National Institute of Neurological Disorders and Stroke
Overview of NINDS Rare Diseases in Children Research Activities, FY 2000FY 2005
NINDS conducts and supports research on the causes, diagnosis, treatment, and prevention of hundreds of
disorders that affect the nervous system. Many of these disorders are caused by rare genetic mutations that
produce symptoms appearing very early in life. As a result, thousands of children are impaired by motor dysfunction, cognitive problems, seizures, and other serious effects of their neurological conditions.
Without effective treatment, a great number of these children will not survive into adulthood, and those who
do will continue to experience debilitating symptoms of the disorder throughout their lives.
As many of the diseases studied by NINDS are rare disorders, and many of these conditions affect children,
the following highlights represent only a snapshot of the involvement of NINDS in this area of research.
Recent Scientific Advances in Rare Diseases in Children Research
Duchenne's Muscular Dystrophy (DMD)
DMD is the most common form of childhood muscular dystrophy, affecting 1 in 3,500 boys, with a
prevalence in the United States of 10,000. In DMD, a mutation in the gene that codes for dystrophin (a
large muscle protein) leads to progressive degeneration of muscle beginning within the first few years of
life. No treatment has been identified that can stop the muscle degeneration, and affected children typically
die of respiratory or cardiac failure by their teens or early twenties. In approximately 15% of individuals with DMD, the mutation is a premature stop codon, an incorrect "code word" in the gene that causes the protein-synthesizing machinery of the cell to halt, resulting in the absence of dystrophin.
For several years scientists have known that specific antibiotics cause misreading of the genetic code and
can sometimes suppress premature stop codons by causing the protein synthesizing machinery to misread
the stop, insert another amino acid protein building block, and continue. In 1999, a team of scientists supported by NIAMS and NINDS developed an antibiotic treatment approach for DMD, first evaluating the therapy in cultured muscle cells and then in live mice with a mutation similar to that which causes DMD in humans. Following treatment with gentamicin, skeletal muscle cells of these mice expressed dystrophin at about 10% to 20% of normal levels, and tests showed that these levels restored muscle strength to that present in normal mice and protected muscle cells against degeneration.
The treatment approach has recently been evaluated in clinical trials to evaluate its effectiveness in
improving the function of the 15% of boys with DMD whose genetic defect is a premature stop codon.
Unfortunately, the results from the initial trial did not show increased dystrophin levels after two weeks of
gentamicin treatment. Indicators of muscle breakdown were reduced in the subjects, however, making these antibiotics an important line of investigation to continue. The results of the gentamicin clinical trial (February through September 2000) were published in April 2001 in the
Annals of Neurology.
Batten disease, the juvenile form of a group of disorders called neuronal ceroid lipofuscinoses (NCLs), is a
fatal, inherited disease of the nervous system that begins in childhood. Early symptoms usually appear between the ages of 5 and 10, when a previously normal child begins to develop vision problems or seizures. Over time, affected children suffer mental impairment, worsening seizures, and progressive loss
of sight and motor skills. Eventually, children with Batten disease become blind, bedridden, and demented,
and the disease is often fatal by the late teens or twenties. Batten is caused by mutations in enzymes that are necessary for the normal breakdown of fats, sugars, and proteins inside the cell. As a result, these materials accumulate in the brain and elsewhere in the body, which leads to the characteristic effects on cognition and behavior.
NINDS currently funds several projects relevant to Batten disease and late infantile NCL, a closely related
disorder. These studies are examining issues such as the molecular basis for the neuronal degeneration that
occurs in Batten and related diseases, and the potential use of therapeutic agents to reduce the cell death that occurs in both the brain and the retina in association with the disease. Several of these studies are funded through FY 2003 and FY 2004.
