Spinal Muscular Atrophy in the Neonate Jennifer A. Markowitz, Mindy B. Tinkle, and Kenneth H. Fischbeck

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1 PRINCIPLES & PRACTICE Spinal Muscular Atrophy in the Neonate Jennifer A. Markowitz, Mindy B. Tinkle, and Kenneth H. Fischbeck Spinal muscular atrophy (SMA) type I is an autosomal recessive disorder characterized by loss of lower motor neurons in the spinal cord. This severe hereditary neurodegenerative disorder is an important cause of morbidity in the neonate and the leading hereditary cause of infant mortality. The characteristic degeneration of anterior horn cells in the spinal cord leads to progressive muscular weakness and atrophy of the skeletal muscles. In SMA type I, the most severe form of SMA, death usually ensues by 2 years of age from respiratory failure or infection. Accurate diagnosis is now available through genetic testing, and progress is being made toward the development of therapy based on understanding of the disease mechanism. The neonatal nurse plays a pivotal role in identifying and caring for these medically fragile infants and in providing support and education for parents and families. JOGNN, 33, 12-20; DOI: / Keywords: End of life care Genetic disorders in the neonate Spinal muscular atrophy Accepted: March 2003 A 27-year-old woman (gravida 1, para 0) had an uneventful pregnancy until she noticed decreased fetal movement at 32 weeks. Her fetus was small for gestational age. Stress tests were inconclusive, and there were no maternal serum or ultrasound abnormalities. Labor was induced at 38 weeks, and the delivery was complicated by a nuchal cord. The infant took several seconds to begin breathing following clamping of the cord, after which he was admitted to the neonatal intensive-care unit (NICU), where he received oxygen. The NICU staff noted that he was floppy and had a chest deformity consistent with respiratory muscle weakness. He was transferred to a local tertiary care center and in transit required intubation. Over the next 2 weeks, his breathing improved with respiratory therapy; at one point, he was weaned from the ventilator and switched to nasal continuous positive airway pressure (CPAP). He had a bright and alert disposition. His suck was weak, his tongue appeared tremulous, and he required nasogastric feeding. Geneticists and neurologists evaluated the patient; after electromyography, muscle biopsy, and a blood sample for DNA testing, he was diagnosed as having spinal muscular atrophy, type I. Although he appeared to improve, at 23 days he developed pneumonia and could not be resuscitated. The underlying cause of this infant s neuromuscular disorder, spinal muscular atrophy (SMA), is deletion of a segment of DNA on chromosome 5. SMA is characterized by progressive weakness and hypotonia resulting from degeneration of the lower motor neurons in the spinal cord. It is the most common hereditary cause of infant mortality, with an incidence estimated at 1 in 10,000 (Nicole, Diaz, Frugier, & Melki, 2002; Ogino, Leonard, Rennert, Ewens, & Wilson, 2002) and a worldwide carrier frequency of between 1 in 50 and 1 in 200 (Coovert et al., 1997; Cusco et al., 2002; Emery, 1991; Wirth et al., 1999). The disease is classified according to age of onset, severity of symptoms, and life expectancy. Type I SMA, or Werdnig-Hoffmann disease, is defined by onset of symptoms before 6 months of age, with inability to sit, and survival is usually less than 2 years. Type II or intermediate SMA is characterized by onset before age 18 months; these patients are able to sit but not walk, and with appropriate supportive care may survive 12 JOGNN Volume 33, Number 1

2 into adulthood. Type III SMA, or Kugelberg Welander disease, is the least severe clinically, with ability to walk and onset in childhood or adolescence; these patients may have a normal life expectancy (Nicole et al., 2002; Schmalbruch & Hasse, 2001; Volpe, 2000). As shown in Table 1, SMA is one in a spectrum of muscle and nerve disorders that affect infants and young children. This overview focuses on the most severe form of SMA, type I, which may present in the neonatal period and pose diagnostic, ethical, and management challenges to the neonatal nurse. The clinical and genetic features of this disease are discussed, followed by current approaches to management and promising strategies for therapeutic development. Clinical Features of Spinal Muscular Atrophy SMA was first described in the 1890s by Guido Werdnig of the University of Vienna and Johann Hoffmann of Heidelberg University. Their papers presented the clinical and pathological aspects of infantile SMA, including early onset, occurrence among siblings of normal parents, progressive weakness, hand tremor, and death from respiratory failure in early childhood (as cited in Iannaccone, 1998). Since the syndrome was first described, there has been debate about how to categorize different forms of SMA. The current nomenclature of SMA types I, II, and III