Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Neurology. 2010 Aug 10;75(6):539-46. doi: 10.1212/WNL.0b013e3181ec800c.
Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA.
Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed.
Ten affected individuals (ages 7-58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 (theta = 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,765-106,368,585. No segregating copy number variations were found within the disease interval.
We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy-lower extremity, dominant.
脊髓性肌萎缩症（SMA）是一种遗传性疾病，其特征是脊髓运动神经元退化导致的肌肉无力。虽然大多数近端肌无力的 SMA 病例是隐性遗传的，但也有报道罕见的显性遗传家族。我们旨在对一个具有常染色体显性遗传近端 SMA 的大型北美家族进行临床、病理和基因特征分析。
受影响的家庭成员接受了临床和电生理评估。20 名家庭成员进行了高密度全基因组 SNP 芯片基因分型，并进行了连锁分析。
10 名受累个体（年龄 7-58 岁）表现出明显的股四头肌萎缩、股四头肌和髋外展肌中度至重度无力，以及其他腿部肌肉较轻程度的无力。上肢力量和感觉正常。下肢无力从儿童早期开始，呈静止或非常缓慢进展。电生理和肌肉活检与慢性去神经支配一致。基于 SNP 的连锁分析显示，rs17679127 上的最大 2 点 lod 得分为 5.10（theta = 0.00）。确定了一个跨越 14q32 的从 114cM 到 14q 端粒的疾病相关单体型。单个重组将最小基因组间隔缩小到 Chr14：100,220,765-106,368,585。在疾病间隔内未发现分离的拷贝数变异。
我们描述了一个具有早期发病、常染色体显性、近端 SMA 的家族，其表型具有独特性：症状仅限于腿部，股四头肌明显具有选择性。我们证明与 14q32 上的 6.1Mb 间隔连锁，并建议将这种疾病称为下肢显性脊髓性肌萎缩症。
