Related Congenital Muscular Dystrophy Research Articles

Infantile-Onset LMNA-Related Congenital Muscular Dystrophy Presenting as Torticollis: A Case Report

Lamin A (<i>LMNA</i>)-related congenital muscular dystrophy usually presents with hypotonia and severe axial muscle weakness in early infancy. We report a patient who initially presented with torticollis but was finally diagnosed with <i>LMNA</i>-related congenital muscular dystrophy. A 7-month-old infant presented to the outpatient clinic with a chief complaint of torticollis. During a thorough physical examination, axial muscle weakness and gross motor delay were noted, and she was admitted to the pediatric rehabilitation department for further evaluation. The serum creatine kinase level was elevated, and electromyography demonstrated the possibility of hereditary myopathy or a motor neuron disorder. A gene study was conducted, and it showed a c.745C>T (p.Arg249Trp) mutation in the <i>LMNA</i> gene, which is known to cause congenital muscular dystrophy in rare cases. Since there are few reports describing nerve conduction and electromyography studies in patients with <i>LMNA</i>-related congenital muscular dystrophy, this case is meaningful.

P.147 Deflazacort treatment in LMNA-related congenital muscular dystrophy: an ongoing Italian cohort pilot study

<i>LMNA</i>-related congenital muscular dystrophy (L-CMD) and <i>LMNA</i>-linked Emery-Dreifuss muscular dystrophy (EDMD2) with early onset (<5 years) may be considered a continuum phenotype. There is no cure for patients with these neuromuscular diseases. Literature data and ongoing clinical approaches suggest the use of steroids. Starting from the collaborative approach and the multidisciplinary effort of the Italian network for laminopathies, we are planning an open-label prospective cohort pilot study aimed to: <i>1)</i> evaluate the effect of the treatment with deflazacort in a cohort of 20 L-CMD or EDMD2 patients with infantile onset, aged 3-30 years; <i>2)</i> analyze the secretome profile at basal condition and during steroid treatment, to evaluate variations and establish a correlation between steroid treatment and clinical outcome; <i>3)</i> validate selected cytokines as biomarkers for L-CMD and EDMD2. Study protocol: Patients will be monitored for a period of six months. Then, they will start therapy with Deflazacort for 12 months. After 12 months, the treatment will be stopped and the patients will continue to be clinically followed every 3 months until the end of the study. Overall, we expect to evaluate whether a 12-month-treatment with deflazacort is effective in improving clinical outcome measures in L-CMD patients. We also expect to identify a panel of cytokines altered in L-CMD that can be considered as biomarkers of disease.

VP.78 Clinical and genetic study of LAMA2-related muscular dystrophy patients with seizures

<i>LAMA2</i>-related muscular dystrophy (LAMA2-MD) is an autosomal recessive muscular dystrophy caused by pathogenic variants in <i>LAMA2</i> gene, including two subgroups: severe, early-onset <i>LAMA2</i>-related congenital muscular dystrophy (LAMA2-CMD) and mild, late-onset autosomal recessive limb-girdle muscular dystrophy-23 (LGMD R23). Seizures frequently occurred in LAMA2-MD, however, the relationship between seizures and genotype in LAMA2-MD is not fully known. The clinical information of seizures including seizure type, frequency, treament, EEG changes, brain MRI and genetic data of LAMA2-MD patients from Peking University First Hospital between January 2003 and March 2022 were collected and analyzed. Among 141 LAMA2-MD patients, seizures were observed in 10.5% (13/124) of LAMA2-CMD patients and 29.4% (5/17) of LGMD R23 patients, including 14 patients with epilepsy and 4 patients with febrile seizures. The median (range) age of first seizure episode was 5 (0.1-20) years in LAMA2-CMD and 14 (1-24) years in LGMD R23. Eight patients with epilepsy showed focal seizures. Abnormal results of electroencephalography were found in 8/10 patients, manifesting as temporal, occipital or temporo-occipital epileptiform abnormalities. Brain magnetic resonance imaging (MRI) was performed in 16 patients with seizures, showing occipital pachygyria in 4 patients, cerebellum and brain stem dysplasia in 2 patients. Brain MRI of 41 LAMA2-MD patients without seizures were reassessed, showing occipital lobe pachygyria in 6 patients. Therefore, there was no significant association between seizures and occipital pachygyria in our cohort (P=0.18). Nine patients received antiepileptic drugs, while patients with occipital lobe pachygyria showed poor seizure control. The pathogenic variants included splice mutation (n=8), nonsense mutation (n=6) and frameshift mutation(n=6) in LAMA2-CMD patients, while missense mutation (n=5), frameshift mutation(n=4) in LGMD R23 patients. Compared with LAMA2-CMD, seizures were more frequently occurred in LGMD R23 patients and mainly manifested as focal seizures. No correlation between genotype and seizures was observed. In this study, we found that seizures occurred in 10.5% of LAMA2-CMD and 29.4% of LGMD R23 patients, and described the features of seizures in LAMA2-MD patients.

