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The AJMG 2012 John M. Opitz Young Investigator Award recognizes a paper identifying a new disorder that causes premature aging, like other progeria syndromes, but is distinct for its causative gene, set of symptoms, and patients' longer lifespan. Given annually since 2002, the award honors Dr. Opitz, the journal's founding Editor-in-Chief, one of the first physicians to recognize and correlate specific grouping of pediatric anomalies with heredity. The award recognizes work by a researcher who is younger than age 40 or has completed doctoral training within the past 10 years.

The winning paper, by Ruben Cabanillas, MD, PhD, Medical Director of the Institute of Molecular and Oncological Medicine of Asturias (MOMA) in Spain, newly identifies Nestor-Guillermo progeria syndrome (NGPS) and explains how it is different from other progeria syndromes [2011]. The disorder is named for the two patients described in the paper, who are the first identified with the disorder.

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Dr. Ruben Cabanillas

Distinct Symptoms

  1. Top of page
  2. Distinct Symptoms
  3. The Importance of Proper Diagnosis
  4. A Mentor's Aid
  5. Reference

Some of these patients' symptoms overlap with classic progerias, such as Hutchinson-Gilford progeria syndrome (HGPS) or mandibuloacral dysplasia. The symptoms common to NGPS and HGPS include aged appearance, growth retardation, decreased subcutaneous fat, thin limbs, and stiff joints. But Dr. Cabanillas's patients, who are young adults ages 32 and 24, have lived longer than other progeria patients, whose age at death averages 13. The NGPS patients lack classic progeria symptoms like cardiovascular impairment, diabetes mellitus, or hypertriglyceridemia. In contrast, the patients suffer from profound, debilitating skeletal abnormalities and localized loss of fat tissue.

Understanding how progeria syndromes differ may help in developing treatment strategies for common skeletal conditions and understanding the normal aging process, Dr. Cabanillas and colleagues write. More immediately, “early identification of the syndrome and intervention can have a profound impact on NGPS patients' quality of live, through medical and rehabilitational measures,” Dr. Cabanillas noted in an interview with “The AJMG Sequence.” “Palliation of osseous manifestations is a priority.” Classic progeria issues such as cardiovascular disorders are not the main problem for NGPS patients, he adds.

The Importance of Proper Diagnosis

  1. Top of page
  2. Distinct Symptoms
  3. The Importance of Proper Diagnosis
  4. A Mentor's Aid
  5. Reference

Differentiating NGPS patients from those with other progerias is critical in determining sound treatment plans, Dr. Cabanillas emphasizes. “NGPS patients seem to benefit from focused intense physical rehabilitation and teriparatide, while other treatments, such as growth hormone or bisphosphonates, useful in other progeroid syndromes, seem useless or even dangerous in their case,” he explains.

Dr. Cabanillas and colleagues are trying to improve, or at least preserve, the NGPS patients' quality of life. In addition to improving the patients' bone density in the past year, Dr. Cabanillas notes, the team also identified members of both men's families with one NGPS allele. Meanwhile, the researchers are developing mouse models of NGPS in order to provide tools to test novel therapeutic approaches.

A Mentor's Aid

  1. Top of page
  2. Distinct Symptoms
  3. The Importance of Proper Diagnosis
  4. A Mentor's Aid
  5. Reference

Dr. Cabanillas credits his mentor, Carlos Lopez-Otin, PhD, with helping him find the two patients and identify the disorder. Dr. Lopez-Otin, who is Professor in Biochemistry and Molecular Biology at the University of Ovideo, had developed a mouse model of human progeria caused by mutations in the ZMPSTE24-Lamin A protease-substrate system and used these mutant mice to develop therapeutic strategies for HGPS patients, which are now being tested in different clinical trials.

But some patients diagnosed with HGPS do not have mutations in ZMPSTE24 or LMNA and thus are unable to enter into those clinical trials, noted Dr. Lopez-Otin in a letter recommending Dr. Cabanillas's work for the award. The pair decided to use next-generation sequencing technologies to find mutations in other genes in these patients.

Two Spanish patients, Nestor and Guillermo, came directly to Dr. Lopez-Otin's lab looking for some relief from their disease. Dr. Lopez-Otin's team sequenced Nestor's exome, which did not have progeria-causing mutations, but did have one in BANF1. Guillermo had an almost identical phenotype, so the team sequenced his exome and found the same mutation, Dr. Cabanillas says. Further genetic and biochemical analysis confirmed that these mutations were responsible for these patients' disease.

“Having identified the molecular basis of their disease, a meticulous characterization of the new syndrome, which we called Nestor-Guillermo Progeria syndrome, was mandatory,” recalls Dr. Cabanillas.

He says the award is special for its association with Dr. Optiz. “It is a great honor for me and my team to receive an award named after Professor Opitz,” he adds. “As a clinician starting on a medical genetics research career, this award represents a validation of my work, and will undoubtedly enhance my professional reputation.”

The award can also serve a higher purpose, Dr. Cabanillas adds. Hopefully, linking Dr. Opitz's name with NGPS will draw attention to the new progeria syndrome, spur geneticists to identify patients with its symptoms, and lead to research that “deepens the knowledge of this devastating disease,” Dr. Cabanillas says.

Reference

  1. Top of page
  2. Distinct Symptoms
  3. The Importance of Proper Diagnosis
  4. A Mentor's Aid
  5. Reference
  • Cabanillas R, Cadiñanos J, Villameytide JAF, Pérez M, Longo J, Richard JM, Álvarez R, Durán NS, Illán R, González DJ, López-Otín C. 2011. Néstor-Guillermo progeria syndrome: A novel premature aging condition with early onset and chronic development caused by BANF1 mutations. Am J Med Genet Part A 155: 26172625.