UNASSIGNED: LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal-recessive disorder and one of the most common congenital muscular dystrophies. Due to promising therapies in preclinical development, there is an increasing effort to better define the epidemiology and natural history of this disease.
UNASSIGNED: The present study aimed to describe a well-characterized baseline cohort of patients with LAMA2-RD in Switzerland.
UNASSIGNED: The study used data collected by the Swiss Registry for Neuromuscular Disorders (Swiss-Reg-NMD). Diagnostic findings were derived from genetics, muscle biopsy, creatine kinase-level and electrophysiological testing, as well as from brain MRIs. Further clinical information included motor assessments (CHOP INTEND, MFM20/32), joint contractures, scoliosis, ophthalmoplegia, weight gain, feeding difficulties, respiratory function, cardiac investigations, EEG findings, IQ and schooling.
UNASSIGNED: Eighteen patients with LAMA-RD were included in the Swiss-Reg-NMD as of May 2023 (age at inclusion into the registry: median age 8.7 years, range 1 month - 31 years F = 8, M = 10). Fourteen patients presented with the severe form of LAMA2-RD (were never able to walk; CMD), whereas four patients presented with the milder form (present or lost walking capability; LGMD). All patients classified as CMD had symptoms before 12 months of age and 11/14 before the age of six months. 15 carried homozygous or compound heterozygous pathogenic or likely pathogenic variants in LAMA2 and two were homozygous for a variant of unknown significance (one patient unknown). Brain MRI was available for 14 patients, 13 had white matter changes and 11 had additional structural abnormalities, including cobblestone malformations, pontine hypoplasia and an enlarged tegmento-vermial angle not reported before.
UNASSIGNED: This study describes the Swiss cohort of patients with LAMA2-RD and gives insights into measuring disease severity and disease progression, which is important for future clinical trials, as well as for a better clinical understanding and management of patients with LAMA2-RD.

UNASSIGNED: LAMA2-related dystrophies (LAMA2-RDs) represent one of the most common forms of congenital muscular dystrophy and have historically been classified into two subtypes: complete or partial deficiency of laminin-211 (merosin). Patients with LAMA2-RD with the typical congenital phenotype manifest severe muscle weakness, delayed motor milestones, joint contractures, failure to thrive, and progressive respiratory insufficiency.
UNASSIGNED: While a comprehensive prospective natural history study has been performed in LAMA2-RD patients over 5 years of age, the early natural history of patients with LAMA2-RD 5 years and younger has not been comprehensively characterized.
UNASSIGNED: We extracted retrospective data for patients with LAMA2-RD ages birth through 5 years via the Congenital Muscle Disease International Registry (CMDIR). We analyzed the data using a phenotypic classification based on maximal motor milestones to divide patients into two phenotypic groups: \"Sit\" for those patients who attained that ability to remain seated and \"Walk\" for those patients who attained the ability to walk independently by 3.5 years of age.
UNASSIGNED: Sixty patients with LAMA2-RD from 10 countries fulfilled the inclusion criteria. Twenty-four patients had initiated non-invasive ventilation by age 5 years. Hospitalizations during the first years of life were often related to respiratory insufficiency. Feeding/nutritional difficulties and orthopedic issues were commonly reported. Significant elevations of creatine kinase (CK) observed during the neonatal period declined rapidly within the first few months of life.
UNASSIGNED: This is the largest international retrospective early natural history study of LAMA2-RD to date, contributing essential data for understanding early clinical findings in LAMA2-RD which, along with the data being collected in international, prospective early natural history studies, will help to establish clinical trial readiness. Our proposed nomenclature of LAMA2-RD1 for patients who attain the ability to sit (remain seated) and LAMA2-RD2 for patients who attain the ability to walk independently is aimed at further improving LAMA2-RD classification.

Mutations in the alpha-2 subunits of the laminin gene (LAMA2) cause an autosomal recessive congenital muscular dystrophy (CMD) subtype known as laminin a2-related muscular dystrophies (LAMA2-RD). LAMA2-RD can present with a wide range of phenotypes ranging from severe infantile congenital muscular dystrophy to milder adult-onset limb-girdle muscular dystrophy. This case describes a 28-year-old Indian gentleman having childhood-onset focal seizures, gradually progressive proximal predominant lower-limb weakness for the past three years, elevated creatinine phosphokinase levels, and MRI brain suggestive of diffuse symmetrical periventricular white matter hyperintensities. The whole exome sequencing revealed a rare homozygous missense variant in exon 4 of the LAMA2 gene on chromosome 6 (c.442C>T[p.Arg148Trp]). Adult-onset limb-girdle muscular dystrophy with white matter imaging abnormalities, hyperCKemia, and seizures should evoke suspicion of LAMA2-RD. This case brings forth an ultra-rare genetic mutation that has not been previously reported in individuals of South Asian ethnicity leading to LAMA2-RD. More cases of late-onset LAMA2-RD from various ethnicities need to be reported to expand our understanding of the clinical-genetic spectrum of the disease.

