Cases Of Congenital Muscular Dystrophy Research Articles

Phenotype-genotype spectrum of a cohort of congenital muscular dystrophies: a single-centre experience from India.

Congenital Muscular Dystrophies (CMD) are phenotypically and genotypically heterogenous disorders with a prevalence of 0.68 to 2.5/100,000, contributing to significant morbidity and mortality. We aimed to study the phenotype-genotype spectrum of genetically confirmed cases of CMD. This was retrospective & descriptive study done at a quaternary care referral centre in south India. Genetically confirmed cases of CMDs seen between 2010 to 2020 were recruited. Detailed clinical history, including pedigree, MRI brain/muscle, next generation sequencing results of 61 CMD cases were collected. Collagen VI-related dystrophy (COL6-RD) (36%) was the most common subtype with variants frequently seen in COL6A1 gene. Other CMDs identified were LAMA2-RD (26%), alpha-dystroglycan-RD (19%), LMNA-RD (8%), CHKB-RD (7%) and SEPN1-RD (3%). Similar to previous cohorts, overall, missense variants were common in COL-6 RD. Variants in triple helical domain (THD) of COL6-RD were seen in 11/22 patients, 5 of whom were ambulatory contrary to previous literature citing severe disease with these variants. However, our follow-up period was shorter. In the LAMA2-RD, 2/16 patients were ambulatory & all 16 carried truncating variants. Among dystroglycanopathies, FKRP-RD was the commonest. Milder phenotype of FKRP- RD was observed with variant c.1343C > T, which was also a recurrent variant in our cohort. p.Arg249Trp variant in LMNA-CMD associated with early loss of ambulation was also identified in 1/5 of our patients who expired at age 2.8years. The current retrospective series provides detailed clinical features and mutation patterns of genetically confirmed cases of CMD from a single center in India.

EP394: Investigation and functional characterization of genomic signatures in congenital muscular dystrophy and congenital myopathy patients from India

Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. The aim of this study was to genetically diagnose a cohort of 36 difficult-to-diagnose CMD and CM cases of Indian origin using next-generation sequencing methods. Furthermore, functional characterization of the novel pathogenic stop-gain variant NM_001927.4:c.448C>T in the DES gene identified in one patient of our cohort was done in order to understand their pathological role in disease phenotypes.

Muscle eye brain disease – A rare case of congenital muscular dystrophy

Congenital muscular dystrophies are a distinct group of inherited muscle disorders that manifest within the 1st year of life accompanied by weakness, hypotonia, and developmental delay. A distinguishing feature of congenital muscular dystrophy from other muscular dystrophies is an increased association with brain malformations, particularly disorders of cortical development such as lissencephaly, pachygyria, and polymicrogyria. Moreover, some subtypes of congenital muscular dystrophies (CMDs) such as muscle eye brain disease and Walker-Warburg syndrome are more commonly associated with structural eye abnormalities apart from brain malformations. The inheritance of CMD is usually autosomal recessive except for CMD with spinal rigidity and lamin A/C abnormality and Ullrich CMD.

Whole-exome analyses of congenital muscular dystrophy and congenital myopathy patients from India reveal a wide spectrum of known and novel mutations.

