On Rare Disease Day, Remember What Family Organizations Can Do

Families who receive a new rare disease diagnosis face seemingly insurmountable challenges. The basic questions that come from any diagnosis, like “what does this mean?” “What is the treatment?” “What should we expect?” are often not known to even the doctors and nurses involved. Learning of a diagnosis for which very little is known and very little research is being done can be isolating. A feeling of being alone is a common reaction, and the idea that there is really nowhere to turn. But as genetic results have become more and more precise and social media has become more a part of everyday life and international in scope a lot of that can change. Families can connect and organize around a rare disease that is shared by a group. They can share experiences, find help, connect with doctors and researchers interested in their condition. They can meet, organize, and raise funds and support for research which they then can drive forward.

This is not hope for the future, this is happening now. In our example, the Global Foundation for Peroxisomal Disorders (GFPD) started as a family email group (with 40 families) in the early days of the internet and grew to a nonprofit public charity in 2010 now serving over 400 families in 39 countries around the world. The GFPD supports families through online support groups and medical and educational advocacy. Additionally, the GFPD supports and funds groundbreaking research that could lead to potential treatments for peroxisomal biogenesis disorders. Peroxisome Biogenesis Disorders (PBD) are a rare group of genetic disorders in which an individual cannot properly produce peroxisomes inside their cells. The peroxisome, a tiny biochemical factory helps us regulate and/or produce a number of specialized fats and other molecules. Without the peroxisome these molecules are thrown out of balance. These disorders cause severe symptoms, particularly affecting the brain, and there are no good treatments. Research into these complex disorders is carried out by relatively small groups of academic physicians and scientists.

This week the results of just one of the many research studies underway driven forward by the GFPD was published online and will be in an upcoming issue of the Nature Publishing group journal, Genetics in Medicine. This paper provides a metabolomics or “small molecule roadmap” of how PBD can affect the chemistry of the bloodstream. A unique characteristic of this study was the partnership between the GFPD and researchers. How was this study achieved? One of us, a physician in medical genetics had treated a family with an individual affected by PBD, and had become inspired (See Peroxisomes and sugar metabolism) to work on the disorder and had been researching the small molecule maps, using animal models. This research had pointed to several pathways but how did the animal models compare with real patients? Would the map have any utility in patients with PBD? Through a unique laboratory effort the possibility of a human study was there. But initially the only participants were families receiving care at Texas Children’s Hospital.

That’s where the GFPD allowed this research to be expanded to more families. One of us (Gamble) has seen the GFPD has grown into an international organization with over 400 families worldwide, with robust research resources, a scientific advisory board spanning the globe, biennial family and scientific meetings, regional family meetups, and a wide variety educational and medical supports for families facing Peroxisomal Biogenesis Disorders.

One of us (Bose) is both a parent and a research scientist. Having this dual point-of-view, we were able to comprehensively explain to families why they should participate in this study, what families hope to gain from an exploration like this, and answer any questions participating in research, from both a caregiver and a researcher perspective.

Indeed these efforts led to a successful study of a rare disease using metabolomics technology, with 19 participants. There are three major initial outcomes from this research. First, it seems PBD produces a recognizable pattern on metabolomics and other patients can be flagged for potential PBD diagnosis using metabolomics. Second, it seems that while young children with PBD have a clear small molecule profile, older subjects somehow normalize these changes. Why the metabolomic findings appear to normalize in older subjects is not currently known. There could be some compensation or effect of growth or aging that remains unexplored. Third, another lipid, sphingomyelin, seems to be unexpectedly low in PBD. This particular finding is novel and just beginning to be explored. The fact that sphingomyelins are a key component of myelin and and neuronal and white matter changes are a characteristic of disease make this finding intriguing.

As an example, the work of the GFPD is advancing research. But what about families with another of the thousands of rare disorders? What about the public and convincing them that PBD and other rare diseases are important. When the Rare Diseases Act of 2002 was passed, it supported initiatives that encouraged physicians, scientists AND patients to work together to make strides in rare diseases. This was largely with the tremendous impact that rare disease studies can have on larger public health questions (See, for example our Top Ten Rare Disease Papers of All Time). Indeed, PBD have pointed to fundamental brain chemistry that is altered in Alzheimer’s disease, and genes implicated in PBD are also linked to obesity in the population. These and other emerging examples make rare disease research of paramount importance.

While this study, one of many involving the GFPD is only one example, and is preliminary insight to us it is an example of families, and scientists working together and driving rare disease research forward.

By Michael Wangler, Mousumi Bose and Melissa Gamble


The doctor in training often hears, “If you hear hoofbeats, think horses not zebras” a practical guideline designed to keep a doctor focused on succeeding at the fundamentals in diagnosis and making the most likely diagnoses consistently rather than being distracted by over-thinking.  As a medical geneticist it is refreshing to dedicate a day to the more “zebra” like disorders. On rare disease day we can reflect on the significant number of individuals in aggregate who struggle with rare disease.  We can also consider the overall cost to our system, and the frequent under-performance of our health care infrastructure in providing for patients with rare disorders, the more difficult road in developing a drug for a smaller group of patients, for example.