was developed by international consensus (Munsat & Davies, 1992) and continues to provide clinical utility, although the boundaries between these SMA types are arbitrary and the disease actually has a continuous range of clinical severity. The cardinal symptom of all forms of SMA is weakness. The weakness is due to loss of motor neurons in the anterior horn of the spinal cord (see Figure 1). When the motor neurons are lost, the skeletal muscles that they innervate become weakened and atrophy. Severely denervated muscles may preserve a few residual motor units (consisting of individual motor neurons and the muscle fibers they innervate). The remaining motor units may fire off sporadically to produce twitching (fasciculation) particularly of the tongue and fingers, a finding often used in diagnosis. Although SMA patients have profound motor deficits, sensation usually remains intact (Crawford, 2002). Type I SMA usually presents at birth or in early infancy. Mothers of infants affected with SMA type I often report a decrease in fetal movements during the 3rd trimester, which indicates that the process of motor neuron loss may begin in utero (Fidzianska & Rafalowska, 2002; MacLeod, Taylor, Lunt, Mathew, & Robb, 1999). At birth, the newborn with SMA may require ventilatory support. Although diaphragmatic strength is generally intact, intercostal weakness can be prominent, resulting in a restrictive lung deficit. A bell-shaped deformity of the chest is typical. Affected infants have truncal and limb hypotonia and are profoundly weak, with the proximal muscles affected more than distal, and legs affected more than arms (see Figure 2). A neonate presenting with SMA may have little voluntary movement of the extremities, even in the fingers and toes. In severe cases, infants with SMA may be born with arthrogryposis multiplex congenita, in which the extremities are deformed by congenital joint contractures (Bingham et al., 1997; Falsaperla et al., 2001). This condition has multiple causes other than SMA, all of which produce decreased fetal movement. In contrast to the extremities, the muscles of facial expression are relatively spared. Indeed, these infants typically appear bright and alert. However, weakness does affect the tongue and the facial muscles involved in feeding. Tongue twitching (fasciculation) is a common sign at diagnosis, as is a poor suck. Such infants are at high risk for failure to thrive, in which case tube feedings may be considered (Crawford, 2002). Severely affected infants have persistent head lag and are never able to sit. Prognosis is very poor, and newborns who present with SMA at birth may survive only 1 month, succumbing to respiratory infection or aspiration. Infants presenting later, but before 6 months, generally live between 1 and 2 years (DeVriendt et al., 1996; Volpe, 2000). This poor outcome points to the difficult ethical decisions that can arise regarding supportive and lifeextending care for these children. Other end-of-life issues such as psychosocial needs of parents and siblings, coordination of care, availability of support services, and bereavement are all integral to caring for these newborns and their families. Genetics of SMA SMA results from deletions and other mutations affecting the survival motor neuron (SMN1) gene on chromosome 5. It is an autosomal recessive condition, and in most cases, affected individuals have inherited a gene deletion from each parent. Therefore, most SMA patients are homozygous for SMN1 deletions. The parents each have one normal (or wild type) copy of the gene and one mutant copy. Although they carry the mutation, they are clinically normal. With every pregnancy, there is a 25% chance that the child will inherit both copies of the mutant gene and be affected with SMA, a 50% chance the child will inherit one copy of the mutant gene and one normal copy (making him or her a heterozygous carrier), and a 25% chance that the child will inherit two normal copies of the gene. Approximately 1 in 50 to 1 in 200 people worldwide carry a mutation of the SMN1 gene. Because the disease is autosomal recessive, there is usually no prior family history of SMA. January/February 2004 JOGNN 13

3 TABLE 1 Inherited Progressive Nerve and Muscle Disorders Affecting Infants and Children Mode of Type Age at Onset Inheritance Clinical Features Progression I. Motor Neuron Disorders Spinal Muscular Before birth to Autosomal Generalized muscle Progresses rapidly; Atrophy Type 1 6 months recessive weakness, no independent death usually by age 2 sitting Spinal Muscular 6 to 18 months Autosomal Muscle weakness but many Variable; most survive Atrophy Type 2 recessive sit independently to 2nd or 3rd decade Spinal Muscular Childhood to Autosomal Some muscle weakness, Slow progression with Atrophy Type 3 adolescence recessive but most ambulate normal lifespan independently II. Muscle Disorders Duchenne s Muscular Early childhood. X-linked Generalized muscle weakness Slow progression; Dystrophy 2 to 6 years recessive