Fabry disease is the second most common type of inherited metabolic storage disease. The disorder
typically first appears during childhood or adolescence with recurrent episodes of severe pain in the
extremities, characteristic skin lesions, and effects on the cornea. Several years ago researchers determined
that the disease is caused by insufficient activity of the enzyme a-galactosidase A that normally degrades a lipid (fatty substance) called globotriaosylceramide. Without adequate enzyme activity, this lipid accumulates throughout the body, damaging the kidneys, heart, and blood vessels of the brain, causing death by the fourth or fifth decade. In the past, NINDS intramural scientists successfully isolated the critical enzyme from placental tissue, and showed that administration of the enzyme to individuals with Fabry disease reduced the levels of globotriaosylceramide in the blood. Lack of sufficient enzyme quantities hampered further tests. To overcome this limitation, scientists developed a procedure to prepare
the enzyme using DNA technology and human cells in culture. With adequate supplies of enzyme in hand,
researchers at NINDS conducted a phase I safety and dose-escalation clinical trial showing that enzyme therapy was safe and that it reduced globotriaosylceramide in the liver, blood, and urine. Moreover, several of the patients were able to permanently discontinue the medications they were taking for the pains
in their hands and feet. This trial provided the basis for a double-blind placebo-controlled phase II clinical
efficacy trial of enzyme replacement therapy in Fabry disease that recently confirmed the reduction of pain
in the hands and feet in subjects, as well as improvements in kidney and heart function. Results of this trial
(conducted FY 1999 through FY 2000) were reported in the
Journal of the American Medical Association
(JAMA) in June 2001.
Canavan disease is a rare, inherited neurological disorder characterized by spongy degeneration of the brain
(in which the white matter is replaced by microscopic fluid-filled spaces). Symptoms of Canavan disease,
which appear in early infancy and progress rapidly, may include mental retardation, loss of previously acquired motor skills, feeding difficulties, abnormal muscle tone (i.e., floppiness or stiffness), poor head control, and megalocephaly (abnormally enlarged head). Paralysis, blindness, or hearing loss
may also occur. The disease is not currently treatable, and death usually occurs by age four. Canavan
disease is one of a group of genetic disorders called the leukodystrophies that affect growth of the myelin
sheath of nerve fibers in the brain. The fatty myelin covering normally acts as an electrical insulator and is
essential for proper nerve cell function.
Canavan disease is caused by inherited defects in the enzyme aspartoacylase (ASPA) encoded by the gene
which was discovered in 1993. An important focus for Canavan disease research has been the effort
to develop a mouse model that carries this genetic mutation. A NINDS-supported scientist recently succeeded in creating a genetically engineered mouse model of Canavan disease, and results were published
in early 2000. Funding for this project has been approved through FY 2002, and it is anticipated that this model will enable researchers to study how the gene defects harm the brain. The model will also be crucial
for developing enzyme and gene therapy.
Friedreich's Ataxia (FRDA)
the most common hereditary ataxia (disorder characterized by a loss of coordinated movement), is
a progressive disease that impacts the nervous system, the heart, and the pancreas. The disease affects about 1 in 50,000 persons, or several thousand individuals in the United States. Loss of coordination, an unsteady gait, slurred speech, and other symptoms usually appear between the ages of 5 and 15 years.
Eventually, most affected children experience an enlargement of the heart and progressive loss of muscle
control, leading to motor incapacitation and wheelchair confinement. Most young people with this disease
die in early adulthood.
The defective gene causing
identified in 1996, codes for a previously unknown protein called
frataxin. This is the first triplet-repeat expansion implicated in an autosomal recessive disorder. The repeat,
GAA in a non-coding region, causes too little frataxin to be made. A mitochondrial frataxin-like protein in
yeast regulates iron metabolism, and following that lead, iron metabolism has been implicated in the human
At a recent international scientific workshop on
co-hosted by NINDS, French investigators reported
promising preliminary research results from a study of the drug compound idebenone. Idebenone was developed as a neuroprotective antioxidant for treatment of stroke and dementia but did not show efficacy in these uses. The French study was based on the hypothesis that the drug acts on iron metabolism pathways in
a subclass of oxidative metabolism for which an effect of idebenone might be achieved. The research results were sufficiently encouraging in reducing cardiomyopathy in
that NINDS plans to initiate a study to determine the effectiveness of idebenone in the treatment of the disease.