Laminin-111 protein therapy after disease onset slows muscle disease in a mouse model of laminin-α2 related congenital muscular dystrophy.

Laminin-α2 related congenital muscular dystrophy (LAMA2-CMD) is a fatal muscle disease caused by mutations in the LAMA2 gene. Laminin-α2 is critical for the formation of laminin-211 and -221 heterotrimers in the muscle basal lamina. LAMA2-CMD patients exhibit hypotonia from birth and progressive muscle loss that results in developmental delay, confinement to a wheelchair, respiratory insufficiency and premature death. There is currently no cure or effective treatment for LAMA2-CMD. Several studies have shown laminin-111 can serve as an effective protein-replacement therapy for LAMA2-CMD. Studies have demonstrated early treatment with laminin-111 protein results in an increase in life expectancy and improvements in muscle pathology and function. Since LAMA2-CMD patients are often diagnosed after advanced disease, it is unclear if laminin-111 protein therapy at an advanced stage of the disease can have beneficial outcomes. In this study, we tested the efficacy of laminin-111 protein therapy after disease onset in a mouse model of LAMA2-CMD. Our results showed laminin-111 treatment after muscle disease onset increased life expectancy, promoted muscle growth and increased muscle stiffness. Together these studies indicate laminin-111 protein therapy either early or late in the disease process could serve as an effective protein replacement therapy for LAMA2-CMD.

Clinical and genomic characteristics of LAMA2 related congenital muscular dystrophy in a patients’ cohort from Qatar. A population specific founder variant

Congenital LAMA2 related muscular dystrophy (LAMA2-RD), the most commonly recognized type of congenital muscular dystrophies, has been described in patients’ cohorts from Europe and the UK but not from Middle-Eastern. This study aimed to reveal the prevalence, clinical and genomic characteristics of congenital LAMA2-RD in a patient's cohort of 17 families (21 patients) from the Gulf and Middle East. Affected subjects exhibited the classic phenotype of generalized hypotonia, developmental delay, and progressive muscular weakness. Despite the homogeneous background of most of our patients, clinical variability was evident; however, none of our patients was able to achieve independent ambulation. The associated features of nephrocalcinosis, infantile-onset osteopenia, and cardiac arrest were first described in this study. LAMA2 mutations constituted 48% of the genetic causes underlying congenital muscular dystrophies (CMDs) in our patients. We estimated a point prevalence of 0.8 in 100.000 for LAMA2-RD in Qatar, relatively higher compared to that described in Europe's studies. The founder mutation and high rate of consanguinity are potential contributors. This study identified five LAMA2 truncating variants, two novel and three recurrent, of which the c.6488delA-frameshift that was found in 12 unrelated Qatari families, highlighting a founder mutation in Qatari patients. The two novel variants involved an acceptor splice site and N-terminus deletion that removes the LAMA2 promoter, exon1, and part of intron1. The “residual” expression of LAMA2 transcript and protein associated with this large N-terminus deletion suggested an alternative promoter that, while seems to be activated, acts less efficiently.

A novel case of MSTO1 gene related congenital muscular dystrophy with progressive neurological involvement

Recessive mutations in the MSTO1 gene, encoding for a mitochondrial distribution and morphology regulator, have been recently described in a very limited number of patients with multisystem involvement, mostly characterized by myopathy or dystrophy, cerebellar ataxia, pigmentary retinopathy and raised creatine kinase levels. Here we report an additional patient with recessive MSTO1-related muscular dystrophy (MSTO1-RD), and clinical and radiological evidence of progressive cerebellar involvement. Whole-exome sequencing identified two novel MSTO1 missense variants, c.766C > T (p. (Arg256Trp) and c.1435C > T (p. (Pro479Ser), predicted as damaging by in silico tools. We also report a distinct pattern of selective involvement on muscle MRI in MSTO1-RD. This case confirms a consistent MSTO1-related neuromuscular phenotype and in addition suggests a progressive neurological component at least in some patients, in keeping with the mitochondrial role of the defective protein.

