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Searching for rare diseases

Number of Brazilians diagnosed with uncommon genetic pathologies increases 150% in four years

Monte Santo, municipality of Bahia with various identified genetic diseases

Eduardo Cesar

In Bela Cruz, Trairi, Fortaleza, Mulungu, and another 10 cities in Ceará, researchers from São Paulo and Ceará identified 27 people from 22 families with a rare genetic disease called pycnodysostosis. Caused by mutations that contribute to calcium buildup in the bones, this illness is characterized by low stature, defects in facial and head structure, short fingers, and fragile bones. By broadening the study, the specialists found 15 individuals with the same disease living in nine cities in the states of Paraíba, Goiás, São Paulo, Maranhão, and Rio Grande do Sul. “Families with pycnodysostosis outside of the Northeast don’t know each other, but they have ancestors in common in Ceará,” explains geneticist Denise Cavalcanti, professor at the School of Medical Sciences at the University of Campinas (FCM-UNICAMP) and coordinator of the study. In November, her team worked on the tests of six residents of Salvador, Bahia, from two families, all of whom had this disease, which is the same illness suffered by the French painter Henri de Toulouse-Lautrec (1864–1901). “The more we search,” she says, “the more we find that rare diseases are not so rare.”

Pycnodysostosis is one of the pathologies included in a new national census on the occurrence of rare diseases of genetic, environmental, or congenital origin, undertaken by researchers from the Federal University of Rio Grande do Sul (UFRGS) and from the Brazilian National Institute for Medical and Population Genetics (INAGEMP). In regard to prior mapping carried out in 2014, the current study was amplified from 88 to 144 municipalities with high prevalence (proportion of cases in the population) of people with rare diseases. The study, which was published in June 2018 in the Journal of Community Genetics, showed that the number of people identified with this type of illness has increased from 4,100 to close to 10,000 throughout the country. “We now have a better idea of the mutations and metabolism deficiencies that cause rare genetic diseases, as well as the number of people who are undergoing or not undergoing treatment,” explains geneticist Lavínia Schuler-Faccini, professor at UFRGS and coordinator of the current and prior studies.

Majority in the Northeast
The sample is still limited. According to the World Health Organization (WHO), Brazil has close to 13 million people with some kind of illness in this category, that is, one in every 16 individuals. “Each disease may affect a lower number of individuals, but the sum of them all affects a significant portion of the population,” adds Schuler-Faccini. There are between 5,000 and 8,000 known rare diseases that are generally chronic and progressive. The majority (80%) are caused by genetic mutations, including some forms of hereditary cancer. Others are caused by environmental factors, such as malformations caused by the Zika virus. For the majority of these diseases, there are no specific medications, but only supportive treatment such as physiotherapy and phonoaudiology. When medication exists, it is usually imported and obtained through legal approval.

Wikimedia commons Photo montage of Toulouse-Lautrec, who had pycnodysostosisWikimedia commons

According to studies by INAGEMP, the majority of people affected live in the Northeast, where marriage between relatives, which contributes to the spread of pathogenic mutations, is more common than in other regions. The city of Monte Santo, in Bahia, has cases of mucopolysaccharidosis, phenylketonuria, and congenital deafness. In seven municipalities of Rio Grande do Norte—Serrinha dos Pintos, Martins, Coronel João Pessoa, Doutor Severiano, Encanto, Pau dos Ferros, and São Miguel—close to 70 related individuals were diagnosed with a degenerative syndrome called Spoan, which causes deformations in the feet and hands. A mutation on the KLC2 gene, which causes Spoan, likely appeared in the country 485 years ago in the children of related Jewish or Moorish couples who may have immigrated from the Iberian peninsula to escape the Inquisition. This population settled along the coast and later in rural areas of the Northeast, according to the study carried out by biologist and researcher from the University of São Paulo (USP) Allysson Allan de Farias, which was published in November in Scientific Reports. “The study of the history of the movement of human populations can enhance the work in medical genetics,” notes Farias.

The studies about rare diseases are part of a field that is still in development. “We need to make adjustments in the studies so that people with this type of problem can be recognized, referred to the public health system, and treated appropriately,” notes geneticist Angelina Acosta, professor at the Federal University of Bahia (UFBA). “There are courses and centers of specialized care, but there is a significant lack of understanding about rare diseases among physicians and the general population, which makes diagnosis difficult.”

Despite the challenges, a team from the hospital at the Federal University of Amazonas (UFAM) identified in a young girl of two and a half years premature baldness and other signs of early senility that are typical of a genetic disease known as progeria or Hutchinson-Gilford syndrome, according to an article from July 2018 in the Journal of the European Academy of Dermatology and Venereology. This pathology is extremely rare, with prevalence of one to four cases out of every eight million people. It is incurable and characterized by accelerated aging that is an average of seven times faster than normal.

Not all clinical manifestations of rare diseases are very evident or easy to recognize, such as in the case of progeria. “In general, its symptoms appear when the disease is already established in the organism, causing damage to central organs, such as the heart or liver, and they can be confused with other more common health problems,” says pediatrician Carmela Maggiuzzo Grindler, manager of the state neonatal triage and the policy implementation project for rare diseases at the São Paulo State Department of Health. Another difficulty is the fact that there are no specific codes for rare diseases in the public health system, another barrier for the development of more precise populational studies.

Contribution to the clinical-etiological study of skeletal dysplasias and dysostosis in Brazil (nº 15/22145-6); Grant Mechanism Regular Research Grant; Principal Investigator Denise Cavalcanti (UNICAMP); Investment R$181,234.54.

Scientific articles
CARDOSO, G. C. et al. Clusters of genetic diseases in Brazil. Journal of Community Genetics. On-line. jun. 2018.
FREIRE-MAIA, A. et al. Genetics of acheiropodia (the handless and footless families of Brazil)American Journal of Human Genetics. v. 27, n. 4, p. 521-7.
FARIAS, A. A. et al. Origin and age of the causative mutations in KLC2, IMPA1, MED25 and WNT7A unravelled through Brazilian admixed populationsScientific Reports. v. 8, n. 1, p. 1-8, 8 nov. 2018.
ARAUJO, T. F. et alMolecular analysis of the CTSK gene in a cohort of 33 Brazilian families with pycnodysostosis from a cluster in a Brazilian Northeast regionEuropean Journal of Medical Research. v. 21, n. 1, p. 33, 24 ago. 2016.
GRANA, A. G. et alProgeria: case report and new drugs perspectivesJournal of the European Academy of Dermatology and Venereology. v. 32, n. 7, p. 293-4, jul. 2018.