Sufficient supplies of the drug have been secured, and an Investigational New Drug (IND) application for a
phase I dose-escalation trial is currently being prepared for submission to the FDA.
NINDS is also supporting research targeted to understanding the normal cellular function of frataxin, the
molecular effects of GAA repeats on gene expression, and how mutations in frataxin lead to the pathological changes associated with the disease. Other studies also involve the development of an animal
by disrupting expression of the frataxin gene. These studies are currently funded through
FY 2002/FY 2003.
Ataxia telangiectasia is an inherited disorder that causes progressive movement problems beginning usually
between one and two years of age. In addition to loss of certain brain cells, children with this disease often
suffer immune deficiency, increased likelihood of cancer, and abnormally high sensitivity to radiation.
Most children are severely disabled by age 10, and many develop cancer. The disease is fatal, typically
resulting in death in the second or third decade. Each year about 500 people inherit damaged copies of the
relevant gene from both parents, and thus the disease ataxia telangiectasia. In 1995, scientists identified the
gene which, when defective, causes ataxia telangiectasia. Subsequent study has revealed that the normal
gene helps prevent a cell from becoming cancerous when its DNA is damaged.
One study currently funded by NINDS through FY 2003 is exploring the mechanism underlying the
increased sensitivity of individuals with ataxia telangiectasia to DNA-damaging agents, such as ultraviolet
and infrared radiation. It is anticipated that this information will assist in understanding the affected individuals' susceptibility to cancer and in developing treatments for the disorder. Another project, funded
through FY 2002, involves the large-scale analysis of DNA defects in ataxia telangiectasia patients, in order to better understand how specific mutations in the
gene lead to individual disease symptoms. It
is also hoped that this knowledge will assist in the design of effective therapies.
Rett syndrome is a severely disabling neurodevelopmental disorder that affects 1 in 10,000 to 15,000
females. Development is apparently normal until age 6-18 months. Diagnostic criteria include impaired
expressive and receptive language, loss of acquired purposeful hand skills, and repetitive hand movements.
Rett syndrome is often misdiagnosed as autism or cerebral palsy.
The genetic abnormality responsible for Rett syndrome interferes with the operation of one of the many
biochemical switches that regulate how genes are expressed. Specifically, the disorder results from the
mutation of the gene that makes methyl cytosine binding protein 2 (MECP2). MECP2 is the lynchpin in
one of the elaborate networks of proteins needed to switch off a group of genes. In the absence of this genetic switch, certain genes fail to shut down, and excessive amounts of otherwise beneficial proteins are
made. The molecular events leading to the children's decline in their second year of life can be explained
by the over-expression of specific genes that govern the development of the nervous system.
NINDS is currently supporting research on this syndrome that involves the use of cultured olfactory
neurons biopsied from Rett patients as a model for understanding the molecular and cellular changes that
lead to the degeneration of these neurons (funded through FY 2005).
Another NINDS-funded study involves extending previously conducted gene mapping studies as a step
toward characterization of both the gene and the protein that are responsible for this disorder (funded through FY 2002).
Hutchinson-Gilford Progeria Syndrome
Hutchinson-Gilford progeria syndrome
is an exceedingly rare disease that causes premature aging in
children. A number of NIH Institutes are committed to enhancing research in this area. To this end, staff
from NINDS, along with NHLBI, NICHD, NIAMS, ORD, and NIA, are working together to organize a scientific workshop on this form of progeria, planned for fall 2001. It is expected that this meeting will assist individual Institutes in identifying promising lines of investigation in this field and in stimulating research on this disorder.
Other Rare Diseases in Children
In addition to the disorders listed above, NINDS is extremely interested in many other rare diseases that
affect children. This list includes (but is not limited to): fragile X syndrome, a disease similar to
that it is caused by expanded repeats of nucleotide sequences; Sturge-Weber syndrome, a congenital, non-familial disorder of vascular development that can affect the nervous system; disorders caused by mutations in Chromosome 18; and holoprosencephaly, a severe neurological birth defect caused by the failure of the cerebral hemispheres to separate into distinct left and right sides during development.
