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The Stepping Stones to Rare Diseases

Mapping effort indicates the distribution of genetic disorders in Brazil

The Monte Santo sacred road: a place of pilgrimage that receives thousands of visitors every year

EDUARDO CESARThe Monte Santo sacred road: a place of pilgrimage that receives thousands of visitors every year EDUARDO CESAR

in Monte Santo, BA

José 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’s reaction was a resounding, “I’m not just going to wait around!”  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.  Doctors examined the little boy and on a subsequent trip, his 11-month-old brother,  concluding that the two suffered from mucopolysaccharidosis type VI, a rare genetic disease that has no cure. Pereira warned him: “There are other children out there with this.” His outlook changed the history of this city in the backlands of Bahia State.

Monte Santo was once a camp for government troops who fought in the War of Canudos [1896-1897].  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.  Pointed at the statue is an English cannon dubbed “the Killer” used in battles that saw the demise of some 25,000 rebels and 5,000 government soldiers.  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’s insistence.  Before that, children with diseases like mucopolysaccharidosis just stayed home.  Their parents thought there was nothing that could be done.

the  former promise-keepers in the chapel at the end of the stone path

Eduardo CesarThe former promise-keepers in the chapel at the end of the stone pathEduardo Cesar

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.  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.

It is thought that marriages between relatives, once quite common, may have favored the appearance of hereditary physical and mental diseases.  Many people married without knowing whether they shared close relatives. José Pereira and his wife, Júlia Isaura dos Santos Pereira, found out they were relatives just a few years ago, when working with researchers from Salvador to compile the family’s genealogical history. They finally understood why they had heard talk of aunts and uncles who had the same disease as their two oldest sons.  Perhaps the deeper roots of these problems lie in the very history of the place.  Several accounts by Bahian historian José Calasans hold that the municipal region–today home to 52,000 residents scattered among 47 towns surrounding the urban nucleus – was a convergence point for the sick who came in search of miracles from the Counselor, reinforcing the site’s 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.  Every year, thousands of pilgrims climb the stone hill, sometimes on their knees or carrying a stone on their head, to fulfill their promises.  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.

Monte Santo at sunset: stage for historic battles

Eduardo CesarMonte Santo at sunset: stage for historic battlesEduardo Cesar

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.  “We come from the universities, but we’ll work with all of you so that what we do will have practical applications,” she said. Itácia Macedo de Andrade Silva, municipal health secretary, was listening with rapt attention.  “I want to do something for my home,” she said, explaining why she came back to the city after studying nursing in Salvador.  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.  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. José Pereira is one of its members.

Rare diseases cause a world of suffering, loneliness, ghosts and guilt, which is beginning to be aired publicly. “The Unified Health System [SUS] has recognized that rare diseases need to be treated,” says  Clarice Alegre Petramale, director of the Secretariat of Science, Technology and Strategic Inputs under the Ministry of Health.  The national health care policy for people with rare diseases – defined as any illness that is prevalent in up to 13 per 20,000 people – 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.

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.  “Medicine 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,” says Magda Carneiro-Sampaio, director of the Children’s Institute at the University of São Paulo (USP). “And the medications may be prescribed at advanced stages of the diseases, when they don’t work as well.  It’s an inconceivable situation, and not just in Brazil.” Maíra Catharina Ramos of the University of Brasília has calculated that the government’s 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.  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. 

From North to South
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.  An updated version of this mapping effort, presented on the previous page, includes  81 municipalies, home to 4,136 people with specific genetic characteristics, called genetic isolates.  They do not always constitute diseases.  The Rio Grande do Sul municipality of Cândido Godói, for example, reports an extraordinary number of twins.  The team of medical geneticist Lavínia Schuler Faccini, professor at the Federal University of Rio Grande do Sul (UFRGS) and a member of INAGEMP’s 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.  Between 1994 and 2006, 2% of all children born in Cândido Godói were twins, twice the national average.  In one of the districts, the rate of twins reached 10%.

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.  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.  

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, São Paulo, Paraná, 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.  

Cousins with controlled phenlyketonuria: at left, Raíra Anielli Carvalho Silva between her mother Eliana Batista Carvalho and brother Ranieri Carvalho Silva (left), 92-year-old grandfather José Lopes de Carvalho and father José Nildo Andrade Silva Below, Camilly Vitória de Souza Andrade, between her father José Armando Moraes de Andrade and mother Cremilda Maria de Souza Andrade

Eduardo CesarCousins with controlled phenlyketonuria: at left, Raíra Anielli Carvalho Silva between her mother Eliana Batista Carvalho and brother Ranieri Carvalho Silva (left), 92-year-old grandfather José Lopes de Carvalho and father José Nildo Andrade SilvaEduardo Cesar

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.  The list keeps growing because researchers continue to find indications of other places that have not yet been mapped.  In June 2014, USP geneticist Carlos Menck traveled to Miracatu, a city of 30,000 residents, 130 km from São 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 Goiás State. Although it is the same disease, the mutations that cause it — the genes and the affected chromosomes — are different in the individuals from the two states.  