MITOCHONDRIAL DISEASES (Posters): P.189A novel case of MSTO1 gene related congenital muscular dystrophy with cerebellar involvement

Recessive mutations in the MSTO1 gene, encoding for a mitochondrial distribution and morphology regulator, have been recently described in 4 families with multisystem involvement, mostly characterized by myopathy or dystrophy, cerebellar ataxia, pigmentary retinopathy and raised CK. Here we report a patient with recessive MSTO1 gene related muscular dystrophy and ataxia. The patient, born to non-consanguineous parents, presented at age 2 years with global developmental delay. At age 15 years he was ambulant and showed axial, upper and lower limb weakness, pronounced proximally, scoliosis, ankle contractures and ataxia. There was no cardiac or respiratory involvement. EMG was normal. Brain MRI at 6 years showed cerebellar atrophy and mild under-opercularisation of the left Sylvian fissure; when repeated at 9 years, there was mild progression of cerebellar atrophy and additional supratentorial sulcal prominence suggestive of volume loss. Muscle MRI showed generalized increase in T1 signal in the lower limb with normal STIR sequences. CK was raised (800-1614 IU/L). Muscle biopsy showed fibre size variability, increased internal nuclei, fatty endomysial infiltration, few regenerating fibres, type 1 predominance and some minicores. Minor changes of uncertain significance on laminin-α and a-dystroglycan staining were observed. Respiratory chain enzyme studies were normal. Whole-exome sequencing revealed 2 missense MSTO1 variants. The first variant (c.766C>T p.(Arg256Trp)), affecting a conserved residue in the tubulin domain of the protein, is reported in the gnomAD dataset with an allelic frequency of 0.00003, while the second (c.1435C>T p. (Pro479Ser)) is novel. In silico tools predict both variants as damaging. Phasing of the variants is in progress. This case confirms a consistent phenotype associated with recessive MSTO1 gene mutations and suggests that progressive cerebellar atrophy can be a feature of the condition.

Improving Reproducibility of Phenotypic Assessments in the DyW Mouse Model of Laminin-α2 Related Congenital Muscular Dystrophy.

Laminin-α2 related Congenital Muscular Dystrophy (LAMA2-CMD) is a progressive muscle disease caused by partial or complete deficiency of laminin-211, a skeletal muscle extracellular matrix protein. In the last decade, basic science research has queried underlying disease mechanisms in existing LAMA2-CMD murine models and identified possible clinical targets and pharmacological interventions. Experimental rigor in preclinical studies is critical to efficiently and accurately quantify both negative and positive results, degree of efficiency of potential therapeutics and determine whether to move a compound forward for additional preclinical testing. In this review, we compare published available data measured to assess three common parameters in the widely used mouse model DyW, that mimics LAMA2-CMD, we quantify variability and analyse its possible sources. Finally, on the basis of this analysis, we suggest standard set of assessments and the use of available standardized protocols, to reduce variability of outcomes in the future and to improve the value of preclinical research.

A.I.5 - Laminopathies: Why make it simple when it can be complex?

Laminopathies are a diverse and complex group of rare genetic conditions due to mutations in the LMNA gene encoding Lamin A and C, constituents of the nuclear lamina, a meshwork of proteins underneath the nuclear envelope. Striated muscle laminopathies (SML) are the most frequent type of laminopathies (≈60% of all laminopathies published cases), that affect skeletal and/or cardiac muscle. SMLcomprise LMNA related congenital muscular dystrophy (L-CMD), Emery–Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy, type 1B (LGMD1B) and dilated cardiomyopathy with conduction system disease (DCM-CD). Associated with this wide clinical heterogeneity, there is also a large genetic variability as more than 400 different LMNA mutations have been reported so far (www.umd.be/LMNA/ and unpublished data). In order to get insights in phenotype/genotype relations as well as better knowledge of the natural history of these different clinical entities, we set up a patient registry, OPALE, and initiate an international retrospective natural history study of the early onset SML. Over the years, numerous studies have reported that lamin A/C provide structural support to the nucleus, maintenance of nuclear architecture, nuclear migration, and apoptosis, and also take part in chromatin organization and epigenetics, transcription, cell cycle regulation, cell development and differentiation. To study the role of lamin A/C in skeletal and cardiac muscles, and to understand the pathophysiological processes induced by LMNA mutations, we created knock-in mouse models that reproduced LMNA mutation identified in SML patients. We demonstrated an aberrant increase in MAP kinases in hearts from Lmna H222P knock-in mice, providing proof of principle for MAP kinase inhibition as a therapeutic option to prevent or delay the onset of the contractile dysfunction and cardiomyopathy in SML. Recent insights of the pathophysiological mechanisms of LMNA mutations leading to skeletal and/or cardiac dysfunction in these mouse models will be presented.

