NEURODEGENERATIVE DISEASES.

The term degenerative is generic and indicates a pejorative change from a previous level of normality. The mn can strictly depend on genetic factors and affect several members of the same family, or occur in isolated cases. However, they can be characterized by an almost identical clinical phenotype in terms of onset and course (such as amyotrophic lateral sclerosis, ALS) or dissimilar and well differentiable (e.g., a picture of dementia associated early with spastic paraparesis is very rare in the forms sporadic cases of Alzheimer's disease, MdA, but far from infrequent in familial forms). While the cause of many MNs remains unknown to this day, for some of them much information has recently been acquired regarding the pathogenesis (ie the sequence of events and biological alterations that determine the dysfunction and finally the neuronal death). Furthermore, if it may happen that sporadic and hereditary forms of single mn do not have a completely superimposable clinical picture, common pathogenetic and biomolecular characteristics have often been identified, an aspect that heralds potential future therapeutic developments. 

For some NMs, such as sporadic forms of AD, a recurrence of late-onset cases (over 60 years of age) is documented within the same family without the identification of a specific pattern of inheritance, which may in any case suggest the intervention of genetic factors,ε4 (the other two are the ε3 and ε2 alleles, respectively the most common and the rarest in the general population), especially if present in duplicate (homozygous), increases the risk and reduces the age of onset of the disease, without confer substantial peculiarities to the clinical phenotype. On the other hand, in other mns such as sporadic Creutzfeldt-Jakob disease (CJD), the polymorphism of the prion protein gene at codon 129, of which there are two allelic variants encoding respectively the amino acids methionine and valine, can modify more significantly the phenotype with regards not only the age of onset but also the clinical presentation and the rapidity of progression.

Although the knowledge of the genetic and molecular basis of many mns has considerably progressed in recent times, their classification based on genetic and/or biomolecular anomalies may not be immediately useful for the clinician, since a single genetic anomaly can be associated with different phenotypes clinical and also to different biomolecular alterations, while, conversely, a single clinical phenotype can be associated with different biomolecular alterations (generally, dysproteinopathies originating from abnormal intra or extracellular accumulation of proteins due to overproduction or decreased degradation) and to different gene anomalies. Furthermore, the possible underlying genetic anomalies of some mn are still unknown and the biomolecular alterations are not clearly known. However,disease-modifying (interfering on the pathophysiological mechanisms of the disease), that individual clinical phenotypes are associated with prevalent biomolecular alterations (e.g., excess deposition of tau protein for corticobasal degeneration and progressive supranuclear palsy, excess deposition of TDP- 43, Transactive response DNA-binding Protein 43, for semantic dementia) and, if present in multiple members of the same family, to prevalent gene abnormalities (e.g., an association of ALS and frontotemporal dementia, DFT, with mutations of the C9ORF72 gene, Chromosome 9 Open Reading Frame 72 ).

In general, the men's are characterized by having a sneaky, insidious onset, of often uncertain dating, after a long period of normal functionality. An inexorable progression follows which, apart from rare exceptions (CJD), is mostly slow and gradual, even over many years. Only a few mn (such as Parkinson's disease, PD) are favorably influenced by pharmacological treatment, moreover with a mostly symptomatic effect. In many of them, there is a selective or preferential involvement of particular neurons, e.g. Purkinje cells of the cerebellum in spinocerebellar ataxias, or of functionally related neurons, e.g. the motor neurons of the cerebral cortex, brainstem, and spinal cord in ALS. Since the slow degeneration and eventually

From a clinical point of view, mn can be classified in pleomorphic clinical syndromes characterized by sensorineural alterations (as in retinitis pigmentosa, Leber's hereditary optic neuropathy, and sensorineural deafness, either pure or associated with retinal alterations), or by alterations of the peripheral nervous system (as in hereditary sensorimotor neuropathies), or by progressive muscle weakness and atrophy (as in ALS), or by progressive ataxia (as in spinocerebellar ataxias), or by alterations in postures and movements (as in PD ), or progressive dementia, whether associated with neurological signs (such as muscle weakness and wasting in DFT associated with ALS or parkinsonism in most cases of dementia with Lewy bodies, DCL) or unassociated, at least at presentation and for most of the clinical course, with neurological signs (as in most cases of AD).