Titin mutation segregates with hereditary myopathy with early respiratory failure

被引:101
作者
Pfeffer, Gerald [1 ,2 ]
Elliott, Hannah R. [1 ]
Griffin, Helen [1 ]
Barresi, Rita [1 ,3 ]
Miller, James [4 ]
Marsh, Julie [3 ]
Evila, Anni [5 ,6 ]
Vihola, Anna [5 ,6 ]
Hackman, Peter [5 ,6 ]
Straub, Volker [1 ]
Dick, David J. [4 ,7 ]
Horvath, Rita [1 ]
Santibanez-Koref, Mauro [1 ]
Udd, Bjarne [5 ,6 ,8 ,9 ,10 ]
Chinnery, Patrick F. [1 ,4 ]
机构
[1] Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England
[2] Univ British Columbia, Clinician Investigator Program, Vancouver, BC V5Z 1M9, Canada
[3] Newcastle Hosp NHS Trust, Muscle Immunoanal Unit, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
[4] Newcastle Upon Tyne Hosp NHS Fdn Trust, Dept Neurol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England
[5] Univ Helsinki, Folkhalsan Inst Genet, FIN-00014 Helsinki, Finland
[6] Univ Helsinki, Dept Med Genet, Haartman Inst, Helsinki 00014, Finland
[7] Norfolk & Norwich Univ Hosp, Dept Neurol, Norwich NR4 7UY, Norfolk, England
[8] Univ Hosp, Dept Neurol, Neuromuscular Res Ctr, Tampere 33520, Finland
[9] Univ Tampere, Tampere 33520, Finland
[10] Vaasa Cent Hosp, Dept Neurol, Vaasa 65130, Finland
基金
英国医学研究理事会; 英国惠康基金; 加拿大健康研究院;
关键词
hereditary myopathy with early respiratory failure; cytoplasmic body; titin; exome sequencing; distal myopathy; CYTOPLASMIC BODY MYOPATHY; AUTOSOMAL-DOMINANT MYOPATHY; TIBIAL MUSCULAR-DYSTROPHY; C-TERMINAL TITIN; DILATED CARDIOMYOPATHY; DISTAL MYOPATHY; KINASE DOMAIN; GENE; SEQUENCE; INVOLVEMENT;
D O I
10.1093/brain/aws102
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
In 2001, we described an autosomal dominant myopathy characterized by neuromuscular ventilatory failure in ambulant patients. Here we describe the underlying genetic basis for the disorder, and we define the neuromuscular, respiratory and radiological phenotype in a study of 31 mutation carriers followed for up to 31 years. A combination of genome-wide linkage and whole exome sequencing revealed the likely causal genetic variant in the titin (TTN) gene (g.274375T > C; p.Cys30071Arg) within a shared haplotype of 2.93 Mbp on chromosome 2. This segregated with the phenotype in 21 individuals from the original family, nine subjects in a second family with the same highly selective pattern of muscle involvement on magnetic resonance imaging and a third familial case with a similar phenotype. Comparing the mutation carriers revealed novel features not apparent in our original report. The clinical presentation included predominant distal, proximal or respiratory muscle weakness. The age of onset was highly variable, from early adulthood, and including a mild phenotype in advanced age. Muscle weakness was earlier onset and more severe in the lower extremities in nearly all patients. Seven patients also had axial muscle weakness. Respiratory function studies demonstrated a gradual deterioration over time, reflecting the progressive nature of this condition. Cardiomyopathy was not present in any of our patients despite up to 31 years of follow-up. Magnetic resonance muscle imaging was performed in 21 affected patients and revealed characteristic abnormalities with semitendinosus involvement in 20 of 21 patients studied, including 3 patients who were presymptomatic. Diagnostic muscle histopathology most frequently revealed eosinophilic inclusions (inclusion bodies) and rimmed vacuoles, but was non-specific in a minority of patients. These findings have important clinical implications. This disease should be considered in patients with adult-onset proximal or distal myopathy and early respiratory failure, even in the presence of non-specific muscle pathology. Muscle magnetic resonance imaging findings are characteristic and should be considered as an initial investigation, and if positive should prompt screening for mutations in TTN. With 363 exons, screening TTN presented a major challenge until recently. However, whole exome sequencing provides a reliable cost-effective approach, providing the gene of interest is adequately captured.
引用
收藏
页码:1695 / 1713
页数:19
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