However another aspect of rare diseases are the dramatic scientific breakthroughs that biomedical research has made in the process of studying rare disease.  Early onset familial forms of Alzheimer’s disease (AD) are much more rare than AD in general, but their study has given insight across the field of AD field.  Rare diseases are often the “exception to a rule” or a dramatic version of something more common.  Researchers who bother to go after the singular examples and the extremes of the distribution are often rewarded with insights into human physiology and genetics that apply to a broad spectrum of disease.  In honor of those researchers on rare disease day 2017 I share my list of the top 10 rare disease scientific papers of all time.


Number 10: Generalized intestinal polyposis and melanin spots of the oral mucosa, a syndrome of diagnostic significance. N Engl Journal of Medicine 1949; (photo)   In 1895 Conner and Hutchinson had evaluated identical twins with dark spots of the lips, at the time thought to be an oddity, however one twin died of intestinal complications from polyps and another of breast cancer at an early age.  Johannes Peutz discussed this condition again in 1949, but it is the paper of Harold Jeghers that makes the list. Jeghers paper is unique in that he proposes that these patients have a syndrome and he goes so far to say that a single pleiotropic gene was responsible.  Four years before Watson and Crick published the structure of DNA the idea of hereditary cancer syndromes due to single gene disorders was being proposed in this paper.  Indeed Peutz-Jeghers syndrome due to mutations in STK11, and the protein encoded by this gene is at the center of cancer pathways linked to metabolism and cellular machinery, insights that have benefited patients far beyond Peutz-Jeghers


Number 9: Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Research 2005   Mendelian inheritance refers to Gregor Mendel’s fundamental insight into genetics and the control of traits by single genes.  The application of single gene (one gene primarily determining one trait) disorders has been extremely fruitful and no effort has aided more than OMIM (www.omim.org) a catalog of single gene disorders, decades of effort started by Victor McKusick.  The story of this remarkable database can be seen in more detail here (https://www.omim.org/about). The 2005 paper, now outdated with respect to the current database and its relation to NCBI, was a reflection of the mature online effort and contribution of OMIM and gives a sense of he scope which continues to broaden in cataloguing monogenic traits in humans.


Number  8: Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease Nature 1991. Early-onset familial AD accounts for less than 4% of AD.   However, the study of these rare forms in this and subsequent papers brought to light the central role of amyloid precursor protein.  APP is normally processed in our brains in a way that favors a less toxic cleaved form.  The rare familial cases were linked to variants in the APP gene in this paper. This evidence related the process of cleavage of this protein leading to toxic aggregates to the genetics of AD.  Indeed, all AD seems to contain aggregates that are composed of this protein suggesting rare and common forms of AD share features.  Treatments for AD that even target this toxic aggregation have been tried as a result of these insights.  While many layers underlie the aggregates it is clear that studying the rare forms of AD has been a significant breakthrough. Another interesting paragraph in the paper discusses the relationship between the APP gene on chromosome 21 and the higher incidence of Alzheimer’s disease in patients with Down syndrome due to Trisomy 21.


Number 7: Identification of the Cystic Fibrosis Gene: Cloning and Characterization of Complementary DNA. Science 1989.  Finding the CFTR. Cystic Fibrosis as a primarily lung and pancreatic disorder seen much more frequently in Europeans is perhaps, as Mendelian disorders go, with an incidence of 1 in 3,000 newborns, one of the more common “rare diseases”.  However the need to identify the genetic cause was a major push in the 1980s and its final identification by positional cloning remains a significant milestone launching an era of gene identification that has intensified and continues today. The paper was a tour-de force describing a meticulous bookkeeping of isolated DNA and RNA sequences with eventual identification of a deletion of a single phenylalanine (508), the most common CF disease causing allele.


Number 6: Mutation and Cancer: Statistical Study of Retinoblastoma. PNAS 1971. In this paper Alfred Knudson brilliantly analyzed cases of Retinoblastoma and laid out the numbers underlying the two-hit hypothesis of cancer.  Starting with patients with the rare condition characterized by germline inheritance of mutations in the Rb gene leading to bilateral or multiple Retinoblastomas, Knudson reasons that the Retinoblastoma required two hits to develop, sporadic forms came from the random chance occurrence of lightning striking twice, while the germline forms started out with one hit and were therefore more likely to develop multiple Rbs.  Even the inherited forms could occasionally not acquire the 2nd hit and that observation was also explained.


