The Big Bluff of Amyotrophic Lateral Sclerosis Diagnosis: The Role of Neurodegenerative Disease Mimics

Abstract

Neurodegenerative diseases include a significant number of pathologies affecting the nervous system. Generally, the primary cause of each disease is specific; however, recently, it was shown that they may be correlated at molecular level. This aspect, together with the exhibition of similar symptoms, renders the diagnosis of these disorders difficult. Amyotrophic lateral sclerosis is one of these pathologies. Herein, we report several cases of amyotrophic lateral sclerosis misdiagnosed as a consequence of features that are common to several neurodegenerative diseases, such as Parkinson's, Huntington's and Alzheimer's disease, spinal muscular atrophy, progressive bulbar palsy, spastic paraplegia and frontotemporal dementia, and mostly with the lysosomal storage disorder GM2 gangliosidosis. Overall reports highlight that the differential diagnosis for amyotrophic lateral sclerosis should include correlated mechanisms.

A Comparison of Lysosomal Enzymes Expression Levels in Peripheral Blood of Mild- and Severe-Alzheimer’s Disease and MCI Patients: Implications for Regenerative Medicine Approaches

“…All subjects enrolled in the study were screened for peripheral blood levels of two classes of lysosomal enzymes: glycohydrolases (which includes: β-Hexosaminidase (Hex), β-Galctosidase (Gal), β-Galactosylcerebrosidase (GALC), β-Glucuronidase (Gluc)) and proteases (which includes Cathepsins S, D, B, L (CatS, CatD, CatB, CatL, respectively)). All lysosomal enzymes were selected based on our studies describing their association either with neurological diseases [ 4 , 32 ], with immune cell functions [ 33 , 34 ] or with AD pathophysiology [ 23 , 26 , 28 , 29 ].…”

“…In neurodegenerative diseases, the autophagy pathway might be blocked at various steps along the signal cascade (selection, sequestration and lysosomal digestion of substrate) giving rise to distinct pathologic patterns that might have implications for the disease therapy [ 52 ]. For instance, autophagolysosomes impairment has been observed in fibroblasts of patients with Huntington’s disease [ 53 ], or in a murine cellular model of Amyotrophic Lateral Sclerosis [ 4 , 54 ] and in several models of AD [ 4 , 29 , 52 , 55 ].…”

“…Alzheimer’s disease (AD) is the most common form of dementia in elderly individuals and, at the present, it is one of the major challenges of the global public health [ 1 ]. However, the pathogenic complexity of the disease together with some clinical signs, common to other neurodegenerative diseases (e.g., elderly dementia, fronto-temporal dementia) [ 1 , 2 , 3 , 4 , 5 , 6 ], make the diagnosis and the development of effective treatments for AD difficult.…”

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

“…The numerous altered biological systems described so far in AD highlight the concept that the characterization of this neurodegenerative disease requires a deep understanding of many diverse pathological events. In this regard, it is crucial to underline that AD shares different pathological aspects with other neurodegenerative diseases, which could make early diagnosis difficult [287]. As a matter of fact, AD shares several features with Parkinson's Disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) [286][287][288][289][290][291][292].…”

“…In this regard, it is crucial to underline that AD shares different pathological aspects with other neurodegenerative diseases, which could make early diagnosis difficult [287]. As a matter of fact, AD shares several features with Parkinson's Disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) [286][287][288][289][290][291][292]. These common general pathways involve protein misfolding and aggregation, mitochondrial dysfunctions, oxidative stress and ROS production, neuroinflammation and phosphorylation impairment, and microRNA-altered expression [290,293,294], which appear to be changed concurrently [287,[295][296][297][298][299].…”