Department of Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Bruxelles, Belgium AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires, Paris Est, France.
AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, U.F. Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Paris, France UMR_S 1166 Equipe "Génomique et Physiopathologie des Maladies Cardiovasculaires", Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
J Neurol Neurosurg Psychiatry. 2015 Dec;86(12):1337-46. doi: 10.1136/jnnp-2013-307245. Epub 2014 Dec 22.
Mutations in one of the 3 genes encoding collagen VI (COLVI) are responsible for a group of heterogeneous phenotypes of which Bethlem myopathy (BM) represents the milder end of the spectrum. Genotype-phenotype correlations and long-term follow-up description in BM remain scarce.
We retrospectively evaluated the long-term clinical evolution, and genotype-phenotype correlations in 35 genetically identified BM patients (23 index cases).
Nineteen patients showed a typical clinical picture with contractures, proximal weakness and slow disease progression while 11 presented a more severe evolution. Five patients showed an atypical presentation, namely a limb girdle muscle weakness in 2 and a congenital myopathy pattern with either no contractures, or only limited to ankles, in 3 of them. Pathogenic COL6A1-3 mutations were mostly missense or in frame exon-skipping resulting in substitutions or deletions. Twenty one different mutations were identified including 12 novel ones. The mode of inheritance was, autosomal dominant in 83% of the index patients (including 17% (N=4) with a de novo mutation), recessive in 13%, and undetermined in one patient. Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe clinical evolution. Missense mutations were detected in 39% of index cases and associated with milder forms of the disease.
Long-term follow-up identified important phenotypic variability in this cohort of 35 BM patients. However, worsening of the functional disability appeared typically after the age of 40 in 47% of our patients, and was frequently associated with COL6A1 exon 14 skipping.
编码胶原 VI（COLVI）的 3 个基因中的突变负责一组异质表型，其中 Bethlem 肌病（BM）代表了该谱的较轻度端。BM 的基因型 - 表型相关性和长期随访描述仍然很少。
我们回顾性评估了 35 名经基因鉴定的 BM 患者（23 名指数病例）的长期临床演变和基因型 - 表型相关性。
19 名患者表现出典型的临床表现，包括挛缩、近端无力和疾病进展缓慢，而 11 名患者表现出更严重的演变。5 名患者表现出非典型表现，即 2 名肢带肌无力和 3 名先天性肌病模式，其中无挛缩，或仅局限于踝关节。致病性 COL6A1-3 突变主要是错义或框架外显子跳跃，导致取代或缺失。共鉴定出 21 种不同的突变，包括 12 种新突变。指数患者的遗传方式为常染色体显性遗传（包括 17%（N=4）为新生突变）占 83%，常染色体隐性遗传占 13%，1 名患者遗传方式不确定。COL6A1 外显子 14 的跳跃在 35%的指数病例中发现，与严重的临床演变密切相关。错义突变在 39%的指数病例中发现，与疾病的轻度形式相关。
在这 35 名 BM 患者的队列中，长期随访发现了重要的表型变异性。然而，在我们的患者中，47%的患者在 40 岁后功能残疾恶化，通常与 COL6A1 外显子 14 跳跃有关。
