{"id":156337,"date":"2014-08-23T16:51:33","date_gmt":"2014-08-23T19:51:33","guid":{"rendered":"http:\/\/revistapesquisa.fapesp.br\/?p=156337"},"modified":"2014-09-23T18:56:05","modified_gmt":"2014-09-23T21:56:05","slug":"stepping-stones-rare-diseases","status":"publish","type":"post","link":"https:\/\/revistapesquisa.fapesp.br\/en\/stepping-stones-rare-diseases\/","title":{"rendered":"The Stepping Stones to Rare Diseases"},"content":{"rendered":"
\"The

EDUARDO CESAR<\/span>The Monte Santo sacred road: a place of pilgrimage that receives thousands of visitors every year EDUARDO CESAR<\/span><\/p><\/div>\n

in Monte Santo, BA<\/em><\/p>\n

Jos\u00e9 de Andrade Pereira is a man of firm character. In 2004, he took his eldest son–who at the age of 3, was very short in stature, had short fingers, a large head and difficulty speaking, and who once again was suffering from a bad earache–to a clinic in Monte Santo, in inland Bahia State. The doctor told him that, aside from treating the earache, there was no more he could do about a disease he knew nothing about; he should just wait for the child to die. Pereira\u2019s reaction was a resounding, \u201cI\u2019m not just going to wait around!\u201d\u00a0 He made the six-hour trip to Salvador and asked a doorman at the Professor Edgard Santos University Hospital who best could care for a boy such as his.\u00a0 Doctors examined the little boy and on a subsequent trip, his 11-month-old brother,\u00a0 concluding that the two suffered from mucopolysaccharidosis type VI, a rare genetic disease that has no cure. Pereira warned him: \u201cThere are other children out there with this.\u201d His outlook changed the history of this city in the backlands of Bahia State.<\/p>\n

Monte Santo was once a camp for government troops who fought in the War of Canudos [1896-1897].\u00a0 The main square still displays a wood statue of Antonio Conselheiro, the devout leader of the backlands settlers who were seen as opponents of the burgeoning republic.\u00a0 Pointed at the statue is an English cannon dubbed \u201cthe Killer\u201d used in battles that saw the demise of some 25,000 rebels and 5,000 government soldiers.\u00a0 In recent years, Monte Santo has served as the stage for other battles: the identification, treatment and prevention of rare genetic diseases whose existence was only acknowledged at Pereira\u2019s insistence.\u00a0 Before that, children with diseases like mucopolysaccharidosis just stayed home.\u00a0 Their parents thought there was nothing that could be done.<\/p>\n

\"the

Eduardo Cesar<\/span>The\u00a0former promise-keepers in the chapel at the end of the stone pathEduardo Cesar<\/span><\/p><\/div>\n

In 2006, physicians and researchers from Salvador, Rio de Janeiro and Porto Alegre visited Monte Santo for the first time and were astounded by the variety of rare diseases they saw in a single place.\u00a0 They have already diagnosed 13 people with mucopolysaccharidosis type VI, a percentage 240 times higher than the national average; 84 with hearing disabilities possibly due to genetics; 12 with congenital hypothyroidism; nine with phenylketonuria, which if untreated can cause intellectual disability; four with osteogenesis imperfecta, characterized by extreme bone fragility; and four with Treacher Collins syndrome, which affects the development of bones in the face.<\/p>\n

It is thought that marriages between relatives, once quite common, may have favored the appearance of hereditary physical and mental diseases.\u00a0 Many people married without knowing whether they shared close relatives. Jos\u00e9 Pereira and his wife, J\u00falia Isaura dos Santos Pereira, found out they were relatives just a few years ago, when working with researchers from Salvador to compile the family\u2019s genealogical history. They finally understood why they had heard talk of aunts and uncles who had the same disease as their two oldest sons.\u00a0 Perhaps the deeper roots of these problems lie in the very history of the place.\u00a0 Several accounts by Bahian historian Jos\u00e9 Calasans hold that the municipal region–today home to 52,000 residents scattered among 47 towns surrounding the urban nucleus \u2013 was a convergence point for the sick who came in search of miracles from the Counselor, reinforcing the site\u2019s religious significance. It was the Counselor who refurbished the chapels along the sacred road, a 2.8-kilometer steep and winding stone path that ends in a chapel built at the top of the hill by an Italian priest in 1786.\u00a0 Every year, thousands of pilgrims climb the stone hill, sometimes on their knees or carrying a stone on their head, to fulfill their promises.\u00a0 Because they were generally poor, the sick, cured or not, their family members, and pilgrims may have found it hard to go back to their homes, or they simply preferred to stay in the area.<\/p>\n