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-α1, which shares significant similarities with laminin-α2, has been proven as a viable compensatory modifier. To evaluate its clinical applicability, we establish a Lama2 exon-3 deletion mouse model (dyH/dyH). The dyH/dyH mice exhibit early lethality and typical LAMA2-CMD phenotypes, allowing the evaluation of various endpoints. In dyH/dyH 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 MRI, serum biochemical indices, and muscle pathology studies. Treating LAMA2-CMD with LAMA1 upregulation is feasible and that early intervention can alleviate symptoms and extend lifespan. Additionally, we reveal limitations of LAMA1 upregulation, including high-dose mortality and non-sustained expression, which require further optimization in future studies.

BACKGROUND: We report a rare case of primary clinical presentation featuring elevated creatine kinase (CK) levels in a neonate, which is associated with the LAMA2 gene. In this case, a heterozygous mutation in exon5 of the LAMA2 gene, c.715C>G (resulting in a change of nucleotide number 715 in the coding region from cytosine to guanine), induced an amino acid alteration p.R239G (No. 239) in the patient, representing a missense mutation. This observation may be elucidated by the neonatal creatine monitoring mechanism, a phenomenon not previously reported.
METHODS: We analysed the case of a neonate presenting solely with elevated CK levels who was eventually discharged after supportive treatment. The chief complaint was identification of increased CK levels for 15 d and higher CK values for 1 d. Admission occurred at 18 d of age, and despite prolonged treatment with creatine and vitamin C, the elevated CK levels showed limited improvement. Whole exome sequencing revealed the presence of a c.715C>G mutation in LAMA2 in the newborn, correlating with a clinical phenotype. However, the available information offers insufficient evidence for clinical pathogenicity.
CONCLUSIONS: Mutations in LAMA2 are associated with the clinical phenotype of increased neonatal CK levels, for which no specific treatment exists. Whole genome sequencing facilitates early diagnosis.

UNASSIGNED: Depression is a heritable brain disorder. Laminin genes were recently identified to affect the brain\'s overall thickness through neurogenesis, differentiation, and migration in depression. This study aims to explore the effects of the LAMA2\'s single nucleotide polymorphisms (SNP), a subunit gene of laminin, on the detected brain regions of patients with major depressive disorder (MDD).
UNASSIGNED: The study included 89 patients with MDD and 60 healthy controls with T1-weighted structural magnetic resonance imaging and blood samples for genotyping. The interactions between LAMA2 gene SNPs and diagnosis as well as duration of illness (DOI) were explored on brain measures controlled for age, gender, and site.
UNASSIGNED: The right transverse temporal gyrus and right parahippocampal gyrus showed reduced thickness in MDD. Almost all seven LAMA2 SNPs showed significant interactions with diagnosis on both gyrus (corrected p < 0.05 or trending). In MDD, rs6569604, rs2229848, rs2229849, rs2229850, and rs2784895 interacted with DOI on the right transverse temporal gyrus (corrected p < 0.05), but not the right parahippocampal gyrus.
UNASSIGNED: The thickness of the right transverse temporal gyrus in patients with MDD may be affected by LAMA2 gene and DOI.

Postpartum absence of estrus exhibition known as postpartum anestrus interval (PPAI) for more than 90 days after calving is a concerning issue for dairy buffalo farmers\' economy. The PPAI duration is influenced by both management practices and animal genetics. Investigating genetic markers associated with PPAI is crucial for incorporating them into marker-assisted selection programs. Towards this goal, our study focused on exploring potential genetic markers from early postpartum adipose tissue gene networks. We successfully identified 24 Single Nucleotide Polymorphisms (SNPs) within 9 candidate genes. In our initial analysis involving 100 buffaloes, we detected a significant association (P = 0.02267) between a specific synonymous SNP within the Lama2 gene (g.36417726C > A) and PPAI. This finding was subsequently validated (P = 0.02937) in a larger cohort of 415 buffaloes, where the SNP explained 1.36 % of the genetic variance. Intriguingly, buffaloes with the CC genotype of this SNP exhibited a PPAI that was 12.71 ± 3.21 days longer compared to buffaloes with AA and CA genotypes. To gain insight into the functional relevance of this SNP, a computational analysis was performed which indicated that the C allele of the SNP (g.36417726C > A) increased the stability of LAMA2 mRNA compared to the A allele. This computational prediction was corroborated by observing a significant increase (P = 0.01798) in Lama2 gene expression (greater than 8-fold) and higher fat percentage (P < 0.05) in adipose tissue of CC genotypes (48.78 ± 1.87 %) compared to AA genotypes (33.59 ± 4.5 %). Furthermore, we noted a significant (P < 0.05) upregulation of C/ebpβ, Pparγ, Fasn, C/ebpα, and Pnpla2 genes, along with the downregulation of Bmp2 and Ptch1 in CC genotypes as opposed to AA genotypes. This observation suggests the involvement of the Pparγ-mediated pathway in both adipogenesis and lipolysis within CC genotypes. In summary, our comprehensive analysis involving association and functional validation underscores the potential of the SNP (g.36417726C > A) within the Lama2 gene as a promising genetic marker against extended PPAI in Murrah buffalo.

