ARTICLE IN BRIEF
In a new study, investigators reported younger patients with ALS were predominantly men who exhibited markedly different clinical signs and had longer survival rates than in classic ALS.
Early adult-onset amyotrophic lateral sclerosis (ALS) is characterized by a unique clinical signature of upper motor neuron dysfunction, suggesting that it might be a variant of the disease completely separate from classic adult-onset ALS, according to a new study by neurologists in Italy.
Investigators at the Neurological Institute of the Catholic University of the Sacred Heart in Rome, led by Mario Sabatelli, MD, found that younger patients were predominantly men who exhibited markedly different clinical signs and had longer survival rates than in classic ALS. According to the researchers, patients with classic ALS exhibit signs of lower motor neuron dysfunction, rather than the purely upper motor neuron signs of primary lateral sclerosis, severe spastic paraparesis seen with the predominantly upper motor neuron (p-UMN) phenotype of ALS.
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The team compared clinical progression and survival rates in 507 ALS patients from the surrounding region, including 57 young adults with onset of symptoms between ages 20 and 40 years and 450 with onset after age 40. Based on clinical examination, they divided the subjects into two phenotypes: p-UMN and classic ALS. All of the patients were given clinical and respiratory evaluations every two to four months, and the follow-up period ranged from two to 226 months.
Almost 60 percent of younger patients carried the p-UMN ALS phenotype, characterized by marked spastic paraparesis with lower motor neuron symptoms confined to the arms and hands, versus 17 percent of older individuals, they reported in a paper published online in advance of the Sep.16 issue of Neurology.
There were many more men in the p-UMN group (5.8:1), while the ratio of men to women with the classic ALS phenotype was equal, 1.1:1 (p=0.01).
Young adults with the p-UMN phenotype also lived longer, with median survival of 74 months — ranging from 10 to 226 months. Median survival in the classic group was 56 months, ranging from six to 106 months.
Half of the patients with the p-UMN phenotype survived for at least five years, compared to just 26 percent of those with classic ALS (p=0.12), while the 10-year survival rate in the p-UMN group was 17.6 percent. None of the patients with classic ALS survived that long.
The different ratio of men-to-women in the two phenotypes was unexpected, according to the researchers. The accepted ratio of men-to-women is 3.0–3.6:1 among young patients, decreasing progressively with age so that the proportion of men and women is equal after age 65. When patients were stratified by phenotype in the current study, however, there was a “striking” male prevalence in the p-UMN group.
The findings suggest that, just as juvenile onset ALS is accepted as a distinct clinical variant or the disease, young-adult onset — especially in patients with the p-UMN phenotype — might likewise represent a distinct form of the disease for purposes of categorization and clinical management, the authors concluded.
“The hypothesis that motor neuron degeneration in ALS may be an orderly and sequential process seems to be confirmed by our data in this peculiar phenotype,” the authors said.
“In young-adult sporadic ALS, genetic factors may play a major role, and the observation of a special phenotype in our series seems to strengthen this hypothesis,” they wrote. “Our findings might be regional and genetically based, but it should be considered that similar data have been described in patients from Serbia. Though clinical studies alone cannot determine whether the different phenotypes of ALS are separate entities, our findings support the idea that splitting ALS into clinical categories may help develop a proper approach for epidemiologic and biologic research.”
Commenting on the study, Hiroshi Mitsumoto, MD, the Wesley J. Howe Professor of Neurology at Columbia University and Medical Director of the Eleanor and Lou Gehrig MDA-ALS Center at the Neurologic Institute in New York City, said the findings need to be further explored in a larger, population-based cohort. Nonetheless, he said, the data are “intriguing” for what they might suggest.
“This is an important study, but it only involved patients seen at one ALS center. We have to be sure the figures are not restricted to the region or the population studied,” he told Neurology Today in a telephone interview. Dr. Mitsumoto was not involved in the study.
“I have to admit we're doing the same thing here at our clinic,” he continued. “It has been well known for a long time, based on population studies, that [young-adult onset-ALS] patients survive longer, and there are several possible explanations for this phenomenon, including this type of upper motor neuron involvement. Another observation is that progressive muscular atrophy, including flail arm and leg symptoms, are all surprisingly male-dominant, while those with bulbar-onset are almost exclusively women. This tells us that ALS is not one single disease but many different entities involving multiple genes.”
As these findings are reported in the media, clinicians can expect to be peppered with questions from patients and their families about what the new data mean, he noted. Regardless of the findings, he emphasized the importance of emphasizing the positive.
“ALS is a complex disease involving the expression of multiple genes, which means it's still poorly understood. I always try to focus on the positive side of findings like these when I see young patients — the good news is that survival is longer with this phenotype,” he said. “I like to give them hope.”
Although there is currently no treatment for the disease, understanding the different variants and subtypes of ALS will ultimately help guide future research in that direction, according to Dr. Mitsumoto.
“The amount of ongoing ALS research is enormous,” he said. “We see a continuous series of papers on different aspects of the disease — molecular, biological, genetic, biochemical, stem cell studies. There has been an incredible surge in new findings. The way I see it is that we finally have all the bases loaded. All we need is one hit, one home run.”