A 5-year Natural History Study in LAMA2-related muscular dystrophy and SELENON-related myopathy: the extended LAST STRONG Study

Selenoprotein N-related congenital myopathy (SELENON-RM) is a rare congenital
myopathy with an estimated prevalence of 0.5 in 1.000.000. Key characteristics
include slowly progressive axial muscle weakness, early-onset rigidity of the
spine, scoliosis and respiratory insufficiency. Delayed motor development is
the most common presenting sign. Laminin α2-related muscular dystrophy
(LAMA2-MD) is a rare congenital muscular dystrophy with similar key features
and an estimated prevalence of 4 in 500.000. It has a disease spectrum ranging
from a severe, early-onset congenital muscular dystrophy type 1A ((MDC1A);
complete merosine deficiency) to a mild, childhood- or adult-onset limb-girdle
type muscular dystrophy (partial merosine deficiency). In addition, patients
may suffer from epileptic seizures and may show characteristic diffuse brain
white matter lesions on magnetic resonance imaging (MRI). The clinical
diagnosis of LAMA2-MD and SELENON-RM is confirmed by recessive pathogenic
loss-of-function variants in the LAMA2 or SELENON gene, respectively.

Currently, no curative treatment options exist for neither SELENON-RM nor
LAMA2-MD. To determine the effectivity of possible treatment options in
clinical trials, it is essential to identify and characterize patients
clinically and genetically, and to select clinical and functional outcome
measures that correlate with muscle function and that are sensitive to change
over time. Up to now, several large clinical studies have been performed. These
studies had major limitations, including a retrospective design, the absence of
standardized functional measurements and convenient muscle visualizing
techniques, and a limited age range.

The LAST STRONG Study, a natural history study to select outcome measures and
reach trial readiness, was initiated in 202010. Consensus on the outcome
measures will be reached after a key-opinion (pediatric and adult) leader
workshop (KOL), which took place in March 2023 at the international LAMA2
conference in Barcelona. Currently, baseline data is analyzed, including
decreased bone quality resulting in fragility fractures and impaired pulmonary
function starting at young age. In both SELENON-RM and LAMA2-MD, axial and
proximal muscle weakness was most pronounced and muscle ultrasound revealed
that echogenicity was symmetrically increased. Further, physical activity as
measured through accelerometry showed strong correlations with the MFM-20/32
score for both SELENON-RM and LAMA2-MD.

In conclusion, a long-term prospective natural history study in an unselected
patient cohort including clinical and functional outcome measures is lacking in
both SELENON-RM and LAMA2-MD. Due to the promising ongoing preclinical trials,
there is a high need to obtain natural history data in order to reach trial
readiness.

With the extended LAST STRONG Study, we aim to (1) collect 3-year and 5-year
natural history data, (2) implement the natural history data collection into
clinical care and international guidelines (reach trial readiness), and (3) do
in-depth analysis of the striking results of the LAST STRONG study and
collection of serum (muscle biomarkers) and urine. This study will enable a
smooth transition towards implementation into clinical care and clinical trials
starting within 5 years.

The extended LAST STRONG Study will be a prospective, single-center,
observational cohort study with repeated measurements performed at the
Department of Neurology and Pediatric Neurology within the neuromuscular center
of the Radboud university medical center, the Netherlands. SELENON-RM and
LAMA2-MD patients are invited to visit our hospital two times (three years
(visit 5) and five years (visit 6) after the first visit in the LAST STRONG
Study (figure 1)).

The aim of this study is to investigate the natural history of SELENON-RM and
LAMA2-MD patients to prepare them for clinical trials that are in preparation.
Since there are few patients with these conditions, we will ask both children
and adults to participate. This study is a preparation for clinical trials in
these conditions, may facilitate the proper conduction of these clinical trials
and may help to implement natural history data collection into clinical care
and international guidelines. The conduction of so many tests is without any
doubt burdensome for patients. Therefore, we reduced the number of tests
to-our-opinion the absolute minimum based on the first results of the 1.5 year
natural history study (LAST STRONG Study) and after the KOL in March 2023. All
tests that will be applied during this study, are considered to be of low risk
for the participants.