Congenital muscular dystrophies (CMDs) and congenital myopathies (CMs) are a group of genetically and clinically heterogeneous degenerative primary muscle disorders with onset at birth or during infancy. Due to vast heterogeneity, clinical examination and protein-based analyses often fail to identify the genetic causes of these diseases. The aim of this study was to genetically diagnose a cohort of 36 difficult-to-diagnose CMD and CM cases of Indian origin using next-generation sequencing methods. Whole-exome sequencing (WES) was performed to identify pathogenic mutations in previously reported CMD and CM-related genes using variant calling and stringent variant filtration process. Subsequently, in silico homology modelling and molecular dynamics simulations (MDS) studies were undertaken for a number of novel and missense variants. A total of 33 and 21 rare and deleterious mutations were identified in 28 genes previously reported in CMD and CM based on OMIM, ClinVar and Orphanet, respectively. We could accurately diagnose 54% patients (n=12/22) in the CMD group and 35% patients (n=5/14) in the CM group. Furthermore, MDS studies for mutations located in LMNA, LAMA2 and RYR1 suggest that the wild-type proteins are more stable than their mutant counterparts, implying a potential mechanism of pathogenesis. The WES findings led us to identify reported as well as novel variants for the first time in Indian patients with CMD and CM. This allowed us to achieve an accurate genetic diagnosis, which was difficult using conventional diagnostic tools. Transferring these WES findings to clinical practice will help guide clinical care of the affected patients and inform genetic counselling.

Utility of Immunohistochemistry and Western Blot in Profiling Clinically Suspected Cases of Congenital Muscular Dystrophy.

Objective:Immunocharacterization of congenital muscular dystrophy (CMD) to determine the frequency of various subtypes in a large Indian Cohort.Materials and Methods:This retrospective (2014-2017) study was carried on muscle biopsies of clinically suspected cases of CMD with histological evidence of dystrophy/myopathic features. Immunohistochemistry (IHC) to antibodies against laminin (α2, α5,β1,γ1), Collagen-VI (A1,2,3), and Western blot (WB) for α-dystroglycan and POMT1 was performed.Results:The study included 57 cases, of which 15 cases (26.3%) had mean age at presentation of 3.5 years, M: F = 1.5:1, elevated creatinine kinase (CK) (mean 1657 U/L), global developmental delay, multiple contractures, abnormal facies, white matter hyperintensities and showed laminin-α2 deficiency (Merosin deficient CMD). In addition, secondary reduction in laminin-β1, over-expression of laminin-α5, and preserved laminin-γ1 was noted. Ullrich CMD constituted 11/57 cases (19.2%) with mean age at presentation of 5.3 years, M: F = 1.2:1 and normal CK. They presented with proximal muscle weakness, soft velvety palms and soles, contractures, and joint hyperextensibility. Collagen-VI (A1,2,3) showed either complete (n = 3) or sarcolemmal specific (n = 8) loss of staining. Out of the remaining 31 cases, WB for α-dystroglycan was performed in 17 cases which showed deficiency in seven (12.3%). Three of these in addition revealed secondary partial loss of laminin-α2. WB for POMT1 showed deficiency in a single case clinically diagnosed Walker–Warburg syndrome, who presented with seizures and classical features of pachygyria, lissencephaly, and cerebellar cyst on MRI. Twenty-four cases (42.2%) remained uncharacterized and need genetic evaluation.Conclusion:The study helped in characterizing 57.8% of the proband. Immunotyping helps to direct mutational analysis for targeted genes and offers a potential route for prenatal diagnosis.

Correlation between thigh muscle magnetic resonance imaging findings and clinical features of congenital muscular dystrophies: a preliminary study

Objective: To analyze the clinical and magnetic resonance imaging (MRI) features of congenital muscular dystrophy (CMD) to improve the diagnostic level. Method: Clinical manifestations and thigh muscle MRI results of 8 cases of CMD diagnosed on genetic level from April 2013 to November 2015 were investigated. MRI was performed on the thigh muscles of all cases. Fatty infiltration of different muscles described in T1WI was graded to evaluate. Clinical symptoms and signs, as well as muscle MRI features were analyzed by statistical description. Result: Among these 8 cases, 2 cases were diagnosed with Ullrich congenital muscular dystrophy (UCMD), 1 case had rigid spine with muscular dystrophy type 1 (RSMD1), 1 case had LMNA related muscular dystrophy (L-CMD), 1 case had congenital muscular dystrophy 1C (MDC1C) and 3 cases had congenital muscular dystrophy 1A (MDC1A), with 4 were males and 4 females, aged from 0.9 year to 4.8 years (median age was 2.2 years). All of these 8 cases presented with muscle weakness and hypotonia from birth to within the first six months, together with delayed motor development and joint contractures. Some cases had spinal deformity or skin changes. Various degrees of fatty infiltration in gluteus maximus and thigh muscles were shown in all of the cases, and differences among CMD subtypes in the form of fatty infiltration were detected; muscle edema was present in 5 cases, and muscle atrophy in 7 cases. However, none of them has muscle hypertrophy. Semimembranous muscle absence was detected in 1 case. Conclusion: The clinical manifestations and thigh muscle MRI findings of CMD have some features, and vary in certain CMD subtypes. MRI examination combined with clinical features may provide useful information to select appropriate genetic or other diagnostic techniques, which may help clinicians to make accurate diagnosis.