and wasting of proximal survival rare beyond (Females are muscles; pseudohypertrophy late 20s carriers) of calf muscles Becker Muscular Adolescence or X-linked Similar to Duchenne s Variable; survival mid Dystrophy young adulthood recessive but much less severe to late adulthood. (Females are carriers) Myotonic Dystrophy Childhood to Autosomal Myotonia, muscle wasting Slow progression in middle age; dominant of face, feet and hands adult form; fatal in Congenital form first; Congenital form about half of infants present at birth particularly severe with congenital form III. Neuromuscular Junction Disorders Congenital Myasthenic Birth to childhood Autosomal Muscle weakness, often in Variable; weakness Syndromes recessive muscles of eyes and face, can fluctuate and general fatigue; more severe symptoms with onset in infancy IV. Peripheral Nerve Disorders Charcot-Marie-Tooth Childhood to Autosomal Progressive muscle weakness; Slow but variable Disease (Type 1A) young adulthood dominant muscle wasting in the progression; normal hands and legs and mild lifespan sensory impairment; hyporeflexia The genetics of SMA are somewhat more complex than other autosomal recessive diseases. The SMN1 gene is normally present in two copies on chromosome 5, arranged as an inverted duplication (see Figure 3). One copy, SMN1, is closer to the telomeric end of the chromosome; this produces the majority of functional SMN protein and is deleted in 95% of SMA patients. The deletion usually involves two important portions of the gene, exons 7 and 8, with the result that no SMN protein is produced (Battaglia, Princivalle, Forti, Lizier, & Zeviani, 1997; Burglen et al., 1996). The other copy, SMN2, is closer to the centromere of the chromosome. It differs 14 JOGNN Volume 33, Number 1

4 Spinal Cord Muscle fiber Chromosome 5 Spinal motor neuron centromere degenerates in SMA Nerve fiber SMN SMN2 SMN1 FIGURE 1 Motor neurons in the anterior horn of the spinal cord degenerate in spinal muscular atrophy. telomere FIGURE 3 The SMN gene is normally present in two copies, SMN1 and SMN2, on chromosome 5. consistently by only one nucleotide from SMN1, but this alters the way the RNA is processed or spliced, so that only a small proportion of its product is full-length, functional SMN protein (Lorson, Hahnen, Androphy, & Wirth, 1999). Thus, patients with SMA must rely on the smaller amount of SMN protein that the SMN2 gene can produce (Lorson & Androphy, 2000). Importantly, there is variability in the number of copies of SMN2 in the normal population, and some individuals have more than one copy of this gene on chromosome 5. Because the level of SMN protein is inversely correlated with severity of disease, patients with more copies of SMN2 are less severely affected (Brahe, 2000). The SMN protein is relatively abundant in all cells, with the highest levels in the brain, spinal cord, and kidney (Burlet et al., 1998; Coovert et al., 1997). It plays a role in the assembly of macromolecular complexes called spliceosomes, which are responsible for mrna processing (Pellizzoni, Kataoka, Charroux, & Dreyfuss, 1998; Terns & Terns, 2001). Animal studies have shown that minimal levels of the SMN protein are required for survival; complete disruption of the SMN gene is embryonic lethal in mice (Hsieh-Li et al., 2000; Monani et al., 2000). In humans, SMN2 appears to be required for the survival of a fetus once the SMN1 gene is lost (Crawford, 2002). However, it is not known why low levels of SMN are particularly deleterious to motor neurons. FIGURE 2 Infant with spinal muscular atrophy, exhibiting hypotomia and head lag. Note. From Medical Disorders in Children by V. Dubowitz, 1978, p W.B. Sanders, Philadelphia. Reprinted with permission. Diagnosis Diagnosing an Affected Newborn When there are clinical grounds for suspecting a diagnosis of SMA in a newborn, confirmation can be made by January/February 2004 JOGNN 15

5 Control (2 SMN1) SMA (0 SMN1) Carrier (1 SMN1) SMN1 SMN2 decreased number of functioning lower motor neurons. An infant with SMA will have EMG findings indicative of denervation, whereas nerve conduction studies may show decreased motor amplitude. Sensory amplitude is normal in most affected infants, but severely affected newborns may have sensory abnormalities. Muscle biopsy may be nondiagnostic early in the disease, although infants with severe weakness exhibit features of denervation, with many small muscle fibers (Crawford, 2002) FIGURE 4 Spinal muscular atrophy mutation analysis by PCR. The control PCR represents an unaffected individual who has 2 normal copies of SMN1 (homozygous wildtype). Patient 2 demonstrates homozygous deletions of SMN1 and is therefore affected with SMA. Patient 3 has only one copy of SMN1 (note the reduced PCR reaction or SMN1 "dosage") and is a carrier (a heterozyote). a DNA-based test for the homozygous SMN1 exon 7 deletion (Scheffer, Cobben, Matthijs, & Wirth, 2001). Polymerase chain reaction (PCR) technique is used to amplify the DNA of exon 