LAMA2-related congenital muscular dystrophy complicated by West syndrome

BackgroundMutations in the LAMA2 gene cause autosomal recessive laminin α2 related congenital muscular dystrophy. In patients with partial laminin α2 deficiency the phenotype is usually milder than in those with absent protein. Apart from the typical white matter abnormalities, there is an increased risk of cerebral complications such as epilepsy and mental retardation, despite a structurally normal brain. Methods/resultsWe present a patient with primary partial laminin α2 deficiency due to a homozygous novel LAMA2 missense mutation who developed West syndrome in his first year of life. To our knowledge, this combination has not previously been reported. A 5 year-old boy exhibited global hypotonia with generalized muscle weakness from birth. At 8 months of age he presented infantile spasms and an EEG finding of hypsarrhythmia. Seizures were controlled in a few weeks with intramuscular synthetic ACTH, followed by valproic acid. Two years later antiepileptic medication was withdrawn. He achieved unsupported walking at the age of 4, but his cognitive status corresponded to a 2 year-old child. Epilepsy has not recurred and brain MRI showed the typical white matter abnormalities without associated neuronal migration defects. ConclusionThis report widens the clinical spectrum of cerebral manifestations related with mutations in LAMA2. The beginning of a severe epileptic encephalopathy modifies the natural history of the disease.

Ullrich Congenital Muscular Dystrophy Possibly Related With COL6A1 p.Gly302Arg Variant

Ullrich congenital muscular dystrophy (UCMD) is characterized by congenital weakness, proximal joint contractures, and hyperlaxity of distal joints. UCMD is basically due to a defect in extra cellular matrix protein, collagen type VI. A 37-year-old woman who cannot walk independently visited our outpatient clinic. She had orthopedic deformities (scoliosis, joint contractures, and distal joint hyperlaxity), difficulty of respiration, and many skin keloids. Her hip computed tomography showed diffuse fatty infiltration and the 'central shadow' sign in thigh muscles. From the clinical information suggesting collagen type VI related muscle disorder, UCMD was highly considered. COL6A1 gene sequencing confirmed this patient as UCMD with novel c.904G>A (p.Gly302Arg) variant. If musculoskeletal and dermatologic manifestations and radiologic findings imply abnormalities in collagen type VI network, COL6A related congenital muscular dystrophy was to be suspected.

Phenotype/genotype analysis of 4 cases of LMNA related congenital muscular dystrophy with inflammatory changes

Objective To analyze the clinical characteristics, muscle pathological features and pathogenic gene mutation in 4 cases with LMNA-related congenital muscular dystrophy(L-CMD). Methods Clinical data of the probands and the parents were collected. Skeletal muscle specimens were biopsied from the probands for pathological analysis. Genomic DNA and RNA were extracted from peripheral blood leukocytes, and PCR, reverse transcription(RT)-PCR and DNA direct sequencing were employed to analyze the LMNA gene to determine the gene mutation and confirm the pathogenicity. Results Four patients had symptoms from fetal period to several months after birth. They presented with motor retardation, muscle weakness with prominent the proximal upper limbs, distal lower limbs and neck extensor, hypotonia, contractures, with mild to moderate elevation of CK level. The muscle biopsies showed muscular dystrophic and with inflammatory changes, and the abnormal nuclear morphology was observed with transmission electron microscopy. Genetic analysis of them detected 4 dominant de novo mutations. Three of them had unreported pathogenic mutations. The same sites of the LMNA gene were wild type in their parents. Conclusions Four cases of L-CMD are genetically identified. Genetic counseling of the family can be possible. The patients should be considered LMNA gene mutation of they present themselves with muscle weakness with the proximal upper limbs, distal lower limbs and neck extensor, hypotonia, contractures, mild to moderate elevation of CK level, and if the biopsies show muscular dystrophic changes but also with inflammatory changes should be considered LMNA gene mutation. Genetic analysis is the most reliable method for diagnosing L-CMD. Key words: LMNA related congenital muscular dystrophy; Inflammatory myopathy; LMNA gene; Mutation