Clinical and skeletal muscle biopsy characteristics of 25 patients with floppy infant syndrome

Floppy infant syndrome (FIS) comprises of a group of disorders with a common symptom of generalized hypotonia at birth or in early life, which causes diagnostic challenge. In the current work, we aimed to describe the clinical and histopathological characteristics of FIS to help improve the diagnosis of this condition. We collected information on the clinical characteristics, laboratory data, electrophysiological test results and detailed skeletal muscle biopsy histopathological features of 25 infants with FIS. We then discussed the final diagnoses and analyzed the neuromuscular features. Among the 25 infants with FIS, there were 7 cases of spinal muscular atrophy (SMA), 4 cases of congenital muscular dystrophy (CMD) (3 cases of merosin-deficient CMD and 1 case of Ullrich CMD), 8 cases of congenital myopathy (2 cases of central core disease, 1 case each of nemaline myopathy and centronuclear myopathy, and 4 cases of congenital fiber-type disproportion), and 6 cases of metabolic myopathy (3 cases of lipid storage myopathy, 2 cases of Pompe's disease, and 1 case of Leigh's syndrome). The histopathological characteristics of muscle biopsy were found to be distinct for these subgroups. FIS is caused by a variety of neuromuscular disorders that have common clinical manifestations, including SMA, CMD, congenital myopathies and metabolic myopathies. Skeletal muscle biopsy is an essential tool for the definite and differential diagnoses of FIS, especially of neuromuscular origin.

A large series of immunohistochemically confirmed cases of congenital muscular dystrophy seen over a period of one decade

Although congenital muscular dystrophies (CMD) is a common condition among primary muscle disorders, there are only a few small series reported from India. AIMS, SETTINGS, AND DESIGN: Retrospective analysis to characterize histopathologically and/or immunohistochemically confirmed cases of CMD. Patients were identified retrospectively from the archived muscle biopsy reports between 1997 and 2007 at the Department of Neuropathology of the institute. Medical records were scrutinized for all details. There were 102 cases which were characterized by clinical phenotype and histopathology. Among these 56 had immunohistochemical staining and were included in the final analysis. Merosin staining performed in 53 samples identified nine patients with merosin negative CMD. The male to female ratio (M:F) was 2:1 and the mean age at presentation was 69.7 ± 62.2 months. All had grossly delayed motor milestones. There were 13 cases of Ullrich CMD confirmed by absent staining for collagen 6A1 in muscle. Mean age at diagnosis was 63.7 ± 27.9 months. Onset of symptoms was in infancy in 12 patients. All had significant delay in motor milestones and had classical features of proximal contractures, distal hyperextensibility, prominent calcaneum, velvety palms and soles with absent palmar creases. Mean creatine kinase (CK) value was 259.1 ± 109.4 IU/l. Alpha-dystroglycan (α-DG) deficiency was identified in three cases. Illness onset was in infancy. Classical magnetic resonance imaging (MRI) features were seen in all. Large group of 31 cases of merosin positive CMD had clinical findings of early onset limb weakness, hypotonia, and contractures; with histopathological evidence of dystrophy, and normal staining pattern of merosin, collagen 6A1 and α-DG. Mean age at evaluation was 58.61 ± 48.4 months. Majority (87.1%) had onset of symptom in infancy with delay in motor milestones. This study provides a significant data on one of the largest cohort of patients with CMDs from India. Immunohistochemistry (IHC) has definitely helped us to categorize 56 patients into specific subtypes of CMDs. This is essential for directing genetic analysis which is imperative for definitive diagnosis and also prenatal diagnosis.

