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

被引：22

作者：

Ben Yaou, Rabah ^{[1
,2
]}

Yun, Pomi ^{[3
]}

Dabaj, Ivana ^{[4
,5
]}

Norato, Gina ^{[3
]}

Donkervoort, Sandra ^{[3
]}

Xiong, Hui ^{[5
]}

Nascimento, Andres ^{[6
]}

Maggi, Lorenzo ^{[7
]}

Sarkozy, Anna ^{[8
,9
]}

Monges, Soledad ^{[10
]}

Bertoli, Marta ^{[11
]}

Komaki, Hirofumi ^{[12
]}

Mayer, Michele ^{[13
]}

Mercuri, Eugenio ^{[14
]}

Zanoteli, Edmar ^{[15
]}

Castiglioni, Claudia ^{[16
]}

Marini-Bettolo, Chiara ^{[17
,18
]}

D'Amico, Adele ^{[19
]}

Deconinck, Nicolas ^{[20
,21
]}

Desguerre, Isabelle ^{[22
]}

Erazo-Torricelli, Ricardo ^{[23
]}

Gurgel-Giannetti, Juliana ^{[24
]}

Ishiyama, Akihiko ^{[12
]}

Kleinsteuber, Karin S. ^{[25
]}

Lagrue, Emmanuelle ^{[26
]}

Laugel, Vincent ^{[27
]}

Mercier, Sandra ^{[28
]}

Messina, Sonia ^{[29
]}

Politano, Luisa ^{[30
]}

Ryan, Monique M. ^{[31
]}

Sabouraud, Pascal ^{[32
]}

Schara, Ulrike ^{[33
]}

Siciliano, Gabriele ^{[34
]}

Vercelli, Liliana ^{[35
]}

Voit, Thomas ^{[8
,36
]}

Yoon, Grace ^{[37
,38
]}

Alvarez, Rachel ^{[39
]}

Muntoni, Francesco ^{[8
,36
]}

Pierson, Tyler M. ^{[40
,41
,42
]}

Gomez-Andres, David ^{[43
]}

Foley, A. Reghan ^{[3
]}

Quijano-Roy, Susana ^{[4
,44
]}

Bonnemann, Carsten G. ^{[3
]}

Bonne, Gisele ^{[1
,45
]}

机构：

[1] Sorbonne Univ, Ctr Rech Myol, Inst Myol, INSERM, F-75013 Paris, France

[2] Sorbonne Univ, GH Pitie Salpetriere, AP HP,FILNEMUS,ERN Euro NMD,Serv Neuromyol,Inst M, Neuromuscular Disorders Reference Ctr Nord Est Il, F-75013 Paris, France

[3] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[4] Univ Paris Saclay, Raymond Poincare Univ Hosp,DMU Sante Enfant Adole, AP HP,FILNEMUS,ERN Euro NMD,Pediat Neurol & ICU D, Neuromuscular Disorders Reference Ctr Nord Est Il, Garches, France

[5] Rouen Univ, Sch Med, ED497, INSERM U1245, Rouen, France

[6] Peking Univ First Hosp, Dept Pediat, Beijing, Peoples R China

[7] Hosp St Joan de Deu, Neuromuscular Unit, Neuropaediat Dept, Inst Recerca St Joan de Deu,CIBERER ISC III, Barcelona, Spain

[8] Fdn IRCCS Inst Neurol Carlo Besta, Neuroimmunol & Neuromuscular Dis Unit, Milan, Italy

[9] Great Ormond St Hosp Trust, Dubowitz Neuromuscular Ctr, UCL Great Ormond St Inst Child Hlth, London, England

[10] Hosp Pediat JP Garrahan, Serv Neurol, Buenos Aires, DF, Argentina

[11] Newcastle Upon Tyne NHS Fdn Trust, Northern Genet Serv, Newcastle Upon Tyne, Tyne & Wear, England

[12] Natl Ctr Hosp, Natl Ctr Neurol & Psychiat NCNP, Dept Child Neurol, Tokyo, Japan

[13] Sorbonne Univ, Hop Armand Trousseau, AP HP,FILNEMUS,ERN Euro NMD,Dept Neuropediat, Neuromuscular Disorders Reference Ctr Nord Est Il, Paris, France

[14] Fdn Policlin Univ Agostino Gemelli IRCCS, Policlin Gemelli, Paediat Neurol, Rome, Italy

