LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness

Abstract

Mutations in the LAMA2 gene affect the production of the α2 subunit of laminin-211 (= merosin) and result in either partial or complete laminin-211 deficiency. Complete merosin deficiency is typically associated with a more severe congenital muscular dystrophy (CMD), clinically manifested by hypotonia and weakness at birth, the development of contractures of large joints, and progressive respiratory involvement. Muscle atrophy and severe weakness typically prevent independent ambulation. Partial merosin deficiency is mostly manifested by later onset limb-girdle weakness and joint contractures so that independent ambulation is typically achieved. Collectively, complete and partial merosin deficiency is referred to as LAMA2-related dystrophies (LAMA2-RDs) and represents one of the most common forms of congenital muscular dystrophies worldwide. LAMA2-RDs are classically characterized by both central and peripheral nervous system involvement with abnormal appearing white matter (WM) on brain MRI and dystrophic appearing muscle on muscle biopsy as well as creatine kinase (CK) levels commonly elevated to >1,000 IU/L. Next-generation sequencing (NGS) has greatly improved diagnostic abilities for LAMA2-RD, and the majority of patients with merosin deficiency carry recessive pathogenic variants in the LAMA2 gene. The existence of multiple animal models for LAMA2-RDs has helped to advance our understanding of laminin-211 and has been instrumental in preclinical research progress and translation to clinical trials. The first clinical trial for the LAMA2-RDs was a phase 1 pharmacokinetic and safety study of the anti-apoptotic compound omigapil, based on preclinical studies performed in the dy ^W/dy ^W and dy ^2J/dy ^2J mouse models. This phase 1 study enabled the collection of pulmonary and motor outcome measures and also provided the opportunity for investigating exploratory outcome measures including muscle ultrasound, muscle MRI and serum, and urine biomarker collection. Natural history studies, including a five-year prospective natural history and comparative outcome measures study in patients with LAMA2-RD, have helped to better delineate the natural history and identify viable outcome measures. Plans for further clinical trials for LAMA2-RDs are presently in progress, highlighting the necessity of identifying adequate, disease-relevant biomarkers, capable of reflecting potential therapeutic changes, in addition to refining the clinical outcome measures and time-to-event trajectory analysis of affected patients.

Keywords: LAMA2; biomarkers; clinical trial; natural history; phenotype.

Figure 1

Clinical phenotype. A patient with complete merosin deficiency, with evidence of hip, knee, and ankle contractures with lordotic posture which is typical of LAMA2-RD patients from an early age (written informed consent for the publication of the clinical image was obtained from a parent of the patient).

Figure 2

Brain and muscle imaging findings in LAMA2-RD. (A–D) Typical brain MRI findings in LAMA2-RD with abnormal appearance of myelin with sparing of the U fibers seen on T2 axial images (A,C,D). T1 sagittal image (B) demonstrates evidence of occipital polymicrogyria, which has been observed in some LAMA2-RD patients and may predispose to occipital lobe seizures. Muscle MRI of the upper leg (E) and lower leg (F) in a 9-year-old patient with complete merosin deficiency with evidence of abnormal signaling in most muscles with relative sparing of the sartorius and gracilis muscles (E). In the lower leg, the muscles of the anterior compartment seem relatively spared compared to muscles of the posterior compartment, namely the soleus and gastrocnemius muscles, which demonstrate the apparent replacement of muscle with fibrofatty tissue.

Figure 3

Laminin-211 deficiency in diagnostic quadriceps muscle biopsies and chorionic villus biopsies. Complete laminin-211 deficiency in quadriceps muscle biopsy (A–D). Hematoxylin and eosin (H & E) stained section (A) shows marked dystrophic changes. Immunolabeling with the 300 kDa laminin-211 antibody (B) shows complete absence at the myofiber basal lamina (B, stars) and on an intramuscular motor nerve (B, arrow). There is widespread secondary upregulation of laminin alpha 5 (C), whereas labeling with the IIH6 antibody against the glycosylated alpha-dystroglycan epitope appears normal. Partial laminin-211 deficiency in quadriceps muscle biopsy (E–H). H&E stained section (E) shows moderate dystrophic changes. Immunolabeling with the 300 kDa laminin-211 antibody shows moderate, patchy reduction at the myofiber basal lamina (F) and complete absence on an intramuscular motor nerve (G, arrows). There is widespread secondary upregulation of laminin alpha 5 (H). Prenatal testing for laminin-211 deficiency in chorionic villus biopsies (I–M). Labeling of a positive control sample (fetus unaffected by LAMA2-RD) (I) with the 300 kDa laminin-211 antibody shows distinct membranous labeling at the trophoblastic basement membrane of chorionic villi. Example of a test case showing normal labeling (J,K) comparable to the positive control, and another case showing complete absence of laminin-211 at the trophoblastic basal lamina (L,M) of first-trimester chorionic villi. In this case, the complete absence of laminin-211 expression suggests that the fetus is affected by LAMA2-RD. Normal labeling for laminin-211 in chorionic villi does not exclude carrier status for LAMA2-RD.