Facioscapulohumeral muscular dystrophy (FSHD): Design of natural history study and results of baseline testing

Objective:To describe the phenomenon of acute illness-associated weakness (AIAW) in patients with dystroglycanopathy (DG), determine the frequency of this phenomenon in DGs, and compare it to the frequency in Duchenne-Becker muscular dystrophy (DBMD).Methods:Patients enrolled in a DG natural history study provided medical history, including major illnesses or hospitalizations, at enrollment and annually. We noted a recurring syndrome of profound transient weakness in the setting of febrile illness. To determine the frequency of this phenomenon in the DG cohort and compare it to a cohort with another membrane-related muscular dystrophy, DBMD, we surveyed patients (e-survey tool), collecting demographics and information about episodes of sudden progression of weakness and events surrounding the episodes.Results:Surveys were completed by 52 (56.6%) patients with DG and 51 (27.3%) patients with DBMD. AIAW was reported in 12 (23%) patients with DG and 2 (4%) patients with DBMD (odds ratio 7.35; 95% confidence interval 1.55, 34.77; p = 0.005). Altogether (history or survey), 21 patients with DG, with mutations in FKRP, FKTN, POMT1, POMT2, or POMGNT1, reported AIAW. These events typically occurred in children <7 years old, and the preceding illness usually included respiratory symptoms. In 10 (47.6%) patients with DG, AIAW preceded the diagnosis of muscular dystrophy.Conclusions:People with DG, across genotypes, can experience acute, transient weakness associated with a febrile illness, a phenomenon that rarely occurs in DBMD. The physiologic basis of this phenomenon is unknown.Clinicaltrials.gov identifier:NCT00313677.

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First results from the international LMNA -related congenital and childhood onset muscular dystrophy retrospective natural history study

Neuromuscular Disorders ◽

10.1016/j.nmd.2017.06.165 ◽

2017 ◽

Vol 27 ◽

pp. S137-S138

Author(s):

R. Ben Yaou ◽

I. Dabaj ◽

P. Yun ◽

G. Norato ◽

H. Xiong ◽

...

Keyword(s):

Muscular Dystrophy ◽

Natural History ◽

Childhood Onset ◽

Natural History Study ◽

First Results

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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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