Inspired by a patient
Villar-Quiles RN, von der Hagen M, Métay C, Gonzalez V,
Donkervoort S, Bertini E, Castiglioni C, Chaigne D, Colomer J, Cuadrado ML, de
Visser M, Desguerre I, Eymard B, Goemans N, Kaindl A, Lagrue E, Lütschg J,
Malfatti E, Mayer M, Merlini L, Orlikowski D, Reuner U, Salih MA,
Schlotter-Weigel B, Stoetter M, Straub V, Topaloglu H, Urtizberea JA, van der
Kooi A, Wilichowski E, Romero NB, Fardeau M, Bönnemann CG, Estournet B, Richard
P, Quijano-Roy S, Schara U, Ferreiro A. The clinical, histologic, and genotypic
spectrum of SEPN1-related myopathy: A case series. Neurology. 2020
Sep 15;95(11):e1512-e1527. doi: 10.1212/WNL.0000000000010327. Epub 2020 Aug 13.
PMID: 32796131; PMCID: PMC7713742.
Abstract
Objective: To clarify the prevalence, long-term natural history, and
severity determinants of SEPN1-related myopathy (SEPN1-RM), we
analyzed a large international case series.
Methods: Retrospective clinical, histologic, and genetic analysis of 132
pediatric and adult patients (2-58 years) followed up for several decades.
Results: The clinical phenotype was marked by severe axial muscle
weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with
relatively preserved limb strength and previously unreported ophthalmoparesis
in severe cases. All patients developed respiratory failure (from 10.1±6
years), 81.7% requiring ventilation while ambulant. Histopathologically, 79
muscle biopsies showed large variability, partly determined by site of biopsy
and age. Multi-minicores were the most common lesion (59.5%), often associated
with mild dystrophic features and occasionally with eosinophilic inclusions.
Identification of 65 SEPN1 mutations, including 32 novel ones
and the first pathogenic copy number variation, unveiled exon 1 as the main
mutational hotspot and revealed the first genotype-phenotype correlations,
bi-allelic null mutations being significantly associated with disease severity
(p = 0.017). SEPN1-RM was more severe and progressive than
previously thought, leading to loss of ambulation in 10% of cases, systematic
functional decline from the end of the third decade, and reduced lifespan even
in mild cases. The main prognosis determinants were scoliosis/respiratory
management, SEPN1 mutations, and body mass abnormalities,
which correlated with disease severity. We propose a set of severity criteria,
provide quantitative data for outcome identification, and establish a need for
age stratification.
Conclusion: Our results inform clinical practice, improving diagnosis and
management, and represent a major breakthrough for clinical trial readiness in
this not so rare disease.
Bouman K, Groothuis JT, Doorduin J, van Alfen
N, Udink Ten Cate FEA, van den Heuvel FMA, Nijveldt R, van Tilburg WCM, Buckens
SCFM, Dittrich ATM, Draaisma JMT, Janssen MCH, Kamsteeg EJ, van Kleef ESB,
Koene S, Smeitink JAM, Küsters B, van Tienen FHJ, Smeets HJM, van Engelen BGM,
Erasmus CE, Voermans NC. 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. BMC Neurol. 2021 Aug
12;21(1):313. doi: 10.1186/s12883-021-02336-z. PMID: 34384384; PMCID:
PMC8357962.
Abstract
Background: SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare
congenital myopathy characterized by slowly progressive proximal muscle
weakness, early onset spine rigidity and respiratory insufficiency. A muscular
dystrophy caused by mutations in the LAMA2 gene (LAMA2-related muscular
dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe,
early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient
congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or
adult-onset due to partial Laminin subunit α2 deficiency. For both muscle
diseases, no curative treatment options exist, yet promising preclinical
studies are ongoing. Currently, there is a paucity on natural history data and
appropriate clinical and functional outcome measures are needed to reach trial
readiness.
Methods: LAST STRONG is a natural history study in Dutch-speaking
patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August
2020. Patients have four visits at our hospital over a period of 1.5 year. At
all visits, they undergo standardized neurological examination, hand-held
dynamometry (age ≥ 5 years), functional measurements, questionnaires (patient
report and/or parent proxy; age ≥ 2 years), muscle ultrasound including
diaphragm, pulmonary function tests (spirometry, maximal inspiratory and
expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), and
accelerometry for 8 days (age ≥ 2 years); at visit one and three, they undergo
cardiac evaluation (electrocardiogram, echocardiography; age ≥ 2 years), spine
X-ray (age ≥ 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2
years) and full body magnetic resonance imaging (MRI) (age ≥ 10 years). All
examinations are adapted to the patient's age and functional abilities.