7 from both the SMN1 and SMN2 genes. The PCR products are then digested with a restriction enzyme (i.e., an enzyme that cuts DNA at specific sites). Because of the difference in the base sequences of the two SMN genes, the enzyme cuts the SMN2 PCR product into two pieces but does not cut the SMN1 PCR product. The digested PCR products are then separated by size on a DNA electrophoresis gel and examined (see Figure 4). Intact SMN1 PCR product is absent in 95% of individuals with SMA, and this is diagnostic for the disease. The test is rapid, reliable, and relatively inexpensive, and it makes more invasive and painful procedures, such as muscle biopsy, unnecessary. Approximately 5% of individuals with SMA do not have homozygous SMN1 deletions and will thus be missed by the test described above. Nearly all of these affected individuals (95% to 96%) are compound heterozygotes, having an SMN1 deletion on one chromosome and a point mutation or other nondeletion mutation on the other chromosome 5 (Scheffer et al., 2001). Quantitative PCR analysis of SMN1 exon 7 can be used in these cases to determine whether the patient has one copy of SMN1 exon 7; if so, mutation analysis for one of the 23 different known mutations can be performed (Wirth, 2000). As many as 2% of individuals with SMA have a de novo mutation; that is, they have a new SMN1 mutation that is not detectable in samples from the parents (Wirth et al., 1997). Other diagnostic studies may include electromyography (EMG), nerve conduction studies, and muscle biopsy. These studies show abnormalities consistent with the Carrier Testing and Prenatal Diagnosis DNA-based tests may be of value to family members of an affected child, as the quantitative SMN1 deletion test can be used to determine if relatives are carrying this deletion (Cusco et al., 2002). However, there are limitations to carrier testing. For example, about 4% of people have two or more copies of SMN1 on the same chromosome (Wirth, 2000). A person carrying the SMN1 gene deletion on one chromosome, but two SMN1 genes on the other, might be falsely reassured by the quantitative test, in that the test cannot detect whether the two SMN1 copies are on the same or different chromosomes. Whereas current clinically accessible testing methods have limitations, newer PCR techniques now under investigation may eventually allow SMA carrier screening for the general population (Falsaperla et al., 2001; Feldkotter, Schwarzer, Wirth, Wienker, & Wirth, 2002; Semprini et al., 2001). In addition to its use in carrier detection, the available genetic test may be applied to prenatal diagnosis. This is done by directly testing the fetal DNA obtained from chorionic villus sampling or amniocentesis samples for homozygous SMN1 deletion (Milunsky & Cheney, 1999). Most couples currently seeking prenatal diagnosis for SMA have had a child or other family member affected by the disease. Identification of a homozygous deletion in an affected family member further increases the predictive value of the fetal DNA test. If there is a nondeletion mutation in the family, other testing methods may be required for assessing the fetus s risk of SMA. In either case, if chorionic villus sampling is the method chosen to acquire fetal cells, the possibility of maternal cell contamination must always be considered when interpreting the test results. Although prenatal diagnosis is offered most often in the context of a positive family history for SMA, it may be appropriate in other instances. There are limited data indicating that subtle findings may be evident prenatally in severe cases of SMA type I. In addition to maternal reports of decreased fetal movements, Stiller et al. (1999) stated that ultrasound examination findings may be suggestive as early as 10 to 14 weeks gestation. These researchers presented a case of increased nuchal translucency in a fetus, later diagnosed with SMA at birth, and they pointed to five other cases in the literature in which 16 JOGNN Volume 33, Number 1

6 infants born with severe SMA exhibited this ultrasound finding. Although increased nuchal translucency is not specific for SMA, it was suggested that following an analysis in which chromosomes are found to be normal, SMA testing may be of value, in addition to targeted ultrasound and fetal echocardiography. DNA-based testing may also extend to other reproductive options for couples at risk for transmitting SMA, including preimplantation genetic diagnosis (PGD) or donor gamete carrier screening (Jones & Fallon, 2001). In PGD, in which the assisted reproductive technique of in vitro fertilization is used, DNA testing is performed on cells of the embryo at the five- to eight-cell stage and only nonaffected embryos are used for transfer. This approach has been found to be highly accurate in several recent studies (Daniels et al., 2001; Dreesen et al., 1998). Management and Therapeutics Management Issues There is no cure for spinal muscular atrophy; current treatment is supportive. Infants with