|Overview of Rare Diseases Research Activities
NIDCD conducts and supports research and research training on normal mechanisms and diseases and disorders of hearing, balance, smell, taste, voice, speech, and language. This mission is achieved through a wide range of research performed in its own laboratories, a program of research grants, individual and institutional research training awards, career development awards, center grants, cooperative clinical trials, and contracts to public and private research institutions and organizations. The Institute also conducts and supports research and research training that is related to disease prevention and health promotion. NIDCD addresses special biomedical and behavioral problems associated with individuals who have communication impairments or disorders. NIDCD also supports efforts to create devices that substitute for lost and impaired sensory and communication functions.
Recent Scientific Advances in Rare Diseases Research
Mitochondrial Genes and Deafness
Mitochondria are specialized structures within cells that play a crucial role in metabolism and energy production. Mitochondria contain their own genes, which replicate during cell division. All of the mitochondria present in individuals are derived from the mother’s egg. Therefore, diseases that appear to be passed exclusively through the maternal lineage are often linked to defective mitochondrial genes.
NIDCD-supported scientists have identified several specific mitochondrial mutations that predispose an individual to hearing damage resulting from toxicity from the aminoglycoside class of antibiotics to the inner ear hair cells. These investigators have determined that genetic loci in the nucleus of the cell act to modify the effects of the mitochondrial mutations. Most recently, a specific gene was identified in mice that modulates the severity of mitochondrial deafness and is also implicated in age-related hearing loss. This mouse model will be extremely valuable for detailed studies of the molecular mechanisms by which mitochondrial mutations contribute to deafness. These findings could be used to develop genetic tests to determine whether an individual has an increased risk for aminoglycoside-induced hearing damage.
Usher syndrome (USH) is characterized by hearing loss and retinitis pigmentosa (RP). About 5 percent of individuals who are deaf have USH, and more than half of the deaf and blind individuals (>10,000) in the United States have USH. The severity of the hearing loss and the presence of vestibular dysfunction distinguish two major clinical subtypes of USH, types 1 and 2. Individuals who have USH type 1 are congenitally deaf and have a balance deficiency at birth, while RP has an onset at about the time of puberty. Individuals with USH type 2 are distinguished from USH type 1 in having a less severe hearing loss. A third form of USH (type 3) is characterized by progressive loss of hearing and retinal function. There are more than 11 different genes in which mutations can cause USH. NIDCD intramural scientists have identified and characterized some of the genes responsible for USH and two common mutations that cause USH in the Ashkenazi Jewish population. They have discovered that the genes for USH type 1D and type 1F both encode cell adhesion proteins cadherin 23 and protocadherin 15, respectively. In addition, several NIDCD-supported scientists reported cloning the gene for USH type 2A. The USH2A gene encodes a protein, Usherin, that has structures similar to other proteins involved in assembling cells and tissues into functional organs. NIDCD-supported scientists also have identified the genes responsible for Usher type 1C. These advances are critical steps toward developing strategies to treat this devastating disease that causes deafness and blindness.
Waardenburg Syndrome (WS) is an autosomal-dominant disorder that is characterized by pigmentary disturbances and deafness. NIDCD-supported scientists are seeking to determine the loci for WS type 2 by utilizing a high-density genome scan coupled with linkage analysis to identify candidate gene mutations that could be the cause of this disorder in three large, multigenerational families and several smaller families with WS2. Other scientists are studying the Dalmatian as an animal model for understanding the genetics of pigment-associated deafness in the dog and human. The relationship between pigmentation and deafness is not unique in Dalmatians and this model offers a unique opportunity to conduct genetic analysis of hereditary deafness.
A small but substantial number of individuals with bilateral hearing loss have normal cochlear function. These individuals have severely abnormal central neural processing of auditor sensory input as evidenced by poor or absent auditory brainstem responses. Standard treatment strategies for bilateral hearing loss, such as hearing aids, are of little use to these individuals. When this disorder strikes young children or infants, it can cause severe disruption of normal language and speech development. The most likely cause of hearing loss is a disorder of the auditory nerve, hence the term “auditory neuropathy.” This disorder is rare but more common than previously expected. Investigation of the physiologic mechanisms, the genetic basis, and possible treatments for this disorder is ongoing.
Endolymphatic Sac Tumors in von Hippel-Lindau Disease
NIDCD intramural scientists are studying individuals affected by von Hippel-Lindau (VHL) disease and tumors of the inner ear. These endolymphatic sac tumors (ELSTs) have been found to develop in approximately 10 percent of individuals carrying mutations of the VHL gene. Hearing loss, balance disturbances, and tinnitus represent the primary clinical manifestations of this disease. Recent molecular genetic studies have confirmed the phenotypic association of ELST with VHL disease by demonstrating loss of heterozygosity at the VHL locus in tumor cells obtained from surgical specimens. In a clinical trial to preserve hearing in individuals with early stage ELST, preliminary results have revealed that these tumors can be safely removed while preserving hearing at preoperative levels and maintaining or improving vestibular function.