Orthognathic Surgery and Partial Glossectomy in a Patient With Merosin-Deficient Congenital Muscular Dystrophy

Muscular dystrophy (MD) describes a group of hereditary muscular diseases. The molecular mechanisms that cause the different forms of MD vary, as do the incidence and impact on a patient’s quality of life. The most common form, Duchenne MD, follows an Xlinked inheritance pattern and occurs with an incidence of approximately 1 in 3,500 live-born male infants. However, rarer forms such as congenital MD (CMD) also exist. CMD has an autosomal recessive inheritance pattern that, according to 1 Italian sample, has an incidence of only 0.7 per 100,000 live births. 1 CMD is characterized by severe muscle hypotonia (first noticeable at birth or within the first months of life), generalized muscle weakness, and muscle contractures of varying severity that result in delayed or missed developmental motor milestones. Each type of CMD is subclassified based on the specific molecular defect or deficiency. One of the more common types of CMD is merosindeficient CMD (MDCMD), which accounts for up to 30% of CMD cases in European countries. CMD results from a deficiency of laminin 2 chains (merosin) because of mutations in the LAMA2 gene located on chromosome 6q22. MDCMD is a severe form of MD that is manifested by an inability to ambulate independently secondary to muscle weakness/contractures and a respiratory insufficiency that may require tracheostomy. 2 Although MDCMD is rare, it and other forms of MD are important to the oral and maxillofacial surgeon because of the impact of the disease on oral and facial anatomy and function. Of particular concern to the oral and maxillofacial surgeon is the phenotype often associated with MDs, which includes bimaxillary discrepancies often presenting with apertognathia. 3 The significance of the malocclusion can be heightened by the compromised masticatory forces resulting from MD. 4,5 Patients with MD may also exhibit limited maximal incisal opening (MIO) because of contracture of the muscles of mastication. In addition, the presence of macroglossia can add to the overall stomatognathic dysfunction and increase the potential for relapse in the postoperative period. 6 Through the surgical treatment of these conditions, the oral and maxillofacial surgeon can address the functional and facial cosmetic concerns the patient may have.

A case of congenital muscular dystrophy similar to Fukuyama-type with a missense mutation in the fukutin gene

The term congenital muscular dystrophy (CMD) refers to a group of inherited disorders in which muscle weakness is present at birth. The Fukuyama-type CMD is an independent subtype of progressive muscular dystrophy in Japan. This report presents the case of a 13-year-old male who applied to our clinic and was diagnosed as CMD similar to the Fukuyama-type based on the results of the genetic analysis. The most frequently defined mutation in these patients is on the fukutin-related protein gene whereas in the present case, one missense mutation in the fukutin gene has been detected. To our knowledge, the case described in this report is the first reported case of one missense mutation in the fukutin gene c.1336A>G (p.Asn446Asp) producing a phenotype similar to the Fukuyama-type.

A Congenital Muscular Dystrophy with Mitochondrial Structural Abnormalities Caused by Defective De Novo Phosphatidylcholine Biosynthesis

Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta (CHKB). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain.

