Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study

Abstract

BackgroundDifferent amyotrophic lateral sclerosis (ALS) phenotypes have been recognised, marked by a varying involvement of spinal and bulbar upper and lower motor neurons. However, the differential characteristics of these phenotypes are still largely unknown.ObjectiveTo define the epidemiology and outcome of ALS phenotypes in a population based setting.MethodsAll ALS cases incident in two Italian regions were prospectively collected from 1995 to 2004 in an epidemiological register. Cases were classified according to established ALS phenotypes: classic, bulbar, flail arm, flail leg, pyramidal, respiratory, pure lower motor neuron (PLMN) and pure upper motor neuron (PUMN).ResultsALS phenotype were determined in 1332 out of 1351 incident patients (98.6%). Classic and bulbar phenotypes had similar mean annual incidence rates. Gender specific incidence rates showed a male preponderance in respiratory, flail arm, classic and PLMN phenotypes; in all other phenotypes, men and women had similar incidence rates. Age at onset was significantly lower in pyramidal, PLMN and PUMN phenotypes and higher in the bulbar phenotype. The best outcomes were observed in PUMN, pyramidal, PLMN and flail arm phenotypes and the worst in respiratory and bulbar phenotypes.ConclusionsOur epidemiological findings suggest that ALS phenotypes carry distinctive and easily distinguishable clinical and prognostic characteristics, strongly related to a complex interplay between gender and age. The categorisation of ALS patients according to more homogenous clinical groups is relevant in identifying biological markers for ALS and should be considered for the design of clinical trials.

An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1

“…Third, in iperOxSOD1-sALS patients, oxidation is not an overall age-associated phenomenon that targets other proteins; rather, it is directed toward the one protein that, if modified genetically, is sufficient to cause ALS, arguing in favor of a potential pathogenic rather than pathological role of iperOxSOD1. The finding that only 30% of sALS involves iperOxSOD1 underscores the concept that, analogous to fALS (triggered by different genetic mutations), sALS comprises multiple subgroups with differing etiologies (27). Taken together, our results indicate the potential to identify biomarkers to subclassify various forms of ALS.…”

“…As for sALS, the etiology of fALS is heterogeneous, with different subgroups of fALS caused by mutations in different genes (27). Although studies in animal and cellular models of mutSOD1-fALS have advanced our understanding of the disease, critical questions remain: How well do these models represent the totality of ALS?…”

Challenges in the Understanding and Treatment of Amyotrophic Lateral Sclerosis/Motor Neuron Disease

“…In the absence of widespread acceptance of diagnostic criteria for specific disease subtypes, there have been a number of clinical phenotypes described [11,37,48,[56][57][58][59]. These phenotypic descriptions, with variable disease progression, severity, and survival often fit into the basic diagnostic criteria of ALS/MND, although they do not necessarily obey the more classically described patterns of regional spread involving upper and lower motor neuron pathology.…”

Point-Of-Care Stem Cell Therapy (POCST): Multisite transplantation of autologous bone marrow-derived mononuclear cells in 85 patients with Amyotrophic Lateral Sclerosis improves survival

“…The contrasting results in based-population reports maybe due to sample bias, disease varieties, diagnostic and follow-up criteria, but mainly due to the plethora of symptoms of ALS [78]. However, we compared our sample mainly with a recent survey published by Pupillo et al [79], in which they pointed out and tried to overcome these errors and bias by a comprehensive method.…”