\"Monte

Eduardo Cesar<\/span>Monte Santo at sunset: stage for historic battlesEduardo Cesar<\/span><\/p><\/div>\n

Because there are likely to be more people who have not yet been diagnosed, medical geneticist Angelina Acosta, a professor at the Federal University of Bahia (UFBA), visited the auditorium of the Town Council in the early afternoon of July 10 to explain to physicians and politicians alike her plan to conduct a health census of the entire population.\u00a0 \u201cWe come from the universities, but we\u2019ll work with all of you so that what we do will have practical applications,\u201d she said. It\u00e1cia Macedo de Andrade Silva, municipal health secretary, was listening with rapt attention.\u00a0 \u201cI want to do something for my home,\u201d she said, explaining why she came back to the city after studying nursing in Salvador.\u00a0 The next morning, the team led by Acosta and Kiyoko Sandes spoke to 80 community health agents who will be visiting the villages in search of other cases, beginning in August 2014.\u00a0 The dialogue has resulted in suggestions of additional individuals yet to be examined as well as the formation of a committee to monitor the census and treatment. Jos\u00e9 Pereira is one of its members.<\/p>\n

Rare diseases cause a world of suffering, loneliness, ghosts and guilt, which is beginning to be aired publicly. \u201cThe Unified Health System [SUS] has recognized that rare diseases need to be treated,\u201d says\u00a0 Clarice Alegre Petramale, director of the Secretariat of Science, Technology and Strategic Inputs under the Ministry of Health.\u00a0 The national health care policy for people with rare diseases \u2013 defined as any illness that is prevalent in up to 13 per 20,000 people \u2013 has been in effect since May 2014. The list of diseases for priority care is expected to be announced by the end of this year.<\/span><\/p>\n

\"\"<\/a>There are no specific medications for most rare diseases, but rather treatment in the form of patient support, such as physical and speech therapy. When there is medication, it is generally imported and obtained through court orders.\u00a0 \u201cMedicine is expensive and often of questionable effectiveness because it has not undergone rigorous assessments since it is only tested on a small number of patients,\u201d says Magda Carneiro-Sampaio, director of the Children\u2019s Institute at the University of S\u00e3o Paulo (USP). \u201cAnd the medications may be prescribed at advanced stages of the diseases, when they don\u2019t work as well.\u00a0 It\u2019s an inconceivable situation, and not just in Brazil.\u201d Ma\u00edra Catharina Ramos of the University of Bras\u00edlia has calculated that the government\u2019s voluntary purchase of just one of the medications used to treat mucopolysaccharidosis would save R$50 million compared to what would be spent to comply with the court orders that force the government to purchase the drugs.\u00a0 It is estimated that 13 million people in Brazil have one or another of the 6,000 different types of rare diseases, most of them genetic in origin, that have been described all over the world.\u00a0<\/span><\/p>\n

From North to South
\n<\/span><\/strong>The work carried out by the academic researchers and local health professionals in search of other residents with unusual diseases places Monte Santo on the frontlines of the National Census of Genetically Isolated Populations (CENISO), organized by the National Institute of Medical Population Genetics (INAGEMP). In April 2014, an article published in the journal Genetics and Molecular Biology presented some of the findings of the CENISO: a national survey of municipalities that have groups of individuals or families with genetic diseases.\u00a0 An updated version of this mapping effort, presented on the previous page, includes\u00a0 81 municipalies, home to 4,136 people with specific genetic characteristics, called genetic isolates.\u00a0 They do not always constitute diseases.\u00a0 The Rio Grande do Sul municipality of C\u00e2ndido God\u00f3i, for example, reports an extraordinary number of twins.\u00a0 The team of medical geneticist Lav\u00ednia Schuler Faccini, professor at the Federal University of Rio Grande do Sul (UFRGS) and a member of INAGEMP\u2019s coordinating committee, 91 pairs of twins and one set of triplets born between 1959 and 2000 in the municipality that today is home to 6,000 residents.\u00a0 Between 1994 and 2006, 2% of all children born in C\u00e2ndido God\u00f3i were twins, twice the national average.\u00a0 In one of the districts, the rate of twins reached 10%.<\/p>\n

