The disease affects men slightly more frequently than women and becomes clinically manifest in the fifth decade or later. It usually begins with subtle asymmetric distal extremity weakness. As the disease progresses, muscle strength and bulk diminish, and involuntary contractions of individual motor units, termed fasciculations, occur. The disease eventually involves the respiratory muscles, leading to recurrent bouts of pulmonary infection, which is the usual cause of death. The balance between upper and lower motor neuron involvement can vary, although most patients exhibit involvement of both. In some patients, degeneration of the lower brain stem cranial motor nuclei occurs early and progresses rapidly, a pattern of disease referred to as bulbar amyotrophic lateral sclerosis. With this disease pattern, abnormalities of swallowing and speaking dominate.
While most cases are sporadic, about 10% are familial, mostly with autosomal dominant inheritance. Familial disease begins earlier in life than sporadic disease, but once symptoms appear, the clinical course is similar in both forms. Mutations in the superoxide dismutase gene, SOD1, on chromosome 21 were the first identified genetic cause of ALS and account for about 20% of the familial forms. These mutations are thought to generate abnormal misfolded forms of the SOD1 protein, which may trigger the unfolded protein response and cause apoptotic death of neurons.
A number of other genetic loci have been identified as associated with ALS. The most common cause of familial ALS is hexanucleotide repeat expansion in a gene with the rather cumbersome name C9orf72, which is also frequently expanded in frontotemporal lobar degeneration. The protein encoded by C9orf72 associates with RNA binding proteins; notably, two other genes that when mutated may cause ALS, TDP43 (also associated with FTLD) and FUS, encode RNA binding proteins. This convergence suggests that an abnormality of RNA processing directly or indirectly contributes to the pathogenesis of ALS, but it is uncertain how mutations in SOD1 fit into this picture, and much remains to be discovered. As expected from the genetic overlap, there is some clinical overlap between ALS and FTLD, such as cognitive impairment.
MORPHOLOGYThemoststrikinggrosschangesarefoundinanteriorrootsofthespinalcord,whicharethinandgray.Inespeciallyseverecases,theprecentralgyrus(motorcortex)ismildlyatrophicduetothedeathofuppermotorneurons.Microscopicexaminationdemonstratesareduction in the number of anterior horn cell neurons throughoutthespinalcordassociatedwithreactivegliosisandlossofanteriorrootmyelinatedfibers.Similarfindingsarefoundwithinvolvementofmotorcranialnervenucleiexceptthosesupplyingtheextraocularmuscles,whicharesparedinallbutafewlongtermsurvivors.CytoplasmicinclusionsthatcontainTDP43maybeseeninasubsetofcases.Withthelossofinnervationfromthedeathofanteriorhorncells,skeletalmusclesshowneurogenicatrophy.
Neurodegenerativediseasescausesymptomsthatdependonthepatternofbraininvolvement.Corticaldiseaseusuallymanifestsascognitivechange,alterationsinpersonality,andmemorydisturbances;basalgangliadisordersusuallymanifestasmovementdisorders.
Manyoftheneurodegenerativediseasesareassociatedwithvariousproteinaggregates,whichserveaspathologichallmarks.Familialformsofthesediseasesareassociatedwithmutationsinthegenesencodingtheseproteinsorcontrollingtheirmetabolism.Someoftheseproteinaggregatescanshowprionlikeproperties,facilitatingspreadfromonecelltothenext.
http://ebooksmedicine.net