International retrospective natural history study of LMNA-related congenital muscular dystrophy

Abstract

Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (Median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never aquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (Median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (Median: 7 years, range 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopedic, cardiac, and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.

In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies

“…There was no apparent connection between the disease phenotypes and the position of an altered amino acid. Our findings are consistent with those noted using smaller datasets [72,73].…”

“…Thus, our finding suggest that R249W is more detrimental to muscle function than R249Q. Consistent with R249W having severe effects, a recent clinical study found R249W to have a worse prognosis compared with four other non-truncating LMNA mutations [72].…”

“…It is unclear if the nature of the replacement amino acid or differences in an individual's genetic background cause disease variation in these cases. Here, we focused on R249W, which is the most prevalent amino acid substitution in cases of L-CMD [72,75], and R249Q, which is more commonly observed with AD-EDMD [50,51]. The substitution of the charged R residue with the aromatic side chain of W or the uncharged polar residue Q might alter lamin homo-dimerization.…”

LMNA-related muscular dystrophy: Identification of variants in alternative genes and personalized clinical translation

“…All variants were identified in heterozygous state (Figure 2). Eleven rare variants (57.89%) were classified as LP and 7 (36.84%) as definitively P. The most frequent rare variant identified in LMNA was p.Arg249Trp (5 patients, 19.23%), as previously reported (Quijano-Roy et al, 2008;Pasqualin et al, 2014;Heller et al, 2017;Ben Yaou et al, 2021;Fan et al, 2021;Jedrzejowska et al, 2021). These 5 patients were diagnosed with L-CMD (4 patients -index case 1, 2, 6, and 26-) and EDMD (1 patient -index case 14-).…”

“…The most common laminopathies are LMNArelated congenital muscular dystrophy (L-CMD) (OMIM: 613205), Emery-Dreifuss muscular dystrophy (EDMD) (OMIM: 181350), limb-girdle muscular dystrophy type 1B (LGMD-1B) (OMIM: 159001), and dilated cardiomyopathy with conduction defects (DCM-CD) (OMIM: 115200). A range of phenotypes have been reported in patients carrying deleterious rare LMNA variants (Bertrand et al, 2011;Worman, 2012;Carboni et al, 2013a;Carboni et al, 2013b;Ben Yaou et al, 2021). It has been suggested that different phenotypes can be explained by post-transcriptional modifications of the nuclear envelope/lamina proteins (Maraldi et al, 2011;Zheng et al, 2022).…”