Spectrums of Amyotrophic Lateral Sclerosis. Группа авторов

de novo mutation in the FUS gene.

      Survival

The median survival of ALS is approximately three years from the onset, and about 70% of patients die within five years from onset. However, the duration of the disease differs widely in individual patients, ranging from a few months to over 10 years. Such remarkable variability is a major factor in favor of the hypothesis of ALS as a syndrome rather than a single disease. Median survival is worse in patients with bulbar onset ALS than with the spinal onset. Patients with disease onset before the age of 40 and patients with predominant UMN signs show a better prognosis. In most ALS patients, the cause of death is respiratory failure due to the degeneration of motor neurons controlling thoracic and diaphragmatic muscles. Of note, both the temporal and spatial patterns of the disease spread are important determinants of survival. Regarding the temporal pattern, the spreading rate of the degenerative process may vary among patients, with some patients showing a very rapid, aggressive course and others a slow progression. The spatial pattern is also important, since the sequence in which various body regions are involved is extremely variable and the survival changes if respiratory muscles are among the first or last to be affected.

      Classic ALS, LMN Form, and UMN Form

      By definition, ALS is characterized by a combination of LMN and UMN clinical and electrophysiological signs. However, the relative mix of UMN and LMN impairment is highly variable among patients, and clinical manifestations of ALS exist on a continuum whose extremes are represented by cases showing pure LMN dysfunction on one side and cases with pure UMN signs on the other side. Classic ALS (Charcot type) is the most frequent form, accounting for about 70–90% of cases, and is characterized by predominant LMN signs combined with slight to moderate pyramidal signs. Patients with pure LMN signs without any accompanying clinical or electrophysiological UMN signs are labeled as having progressive muscular atrophy (PMA) and represent about 5–10% of cases. However, the demonstration that UMN pathology is present at autopsy in 50% of PMA patients indicates that, in at least some cases, pyramidal signs are simply masked by LMN dysfunction on both clinical and electrophysiological grounds. For this reason, the presence of preserved but not hyperactive reflexes in atrophic limbs should be interpreted as UMN impairment. PMA and ALS are not distinct entities, as they show significant phenotypic and genetic overlap. About 2–5% of patients with motor neuron disease show a pure pyramidal form with predominant spino‐bulbar spasticity, known as primary lateral sclerosis (PLS). The onset of PLS is generally after 40 years, and the disease duration is significantly longer than in classic ALS. A small proportion of PLS patients develop a clear ALS phenotype, usually within three to four years from the onset, while others show only minimal LMN impairment; most cases remain PLS for decades. ALS patients with predominant pyramidal signs consisting mainly of severe spino‐bulbar spasticity are said to have upper motor neuron‐dominant amyotrophic lateral sclerosis (UMN‐D ALS). These signs are associated with slight LMN signs, usually in the hands. This phenotype is frequent in the young‐adult group and males, and it has a better prognosis than classic ALS [8–10].

      Site of Onset

ALS begins focally at a seemingly random location and progresses to involve other body regions through anatomically connected pathways and/or neighboring regions. Approximately one‐fourth of patients show initial manifestations in the muscles innervated by motor neurons residing in the medulla (bulbar onset), one‐third in the upper limb muscles, and one‐third in the lower limb muscles whose motor neurons lie in the spinal cord (spinal onset). A small proportion of patients (2–5%) show respiratory symptoms at presentation. These cases are often difficult to diagnose because the absence of additional neurological signs can be misleading. The clinical phenotype at the onset, when temporal–spatial summation hasn't yet occurred, together with additional characteristics, may be important tools to delineate peculiar phenotypes, including spinal, bulbar, pseudopolyneuritic, emiparetic, and flail‐arm forms. It remains to be clarified if these clinical pictures correspond to distinct nosological entities or are the simple consequence of stochastic phenomena.

