远端起病的Dna热休克蛋白家族6肌病一家系临床分析

Clinical analysis of a family with distal-onset DnaJ (heat-shock protein 40) homolog subfamily B member 6 myopathy

目的对远端起病的Dna热休克蛋白家族6(DNAJB6)肌病一家系临床资料及基因突变进行分析。方法收集2019年9月就诊于解放军总医院第一医学中心神经内科的DNAJB6肌病一家系共3代人,其中有3例患者,遗传方式为常染色体显性遗传。对家系先证者行肌酶、左侧肱二头肌活组织检查、骨骼肌磁共振成像(MRI)及肌电图等检查。应用全外显子测序对先证者进行致病基因筛查,应用Sanger测序技术对先证者家系成员进行突变位点的验证。结果先证者为30岁男性,少年时期开始出现四肢远端肌肉无力,后发展至近端,同时伴有肌肉萎缩,以手部小肌肉、下肢远端肌肉为主。经检查先证者肌酶轻度升高,骨骼肌MRI提示其四肢远近端均出现肌肉萎缩及脂肪化,以下肢远端后组肌群为著;肌电图提示慢性肌源性损害;肌肉病理提示慢性肌纤维性损害并数个镶边空泡改变。基因筛查发现先证者携带DNAJB6基因的杂合突变c.298T>G(p.F100V),为错义突变,其胞弟(有相似病史)、二女儿也存在着相同位点的突变;大女儿未检测到上述位点变异。二女儿目前未发病,为变异携带者。先证者父亲已去世,生前也有类似症状。结论 DNAJB6基因上述位点突变为该家系的致病基因。该病临床特点为青少年时期以四肢远端起病的肌肉无力及萎缩。本研究为国内该位点突变所致的远端起病的DNAJB6肌病家系的首次报道。

Objective To analyze the clinical manifestations,skeletal muscle pathology,electromyography,skeletal muscle magnetic resonance imaging and gene mutations of a family with distant-onset DnaJ(heat-shock protein 40)homolog subfamily B member 6(DNAJB6)myopathy.Methods A total of three generations with three cases of the disease in a family,inherited by autosomal dominant inheritance,were collected.The examination of muscle enzymes,left biceps biopsy,skeletal muscle magnetic resonance imaging(MRI)and electromyography,etc,were performed for the family's proband.Whole-exon sequencing was performed to screen the proband for pathogenic genes,and Sanger sequencing technology was performed to verify mutation sites of the proband′s family members.Results The proband is a 30-year-old male who began to show weakness in the distal muscles as a teenager,and then gradually developed to the proximal muscles,accompanied by muscle atrophy of the limbs,mainly affecting small muscles in the hands and distal muscles of the lower limbs.Muscle enzymes of the proband were slightly elevated.Skeletal muscle MRI indicated muscle atrophy and fatty degeneration in the proximal and distal extremities,which in the distal extremities were more severe,mainly affecting the muscle groups of the posterior group.Electromyography indicated chronic myopathic damage.Muscle pathology suggested chronic muscle fiber damage and rimmed vacuoles could be found.The proband was found a heterozygous mutation[c.298T>G(p.F100V)]in DNAJB6 gene by all-exon sequencing.Sanger sequencing confirmed that his brother(similar medical history)and the second daughter also had the same mutation,and the eldest daughter was not detected the mutation at the above site.The second daughter is not ill and is a carrier of the mutation.The father of the proband died of pancreatic cancer and had similar symptoms during his lifetime.Conclusions The above mutation of DNAJB6 gene is the pathogenic gene of this family.The clinical features are adolescence-onset muscle weakness and atrophy in distal extremities.This is the first family report of distal-onset DNAJB6 myopathy caused by mutations at this site in China.