'Clear Signature' of ALS Found in Children's Teeth

Megan Brooks

May 22, 2020

Adults who develop amyotrophic lateral sclerosis (ALS) metabolize metals differently than those who do not develop the neurodegenerative disease, and this shows up in teeth during childhood, new research suggests.

Investigators found increased uptake of a mixture of metals — including chromium, manganese, nickel, tin, and zinc — in the teeth of those who developed ALS.

"This study shows that metal dysregulation during specific periods in childhood and early adolescence is linked with the decades-later onset of ALS," senior author Manish Arora, PhD, MPH, vice chair, environmental medicine and public health, Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.

"This is the first study to show a clear signature at birth and within the first decade of life, well before any clinical signs or symptoms of the disease," he added in a news release.

The study was published online May 21 in Annals of Clinical and Translational Neurology.

Dysregulated Metal Uptake

ALS typically manifests in individuals in their 50s or 60s. Deficiencies and an excess of essential elements and toxic metals are implicated in the disease, but the age when metal dysregulation appears is unknown.

The Mount Sinai team, along with colleagues at the University of Michigan in Ann Arbor, determined that metal uptake is dysregulated during childhood in adults diagnosed with ALS. 

For the study, the investigators used laser ablation-inductively coupled plasma-mass spectrometry to map data of metal uptake using biomarkers in teeth from autopsies or dental extractions from 36 ALS patients and 31 controls without ALS.

They found that metal levels were higher in the ALS group compared with controls.

Specifically, in patients with ALS, they found that chromium uptake increased after age 10, whereas manganese was significantly higher from birth until approximately 6 years and it was significantly lower between age 12 and 15 years.

Nickel and tin showed discrete windows of increased uptake in the ALS group, from age 6 to 10 years for nickel and from birth to age 2 1/2 for tin. Zinc levels were significantly higher throughout the study period.

Individuals with ALS also showed an increasing trend for copper uptake between birth and 10 years and for lead from age 12 to 15 years, and a decreasing trend for lithium from birth to 15 years.

At the point of maximal difference in metal levels, compared with controls, ALS patients had higher uptake by 1.49 times for chromium (95% confidence interval [CI], 1.11 - 1.82; at 15 years), 1.82 times for manganese (95% CI, 1.34 - 2.46; at birth), 1.65 times for nickel (95% CI, 1.22 - 2.01; at 8 years), 2.46 times for tin (95% CI, 1.65 - 3.30; at 2 years) and 2.46 times for zinc (95% CI, 1.49 - 3.67; at 6 years).

The markers of metal uptake dysregulation were also found in teeth from an ALS mouse model where researchers also found differences in the distribution of metals in the brains of ALS mice compared with control mice.

"This is a small study and much more work has to be done, but the general direction we are taking is very much toward clinical application," Arora told Medscape Medical News. "What's exciting is that we are looking at biological pathways that we could potentially modify with drug development," he said.

Solid Research

Commenting on the study for Medscape Medical News, Anthony Geraci, MD, director of neuromuscular medicine at Northwell Health in Great Neck, New York, noted the "scientific rigor of this study is solid and was well-conducted."

The findings, he added, are interesting in that they are among the first to identify potential neuronal abnormalities that may occur early in life and lead to subsequent ALS.

"Metal uptake is an essential function of most cells of the human body and neurons of the central and peripheral nervous systems, which are the cells that degenerate and die, leading to ALS," explained Geraci, who was not involved with the study. 

"Metal is crucial for formation of critical metalloproteinase and DNA regulation and as cofactors in many enzymatic reactions within the cell. Caution, however, should be applied as the results of this study do not establish a causative link between altered metal uptake and later expression of ALS," he added.

However, Geraci said these results are "in line with more recent theories that implicate an abnormal and imbalanced formation of excitatory and inhibitory connections in the human brain during embryogenesis, with the result of a slightly abnormal cell-signaling mechanism between neurons that, over the span of one's life, may lead to the hyperexcitability and abnormal calcium flux into neurons that die during the course of ALS."

"More research along these lines will hopefully begin to unlock the earliest origins and genetic bases for the development later in life of degenerative diseases such as ALS," Geraci added. "The hope is that earlier identification of persons with ALS may one day lead to early intervention and prevention of the devastating manifestations of this disease."

The study was funded in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Environmental Health Sciences. Arora and Geraci have disclosed no relevant financial relationships. 

Ann Clin Transl Neurol. Published online May 21, 2020. Full text

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