\"\"<\/a>Some genetic diseases manifest themselves during adulthood or even after age 40, such as Machado-Joseph disease, which causes a progressive loss of balance, mobility and speech.\u00a0 Faccini, along with her team that conducts genetic counseling of family members of nearly 400 people with ataxia in Porto Alegre, has observed that the diagnosis at a generally advanced age causes anxiety and guilt because the affected individuals may have already had children or grandchildren born with the mutations that cause the disease. \u00a0<\/span><\/p>\n

Some diseases are regional in scale, such as Li-Fraumeni syndrome, an inherited genetic disorder that increases the risk of developing cancer, already identified in 325 individuals in the states of Rio de Janeiro, S\u00e3o Paulo, Paran\u00e1, Santa Catarina and Rio Grande do Sul. One recent study reported a high prevalence, .27%, of the mutation that causes the disorder in 171,000 babies examined in the city of Curitiba, indicating that in some places, this disease is not considered rare and requires intensive monitoring, especially among those considered to be at higher risk. \u00a0<\/span><\/p>\n

\"Cousins

Eduardo Cesar<\/span>Cousins with controlled phenlyketonuria: at left, Ra\u00edra Anielli Carvalho Silva between her mother Eliana Batista Carvalho and brother Ranieri Carvalho Silva (left<\/em>), 92-year-old grandfather Jos\u00e9 Lopes de Carvalho and father Jos\u00e9 Nildo Andrade SilvaEduardo Cesar<\/span><\/p><\/div>\n

Physician Eduardo Enrique Castilla, researcher at the Oswaldo Cruz Institute (Fiocruz) of Rio de Janeiro and one of the census designers, believes that the number of municipalities already identified as having rare genetic diseases in Brazil may represent just 20% of total estimates.\u00a0 The list keeps growing because researchers continue to find indications of other places that have not yet been mapped.\u00a0 In June 2014, USP geneticist Carlos Menck traveled to Miracatu, a city of 30,000 residents, 130 km from S\u00e3o Paulo, where he identified four people from a single family with Schleroderma pigmentoso, a disease that has already been diagnosed in 22 of the residents of a town in inland Goi\u00e1s State. Although it is the same disease, the mutations that cause it \u2014 the genes and the affected chromosomes \u2014 are different in the individuals from the two states. \u00a0<\/span><\/p>\n

Since 2013, the team of medical geneticist Denise Cavalcanti of the University of Campinas (Unicamp) has identified new clusters \u2014 another name for the genetic isolates \u2014 of different skeletal aphasias, which are diseases that affect bone growth. The clusters are found in five municipalities of the states of Cear\u00e1, Alagoas, Pernambuco and S\u00e3o Paulo. One of them, identified in collaboration with a medical geneticist from Fortaleza, is impressive due to the number of people diagnosed up to now:\u00a0 27 in 22 families.\u00a0 Scattered among at least 10 small cities in inland Cear\u00e1 State, the individuals have a very rare disease called\u00a0 pycnodisostosis, the same disease that resulted in the short stature of French artist Henri de Toulouse-Lautrec. Cavalcanti and her team are now working to identify the possible site of origin in Cear\u00e1 for the mutation that causes the disease, what is known as the \u201cfounder effect.\u201d\u00a0<\/span><\/p>\n

\"Camilly

Eduardo Cesar<\/span>Camilly Vit\u00f3ria de Souza Andrade, between her father Jos\u00e9 Armando Moraes de Andrade and mother Cremilda Maria de Souza AndradeEduardo Cesar<\/span><\/p><\/div>\n