Number 5: Binding and Degradation of Low Density Lipoproteins by Cultured Human Fibroblasts. Many people have high cholesterol and the health implications are broad and affect billions.  However, only one in a million individuals have homozygous hypercholesterolemia, a rare disease the study of which was a crucial part of the groundbreaking work of Brown and Goldstein. The elucidation of the binding of low density lipoproteins to cell surface receptors and the resultant inhibition of cholesterol synthesis was a pathway worked out by Brown and Goldstein in a series of papers and is a famous Nobel prize winning series of discoveries that also laid the groundwork for statin drugs in wide use today. This paper, representing only one chapter in their work includes a crucial clue in the overall story, the fact that cells from those rare patients with homozygous familial hypercholesterolemia fail to suppress their cholesterol synthesis in the presence of LDL, a suppression that is seen in normal cells. This paper, outlines the mechanism in the rare forms of hypercholesterolemia and because of this link between a group of patients with rare disease and the millions of people benefiting from statins and the understanding of the cholesterol transport pathways, this paper should be considered a rare disease classic.


Number 4: A Simple Phenylalanine Method for Detecting Phenylketonuria in Large Populations of Newborn Infants Pediatrics 1963. Prior to the 1960s children with Phenylketonuria were born with normal brains and gradually their neurons were poisoned by their phenylalanine metabolic defect, by the time they were a year old the damage was already largely done.  Simply withholding phenylalanine from the diet (which sounds easier than it is in real life) allows normal brain development.  The problem was this was a rare disease but treatable if caught in time, so the question was how to catch this rare disease in time to make a difference.  It was this problem and a brilliant assay developed by Guthrie, which utilized inhibition of bacterial growth in the presence of phenylalanine, was the subject of this classic paper.  The Guthrie test evolved and was eventually entirely replaced by mass spectrometry based methods in use in newborn screening today, but the principle of screening newborns for inborn errors of metabolism has been a major public health success with >40 disorders screened and treated systematically in most states in the U.S. This groundbreaking paper was the beginning of this effort and makes this a clear landmark in rare disease research.


Number 3: William Harvey Letter to Lord Fielding: In the 1600s Anatomists were the medical research pioneers. One of the father’s of circulation William Harvey created the elaborate maps of human blood flow. But his letter to Lord Fielding pertaining to a unique patient that Fielding wrote Harvey about makes the letter a rare disease classic.  “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease”


Number 2: Sickle Cell Anemia, a Molecular Disease Science 1949. Linus Pauling a biochemistry scientific giant was studying hemoglobin from individuals with sickle cell anemia an autosomal recessive genetic disorder, alongside hemoglobin from sickle cell trait (carriers) and those without sickle cell. In this paper by characterizing the properties of the different hemoglobins the overall cellular sickling property can be directly traced back to differences in the response to low oxygen in the different hemoglobin molecules. By further characterizing these hemoglobins chemically and performing some mixing experiments, Pauling reasons that the carriers have approximately equal mixtures of two distinct types of hemoglobin. Without any knowledge of what gene was involved, nor even an understanding of DNA the paper describes the single gene basis of this molecular disease. This is clearly a seminal paper in defining the molecular basis of a rare disease.


Number 1: The Incidence of Alkaptonuria: A study of chemical individuality Lancet 1902. Gregor Mendel had made careful observations about pea plants to derive some fundamental genetic laws, that traits of an organism could be determined by hereditary packets of information (genes) that seemed to remain intact and could assort independently from those of other traits and did not intermix or “average” as was the competing theories of inheritance. Physician Archibald Garrod was the first to apply Mendelian laws to humans. In his study of a rare disease alkaptonuria, Garrod first lays out the observation that the disorder seems to occur in children whose parents are first cousins. About this he states, “The question of the liability of children of consanguineous marriages to exhibit certain abnormalities or to develop certain diseases has been much discussed, but seldom in a strictly scientific spirit. Those who have written on the subject have too often aimed at demonstrating the deleterious results of such unions on the one hand, or their harmlessness on the other, questions which do not here concern us at all.” He goes on to outline Bateson’s writings on Mendel’s laws and explain autosomal recessive inheritance. He predicts that alkaptonuria could occur in the offspring of unrelated parents if both parents are carriers by chance. His studies were the first demonstration of Mendelian inheritance in humans.


Each of these classic papers focused on disorders that were not the most common or most “pressing” health problem at the time. However the researchers involved recognized that the value of understanding rare disease would extend out into other arms of biomedical science, or perhaps they were simply curious, unwilling to let the questions go unanswered. In either case, without the discoveries outlined in these papers our understanding of the molecular basis of disease (e.g. Sickle cell anemia), the inheritance or genetic basis of human disorders (e.g.cystic fibrosis, alkaptonuria, OMIM catalog), our understanding of cancer (e.g Retinoblastoma, Peutz-Jeghers) and our ability to understand and treat common disorders like Alzheimer’s and high cholesterol would have taken much longer for science to understand. Something important to keep in mind on Rare disease day.