PRENATAL REPAIR OF MYELOMENINGOCELE

Open spina bifida is a congenital neural tube defect caused by primary failure of neural tube closure during the embryologic period. In myelomeningocele, the most severe form of spinal bifida, there is protrusion of the meninges and spinal cord through open vertebral arches. The consequences of myelomeningocele depend on the anatomical location of the defect, and include hindbrain herniation, hydrocephalus (with need for a ventriculoperitoneal shunt), paralysis and motor impairment, cognitive impairment, and bladder and bowel incontinence. Traditionally, when an infant is born with myelomeningocele, pediatric neurosurgeons perform surgical closure of the defect, and most infants will require a ventriculoperitoneal shunt, often followed by multiple shunt revisions. Many infants do not survive beyond 5 years of age.

For 3 decades, teams of surgeons at the University of California San Francisco and the Children's Hospital of Philadelphia have been working on the development of fetal surgical techniques that allow prenatal closure of myelomeningocele. They finally tested this technique in a randomized controlled trial, the Management of Myelomeningocele Study.1 Women were randomly assigned to undergo prenatal surgery before 26 weeks of gestation or standard postnatal repair. The trial was stopped early by the Data Safety Monitoring Board for efficacy of prenatal surgery. Infants who had surgery before birth had a 40% incidence of shunt placement compared with 82% of those who had postnatal surgery. Prenatal surgery was associated with improved mental and motor function scores at 30 months, improved ambulation, and less hindbrain herniation. However, prenatal surgery was associated with an increased risk for preterm delivery and uterine dehiscence.

Prenatal surgery for myelomeningocele was recently highlighted in a PBS documentary titled "Twice Born."

1. Adzick NS, Thom EA, Spong CY, et al. MOMS investigators. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011;364:993-1004. [Context Link]

RARE DISEASE DETECTIVES

A little-known fact about rare diseases is that many individuals who suffer from the symptoms of a rare disease spend years bouncing from one specialist to another, and undergoing test after test before they get a definitive diagnosis. The average time to diagnosis for a rare disease is 7.2 years. Even more frustrating, however, is the situation faced by families of children who never receive a definitive diagnosis at all, and therefore, fail to receive appropriate treatment for their rare disease.

In 2008, the National Human Genome Research Institute, the National Institutes of Health (NIH) Office of Rare Diseases Research, and the NIH Clinical Center launched the Undiagnosed Diseases Program (UDP) at the NIH's Bethesda, Maryland campus.

The UDP was designed to leverage the NIH's expert staff and cutting-edge research tools to diagnose rare diseases in patients who have signs and symptoms that have eluded a definitive diagnosis. A second goal of the UDP is to advance knowledge of rare diseases and new presentations of common diseases.

In its first 6 years, the UDP enrolled more than 800 undiagnosed children and adults in its clinical protocols. In addition to providing partial or complete diagnoses for up to 40% of those evaluated, the program's multidisciplinary team of experts has discovered 2 unknown diseases and identified 15 genes not previously known to be associated with any other human disease. However, the UDP has been able to accept only a fraction of the patients who apply to the program-more than 10,000 inquiries to date. The popularity of the UDP has demonstrated that a substantial unmet need exists for intensive evaluation of undiagnosed diseases among the population. Therefore, an extension of the program is underway that will add 6 new clinical sites at the Baylor College of Medicine; Harvard teaching hospitals (including Boston Children's Hospital, Brigham and Women's Hospital, and Massachusetts General Hospital); Duke University; Stanford University; University of California, Los Angeles; and Vanderbilt University Medical Center.

DRUG DEVELOPMENT FOR RARE DISEASES TAKES OFF

The global pharmaceutical industry is pouring billions of dollars into developing drugs for rare diseases. This is very good news for the families of infants diagnosed with rare diseases because, traditionally, drug makers were reluctant to pursue treatments for rare diseases, leaving those affected by these diseases with no effective treatments at all.

Most rare diseases cannot be cured, so the focus of research is on drugs and products that can alleviate the symptoms or slow the progression of the disease. Fortunately for patients and families, the industry is seeing a remarkable increase in the number of drugs for rare diseases reaching the market. Last year, the US Food and Drug Administration approved 17 new drugs for rare diseases, and hundreds more are in development. This increase has been largely fueled by legislation that makes it easier and more profitable for manufacturers to develop drugs for rare diseases. These incentives have reduced the cost of development, which, along with the high price tags on these drugs has allowed drug companies to realize profits from rare disease drugs even though the number of patients taking them is relatively small.

A CHILD WITH ONDINE'S CURSE AND AN OSCAR-NOMINATED FILM

You really must watch this 30-minute film, Our Curse, (http://www.nytimes.com/video/opinion/100000003489430/our-curse.htm). It is the story of a young Polish couple whose first child, Leo, was born with a rare disease called Ondine's Curse (congenital central hypoventilation syndrome). Every night when he goes to sleep, Leo must be put on a ventilator to prevent potentially fatal episodes of hypoventilation during sleep. The film covers the period of time from when Leo first comes home from the hospital, and how his parents cope with the possibility that Leo will require a ventilator throughout his life. Leo is adorable, and his parents are both courageous and terrified, as well as brutally honest about their feelings and their fears about Leo's future. The film was nominated for an Oscar.

Congenital central hypoventilation disorder (CCHD) is a rare neurorespiratory disorder caused by a mutation of the PHOX2B gene.1 Depending on the mutation, a range of severity in the phenotype for CCHD is possible. In the most severe form, the affected individual requires continuous mechanical ventilation. Individuals with CCHD rarely live beyond the age of 30 years.

1. Weese-Mayer DE, Marazia ML, Rand CM, Berry-Kravis EM. Congenital central hypoventilation syndrome. Gene Reviews. Updated January 30, 3014