\u201cYou can\u2019t even imagine how important it is for the mothers to learn the name of the disease their children have even if there is no treatment, because then they can stop going from one doctor to the next,\u201d says Cavalcanti.\u00a0 One day, she received a letter from a woman in Bel\u00e9m who thanked her for diagnosing her son, writing, \u201cWe were so upset by not having a diagnosis.\u00a0 It was like walking in the dark or wandering aimlessly.\u201d\u00a0 When they know the name of the disease, they can \u201cgo back to supporting their children,\u201d notes Isabella Queiroz, professor at the Bahia School of Medicine and psychologist at the Salvador APAE (Association of Parents and Friends of the Mentally Disabled) who cares for the Monte Santo families with genetic diseases. \u201cWe\u2019ve already had more than 200 genetic counseling sessions.\u201d In these sessions, the medical team explains that the inherited genetic diseases are the result of the transmission of genes with alterations (or mutations), because inter-marriage is not the only explanation.\u00a0 When she saw a genetic map of the family that lists the members who are healthy as well as who are sick, one woman understood what happened in her own way: \u201cA little spot of mine got mixed up with one from my husband and was born damaged, right?\u201d\u00a0 It is also the time when guilt over having given birth to sick children, the helplessness, and the anger overflow. One of the men asked the person he was meeting with: \u201cSo I can\u2019t have more children?\u00a0 I\u2019m condemned?\u201d\u00a0 The genetic counseling team knows that they have to explain the risks of inherited diseases without interfering in the couple\u2019s choice to have children.\u00a0<\/span><\/p>\n

Sometimes, younger couples voluntarily seek out medical services before they have children in order to detect possible harmful mutations, a fact that may indicate a decline in the number of cases of some genetic diseases in the coming years. The habit of marrying cousins, a practice that is much more common in Moslem countries than in Brazil, is perhaps the hardest to change, though, because it has been done for so long as a way to keep land in families or because of personal preferences.\u00a0 When researchers visited Tabuleiro do Norte, a municipality 200 km from Fortaleza, with high rates of a metabolic disorder known as Gaucher disease, they heard men say that it was fine to date women from the capital but the women to marry were those from Tabuleiro.\u00a0 Remaining tied to the same place can also cause increased rates of genetic diseases, however.\u00a0 A priest from Monte Santo talks about how he offered the boys bicycles so they could look for brides in other places, but no one took him up on it.<\/span><\/p>\n

\"The

Eduardo Cesar<\/span>The 1938 Book of Marriages of the Monte Parish: in the case of cousins, the vicar had to record \u201cwaiver of impediment\u201dEduardo Cesar<\/span><\/p><\/div>\n

\u201cA lot has changed,\u201d notes Maria Ol\u00edvia Sousa Costa, health secretary of Monte Santo from 2008 to 2011. \u201cThe doctors became responsible for identifying the rare diseases and the mothers became aware of their health rights and complained when there wasn\u2019t enough infusion.\u201d\u00a0 Infusion is a preparation made with the arylsulfatase B enzyme that children with mucopolysaccharidosis type VI do not produce, and it is administered in four-hour sessions once a week.\u00a0 For years, parents have taken their children to Salvador to receive the medication, which since 2011 has been administered in an annex to the city\u2019s hospital.\u00a0 Not everything changed, though, because there isn\u2019t always medication available.\u00a0 \u201cThey always charge me, but I don\u2019t get discouraged,\u201d Pereira says. His two sons began treatment in Salvador in 2008, four years after being diagnosed, because the enzyme had not been released for use in Brazil.\u00a0 The disease is irreversible.\u00a0 Today, Jorge, 17, and his brother Sidney, 14, are both less than three feet tall and have limited mobility.\u00a0 Vitor Gonzaga Andrade, the son of Pereira\u2019s cousin, Ala\u00edde Gonzaga Andrade, began receiving the medication when he was two, and today, at age 6, he runs around like a normal healthy boy.\u00a0<\/span><\/p>\n