Prospective studies of this population of individuals should provide insight into the natural history of hearing and balance disturbances associated with ELST, while basic investigations will focus on the mechanisms by which ELSTs cause dysfunction of hearing and balance.
Enlarged Vestibular Aqueduct
Enlarged vestibular aqueduct (EVA) is characterized by progressive childhood sensorineural hearing loss in association with enlarged vestibular aqueducts. Recent data indicate that at least some cases are associated with mutations in the Pendred syndrome gene (PDS). Individuals with Pendred syndrome have sensorineural deafness and goiter. NIDCD intramural scientists are working to identify the genetic basis of EVA, including several cases where it is clearly not caused by mutations in PDS. In addition, the role of congenital cytomegalovirus infection in this form of hearing loss is also being studied.
Stickler syndrome is a genetic disease affecting the connective tissues of organs throughout the body. Stickler syndrome can affect the inner ears, resulting in permanent sensorineural hearing loss. Studies on inner ears of normal mice as well as a mouse model for Stickler syndrome (the chondrodysplasia mouse) have been completed by NIDCD intramural scientists and reveal how and where mutations in fibrillar collagen genes cause hearing loss in Stickler syndrome. The mutations act to disrupt the functions of normal genes and their corresponding protein products in the tectorial or basilar membranes of the cochlea, where these genes are specifically expressed. This disruption of gene function likely causes hearing loss by disrupting the biomechanical properties of sound wave propagation within the cochlea.
Isolated deafness affects approximately 1 in 1,000 newborns and infants. Mutations in any one of nearly 100 genes can cause childhood deafness. NIDCD intramural scientists have recently identified several novel deafness genes through genetic mapping studies of large families with hereditary deafness from Pakistan and India. Identification of these genes increases our ability to diagnose hereditary deafness with molecular tests, and studies of their function in normal and pathologic states provide fundamental insights into normal hearing and the pathogenesis of hearing loss.
Pendred syndrome is a genetic disorder causing deafness in combination with, in some cases, enlargement (goiter) of the thyroid gland. Pendred syndrome is caused by mutations in the SLC26A4 gene. NIDCD intramural scientists have studied the genetic epidemiology of deafness (and thus Pendred syndrome) caused by SLC26A4 mutations in east and south Asia, which contain approximately one-half of the global population. In some populations, such as Koreans, SLC26A4 mutations are the most common known cause of deafness. In all studied populations, SLC26A4 mutations account for approximately 10 percent of all genetic deafness in childhood. This is a significant proportion, given that there are dozens of genes in which mutations can cause genetic deafness. This study also demonstrated that ethnic groups each have their own distinctive spectrum of mutations, with one or a few most prevalent mutations. These results have significant implications for the design and implementation of molecular genetic tests for childhood deafness.
Resistance to Thyroid Hormone
Resistance to thyroid hormone (RTH) is a genetic disease causing resistance of target tissues to the actions of circulating thyroid hormone. RTH is caused by dominant mutations in the gene encoding the thyroid hormone receptor beta subunit. Intramural scientists from NIDCD and the National Institute of Diabetes and Digestive and Kidney Diseases have demonstrated that some individuals with RTH develop permanent sensorineural hearing loss. A mouse model for RTH was generated at the NCI and used for studies of auditory function and structure by NIDCD scientists. The results indicate that RTH mutations cause hearing loss through dominant-negative effects upon one or more other genes. Other studies by NIDCD-sponsored scientists revealed that this other affected gene likely encodes the thyroid hormone receptor alpha subunit. The disruption of the functions of the thyroid hormone receptor alpha and beta genes by RTH mutations results in hearing loss due to retarded development of the neurosensory tissues of the inner ear, which are dependent upon thyroid hormone for normal development and function.
Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder that occurs in about 1 out of every 40,000 Americans. This mutation on chromosome 22 is strongly associated with the development of bilateral vestibular schwannomas, which then results in damage to both auditory nerves. Treatment of these acoustic neuromas often requires bilateral removal of the auditory nerves, which usually renders the individual deaf. Electrical stimulation of the residual neural pathways within the cochlear nucleus can provide a sense of hearing after this surgery. NIDCD-supported scientists are working to optimize the design of a neural implant used for electrical stimulation of the cochlear nucleus in these individuals, with the goal of providing a device equal in performance to the cochlear implant used in individuals with profound hearing loss.