OBJECTIVE: Merosin is a protein complex located in the basement membrane of skeletal muscles and laminin α2-containing regions of the central and peripheral nervous systems. However, because of the prominence of muscle-related symptoms, peripheral neuropathy associated with merosin-deficient congenital muscular dystrophy type 1A (MDC1A) has received little clinical attention. This study aimed to present pathological changes in intramuscular nerves of three patients with MDC1A and discuss their relationship with electrophysiological findings to provide new evidence of peripheral nerve involvement in MDC1A.
METHODS: MDC1A was confirmed by clinical features, muscle biopsy, and genetic testing for variants in LAMA2. To clarify peripheral nerve involvement, we statistically evaluated electrophysiological and muscle pathology findings of intramuscular nerves. These findings were compared with those of age-matched boys with Duchenne muscular dystrophy (DMD) as controls with normal nerves. Nerve conduction studies (NCS) were performed before biopsy. Biopsied intramuscular nerves were examined with electron microscopy using g-ratio, which is the ratio of axon diameter to myelinated fiber diameter.
RESULTS: The myelin sheaths were significantly thinner in MDC1A patients than in age-matched DMD patients, with a mean g-ratio of 0.76 ± 0.07 in MDC1A patients and 0.65 ± 0.14 in DMD patients (p < .0001). No neuropathic changes were identified in muscle pathology. Low compound muscle action potential amplitudes, positive sharp waves and fibrillation potentials, and low-amplitude motor unit potentials with increased polyphasia indicated myopathic changes; no neurogenic changes were seen.
CONCLUSIONS: We postulate that the thin myelin associated with MDC1A reflects the role of merosin in myelin maturation.

BACKGROUND: Bladder urothelial carcinoma (BLCA) is the most common genitourinary cancer and the prognosis of patients is often poor. However, studies of basement membrane-related genes (BM-related genes) in BLCA are less reported. Therefore, we established a BM-related genes signature to explore their functional and prognostic value in BLCA.
METHODS: In this study, a BM-related genes signature was constructed by LASSO-Cox regression analysis, and then a series of bioinformatics methods was used to assess the accuracy and validity of the signature. We constructed a nomogram for clinical application and also screened for possible therapeutic drugs. To investigate the functions and pathways affected by BM-related genes in BLCA, we performed functional enrichment analyses. In addition, we analyzed the immune cell infiltration landscape and immune checkpoint-related genes in the high and low-risk groups. Finally, we confirmed the prognostic value of BM-related genes in BLCA in vitro.
RESULTS: Combining multiple bioinformatics approaches, we identified a seven-gene signature. The accuracy and validity of this signature in predicting BLCA patients were confirmed by the test cohort. In addition, the risk score was strongly correlated with prognosis, immune checkpoint genes, drug sensitivity, and immune cell infiltration landscape. The risk score is an independent prognostic factor for BLCA patients. Further experiments revealed that all seven signature genes were differentially expressed between BLCA cell lines and normal bladder cells. Finally, overexpression of LAMA2 inhibited the migration and invasion ability of BLCA cell lines.
CONCLUSIONS: In summary, the BM-related genes signature was able to predict the prognosis of BLCA patients accurately, indicating that the BM-related genes possess great clinical value in the diagnosis and treatment of BLCA. Moreover, LAMA2 could be a potential therapeutic target, which provides new insights into the application of the BM-related genes in BLCA patients.

UNASSIGNED: Mutations of LAMA2 gene are associated with congenital muscular dystrophy (CMD). The LAMA2-related CMD mainly consists of two diseases, merosin deficient congenital muscular dystrophies type 1A (MDC1A) and limb girdle muscular dystrophy 23 (LGMD23). LGMD23 is characterized by slowly progressive proximal muscle weakness, which primarily affects the lower limbs and results in gait difficulties. Additional clinical features include increased serum creatine kinase, abnormal electromyography with or without white matter abnormalities on brain imaging.
UNASSIGNED: Clinical data were collected from a Chinese Han family. Whole-exome sequencing, Sanger sequencing, RT-PCR and TA clone sequencing were performed on the family members.
UNASSIGNED: Compound heterozygous mutations of LAMA2: c.1693C > T (p. Q565*) (maternally inherited) and c.9212-6T > G (paternally inherited) were identified and confirmed in the proband. The mutation c.1693C > T (p. Q565*) was classified as pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. By performing RT-PCR and TA clone sequencing, an insertion of 40-bp intronic sequence (intron 64) was found in the transcripts of the proband and her father, which resulted in a frameshift and premature truncation codon of the LAMA2. In particular, the variant truncated the LamG domain of the LAMA2. Therefore, the c.9212-6T>G was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines.
UNASSIGNED: Our findings described two novel mutations in a girl with LGMDR23, which contributes to the genetic counseling of the family and expands the clinical and molecular spectrums of the rare disease.