Cremilda Maria de Souza Andrade became worried when she discovered that her daughter Camilly had phenylketonuria, diagnosed a month after birth.\u00a0 She took her to Salvador to begin treatment, which consists of a strict diet, free of protein that contains phenylalanine, which the body is unable to process.\u00a0 \u201cToday I\u2019m happy,\u201d Andrade says, proudly showing off the notebooks of her now 11-year-old daughter, ever vigilant of her diet. Camilly is the cousin of 12 year-old Ra\u00edra Anielli Carvalho Silva, who also has phenylketonuria, detected shortly after birth and controlled by diet.\u00a0 In the same town as Ra\u00edra, however, there live two brothers, today 40 and 27, with the same mutation as the girls.\u00a0 Since the heel test was not yet common in the region when they were born, their disease was detected much later, was not controlled and caused mental disturbances that render them housebound. \u00a0<\/span><\/p>\n

Hitting the road
\n<\/span><\/strong>In order to do a comprehensive study, the researchers are having to leave the laboratory, put on their street clothes and travel to unimaginable places, learning the habits and silences of the residents in the hinterlands of Brazil and seeking information from other sources.\u00a0 To locate people with the highest risk of genetic diseases, Angelina Acosta and her team have consulted records of marriages, baptisms and deaths in the parish of Monte Santo dating back to 1831, and have redone the histories of 1,419 families. After having lost their way, they rediscovered the stepping stones, valuable even to historians, when they saw that women only got a last name when they married, that couples registered their daughters under the mother\u2019s last name and their sons under the father\u2019s last name, and that sometimes nicknames are used as names (a man known as Santana was really named Jos\u00e9 da Silva). In Monte Santo, first and last names were repeated in a labyrinth much like that of the Buend\u00eda family in One Hundred Years of Solitude<\/i>, whose members always inter-married and feared their children would be born with pigs\u2019 tails.<\/p>\n

Castilla emphasizes that while the publication of scientific articles is still important, but is not a priority because there is \u201ca moral obligation\u201d to first reveal the discoveries to the communities studied.\u00a0 On a recent Saturday morning, Faccini and her team stood before 200 people in the banquet hall of the C\u00e2ndido God\u00f3i church to explain why there were so many twins, many of whom were in the audience: it was likely the result of a variation of the gene that encodes the P53 protein, which\u00a0 often leads to the development of two embryos per pregnancy.\u00a0 For decades, people had believed that the twins were the result of the supposedly special power in the municipality\u2019s water.\u00a0<\/span><\/p>\n

Scientific articles
\n<\/span><\/em>CASTILLA, E. E. & SCHULER-FACCINI, L.\u00a0From\u00a0rumors\u00a0to genetic\u00a0isolates<\/a>.\u00a0Genetics and Molecular Biology<\/strong>. v. 1, n. 37, p. 186-93. 2014.
\nTAGLIANI-RIBEIRO A.\u00a0et al<\/em>.\u00a0High twinning rate in C\u00e2ndido God\u00f3i: a new role for p53 in human fertility<\/a>.\u00a0Human Reproduction<\/strong>. v. 27, n. 9, p. 2866-71. 2012.
\nMACHADO, T. M. B.\u00a0et al<\/em>.\u00a0Types of marriages, population structure and genetic disease<\/a>.\u00a0Journal of Biosocial Science<\/strong>. v. 45, n. 4, p. 461-70. 2013.<\/p>\n","protected":false},"excerpt":{"rendered":"Mapping indicates the distribution of genetic disorders in Brazil ","protected":false},"author":17,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_exactmetrics_skip_tracking":false,"_exactmetrics_sitenote_active":false,"_exactmetrics_sitenote_note":"","_exactmetrics_sitenote_category":0,"footnotes":""},"categories":[156],"tags":[209,237,247],"coauthors":[5968],"class_list":["post-156337","post","type-post","status-publish","format-standard","hentry","category-cover","tag-biology","tag-genetics","tag-medicine"],"acf":[],"_links":{"self":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/156337","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/users\/17"}],"replies":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/comments?post=156337"}],"version-history":[{"count":0,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/156337\/revisions"}],"wp:attachment":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/media?parent=156337"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/categories?post=156337"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/tags?post=156337"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/coauthors?post=156337"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}