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 acquired 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, orthopaedic, 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.

Keywords: LMNA; early onset; laminopathies; muscular dystrophy; striated muscle.

Graphical Abstract

Figure 1

Clinical characteristics of the cohort. (A) Maximal motor function achieved for individuals at a given age of onset. This demonstrates that individuals with an earlier age of onset may still reach a maximum functional ability of independent ambulation; however, those with later ages of onset tend to have better maximal motor function (P < 0.01). (B) Age at first cardiac intervention (left panel) and age at first respiratory intervention (right panel) mapped against age at loss of ambulation. Although there is a strong relationship when all data is included (r = 0.80, P < 0.01; r = 0.81, P < 0.01, respectively), this relationship is greatly reduced after removal of the two individuals with late interventions (r = 0.22, P = 0.37; r = 0.38, P = 0.04, respectively). (C) Kaplan–Meier time to event analysis for loss of ambulation. About half of the individuals who acquired independent ambulation lost this ability by age 14 years.

Figure 2

Map of heterozygous LMNA variants identified in the 151 patients with onset before 2 years of age. (A) Distribution of variants in the different exons of the LMNA gene. The LMNA c.745C>T, p.Arg249Trp variant was found in 30 patients, the c.116A>G, p.Asn39Ser in 13, the c.1072G>A, p.Glu358Lys in 10, the c.94_96delAAG, p.Lys32del in 9 and the c.1357C>T, p.Arg453Trp in 7. Variants identified in six or fewer patients are depicted together. (B) Mutation map at the protein structure level. Mutations are depicted and aligned according to their position on both exons and lamins A and C protein domains. The height of each mutation position corresponds to the number of patients carrying mutation at the specific position.

Figure 3

Time-to-event analysis. (A) Time-to-event analysis to NIV (non-invasive ventilation) and (B) first rhythm abnormality demonstrate that these events are reached earlier in patients who were never ambulatory when compared to those who had achieved ambulation.

Figure 4

Histogram plot of ages for disease-related symptoms and interventions. An initial rhythm abnormality (46% of the cohort) was seen at a median estimated age of 11 years old, followed by the initiation of NIV (non-invasive ventilation) at a median estimated age of 16 years. Cardiac medication was taken by 25% of the cohort with echocardiogram abnormalities present in 22%. ICD and pacemakers were relatively uncommon (9% and 7%, respectively).

Figure 5

Genotype–phenotype analysis stratified time-to-event analysis for the most common variant (p.Arg249Trp) against all other variants. (A) Visual analysis of the curve for loss of ambulation suggests that half of individuals lose ambulation by five years of age for patients with the p.Arg249Trp variant. (B) A similar difference is shown for time to NIV (non-invasive ventilation) (n = 12 p.Arg249Trp, n = 29 other variants). (C) No difference is noted for time to first rhythm abnormality (n = 12 p.Arg249Trp, n = 11 other variants).