Correlation between key parameters within and between subsequent visits will be
assessed.
Discussion: Our study will describe the natural history of patients
diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical
and functional outcome measures for reaching clinical trial-readiness.
Moreover, our detailed description (deep phenotyping) of the clinical features
will optimize clinical management and will establish a well-characterized
baseline cohort for prospective follow-up.
Conclusion: Our natural history study is an essential step for reaching
trial readiness in SELENON-RM and LAMA2-MD.
Varone E, Pozzer D, Di Modica S, Chernorudskiy
A, Nogara L, Baraldo M, Cinquanta M, Fumagalli S, Villar-Quiles RN, De Simoni
MG, Blaauw B, Ferreiro A, Zito E. SELENON (SEPN1) protects skeletal muscle from
saturated fatty acid-induced ER stress and insulin resistance. Redox Biol. 2019
Jun;24:101176. doi: 10.1016/j.redox.2019.101176. Epub 2019 Mar 23. PMID:
30921636; PMCID: PMC6438913.
Abstract
Selenoprotein N
(SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads
to a congenital myopathy associated with insulin resistance (SEPN1-related
myopathy). The exact cause of the insulin resistance in patients with SELENON
loss of function is not known. Skeletal muscle is the main contributor to
insulin-mediated glucose uptake, and a defect in this muscle-related mechanism
triggers insulin resistance and glucose intolerance. We have studied the chain
of events that connect the loss of SELENON with defects in insulin-mediated
glucose uptake in muscle cells and the effects of this on muscle performance.
Here, we show that saturated fatty acids are more lipotoxic in SELENON-devoid
cells, and blunt the insulin-mediated glucose uptake of SELENON-devoid myotubes
by increasing ER stress and mounting a maladaptive ER stress response.
Furthermore, the hind limb skeletal muscles of SELENON KO mice fed a high-fat
diet mirrors the features of saturated fatty acid-treated myotubes, and show
signs of myopathy with a compromised force production. These findings suggest
that the absence of SELENON together with a high-fat dietary regimen increases
susceptibility to insulin resistance by triggering a chronic ER stress in
skeletal muscle and muscle weakness. Importantly, our findings suggest that
environmental cues eliciting ER stress in skeletal muscle (such as a high-fat
diet) affect the pathological phenotype of SEPN1-related myopathy and can
therefore contribute to the assessment of prognosis beyond simple
genotype-phenotype correlations.
Bachmann C, Noreen F, Voermans NC, Schär PL, Vissing J, Fock JM,
Bulk S, Kusters B, Moore SA, Beggs AH, Mathews KD, Meyer M, Genetti CA, Meola
G, Cardani R, Mathews E, Jungbluth H, Muntoni F, Zorzato F, Treves S. Aberrant
regulation of epigenetic modifiers contributes to the pathogenesis in patients
with selenoprotein N-related myopathies. Hum Mutat. 2019 Jul;40(7):962-974.
doi: 10.1002/humu.23745. Epub 2019 Apr 1. PMID: 30932294; PMCID: PMC6660981.
Abstract
Congenital myopathies are early onset, slowly progressive
neuromuscular disorders of variable severity. They are genetically and
phenotypically heterogeneous and caused by pathogenic variants in several genes.
Multi-minicore Disease, one of the more common congenital myopathies, is
frequently caused by recessive variants in either SELENON, encoding the
endoplasmic reticulum glycoprotein selenoprotein N or RYR1, encoding a protein
involved in calcium homeostasis and excitation-contraction coupling. The
mechanism by which recessive SELENON variants cause Multiminicore disease (MmD)
is unclear. Here, we extensively investigated muscle physiological, biochemical
and epigenetic modifications, including DNA methylation, histone modification,
and noncoding RNA expression, to understand the pathomechanism of MmD. We
identified biochemical changes that are common in patients harboring recessive
RYR1 and SELENON variants, including depletion of transcripts encoding proteins
involved in skeletal muscle calcium homeostasis, increased levels of Class II
histone deacetylases (HDACs) and DNA methyltransferases. CpG methylation
analysis of genomic DNA of patients with RYR1 and SELENON variants identified
>3,500 common aberrantly methylated genes, many of which are involved in
calcium signaling. These results provide the proof of concept for the potential
use of drugs targeting HDACs and DNA methyltransferases to treat patients with
specific forms of congenital myopathies.