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

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. Trial registration This study has been approved by medical ethical reviewing committee Region Arnhem-Nijmegen (NL64269.091.17, 2017–3911) and is registered at ClinicalTrial.gov (NCT04478981).

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Functional Outcome Measures Correlated with Strength in Becker Muscular Dystrophy (P02.001)

Neurology ◽

10.1212/wnl.78.1_meetingabstracts.p02.001 ◽

2012 ◽

Vol 78 (Meeting Abstracts 1) ◽

pp. P02.001-P02.001

Author(s):

L. Alfano ◽

L. Lowes ◽

L. Viollet ◽

K. Flanigan ◽

J. Mendell

Keyword(s):

Muscular Dystrophy ◽

Functional Outcome ◽

Outcome Measures ◽

Becker Muscular Dystrophy ◽

Functional Outcome Measures

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International retrospective natural history study of LMNA-related congenital muscular dystrophy

Brain Communications ◽

10.1093/braincomms/fcab075 ◽

2021 ◽

Author(s):

Rabah Ben Yaou ◽

Pomi Yun ◽

Ivana Dabaj ◽

Gina Norato ◽

Sandra Donkervoort ◽

...

Keyword(s):

Clinical Trial ◽

Muscular Dystrophy ◽

Natural History ◽

Early Onset ◽

Age Of Onset ◽

Clinical Care ◽

Common Mutation ◽

Natural History Study ◽

Cardiac Symptoms ◽

Independent Ambulation

Abstract Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (Median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never aquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (Median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (Median: 7 years, range 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopedic, cardiac, and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.

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P4.25 Functional outcome measures in limb girdle muscular dystrophy 2I: Correlations with MRI

Neuromuscular Disorders ◽

10.1016/j.nmd.2010.07.221 ◽

2010 ◽

Vol 20 (9-10) ◽

pp. 665-666

Author(s):

M. Eagle ◽

A. Mayhew ◽

T.A. Willis ◽

H. Lochmuller ◽

K. Bushby ◽

...

Keyword(s):

Muscular Dystrophy ◽

Functional Outcome ◽

Outcome Measures ◽

Limb Girdle Muscular Dystrophy ◽

Functional Outcome Measures

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Lower Extremity Functional Outcome Measures in Duchenne Muscular Dystrophy-A Delphi Survey

Journal of Neuromuscular Diseases ◽

10.3233/jnd-180337 ◽

2019 ◽

Vol 6 (1) ◽

pp. 75-83 ◽

Cited By ~ 1

Author(s):

Claudia R. Senesac ◽

Donovan J. Lott ◽

Rebecca J. Willcocks ◽

Tina Duong ◽

Barbara K. Smith

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Lower Extremity ◽

Functional Outcome ◽

Outcome Measures ◽

Delphi Survey ◽

Functional Outcome Measures

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Longitudinal study of MRI and functional outcome measures in facioscapulohumeral muscular dystrophy

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-04134-7 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Leo H. Wang ◽

Dennis W. W. Shaw ◽

Anna Faino ◽

Christopher B. Budech ◽

Leann M. Lewis ◽

...

Keyword(s):

Muscular Dystrophy ◽

Lower Extremity ◽

Functional Outcome ◽

Outcome Measures ◽

Facioscapulohumeral Muscular Dystrophy ◽

Strength Measurement ◽

Small Shift ◽

Lower Extremity Weakness ◽

Fat Fraction ◽

Functional Outcome Measures

Abstract Background Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. For MRI to be a useful biomarker in an FSHD clinical trial, it should reliably detect changes over relatively short time-intervals (~ 1 year). We hypothesized that fatty change over the study course would be most likely in muscles already demonstrating disease progression, and that the degree of MRI burden would be correlated with function. Methods We studied 36 patients with FSHD and lower-extremity weakness at baseline. Thirty-two patients returned in our 12-month longitudinal observational study. We analyzed DIXON MRI images of 16 lower-extremity muscles in each patient and compared them to quantitative strength measurement and ambulatory functional outcome measures. Results There was a small shift to higher fat fractions in the summed muscle data for each patient, however individual muscles demonstrated much larger magnitudes of change. The greatest increase in fat fraction was observed in muscles having an intermediate fat replacement at baseline, with minimally (baseline fat fraction < 0.10) or severely (> 0.70) affected muscles less likely to progress. Functional outcome measures did not demonstrate marked change over the interval; however, overall MRI disease burden was correlated with functional outcome measures. Direct comparison of the tibialis anterior (TA) fat fraction and quantitative strength measurement showed a sigmoidal relationship, with steepest drop being when the muscle gets more than ~ 20% fatty replaced. Conclusions Assessing MRI changes in 16 lower-extremity muscles across 1 year demonstrated that those muscles having an intermediate baseline fat fraction were more likely to progress. Ambulatory functional outcome measures are generally related to overall muscle MRI burden but remain unchanged in the short term. Quantitative strength measurement of the TA showed a steep loss of strength when more fatty infiltration is present suggesting that MRI may be preferable for following incremental change or modulation with drug therapy.

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Muscle MRI and functional outcome measures in Becker muscular dystrophy

Scientific Reports ◽

10.1038/s41598-017-16170-2 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Andrea Barp ◽

Luca Bello ◽

Luca Caumo ◽

Paola Campadello ◽

Claudio Semplicini ◽

...

Keyword(s):

Muscular Dystrophy ◽

Functional Outcome ◽

Outcome Measures ◽

Becker Muscular Dystrophy ◽

Muscle Mri ◽

Functional Outcome Measures

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Adapting MRI as a clinical outcome measure for a facioscapulohumeral muscular dystrophy trial of prednisone and tacrolimus: case report

BMC Musculoskeletal Disorders ◽

10.1186/s12891-020-03910-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Leo H. Wang ◽

Laura M. Johnstone ◽

Michael Bindschadler ◽

Stephen J. Tapscott ◽

Seth D. Friedman

Keyword(s):

Muscular Dystrophy ◽

Functional Outcome ◽

Immunosuppressive Therapy ◽

Outcome Measures ◽

Facioscapulohumeral Muscular Dystrophy ◽

Muscle Mri ◽

Patient Reported ◽

Fat Fraction ◽

Functional Outcome Measures ◽

Autoimmune Myopathy

Abstract Background Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. MRI short tau inversion recovery (STIR) sequences of patient muscles often show increased hyperintensity that is hypothesized to be associated with inflammation. This is supported by the presence of inflammatory changes on biopsies of STIR-positive muscles. We hypothesized that the STIR positivity would normalize with targeted immunosuppressive therapy. Case presentation 45-year-old male with FSHD type 1 was treated with 12 weeks of immunosuppressive therapy, tacrolimus and prednisone. Tacrolimus was treated to a goal serum trough of > 5 ng/mL and prednisone was tapered every month. Quantitative strength exam, functional outcome measures, and muscle MRI were performed at baseline, week 6, and week 12. The patient reported subjective worsening as reflected in quantitative strength exam. The MRI STIR signal was slightly increased from 0.02 to 0.03 of total muscle; while the T1 fat fraction was stable. Functional outcome measures also were stable. Conclusions Immunosuppressive therapy in refractive autoimmune myopathy in other contexts has been shown to reverse STIR signal hyperintensity, however this treatment did not reverse STIR signal in this patient with FSHD. In fact, STIR signal slightly increased throughout the treatment period. This is the first study of using MRI STIR and T1 fat fraction to follow treatment effect in FSHD. We find that STIR might not be a dynamic marker for suppressing inflammation in FSHD.

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