      Bulbar ALS usually presents with dysarthria and dysphagia due to a variable combination of impairment of LMNs located in the IX, X, and XII nuclei and of the corticobulbar fibers. Bulbar symptoms and signs may be the only manifestation for several months before limb symptoms occur and when only corticobulbar signs are present, the diagnosis of ALS is frequently overlooked. Bulbar onset is more frequent in females and has a worse prognosis than the spinal onset form. In pseudopolyneuritic ALS (Patrikios' disease), weakness and atrophy start in distal limb muscles with frequent absence of tendon reflexes, thus mimicking a neuropathy [11]. The flail‐arm form (Vulpian‐Bernhart syndrome) is characterized by symmetric, predominantly proximal, wasting and weakness of both arms with relative sparing of lower limbs in the initial phases. This ALS form is prevalent in males, starts after the age of 40, and shows a slightly slower disease progression than classic ALS [12, 13].

      Diagnosis of ALS

      To date, there are no reliable diagnostic tests for ALS, and clinicians rely on the clinical evidence of a combination of UMNs and LMNs in the same body region, electromyographic confirmation of ongoing LMN degeneration, and the exclusion of mimicking conditions. Motor multifocal neuropathy, Kennedy disease, inclusion body myopathy, Sandoff disease, Morvan syndrome, paraneoplastic encephalomyelitis, inflammatory multineuropathies, and compressive myelopathies are conditions that may be confused with ALS and should be accurately evaluated. Criteria for the diagnosis of ALS have been established and are known as the El Escorial criteria, but they are more useful in the research field than in the clinical setting [14, 15].

      ALS and Its Relationship with Frontotemporal Dementia and Myopathies

ALS has long been considered a paradigm of pure motor neuron disorder. However, genetic discoveries have shown that other cell types may be involved, linking ALS to other diseases. The most common and well‐established condition connected with ALS is frontotemporal dementia (FTD). Frontotemporal lobar degeneration (FTLD) consists of the degeneration of the frontal and temporal lobes of the brain, leading to atrophy, and occurs with an incidence of 3.5–4.1/100 000 per year in individuals under 65 [16, 17]. Clinically, this is the second most common cause of early‐onset dementia, referred to as FTD, and is familial in 20–30% of cases. Variants of FTLD have been described based on clinical signs. Behavioral variant frontotemporal dementia (bvFTD) is the most frequent form and is characterized by behavioral problems – apathy and disinhibition – and a decline in executive functions. Progressive nonfluent aphasia (PNFA) is characterized by language problems including nonfluent speech, dysarthria, poor articulation, and agrammatism with preserved comprehension. The third variant is semantic dementia (SD), also called progressive fluent aphasia (PFA), characterized by the loss of semantic and conceptual knowledge. All these FTLD variants have been described in patients with ALS.

      Insoluble proteins aggregate in the neurons of patients with FTLD, leading to three different pathological variants: FTLD‐Tau, characterized by the accumulation of the microtubule‐associated protein and often by mutations in the gene encoding for the same protein (MAPT) (~30–40% of cases) [18]; FTLD‐FUS, containing the FUS sarcoma protein (~10% of cases) [19]; and the most frequent, FTLD‐TDP, with TDP‐43 aggregates (~50–60% of cases) [18–21].

      From a clinical point of view, FTD and ALS overlap since 15–18% of ALS patients have FTD and 15% of FTD patients show motor dysfunctions [22, 23]. ALS and FTD also share genetic and neuropathological features, thus leading to the definition of the ALS/FTD spectrum where ALS and FTD are the extremes of a continuum. From a genetic point of view, this idea has been consolidated by the identification of the gene C9orf72 [24, 25], whose pathogenic expansion has been described in 30–50% of fALS, 25% of familial FTD, 5–7% of sALS, and 6% of sporadic FTD cases in different populations [26, 27]. Furthermore, other genes have been associated with the ALS/FTD spectrum: TBK1, TARDBP, FUS, and SQSTM1 [28]. Finally, with regard to neuropathology, TDP‐43 inclusions in neuronal cells are a hallmark of ALS as well as of a proportion of FTD.

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