Index Of Suspicion In The Nursery

A male infant who has trisomy 21 is born large for gestational age at 36 weeks' gestation to a 40-year-old G4P2 mother. The mother experienced gestational diabetes and hypertension during the pregnancy. The hospital course in the neonatal intensive care unit (NICU) is uneventful. The infant consumes human milk supplemented with formula every 3 hours. Due to decreased intake, nutritional supplementation by nasogastric tube is initiated. He requires 25 to 30 minutes to feed by mouth with chin support and pacing. There is minimal emesis with feedings until 9 days after birth, when he begins vomiting with each feeding. The amount of emesis varies, consists of undigested milk, and is otherwise nonbilious and nonbloody. The infant can tolerate only small amounts of his feedings by either mouth or nasogastric tube before vomiting, but he continues to have two to three bowel movements per day and good urine output. On physical examination, the baby has physical features consistent with trisomy 21, including epicanthal folds, a flat nasal bridge, macroglossia, Brushfield spots, widened space between the first and second toes, single palmar creases, and generalized hypotonia. There is no notable abdominal distention or palpable abdominal masses. The remainder of the examination yields normal results. A radiologic study helps to reveal the diagnosis. A term male infant is admitted to the NICU after difficulty feeding and respiratory distress at 5 hours of age. The baby was born to a 35-year-old G3T2P0A0L2 woman. All maternal laboratory results were negative during prenatal screening, although prenatal ultrasonography during the third trimester showed oligohydramnios and intrauterine growth restriction. The initial evaluation after delivery revealed an asymmetric, small-for-gestational age infant whose birthweight was 2,215 g and Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. On physical examination, the infant exhibited generalized hypotonia, poor suck …

POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental retardation

Background Alpha-dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance characterized by abnormal glycosylation of alpha-dystroglycan. Although six genetic causes have been identified ( FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE) many alpha-dystroglycanopathy patients remain without a genetic diagnosis after standard exon sequencing. To date POMT2 mutations have been identified in CMD cases with a wide range of clinical severities from Walker–Warburg syndrome to limb girdle muscular dystrophy without structural brain or ocular involvement. Methods We analyzed POMT2 in six CMD patients, who had severe diffuse muscle weakness, generalized joint contractures, microcephaly, severe mental retardation and elevated CK levels. Eye involvement was absent or limited to myopia or strabismus. We sequenced the coding regions of POMT2 using genomic DNA and cDNA generated from blood lymphocytes or B lymphoblastoid cell lines. Quantitative PCR analysis of genomic DNA was used to identify and determine the breakpoints of large deletions. Results We report five novel mutations in POMT2, four of which were outside of coding exons, two large genomic deletions and two intronic single base substitutions that induced aberrant mRNA splicing. Conclusions Large scale DNA rearrangements (such as large deletions) and cryptic splice mutations, that can be missed on standard sequencing of genomic DNA, may be relatively common in POMT2. Additional techniques, such as sequencing of cDNA are needed to identify all mutations. These results also confirm that POMT2 mutations are an important cause of the less severe alpha-dystroglycanopathy phenotypes.

Congenital muscular dystrophy in a new age

Muscular dystrophies are an infrequent but important cause of infantile weakness. While recent discoveries have helped define these conditions, they have also revealed the developmental and degenerative as well as peripheral and CNS aspects of these complex disorders. A new study from the laboratory of Dr. Kathryn North now provides an important and timely survey of congenital muscular dystrophy cases in a diverse population, detailing clinical, histologic, and genetic features essential for accurate diagnosis.1 Congenital forms of muscular dystrophy (CMD) differ clinically in several important ways from the more common juvenile and adult-onset forms of muscular dystrophy, such as Duchenne or Becker MD.2 Most notably, the time course of CMD is distinct not only because of the early onset, but because it can follow a less aggressive or even static course, though an aggressive fatal course is seen in some …

An unusual case of congenital muscular dystrophy with normal serum CK level, external ophtalmoplegia, and white matter changes on brain MRI

