LAMA2‐related muscular dystrophy: Natural history of a large pediatric cohort

Abstract

Objective: To characterize natural history of Laminin-a2 related muscular dystrophies (LAMA2-RD) to help anticipating complications and identifying reliable outcome measures for clinical trial design and powering. Methods: We conducted a retrospective, single-center, cross-sectional and longitudinal study on 46 LAMA2-RD pediatric patients (37 families). Patients were seen at the Dubowitz Neuromuscular Centre, London between 1985 and 2019. Data were collected by case note reviews. Time-to-event analysis was performed to estimate median age at complications occurrence. Results: Forty two patients had complete deficiency of Laminin-a2 (CD) and four had partial deficiency (PD). Median age at first and last assessment was 2 years and 12.1 years, respectively. Median follow-up length was 7.8 years (range 0-18 years). Seven CD patients died at median age 12 years. One CD and two PD subjects achieved independent ambulation. We observed a linear increase in elbow flexor contractures in CD subjects. Thirty-two CD and one PD patient developed scoliosis, nine underwent spinal surgery. Twenty-two CD required nocturnal noninvasive ventilation (median age 11.7 years). CD subjects showed a 2.9% linear annual decline in forced vital capacity % predicted. Nineteen CD and one PD patient required gastrostomy insertion for failure to thrive and/or unsafe swallow (median age 10.9 years). Four CD patients had partial seizures. Mild left cardiac ventricular dysfunction and rhythm disturbances were identified in seven CD patients. Interpretation: This retrospective longitudinal study provides longterm natural history of LAMA2-RD. This will help management and identification of key milestones of disease progression that could be considered for future therapeutic intervention.

Natural history and genetic study of LAMA2-related muscular dystrophy in a large Chinese cohort

“…Though muscular dystrophies due to LAMA2 -related muscular dystrophy is relatively rare, they cover a distinct clinical presentations and severity with high disability and disease burden, and the further mechanism how the pathogenic variants affect the function of laminin-α2 leading to clinical heterogeneity is still unclear. Recently, two natural history studies on 46 LAMA2 -related muscular dystrophy pediatric patients in the Dubowitz Neuromuscular Centre [ 5 ] and 24 LAMA2 -related muscular dystrophy patients in National Institutes of Health [ 17 ] provided useful information towards trial readiness. However, international multicenter studies with detailed knowledge on long-term progression of disease as well as genotype–phenotype correlations remain challenging.…”

“…The causes of death in LAMA2 -CMD were respiratory failure and pneumonia (78.3%), status epilepticus (8.7%) and malnutrition (8.7%). Respiratory insufficiency could manifest with recurrent chest infection starting from first two years of life [ 5 ], and the need for ventilation longer than 4 weeks was reported as a predictor of sudden death [ 33 ]. Therefore, LAMA2 -CMD patients should receive standardized respiratory care according to current guidelines [ 34 ].…”

“…The clinical spectrum ranges from a severe, earlyonset LAMA2-related congenital muscular dystrophy (LAMA2-CMD, OMIM 607,855) to a mild, childhoodonset autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23, OMIM 618,138) [2,3]. The phenotypic difference seems to be related not only to the residual amount of laminin-α2, but also to the location and type of pathogenic variants [4,5]. LAMA2-CMD is one of the most common congenital muscular dystrophies (CMDs) in the world, accounting for 36.4%-48% of CMD patients [6][7][8].…”

Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study

“…Moreover, the age range limits the availability on natural history data in the very young children (< 4 years) and in older adult patients (> 22 years). Recently, Zambon et al published a retrospective longitudinal study on 46 patients with LAMA2-MD of whom 42 patients had a complete and 4 patients had a partial Laminin subunit α2 deficiency (age range at last examination 12 to 22 years) [ 37 ]. They found a linear decrease in passive range of motion of left elbow extension and a linear decline in percentage predicted forced vital capacity.…”

Corrigendum

“…In the article by Zambon et al., 1 the original version of Figure 1 showed the age at attaining developmental milestones in 24 patients with LAMA2‐RD. Tick marks on vertical axis indicated single patients.…”