Researcher from CIRAH, a tireless unraveler of mysteries

Dr. Luis Enrique Almaguer Mederos, a researcher in the laboratories of the Center for Research and Rehabilitation of Hereditary Ataxias (CIRAH) in Holguín, is a tireless unraveler of mysteries.

The Holguín scientist recently returned to his hometown as part of a group of prominent researchers from the United Kingdom, who from the 8th to the 12th of this month, completed an intensive academic exchange program with professionals from various health institutions in the province and engaged in direct interaction with patients suffering from Spinocerebellar Ataxia Type 2 (SCA2), a highly prevalent condition in Holguín province, as well as Parkinson's disease and other neurodegenerative and rare diseases.

With more than two decades dedicated to the clinical and molecular study of neurodegenerative diseases, Dr. Almaguer Mederos now serves as an Associate Researcher at the Neurogenetics Laboratory of the Institute of Neurology at University College London, after completing four years of postdoctoral studies at an experimental neurology center in Germany.

Regarding the presence of the team of prestigious professors, he explained that they were interested in contributing to ongoing projects at CIRH on SCA2 and extending the collaboration to other genetic diseases present in this northeastern region, where this type of ataxia has a prevalence of more than 47 per 100,000 inhabitants—six times higher than the global average, according to the latest national epidemiological study.

“The visit is aimed at advancing the project on genetic modifiers for fluid biomarkers, laying the groundwork for future collaborations, and extending it to other genetic diseases in the region. This will help in the diagnosis of patients, who in Holguín generally have clinical and imaging diagnoses, but lack genetic testing due to infrastructure limitations. Therefore, this clinical and academic assistance opens the possibility of providing them with genetic testing,” he explained.

Therefore, one of the main projects he is working on involves using high-density genotyping technologies to study more than 1.2 million genetic variants distributed throughout the genome in patients with SCA2 and other types of ataxia. “We aim to identify modifier variants, changes in DNA that do not directly cause the disease, but do influence the age of onset, the severity of symptoms, or the rate of progression.”

The doctor explained that “throughout all these years of study, we have seen patients with the same repeat size in the gene associated with SCA2, although with very different progressions. For example, some develop symptoms earlier, while others progress more slowly and less severely.”

It should be noted that SCA2 is considered one of the most severe forms of the disease—currently, there are 50 known molecular forms—because its clinical course is characterized by a cerebellar syndrome that affects gait, balance, speech, and the coordination of fine and rapid alternating movements, among other functions. It is progressive and debilitating, leading to bed rest and a life expectancy of 20 to 30 years when it begins in adulthood, but shorter if it begins in childhood.

“Some of these contrasts could be explained by modifying variants in other genes; therefore, the essential purpose is to discover these variants so that they can later be used in the design of therapies for patients with this debilitating, hereditary degenerative disease.”

He clarified that “at Cirah we conducted some research aimed at identifying genetic variants that modify the disease using the technology available at the center; however, studies on candidate genes selected for their function or previous results were necessary, and we had to work with a relatively small number of variants.”

“By having access to state-of-the-art microarrays and the analysis platforms at University College London, it’s possible to study dozens of variants, analyzing more than a million, simultaneously, with a truly genomic approach.

“All of this will allow us to discover regions of the genome that have never before been associated with the clinical variability of ataxias. And although our priority is SCA2, as has been reiterated, due to its high incidence in Cuba and specifically in the province of Holguín, we wanted to extend the research to other types of ataxia present in the country. This will allow us to build a much more complete map of the genetic factors that influence these diseases,” he explained.

He clarified that in Cuba, and specifically in Holguín, there are patients who, along with ataxia, have atypical clinical manifestations, such as parkinsonism, signs of motor neuron disease, or other complex combinations of symptoms. “Therefore, in these cases, we propose to perform exome sequencing or even whole-genome sequencing, which covers all the variants present in the 23 pairs of chromosomes, to try to identify additional mutations that help explain why the disease manifests in that specific way.”

“These studies are more expensive than microarrays, so they are reserved for a smaller number of highly selected cases in which standard diagnostic methods have not allowed for a clear diagnosis or where the clinical presentation suggests that more than one process may be involved. Thus, large-scale population studies are supported by microarrays, and individual cases that may open new lines of research are addressed with exome or whole-genome sequencing.”

“Biomarkers measurable in blood and other fluids have become key tools for the early diagnosis and monitoring of neurodegenerative diseases. Thanks to German expertise and the infrastructure of the Institute of Neurology, we can now expand this line of research into hereditary ataxias.”

The doctor emphasized that “another very important component of our work is the study of fluid biomarkers for ataxias. That is, we are referring to molecules measurable in blood, cerebrospinal fluid, or other biological fluids, which reflect pathological processes linked to the disease.”

“This is a project we began during my time in Germany, and which we are now resuming, taking advantage of the technology at the Institute of Neurology at University College London, one of the top five centers of its kind worldwide for neurological research. Therefore, we must utilize these resources and opportunities for the benefit of patients.”

“Because if we can better understand the genetic background in people with ataxia, we can move toward applied pharmacogenomics, allowing us to select the most appropriate medication and the safest and most effective dose for each patient.

Finally, he indicated that the presence in Holguín of Professors John Anthony Hardy, Head of the Department of Molecular Biology of Neurodegenerative Diseases at the Institute of Neurology, University College London; Henry James Houlden, Head of the Neurogenetics Laboratory in the Department of Neuromuscular Diseases, University College London; Sigurlaug Sveinbjornsdottir, a consulting neurologist with the National Health Service in Essex; and Anupriya Dalmia, a bioinformatics specialist, is part of a national project approved by the Cuban Ministry of Public Health. This project will undoubtedly provide valuable information for the future development of clinical trials and the design of therapies, strengthening the link in the field of neuroscience.”