Ongoing, New, and Planned Research Initiatives in Rare Diseases in Children
Program Actions on Rare Diseases in Children
"Rett Syndrome: Genetics, Pathophysiology, and Biomarkers" (PAS-99-037, revised as NOT-HD-00-001,
jointly with NICHD, released 1/18/2000).
"Exploratory Grant in Pediatric Brain Disorders: Integrating the Science" (PAS-99-080, revised as
NOT-NS-00-009, jointly with NICHD, NIMH, released 7/14/2000) includes
Batten disease, DMD, fragile X syndrome, Sturge-Weber syndrome, holoprosencephaly, and many others.
"Development of Innovative Treatment Approaches to Autism" (RFA-MH-01-010, jointly with NIMH,
NICHD, and NIDCD, released 11/29/2000) includes Rett syndrome.
"Research on Autism and Autism Spectrum Disorders" (PA-01-051, jointly with NIDCD, NIMH, NICHD,
NIEHS, released 2/13/01) includes Rett syndrome.
Workshops and Meetings
The workshops/meetings sponsored by NINDS on rare diseases in children are often joint ventures with
other NIH Institutes and frequently involve the participation of outside disease advocacy organizations.
The following list provides information about the topics of workshops held in FY 2000 and those planned
for the upcoming year.
"Brain Fatty Acid Uptake, Utilization and Relevance to PB," held March 2-4, 2000; jointly sponsored by
NINDS, NIDDK, NICHD, and ORD.
"Symposium on Hereditary Spastic Paraplegia," held March 16-18, 2000; jointly sponsored by NINDS,
NICHD, and ORD.
"Conference on Cause and Treatment of FSH Dystrophy," held May 8-9, 2000; jointly sponsored by
NINDS, NIAMS, and ORD.
"Workshop on Therapeutic Approaches for Duchenne's Muscular Dystrophy," held May 15-16, 2000;
jointly sponsored by NINDS, NIAMS, and ORD.
"First Scientific Workshop of Hallervorden-Spatz Syndrome," held May 19-20, 2001; jointly sponsored by
NINDS, NICHD, and ORD.
"Cerebral Blood Flow and Development Metabolism," held June 8-11, 2000; sponsored by NINDS.
"The Olfactory Model System and Rett and Kallmann Syndromes: Sniffing Out Insights into Brain
Development," held September 12, 2000; jointly sponsored by NINDS, ORD, NIDCD, NIMH, and
"International Conference on the Neuronal-Lipofuscinosis," held September 20-24, 2000; jointly sponsored
by NINDS, NIDDK, and NICHD.
"Gene Therapy for Neurological Disorders," held October 23-24, 2000; jointly sponsored by NINDS and
ORD. [Gene therapy for metabolic storage disorders, such as Batten and Fabry disease, were a focus of the
"From Gene to Function in Dystonia," held January 19-21, 2001; sponsored by NINDS.
"Hypertonic Movement Disorders Workshop," to be held April 22-24, 2001; jointly sponsored by NINDS
and ORD. [Relevant to disorders in children that cause increased muscle tone, leading to rigidity, spasticity, and dystonia]
"Strategies for Therapy of MPS and Related Diseases," to be held June 21-24, 2001; jointly sponsored by
NINDS, NIDDK, and NICHD.
"2001 CAG Triplet Repeat Disorders," a Gordon Conference, to be held July 15-19, 2001; jointly
sponsored by NINDS and NIA.
"Mucolipin, TRPs and Human Disease," September 8-10, 2001; jointly sponsored by NINDS, NIDDK,
NICHD, NIMH, and ORD.
"Fourth International Dystonia Symposium," to be held September 20-23, 2001; jointly sponsored by
NINDS, NIA, NIAMS, and ORD.
"Neurobiology of Disease in Children Conferences," to be held October 17, 2001; jointly sponsored by
NINDS, NIAMS, NICHD, and NIMH.
In addition to these meetings, a workshop on pediatric neurotransmitter diseases
is planned for 2002.