Epidemiological, Clinical and Genetic Features of ALS in the Last Decade: A Prospective Population-Based Study in the Emilia Romagna Region of Italy

Abstract

Increased incidence rates of amyotrophic lateral sclerosis (ALS) have been recently reported across various Western countries, although geographic and temporal variations in terms of incidence, clinical features and genetics are not fully elucidated. This study aimed to describe demographic, clinical feature and genotype–phenotype correlations of ALS cases over the last decade in the Emilia Romagna Region (ERR). From 2009 to 2019, our prospective population-based registry of ALS in the ERR of Northern Italy recorded 1613 patients receiving a diagnosis of ALS. The age- and sex-adjusted incidence rate was 3.13/100,000 population (M/F ratio: 1.21). The mean age at onset was 67.01 years; women, bulbar and respiratory phenotypes were associated with an older age, while C9orf72-mutated patients were generally younger. After peaking at 70–75 years, incidence rates, among women only, showed a bimodal distribution with a second slight increase after reaching 90 years of age. Familial cases comprised 12%, of which one quarter could be attributed to an ALS-related mutation. More than 70% of C9orf72-expanded patients had a family history of ALS/fronto-temporal dementia (FTD); 22.58% of patients with FTD at diagnosis had C9orf72 expansion (OR 6.34, p = 0.004). In addition to a high ALS incidence suggesting exhaustiveness of case ascertainment, this study highlights interesting phenotype–genotype correlations in the ALS population of ERR.

Amyotrophic Lateral Sclerosis—The Complex Phenotype—From an Epidemiological Perspective: A Focus on Extrapyramidal and Non-Motor Features

“…Traditionally, ALS has always been considered a disastrous disease that afflicts motor neurons and leads to devastating immobility whilst cognition remains intact [ 27 ]. This assumption has been debunked in recent years with numerous studies that have demonstrated the presence of cognitive and behavioral dysfunctions in ALS [ 6 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. In particular, an association between ALS and FTD has been increasingly recognized, and with the advent of new genetic discoveries [ 29 , 30 ], as well as new neuropathological and neuroimages evidence, the concept of the frontotemporal dementia–motor neuron disease continuum has progressively emerged.…”

“…In particular, an association between ALS and FTD has been increasingly recognized, and with the advent of new genetic discoveries [ 29 , 30 ], as well as new neuropathological and neuroimages evidence, the concept of the frontotemporal dementia–motor neuron disease continuum has progressively emerged. Five population-based studies have explored the presence of cognitive impairment and frontotemporal dementia–motor neurons ( Table 3 ) [ 6 , 31 , 32 , 33 , 34 ]. Evidence has shown that patients with ALS may present executive dysfunction, personality changes, poor insight, obsessions, aggressiveness, irritability and verbal fluency alteration.…”

“…Up to 40% of patients with ALS present with cognitive impairment, whilst between 7–20% of patients with ALS also fulfilled the criteria for frontotemporal dementia at baseline [ 6 , 31 , 32 , 33 , 34 ]. Specifically, the ASL–FTD spectrum is consistent with features of behavioral variant FTD.…”

“…Finally, other regions such as the hypothalamus may be implicated as defects in energy metabolism including weight loss, hypermetabolism, and hyperlipidemia have been associated with ALS [ 5 ]. Based on these observations, ALS can no longer be considered a disease limited to the motor system but rather a multisystem neurodegenerative disorder that involves other motor and non-motor domains [ 6 ]. This review aims to describe the available data from epidemiological studies on extrapyramidal and non-motor features during the course of ALS.…”

Mitochondrial and Endoplasmic Reticulum Alterations in a Case of Amyotrophic Lateral Sclerosis Caused by TDP-43 A382T Mutation

“…The majority of the mutations affect the C-terminal glycin-rich domain of the protein [ 3 , 4 ]. Phenotypically, TARDBP mutations are associated with a wide range of clinical manifestations [ 5 ], including cases with slow, medium, and fast disease progression [ 6 ], bulbar or upper limb onset, with or without cognitive and/or behavioral impairment [ 7 ]. The frequency and kind of TARDBP mutations are not homogeneous among different populations with higher frequency in Southern Europe (up to three times higher, especially in France and in Italy) than in other Caucasian populations [ 8 ] where an additional founder effect for A382T mutation has been described in Sardinia [ 9 ].…”