Siddique T, Hentati A
Department of Neurology, Northwestern University Medical School, Chicago, IL 60611, USA.
Clin Neurosci. 1995;3(6):338-47.
Amyotrophic lateral sclerosis (ALS) is inherited in ten percent of cases as a Mendelien trait. Familial ALS (FALS) is genetically heterogeneous and transmitted either as an autosomal dominant (DFALS) or an autosomal recessive (RFALS) trait. Fifteen percent of DFALS families have mutations in the gene for Cu,Zn superoxide dismutase (SOD1) which is coded on chromosome 21. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Several observations suggest that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed. The role of eventual neurofilament involvement in the pathogenesis of ALS is also discussed. The locus for one form of RFALS has been mapped to chromosome 2q33. FALS can also be associated with dementia and the gene locus for one form of hereditary ALS-dementia syndrome maps to chromosome 17q21-22.
肌萎缩侧索硬化症（ALS）在10%的病例中呈孟德尔遗传性状。家族性ALS（FALS）在遗传上具有异质性，以常染色体显性（DFALS）或常染色体隐性（RFALS）性状遗传。15%的DFALS家族在位于21号染色体上的铜锌超氧化物歧化酶（SOD1）基因中有突变。在大多数情况下，这些突变导致SOD1活性降低和该蛋白质半衰期缩短。多项观察结果表明，DFALS中运动神经元的退化是由突变的SOD1获得了一种新的毒性功能所致，而非SOD1活性降低所致。文中讨论了突变SOD1新的神经毒性功能的可能机制。还讨论了最终神经丝参与ALS发病机制的作用。一种形式的RFALS的基因座已被定位到2号染色体的q33区域。FALS也可能与痴呆有关，一种形式的遗传性ALS-痴呆综合征的基因座定位于17号染色体的q21-22区域。
