a population of inhibitory cells in the forebrain. However, the mechanism by which dystroglycan regulates the development of CCK/CB1R+ inhibitory synapses remains unknown. In the present study, we use multiple mouse lines to determine how dystroglycan regulates CB1R+ synapse development, including mouse models of dystroglycanopathy (B4gat1, ISPD), conditional genetic deletion of dystroglycan from neurons and glia (Dag1‐cKO: Nex‐Cre, Emx‐Cre, Nestin‐Cre), and a mouse lacking the intracellular signaling domain of dystroglycan (Dag1ICD). We found that deletion of dystroglycan specifically from excitatory neurons resulted in the loss of nearly all presynaptic CB1R+ terminals within the first week after birth. Surprisingly, deletion of dystroglycan from both neurons and glia using Nestin‐Cre or Emx‐Cre resulted in abnormal targeting of CB1R+ terminals. We also find that maintenance of CB1R+ terminals in adulthood does not require full glycosylation of a‐DG or the intracellular signaling domain of b‐DG. Collectively, these results suggest that dystroglycan may be required for the proper targeting of CB1R+ synapses during postnatal brain development.Support or Funding InformationNINDS R01 NS091027 (KMW)NINDS F31 NS108522 (DSM)ARCS Fellowship (DSM)Tartar Fellowship (DSM)

Collagen VI Deficiency Results in Structural Abnormalities in the Mouse Lung

Collagen VI (COL6) is known for its role in a spectrum of congenital muscular dystrophies, which are often accompanied by respiratory dysfunction. However, little is known regarding the function of COL6 in the lung. We confirmed the presence of COL6 throughout the basement membrane region of mouse lung tissue. Lung structure and organization were studied in a previously described Col6a1-/- mouse, which does not produce detectable COL6 in the lung. The Col6a1-/- mouse displayed histopathologic alveolar and airway abnormalities. The airspaces of Col6a1-/- lungs appeared simplified, with larger (29%; P<0.01) and fewer (31%; P<0.001) alveoli. These airspace abnormalities included reduced isolectin B4+ alveolar capillaries and surfactant protein C-positive alveolar epithelial type-II cells. Alterations in lung function consistent with these histopathologic changes were evident. Col6a1-/- mice also displayed multiple airway changes, including increased branching (59%; P<0.001), increased mucosal thickness (34%; P<0.001), and increased epithelial cell density (13%; P<0.001). Comprehensive transcriptome analysis revealed that the loss of COL6 is associated with reductions in integrin-paxillin-phosphatidylinositol 3-kinase signaling invivo. Invitro, COL6 promoted steady-state phosphorylated paxillin levels and reduced cell density (16% to 28%; P<0.05) at confluence. Inhibition of phosphatidylinositol 3-kinase, or its downstream effectors, resulted in increased cell density to a level similar to that seen on matrices lacking COL6.

Molecular genetics of the POMT1-related muscular dystrophy-dystroglycanopathies.

Protein O-mannosyltransferase 1 (POMT1) is a critical enzyme participating in the first step of protein O-mannosylation. Mutations in the coding gene, POMT1, have been described to be related to a series of autosomal recessive disorders associated with defective alpha-dystroglycan glycosylation, later termed muscular dystrophy-dystroglycanopathies (MDDGs). MDDGs are characterized by a broad phenotypic spectrum of congenital muscular dystrophy or later-onset limb-girdle muscular dystrophy, accompanied by variable degrees of intellectual disability, brain defects, and ocular abnormalities. To date, at least 76 disease-associated mutations in the POMT1 gene, including missense, nonsense, splicing, deletion, insertion/duplication, and insertion-deletion mutations, have been reported in the literature. In this review, we highlight the present knowledge of the identified disease-associated POMT1 gene mutations and genetic animal models related to the POMT1 gene. This review may help further normative classification of phenotypes, assist in definite clinical and genetic diagnoses, and genetic counseling, and may comprehensively improve our understanding of the basis of complex phenotypes and possible pathogenic mechanisms involved.

P.251 - Clinical and mutational spectrum of congenital muscular dystrophy with defective alpha-dystroglycan glycosylation in Korea

P.251 - Clinical and mutational spectrum of congenital muscular dystrophy with defective alpha-dystroglycan glycosylation in Korea

High creatine kinase levels and white matter changes: Clinical and genetic spectrum of congenital muscular dystrophies with laminin alpha-2 deficiency

Primary deficiency of laminin alpha-2 due to mutations in the LAMA2 gene accounts for 30% of all patients with congenital muscular dystrophy. Here, we present seven patients with partial or total laminin alpha-2 deficiency (MDC1A) with a wide clinical spectrum, ranging from ambulant patients to patients who were never able to stand or sit. We identified two pathogenic mutations in the LAMA2 gene in all patients except for one patient in whom only one mutation was found. Six of the mutations were previously undescribed. In some of the milder cases, laminin alpha-2 expression in the muscle biopsy was only slightly reduced. These findings emphasize that analysis of the LAMA2 gene might be necessary in patients with muscle weakness, cerebral white matter changes and high creatine kinase levels, even in the presence of laminin alpha-2 in the muscle biopsy.