Since 2013, the team of medical geneticist Denise Cavalcanti of the University of Campinas (Unicamp) has identified new clusters — another name for the genetic isolates — of different skeletal aphasias, which are diseases that affect bone growth. The clusters are found in five municipalities of the states of Ceará, Alagoas, Pernambuco and São 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:  27 in 22 families.  Scattered among at least 10 small cities in inland Ceará State, the individuals have a very rare disease called  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 Ceará for the mutation that causes the disease, what is known as the “founder effect.” 

Camilly Vitória de Souza Andrade, between her father José Armando Moraes de Andrade and mother Cremilda Maria de Souza Andrade

Eduardo CesarCamilly Vitória de Souza Andrade, between her father José Armando Moraes de Andrade and mother Cremilda Maria de Souza AndradeEduardo Cesar

“You can’t 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,” says Cavalcanti.  One day, she received a letter from a woman in Belém who thanked her for diagnosing her son, writing, “We were so upset by not having a diagnosis.  It was like walking in the dark or wandering aimlessly.”  When they know the name of the disease, they can “go back to supporting their children,” 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. “We’ve already had more than 200 genetic counseling sessions.” 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.  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: “A little spot of mine got mixed up with one from my husband and was born damaged, right?”  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: “So I can’t have more children?  I’m condemned?”  The genetic counseling team knows that they have to explain the risks of inherited diseases without interfering in the couple’s choice to have children. 

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.  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.  Remaining tied to the same place can also cause increased rates of genetic diseases, however.  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.

The 1938 Book of Marriages of the Monte Parish: in the case of cousins, the vicar had to record “waiver of impediment”

Eduardo CesarThe 1938 Book of Marriages of the Monte Parish: in the case of cousins, the vicar had to record “waiver of impediment”Eduardo Cesar

“A lot has changed,” notes Maria Olívia Sousa Costa, health secretary of Monte Santo from 2008 to 2011. “The doctors became responsible for identifying the rare diseases and the mothers became aware of their health rights and complained when there wasn’t enough infusion.”  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.  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’s hospital.  Not everything changed, though, because there isn’t always medication available.  “They always charge me, but I don’t get discouraged,” 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.  The disease is irreversible.  Today, Jorge, 17, and his brother Sidney, 14, are both less than three feet tall and have limited mobility.  Vitor Gonzaga Andrade, the son of Pereira’s cousin, Alaíde Gonzaga Andrade, began receiving the medication when he was two, and today, at age 6, he runs around like a normal healthy boy. 

Cremilda Maria de Souza Andrade became worried when she discovered that her daughter Camilly had phenylketonuria, diagnosed a month after birth.  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.  “Today I’m happy,” 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 Raíra Anielli Carvalho Silva, who also has phenylketonuria, detected shortly after birth and controlled by diet.  In the same town as Raíra, however, there live two brothers, today 40 and 27, with the same mutation as the girls.  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.  

Hitting the road
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.  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’s last name and their sons under the father’s last name, and that sometimes nicknames are used as names (a man known as Santana was really named José da Silva). In Monte Santo, first and last names were repeated in a labyrinth much like that of the Buendía family in One Hundred Years of Solitude, whose members always inter-married and feared their children would be born with pigs’ tails.

Castilla emphasizes that while the publication of scientific articles is still important, but is not a priority because there is “a moral obligation” to first reveal the discoveries to the communities studied.  On a recent Saturday morning, Faccini and her team stood before 200 people in the banquet hall of the Cândido Godói 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  often leads to the development of two embryos per pregnancy.  For decades, people had believed that the twins were the result of the supposedly special power in the municipality’s water. 

Scientific articles
CASTILLA, E. E. & SCHULER-FACCINI, L. From rumors to genetic isolatesGenetics and Molecular Biology. v. 1, n. 37, p. 186-93. 2014.
TAGLIANI-RIBEIRO A. et alHigh twinning rate in Cândido Godói: a new role for p53 in human fertilityHuman Reproduction. v. 27, n. 9, p. 2866-71. 2012.
MACHADO, T. M. B. et alTypes of marriages, population structure and genetic diseaseJournal of Biosocial Science. v. 45, n. 4, p. 461-70. 2013.