The treatments for rare diseases are as variable as the diseases themselves. Treatments can range from specific FDA approved orphan drugs, to diet and lifestyle changes, to surgical intervention, or they can include all 3.

Orphan Drugs

To date, there are over 450 orphan drugs approved for rare diseases, but many conditions have multiple orphan drugs (see Appendix A). Many of the orphan drugs are for treating rare cancers, but the diseases covered are related to endocrinology, neurology, and other categories as well.

Lifestyle Changes

There are also rare diseases that can be managed by surgery, diet, and lifestyle changes, for which orphan drugs are not necessary. For example, phenylketonuria—an inherited disorder causing toxic levels of phenylalanine—may be managed with a phenylalanine-restricted diet in some patients (they may also benefit from the orphan drug Kuvan). Xeroderma pigmentosa—an inherited condition characterized by extreme sensitivity to ultraviolet sunlight—is generally treated behaviorally by avoiding direct exposure to the sun (and by use of sunscreens). Ménière’s disease is an abnormality of the inner ear leading to vertigo and dizziness. In most cases, a restrictive diet (no salt) and possibly antihistamines and/or diuretics are used to manage the condition.


Surgery can also be the primary treatment. For example, a patient with tetralogy of Fallot, a congenital heart defect, can be treated with open-heart surgery, while a child with craniosynostosis can often lead a normal life following neurosurgery and plastic surgery early in development. Most rare diseases, however, do not have a treatment, and for those that do, whether it is surgery, lifestyle change, or an orphan drug, the data on the safety and efficacy of that treatment are often limited.

Treatment vs Cure

Treatment options may be grouped into the categories of: (1) curative; (2) disease-modifying; or (3) symptom- or function-modifying.

Curative Treatments. These are rare for rare diseases. They include treatment for most rare infections (eg, Tropheryma whipplei) or rare poisonings (eg, from snakebites or cyanide). Surgery can  also “cure” many anatomical defects such as craniosynostosis or coarctation of the aorta.

Disease-Modifying Treatments. These treatments may receive orphan drug approval to treat rare diseases. For example, enzyme replacement therapy for Gaucher disease may delay or stop the progression of the disease, but not cure it. Many patients can lead normal lives following treatment, but the underlying cause of the disease remains. For others, the treatment may delay progression but will not stop it.

Function-Modifying Treatments. These types of therapies may not be approved orphan drugs but are necessary to treat the plethora of symptoms that result from a rare disease (eg, pain, nausea, GI problems, anemia). One of the major concerns with treating these symptoms is that they may not be covered by insurance, and this can lead to major financial setbacks for a family--especially if surgery, complicated medical/communication devices, and/or physical therapy are necessary.

Long-Term Effects of Treatment

A common concern with many treatments for rare diseases is that we do not know the long-term effects of treatment, nor do we know how treatment will change as a patient ages or as his or her disease progresses. While every effort is made by the FDA to approve drugs that are safe and effective, most clinical trials that have led to orphan drug approval have been limited in size and design. And it is only recently that we have begun to address the natural history of these conditions, and how the natural history may change with improvements in medical care.

The long-term follow-up of patients through carefully designed and maintained patient registries is becoming increasingly important. Such registries can provide critical data on the natural history of a specific disorder, and also how a specific treatment changes this natural  history. Increasingly, patient advocacy organizations are taking the lead in establishing registries. With the aid of the Internet and globalization of patient communities, foundations are becoming increasingly effective at encouraging participation in registries by their patient and family stakeholders.

In some instances, well-designed and carefully maintained registries may serve a “clinical trial–like” function, enabling the following of relatively large numbers of patients distributed over a national or worldwide region, on and off a particular drug or treatment regimen. These efforts become increasingly important as regulatory agencies begin to embrace “accelerated approvals” for orphan drugs, and healthcare systems (private and governmental) want to see that a treatment is effective in improving the lives of patients in the long term.

Guidelines for Rare Diseases

There are increasing efforts to develop and publish international consensus documents regarding care guidelines and standard of care for specific rare disorders. However, these efforts have generally been limited to the most common of the rare disorders, where adequate data exist to develop guidelines. Most rare diseases do not have well-researched treatment guidelines. Websites of patient advocacy groups are often the entry point to determine whether guidelines exist and where they can be found (see Appendix B). Many patient advocacy groups have sections for healthcare professionals to assist or recommend treatment. Many advocacy groups also provide locations of specialized clinics that can be contacted for advice on where the rare disease patient may need to visit.

As Treatments Improve Outcomes, They Also Create New Unknowns

Since many rare diseases occur in children, it is not uncommon for pediatricians to be familiar with managing or seeing rare diseases in their career. In contrast, facilities that manage adult patients tend to treat more common ailments. Ironically, as the treatment of rare diseases has improved, many children with a rare disease live into adolescence and adulthood only to find that their treating physician is less familiar with the rare disease than they. In other words, as patients age, they may be the ones who provide the knowledge necessary to aid the doctors with information about the condition.

In addition, the lack of natural history studies for many diseases—especially in light of recent advances in treatment—means that we do not know how a disease will progress or how a treatment will affect other body systems. As  discussed in the Patient Education Section, patients with rare diseases are encouraged to enroll in patient registries and/or natural history studies to help advance the medical community’s understanding of each rare disease.
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