SMA require intensive supportive care to manage secretions and atelectasis because they are at high risk of aspiration and respiratory failure. Infants with SMA often develop feeding problems due to a weak suck; gastrostomy tube placement may be necessary to maintain nutrition. Hypokinesia necessitates frequent turning and careful positioning to minimize skin breakdown and development of contractures. Families with an affected infant need emotional support as they cope with the child s illness and face difficult decisions about the infant s care. The prognosis is poor for neonates with SMA type I; 75% die by the age of 1 year, 95% by age 2. There is a tendency for the weakness to stabilize over time, but for the affected neonate this may mean stabilization in a state TABLE 2 Resources for Families and Health Care Providers Families of Spinal P.O. Box 196 Muscular Atrophy Libertyville, IL (800) Fax (847) Andrew s Buddies P.O. Box 785 Richmond, VA (804) Fax (804) Genetic Alliance, Inc Connecticut Ave., NW, Suite 404 Washington, DC (202) Fax (202) Muscular Dystrophy 3300 East Sunrise Drive Association-USA Tucson, AZ (800) Online Mendelian Inheritance in Man entry # (OMIM) Gene Reviews NCBI Genes and Disease Web page SMA.html Investigations of promising treatments are aimed at finding drugs that increase the expression of SMN2, a gene that remains intact in spinal muscular atrophy. of profound limb weakness with severe impairment of intercostal and bulbar strength (Crawford, 2002). Families with an affected neonate and the caregivers may need to make difficult ethical decisions regarding prolongation of life with ventilation and tube feeding. Issues such as the infant s quality of life and the high burden of care must be considered, as well as the ethical values and needs of the family. Such decisions require a sensitive and often delicate collaboration between families, neonatal nurses, social workers, physicians, and others. In the NICU, the neonatal nurse plays a key role in integrating the family into the care of the neonate with SMA. Assessment of the family members needs and resources is critical to providing supportive care. Families require accurate and specific medical and genetic information about their infant s condition. The nurse must be prepared with knowledge about this genetic condition and community resources to participate fully in the education process. Table 2 provides a list of information and January/February 2004 JOGNN 17

7 Mutations are responsible for spinal muscular atrophy, and accurate genetic testing for this condition is now available. support resources related to SMA that may be appropriate for health care professionals and family members. The genetic nature of SMA may impose several unique challenges for families. Because SMA is an autosomal recessive disease, families may have faced the death of one child from SMA and now face another. In addition, parents of an infant with a genetic disorder such as SMA may experience ostracism from their families, who may not want to acknowledge that this disease could happen to them (Knebel & Hudgings, 2002). Parents may experience feelings of guilt, shame, and remorse at the possibility of having passed on a life-threatening disease. They also may have concerns about future reproductive decisions. An interdisciplinary team approach is essential to help with the complex array of physical, psychosocial, spiritual, and cognitive needs these families may face. Many infants affected with SMA type I will leave the NICU for home care, and discharge planning is an essential nursing role. The following are all important elements in this planning process: assuring coordination and continuity of care in the home, including equipment requirements; providing education and skills training to parents and other family members; exploring development of advanced directives with the family; referring families, including siblings, to support groups and advocacy organizations; and linking families with respite and bereavement care and genetic services. A study of 13 families with an infant or child with Duchenne s muscular dystrophy or spinal muscular atrophy validated the importance of a comprehensive discharge plan (Parker, Maddocks, & Stern, 1999). Families reported concerns over lack of continuity of care and difficulties in finding trained, experienced caregivers in the home setting. Parents accessed support groups not only for emotional support but also to learn practical information about how to manage symptoms or medical equipment. Siblings of the ill infant or child also need attention and often expressed their grief by acting out in school or having other behavioral or performance problems. Families also benefited from bereavement care but expressed the importance of having a sustained relationship with a professional over time, such as working with a social worker who knew the family and had rapport with them. The need is great for nursing research to help guide the care of dying