[15] Univ Sao Paulo FMUSP, Dept Neurol, Fac Med, Sao Paulo, Brazil

[16] Clin Las Condes, Pediat Neurol Dept, Santiago, Chile

[17] Newcastle Univ, Inst Integrated Lab Med, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[18] Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England

[19] Bambino Gesu Pediat Hosp, Dept Neurol & Psychiat Sci, Unit Muscular & Neurodegenerat Dis, Rome, Italy

[20] Univ Libre Bruxelles, Hop Univ Enfants Reine Fabiola, Paediat Neurol Dept, Brussels, Belgium

[21] Univ Libre Bruxelles, Hop Univ Enfants Reine Fabiola, Neuromuscular Ctr, Brussels, Belgium

[22] Univ Paris, Necker Enfants Malad Hosp, APHP Ctr,FILNEMUS,ERN Euro NMD, Neuromuscular Disorders Reference Ctr Nord Est Il, Paris, France

[23] Hosp Ninos Luis Calvo Mackenna, Clin Alemana Santiago, Unidad Neuromuscular, Neurol Pediat, Santiago, Chile

[24] Univ Fed Minas Gerais, Med Sch, Dept Pediat, Pediat Neurol Serv, Belo Horizonte, MG, Brazil

[25] Univ Chile, Neurol Pediat Hosp Roberto del Rio, Clin Las Condes, Santiago, Chile

[26] Univ Francois Rabelais Tours, INSERM U1253, CHRU Tours, Tours, France

[27] CHU Strasbourg Hautepierre, Dept Neuropediat, Strasbourg, France

[28] UNIV Nantes, Inst Thorax, Serv Genet Med, CHU Nantes,INSERM,CNRS, Nantes, France

[29] Univ Messina, Dept Clin & Expt Med, Unit Neurol, Messina, Italy

[30] Univ Campania, Dept Expt Med, Cardiomiol & Med Genet, Naples, Italy

[31] Royal Childrens Hosp, Childrens Neurosci Ctr, Melbourne, Vic, Australia

[32] Amer Mem Hosp, Serv Pediat A, CHU Reims, Neurol Pediat, Reims, France

[33] Univ Duisburg Essen, Dept Neuropediat Dev Neurol & Social Pediat, Childrens Hosp 1, Essen, Germany

[34] Univ Pisa, Dept Clin & Expt Med, Pisa, Italy

[35] Univ Turin, Ctr Neuromuscular Dis, Dept Neurosci, Turin, Italy

[36] UCL, Great Ormond St Inst Child Hlth, Natl Inst Hlth Res, Great Ormond St Hosp Biomed Res Ctr, London, England

[37] Univ Toronto, Hosp Sick Children, Dept Paediat, Div Neurol & Clin, Toronto, ON, Canada

[38] Univ Toronto, Hosp Sick Children, Dept Paediat, Div Clin & Metab Genet, Toronto, ON, Canada

[39] Cure CMD, Congenital Muscle Dis Int Registry CMDIR, Lakewood, CA USA

[40] Cedars Sinai Med Ctr, Dept Pediat, Los Angeles, CA 90048 USA

[41] Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA 90048 USA

[42] Cedars Sinai Med Ctr, Board Governors Regenerat Med Inst, Los Angeles, CA 90048 USA

[43] Hosp Univ Vall dHebron, Vall dHebron Inst Recerca VHIR, Pediat Neurol ERN RND EURO NMD, Vall dHebron Barcelona Hosp Campus, Barcelona, Spain

[44] Univ Versailles St Quentin En Yvelines UVSQ, INSERM U1179, Versailles, France

[45] Sorbonne Univ, AP HP, Neuromuscular Disorders Reference Ctr Nord Est Il, FILNEMUS France,ERN Euro NMD, Paris, France

来源：

BRAIN COMMUNICATIONS | 2021年 / 3卷 / 03期

基金：

美国国家卫生研究院;

关键词：

laminopathies; striated muscle; LMNA; early onset; muscular dystrophy; DROPPED HEAD SYNDROME; LAMIN A/C GENE; MUTATIONS; LAMINOPATHIES; PHENOTYPE; ONSET; CHILDREN; SPECTRUM;

D O I：

10.1093/braincomms/fcab075

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 acquired 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, orthopaedic, 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.

引用

页数：15

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