Hedera Peter, Petty Elizabeth M, Bui Melanie R, Blaivas Mila, Fink John K
Department of Neurology, University of Michigan Medical Center, Ann Arbor, USA.
Arch Neurol. 2003 Sep;60(9):1321-5. doi: 10.1001/archneur.60.9.1321.
Distal myopathies (MPDs) are genetically heterogeneous. Genetic causes within this subgroup of muscle disorders remain largely unknown. An MPD linked to chromosome 14q11-q13 (MPD1) is rare, and to our knowledge, only one family with definitive linkage has been described.
To describe the results of clinical and genetic analysis of the second kindred with MPD1.
We have identified a family with an MPD segregating in an autosomal dominant fashion. We tested linkage to previously identified genetic loci on chromosomes 2p, 2q, and 14q. The coding sequence of PABP2 (the polyadenylate-binding protein 2 gene) was analyzed.
Every affected individual had selective weakness of foot extensors, with the average age of symptom onset at 20 years. Some patients also had proximal weakness, but none had signs of finger or hand extensor muscle involvement, even in advanced stages of the disease. Two typically affected individuals had signs of idiopathic dilated cardiomyopathy. Genetic analysis detected a tight linkage to chromosome 14q11-q13. Recombination at the telomeric end of the 14q11-q13 locus was found in an unaffected individual who was not considered to be at risk, potentially reducing the locus interval by 2 centimorgans. No mutations in the PABP2 gene were identified.
To our knowledge, our described family is only the second known kindred with a chromosome 14-linked MPD in whom the linkage has been unequivocally established. We did not detect signs of involvement of hand or finger extensors and neck muscles, seen in the original family with MPD1. The degree and frequency of proximal weakness seem to be more prominent than in other patients with MPD1. Haplotype analysis suggests that the gene is located between polymorphic microsatellite markers D14S283 and D14S1034 on chromosome 14q11-q13. The presence of cardiomyopathy in some affected individuals may help in the identification of candidate genes.
远端肌病（MPD）具有遗传异质性。在这一肌肉疾病亚组中，遗传病因在很大程度上仍不明确。与14号染色体q11 - q13区域相关的MPD（MPD1）较为罕见，据我们所知，仅报道过一个具有明确连锁关系的家系。
描述第二个MPD1家系的临床和遗传分析结果。
我们鉴定出一个以常染色体显性方式遗传的MPD家系。我们检测了与先前在2号染色体p区、2号染色体q区和14号染色体q区鉴定出的基因座的连锁关系。分析了聚腺苷酸结合蛋白2基因（PABP2）的编码序列。
每位受影响个体均有足背伸肌选择性无力，症状出现的平均年龄为20岁。部分患者也有近端肌无力，但即使在疾病晚期，也无手指或手部伸肌受累迹象。两名典型受累个体有特发性扩张型心肌病体征。遗传分析检测到与14号染色体q11 - q13紧密连锁。在一名被认为无风险的未受影响个体中，发现14q11 - q13基因座端粒末端发生重组，这可能使基因座间隔缩短2厘摩。未在PABP2基因中鉴定到突变。
据我们所知，我们所描述的家系是第二个已知的与14号染色体连锁的MPD家系，且连锁关系已明确确立。我们未检测到在最初的MPD1家系中所见的手部或手指伸肌及颈部肌肉受累迹象。近端肌无力的程度和频率似乎比其他MPD1患者更为突出。单倍型分析表明该基因位于14号染色体q11 - q13上的多态微卫星标记D14S283和D14S1034之间。部分受累个体中存在心肌病可能有助于鉴定候选基因。