Hereditary Cerebellar Ataxia Syndrome of Early Onset
Several abnormal genes that are associated with inherited cerebellar syndromes that cause disorders of balance and coordination have been identified. Relatively little is known about how different mutations lead to specific types of the disorder. There are typically great differences in the clinical signs and symptoms within families that segregate the same mutation and across families with mutations in the same gene. NIDCD-supported scientists have previously demonstrated linkage to chromosome 19p in four families with episodic vertigo and the inability to coordinate muscle movement (ataxia). The scientists have identified a missense mutation in the calcium channel gene on chromosome 19p in a family with severe progressive cerebellar ataxia of early onset involving the trunk, the limbs, and speech function.
NIDCD-supported scientists are investigating relationships between decreased olfactory function and a number of rare diseases. Studies have shown that olfactory loss appears to be among the first signs of common neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Recent psychophysical studies have evaluated the prevalence and magnitude of olfactory loss in subtypes of Parkinson’s disease, Down syndrome, schizophrenia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and the rare amyotrophic lateral sclerosis/Parkinsonism/dementia complex of Guam. Better understanding of the associations between olfactory function and rare diseases may lead to earlier diagnosis and improvement in monitoring of these rare diseases.
Kallmann syndrome is a rare genetic disorder with two main symptoms: an absence of the ability to smell and failure of the gonads to mature. There is a five- to seven-fold chance that this syndrome occurs in males in comparison to females, suggesting that the X-linked form of the disease is the most frequent. NIDCD-supported research has led to the identification of a common developmental defect in nerve migration, which links the two major disease symptoms. A unique family of proteins and their receptors that regulate nerve migration and direction during development are under investigation by NIDCD-supported scientists. Additional research is focused on isolating and cloning an X-linked gene responsible for Kallmann syndrome.
Carcinoma of the Vocal Tract
Cancers that occur in the mouth, throat, and vocal tract are less common than breast, prostate, or lung cancer but have a significant impact on voice, speech, and swallowing. There are approximately 40,000 new cases and 12,000 deaths each year and more than 320,000 survivors of head and neck cancer living in the United States. Approximately 80 percent of these cancers occur in persons who use tobacco and alcohol. A subset of tumors occurring in the tonsillar and adenoid areas have been associated with human papilloma viruses that also cause cervical cancer and Epstein-Barr virus that also causes mononucleosis. There is also an increased risk of this type of cancer in persons with Fanconi’s anemia, a rare inherited disorder in which there is increased susceptibility to DNA damage, anemia, and cancer. NIDCD intramural scientists are collaborating with molecular biologists and clinicians from the National Cancer Institute to address the molecular basis for the disease and possible new treatments. These tumors show an increased response to growth factors when compared to other cells. Specific intracellular signaling molecules that mediate this effect have been identified. In addition, these tumors produce factors that stimulate the blood supply and immune cells in ways that help promote tumor growth and spread. Drugs that block the effects of these signaling pathways and factors may provide new approaches for prevention and therapy of these cancers.
Velo-Cardio-Facial Syndrome/Di George Syndrome
Velo-cardio-facial syndrome (VCFS) is a disorder that has been associated with more 30 different features, the most common being cleft palate, heart defects, characteristic facial features, minor learning problems, and speech and feeding problems. VCFS is also known as Shprintzen, DiGeorge, cardiofacial, or conotruncal anomaly unusual face syndrome. These syndromes result from a large deletion at chromosome 22q11. VCFS is inherited in only about 10 percent to 15 percent of cases; however, in most instances, neither parent has the syndrome or carries the defective gene, and the cause of the deletion in the affected child is unknown. NIDCD-supported scientists have completed a detailed sequence analysis of the DiGeorge chromosomal region (DGCR) of chromosome 22q11. The 22q11.2 deletion occurs more frequently than originally anticipated, and the end points of the deletions occur in clusters. There is considerable variability in the abnormalities associated with deletions of similar size. The presence of a deletion is not always sufficient to cause cleft palate, strongly suggesting that modifier genes interact with the genes of the deletion region. Recent research has shown that the Clathrin heavy chain-like gene is a strong candidate gene for VCFS.
Rare Disease-specific Scientific Conferences, Symposia, and Meetings
On June 16–17, 2003, the NIDCD conducted a workshop on “Neurological Motor Speech Disorders in Adults: Research Needs and Opportunities,” to discuss neuroimaging in speech production disorders, central neural control of speech production, and how speech can be better assessed in neurological disease. The NIH Office of Rare Diseases co-sponsored the workshop.