We report a sporadic case of congenital muscular dystrophy (CMD) in a 13-year-old girl with early manifestation of muscle weakness and hypotonia, severe contractures, bulbar syndrome, progressive external ophtalmoplegia, and white matter changes on magnetic resonance imaging (MRI) of the brain, but no mental defect. Serum creatine kinase (CK) level was normal. Muscle biopsy revealed a dystrophic picture with a prominent inflammatory infiltrate mimicking inflammatory myopathy—typical histological findings in CMD. Immunostaining showed normal expression of merosin, α and β-dystroglycans. Mutation analyses of calpain3, dysferlin, and SEPN1 genes were negative. An electron microscopy revealed the accumulation of abnormally enlarged mitochondria located under the sarcolemma. Measurement of respiratory chain enzyme activities did not reveal any biochemical defect and mitochondrial genetic studies, including sequencing of the entire mitochondrial genome, were unremarkable. Phenotypic presentation of our patient is very unusual and differs considerably from other CMD variants.

Absence of the basilar pons in mice lacking a functional Large glycosyltransferase gene suggests a defect in pontine neuron migration

Several forms of congenital muscular dystrophy result from mutations in glycosyltransferases that modify α-dystroglycan. As pontine hypoplasia has been reported in some clinical cases of congenital muscular dystrophy, we have begun to examine whether these glycosyltransferases are required for the normal development of the basilar pons, one of several precerebellar nuclei of the hindbrain. In veils ( Large vls ) mice, which carry a loss-of-function mutation in the Large glycosyltransferase gene, the basilar pons is absent. Instead, ectopic clusters of pontine neurons are found lateral to their normal site, suggesting that these neurons are unable to migrate to their appropriate site. Two other precerebellar nuclei, the lateral reticular nucleus and the inferior olive, are present in Large vls mice. In addition, the basilar pons forms normally in dystrophin-deficient mice. These results demonstrate that the Large glycosyltransferase but not dystrophin is required for normal basilar pontine development.

G.P.3 06 An unusual case of congenital muscular dystrophy with mitochondrial structural abnormalities

An unusual case of congenital muscular dystrophy with mitochodnrial structural abnormalities is described

Amelioration of laminin-α2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin

Congenital muscular dystrophy (CMD) is characterized by severe muscle wasting, premature death in early childhood, and lack of effective treatment. Most of the CMD cases are caused by genetic mutations of laminin-alpha2, which is essential for the structural integrity of muscle extracellular matrix. Here, we report that somatic gene delivery of a structurally unrelated protein, a miniature version of agrin, functionally compensates for laminin-alpha2 deficiency in the murine models of CMD. Adeno-associated virus-mediated overexpression of miniagrin restored the structural integrity of myofiber basal lamina, inhibited interstitial fibrosis, and ameliorated dystrophic pathology. Furthermore, systemic gene delivery of miniagrin into multiple vital muscles significantly improved whole body growth and motility and quadrupled the lifespan (50% survival) of the dystrophic mice. Thus, our study demonstrated the efficacy of somatic gene therapy in a mouse model of CMD.

Kongenitale Muskeldystrophie mit Merosin-(Laminin-a2)-Mangel im frühen Säuglingsalter: Diagnostik und Langzeitverlauf

Congenital muscular dystrophy (CMD) is a heterogeneous group of neuromuscular disorders characterized by muscle weakness and hypotonia at birth or within the first few months of life. It is inherited in an autosomal recessive pattern. About half of the patients have a deficiency of the alpha-2-chain of laminin (merosin). We describe a case of congenital muscular dystrophy in an infant with laminin-a2-chain deficiency, which appeared hypotonia in early infancy. Diagnosis was made by clinical features and the histological and immunohistochemical studies on muscle biopsy.

111th ENMC International Workshop on Multi-minicore Disease. 2nd International MmD Workshop, 9–11 November 2002, Naarden, The Netherlands

111th ENMC International Workshop on Multi-minicore Disease. 2nd International MmD Workshop, 9–11 November 2002, Naarden, The Netherlands