A Multicenter Cross-Sectional Study of the Swiss Cohort of LAMA2-Related Muscular Dystrophy

Abstract

Background: 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.

Objective: The present study aimed to describe a well-characterized baseline cohort of patients with LAMA2-RD in Switzerland.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: LAMA2; Swiss-Reg-NMD; congenital muscular dystrophy. MDC1A; natural history.

Fig. 1

White matter changes and structural abnormalities. Legend. A, White matter changes – diffuse (FLAIR); B, White matter changes – patchy (T2); C, Cobblestone malformation occipital (T2 left and T1 right); D, Brainstem – pons hypoplasia and vermis rotation (T1); E, Pons hypoplasia and large interthalamic adhesion; F, Pons hypoplasia, Midbrain-Pons-Medulla Proportions (ac. Barkovitch); G: normal midbrain-pons-medulla proportions.

Fig. 2

Qualitative measurements of motor functions for eighteen patients. Legend. Qualitative motor abilities were recorded in accordance with the TREAT-NMD SMA Patient Registry Dataset, Version 2.1 (https://datasets.treat-nmd.org/sma/groups/motor-function).