infants and young children with conditions such as SMA and their families. In general, there are few studies to inform care for this population, and what is known is largely anecdotal. A recent Institute of Medicine report highlighted recommendations to improve this care, including directions for future research (Field, Behrman, & Committee on Palliative and End-of-Life Care for Children and Their Families, Institute of Medicine, 2003). The National Institute of Nursing Research is the lead Institute at the National Institutes of Health for the endof-life science area and periodically announces initiatives to stimulate nursing research on this very important and understudied topic. Clearly, preconceptional or antenatal identification of couples at risk for having an infant who is affected with SMA would be ideal. However, there are few specific risk factors that make this identification possible. Because SMA is an autosomal recessive disorder, a positive family history of this condition is usually not present. If more than one member of a family is affected with SMA, it is most often seen only in the sibship of the affected individual, not in the parents, or other relatives. However, nurses providing prenatal care to families should take a careful family history and refer couples for genetic counseling in the presence of a positive family history for SMA or a history of recurrent, spontaneous abortion or stillbirth. Other antenatal factors, such as sonographic evidence of increased nuchal translucency or maternal reports of decreased fetal movements, have been described recently, and SMA should be considered in the differential diagnosis. However, these findings are fairly nonspecific, and it is more likely that SMA will be first recognized in the neonatal period. Nurses can play an important role in reassuring couples with an affected infant that this outcome was not due to anything that they did or should have known to look for during the pregnancy. Approaches to Treatment Efforts are currently under way to develop treatment for SMA. Although this disease may someday be a candidate for gene therapy or stem cell treatment, such approaches remain far in the future. An approach that may prove fruitful sooner is the search for drugs that increase the expression of SMN2, the gene that remains intact in SMA. Current studies are aimed at finding agents that either correct the splicing of this gene, so that a greater proportion of full-length mrna is produced, or increase the overall expression of the gene so that more SMN protein is made. Aclarubicin is an example of a drug currently under investigation that has been shown to correct the splicing of transcripts from the SMN2 gene and increase the levels of functional SMN protein (Andreassi et al., 2001). Other such agents have also shown promise (Chang et al., 2001), and future clinical trials of these and other treatments are likely. 18 JOGNN Volume 33, Number 1

8 The neonatal nurse plays a critical role in integrating the family in the care of the neonate with spinal muscular atrophy. Another pharmacologic approach to this disease is treatment with neuroprotective or neurotrophic agents that could compensate for SMN deficiency and protect the lower motor neurons from degeneration. A recent trial of gabapentin, a drug that may protect neurons by blocking the production of glutamate, showed no benefit in SMA patients (Miller et al., 2001), but investigators remain interested in exploring the potential of similar agents for treatment. Conclusion Spinal muscular atrophy, the most common hereditary cause of infant mortality, is a potentially life-threatening disease that can present in the newborn. Neonatal nurses who are familiar with this condition and its ramifications can be invaluable in helping patients, families, and the rest of the health care team. 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De novo rearrangements found in 2% of index patients with spinal muscular atrophy: Mutational mechanisms, parental origins, mutation rate, and implications for genetic counseling. American Journal of Human Genetics, 61, Jennifer A. Markowitz, MD, was a fellow in the Clinical Research Training Program, National Institute of Neurological Diseases and Stroke, Neurogenetics Branch, National Institutes of Health, Bethesda, MD, at the time this article was written. Currently, she is a resident in pediatrics at the Children s Hospital of Philadelphia, Philadelphia, PA. Mindy B. Tinkle, PhD, RN, is intramural program director for research and training, National Institute of Nursing Research, National Institutes of Health, Bethesda, MD. Kenneth H. Fischbeck, MD, is chief, Neurogenetics Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD. Address for correspondence: Mindy B. Tinkle, PhD, RN, Intramural Program Director for Research and Training, National Institute of Nursing Research, National Institutes of Health, 31 Center Drive, Rm 5B-13, Bethesda, MD tinklem@mail.nih.gov. 20 JOGNN Volume 33, Number 1