G.P.124 Fiber type disproportion caused by LMNA mutations

<h2>Abstract</h2> Mutations in the gene encoding nuclear envelope proteins of A-type lamins (<i>LMNA</i>) are known to cause Emery–Dreifuss muscular dystrophy, limb girdle muscular dystrophy type 1B, and <i>LMNA</i>-related congenital muscular dystrophy. Pathological features of <i>LMNA</i>-myopathy are nonspecific dystrophic changes including variation in fiber size, necrotic and regenerating process, and increased muscle fibers with internal nuclei. Congenital fiber type disproportion (CFTD) is a congenital myopathy pathologically designated by smaller sized type 1 fibers at least 12% than type 2 fibers with no structural abnormalities. We recently came across a <i>LMNA</i>-myopathy patient whose earlier diagnosis was CFTD. In this study, we searched for <i>LMNA</i> mutations in 94 unrelated patients pathologically diagnosed as CFTD. Genetically confirmed 29 <i>LMNA</i>-myopathy patients were also reevaluated pathologically. We identified two patients carrying a novel heterozygous <i>LMNA</i> mutation (p.Glu33del or p.Lys123del) among 94 CFTD patients. On the other hand, 5 of 29 (17%) <i>LMNA</i>-myopathy patients showed fiber type disproportion (FTD) on muscle pathology. The age at onset of the 7 <i>LMNA</i>-myopathy patients with FTD was from 1y2m to 4y (mean 2y8m) except for one adult-onset patient. None of the <i>LMNA</i>-myopathy patients with FTD had high arched palate or respiratory involvement. Serum creatine kinase levels were mildly elevated (mean 915□} 698IU/L). The ratio of fiber size disproportion (%FSD) was not significantly different between <i>LMNA</i>-myopathy withFTD and 9 CFTD patients with <i>ACTA1</i> or <i>TPM3</i> mutations. Importantly, CFTD with <i>ACTA1</i> or <i>TPM3</i> mutations showed type 1 fiber atrophy compared to age-matched controls, while <i>LMNA</i>-myopathy with FTD showed type 2 fiber hypertrophy. From our results, we encourage <i>LMNA</i> mutation analysis in CFTD patients with no high arched palate and respiratory involvement.

S.P.21 Clinical outcome measures in Collagen 6 (COL6) and Laminin α2(LAMA2) related congenital muscular dystrophy

Abstract Potential therapies targeting primary deficiencies and downstream targets are under development for two extracellular matrix related congenital muscular dystrophy (CMD) subtypes, COL6 and LAMA2. However, outcome measures for clinical trials have not been validated in CMD. We performed a pilot study of various outcomes measures to test the feasibility of obtaining measurements in CMD and to validate their use for future clinical trials. Twenty-nine patients participated in the study (16 COL6 and 13 LAMA2). Measures tested included: myometry (knee flexion, elbow flexion and extension, cervical flexion in sitting) forced vital capacity sitting in liters (FVC), Motor Function Measure 32 (MFM32), North Star Ambulatory Assessment (NSAA), and Hammersmith Functional Motor Scales. We performed Spearman Rank analysis to assess their correlations. Our study revealed the following: myometry measures reflect feasibility of obtaining reproducible measurements, including knee flexion, elbow flexion and elbow extension, which correlated with MFM32 total score (r = 0.59–0.69, p

Germinal mosaicism for LMNA mimics autosomal recessive congenital muscular dystrophy

Life-threatening cardiac and respiratory complications are common in LMNA-related myopathies and early diagnosis is important for optimal patient care. Lamin A/C related congenital muscular dystrophy (L-CMD) is often caused by de novo mutation in LMNA, affecting a single child in a family. Germinal mosaicism is a rarer variant that can lead to two children inheriting the same new heterozygous mutation from a clinically unaffected parent. Both patterns mimic autosomal recessive (AR) inheritance and the possibility of de novo L-CMD may be forgotten since most causes of congenital muscular dystrophy follow AR inheritance. To illustrate the challenge of diagnosing L-CMD, we present a consanguineous family in which two children have early onset LMNA-related myopathy likely due to paternal germinal mosaicism. This emphasises that germinal mosaicism (and de novo mutations) for LMNA can arise in any family and direct gene sequencing is required to confirm or exclude the diagnosis.