      
|
 IntroductionGeneticsTrialsOutcome MeasuresSpecialists ExerciseNutrition Standard of Care in SMA
The Pediatric Neuromuscular Clinical Research Network is conducting a "Clinical Study of Spinal Muscular Atrophy". The goal of this study is to obtain information needed to plan a clinical trial in spinal muscular atrophy. We are looking for patients of any age with SMA diagnosed before age 19 years. While we are looking to recruit patients with all clinical types of SMA, we can only enroll patients with a deletion of exon 7 and those stable enough to travel to one of the clinical sites for study visits. We anticipate starting a clinical trial and this study will help us prepare. This research is being done at three clinical sites on the east coast
Participants will be evaluated at one of these clinics regularly at no charge. During each visit, participants undergo several tests. Participants would be expected to travel to their enrolling clinic every two months for the first six months, every three months for the next 6 months, and every 6 months thereafter, not to exceed a period of 36 months. To find out whether you/your child qualifies, please call or email:
If you have any questions or comments about the research please feel free to contact us. PNCR Partners Columbia University: http://www.columbiasma.org/ Children's Hospital (Boston): http://www.childrenshospital.org/cfapps/research/data_admin/Site2220/mainpageS2220P0.html The Children’s Hospital of Philadelphia: CHOP Neuromuscular Program: http://www.chop.edu/consumer/jsp/division/service.jsp?id=26693 Spinal Muscular Atrophy (SMA) is a genetic condition in which the muscles throughout the body are weakened because the cells in the spinal cord and motor nerves do not work properly. Approximately 10-16 people out of every 100,000 children are born with this condition. SMA is characterized by muscle weakness and decreased muscle tone. This weakness affects legs more than arms and proximal muscles (those closest to the body like hips and shoulders) more than distal muscles (those farthest from the body like fingers and toes). This weakness tends to be equal between the right and left sides of the body. In addition to the muscles we have in our arms and our legs, we also have muscles in our chest which help us with breathing. In many cases of SMA these muscles are also affected, leading to some breathing problems. The severity of this condition varies greatly between individuals, so the disease is broken up into three main groups. These are referred to as SMA type I, SMA type II, and SMA type III. The type of SMA a child has is determined by the highest motor function a child achieves. SMA type I, also known as Werdnig-Hoffmann Disease, is the most severe form of SMA and defined as children who are not able to sit independently. Children with SMA type I usually present to the doctors before six months of age because of their severe low muscle tone, delayed gross motor skills, breathing difficulties, lack of reflexes, and spontaneous tongue movements (referred to as tongue fasciculations). Due to respiratory problems, children with SMA type I often have a significantly shortened life span. SMA type II is an intermediate form of SMA and is defined as children who can sit unassisted but cannot walk or stand. Children with this form of SMA usually present to the doctors before 18 months of age because of low muscle tone and delayed gross motor skills. Individuals with SMA type II can also have the typical tongue movements and/or a minor tremor of both hands. SMA type II can cause varying degrees of breathing difficulties. In many cases of SMA type II children and adults also experience a shortened lifespan. SMA type III, also known as Kugelberg-Welander Disease, is the least severe form of SMA and is defined as individuals who are able to stand and walk unassisted. Usually individuals with this form of SMA have limited, if any, breathing difficulties, and may show little or no decline. This form of SMA often resembles muscular dystrophy but can be identified by specialized testing. While these three forms are considered one disease with one genetic cause, there is great variability in the severity of the condition and the challenges a child or individual faces.
Genetics of Spinal Muscular Atrophy: SMA is a genetic disease. To understand the inheritance of SMA, let us review some fundamentals of genetics. Our bodies are made of billions of cells. Each cell has a nucleus containing 46 chromosomes. Chromosomes carry the complete set of instructions for directing the form, growth, and function of every cell in our body. Our 46 chromosomes are arranged as 23 pairs. One member of each pair is inherited from each parent at the time of conception. Each chromosome is made up of a long spiral of DNA (deoxyriboneucleic acids). A gene is a particular sequence of DNA, found on a chromosome containing a particular set of instructions. The gene for SMA is called survival motor neuron (SMN) and is located on chromosome 5. SMN encodes instructions for a protein that is necessary for certain nerve cells to continue living and functioning. Genetic disorders can occur when genes are altered or contain mistakes called mutations. The most common mutation seen in 95% of individuals with SMA is a deletion of one portion of the gene (exon 7). In most individuals with SMA the mutations are inherited from a parent. The mutations are transmitted in an autosomal recessive manner. Autosomal recessive traits require two copies of the gene to be mutated for the disease to manifest itself. A person who inherits one copy of the recessive gene does not develop disease because the normal gene compensates for its non-functioning copy. If only one parent is a carrier, there is a 50 percent chance of passing the mutation to each of his or her children. Children who are carriers do not have any medical problems. When both parents are carriers, there is 25 percent chance that any of their children (boys or girls) will inherit two recessive mutations (one copy from each parent) and develop SMA. Genetic testing is available to diagnose SMA and determine if parents or other members of the family are carriers for SMA. It is always best to start the genetic testing on the individual with SMA. Once the two mutations are identified in the person with SMA, the parents and/or siblings should be tested for the mutation(s) identified in the SMA patient as well as the most common mutation (exon 7 deletion). Your pediatrician, internist, or OB/GYN should be able to provide you with a referral to a genetics center to have this carrier testing. Genetic testing will require one tube of blood and generally takes approximately 4 weeks until results are available. The cost of carrier testing varies by laboratory but is several hundred dollars. Many insurance plans pay for some or all of the cost testing, but you should check with your insurance company for coverage before testing is sent. If the genetic testing demonstrates that the relative of the patient with SMA is a carrier, the spouse or partner of that family member should then be genetically tested for the common exon 7 deletion. Because SMA is an autosomal recessive condition, both parents must be carriers to have a child with SMA. The genetic test results should be interpreted by a clinical geneticist to accurately determine the risk of having a child with SMA. There are unusual circumstances in which the common exon 7 deletion will not be detected in the general population. Therefore, genetic counseling and interpretation should accompany any genetic testing for SMA. If both parents are carriers, there is a 25% chance they will have a child with SMA. There are a variety of reproductive options available. Regardless of how many previous children they have had with SMA, each pregnancy is independently at 25% risk of SMA. Prenatal testing with either amniocentesis at 15 weeks of gestation or beyond or chorionic villus sampling at 10 weeks of gestation or beyond is available to genetically test a fetus for SMA. Amniocentesis and chorionic villus sampling are generally safe but carry 0.5% and 1%, respectively, risks of complication or pregnancy loss. Therefore, amniocentesis and chorionic villus sampling should only be performed by experienced obstetricians. Genetic results are usually available within two to four weeks of the procedure. In addition, in vitro fertilization with preimplantation genetic diagnosis is available to genetically test embryos prior to implantation. In vitro fertilization with preimplantation genetic diagnosis allows for reproductive choice prior to pregnancy. Couples who are both carriers for SMA should consult a genetics professional to review these reproductive options prior to conception to review the medical risks and benefits of each procedure.
What are controlled clinical trials? Why do we need them? The term “Clinical Trial” typically refers to a research study that evaluates a new treatment or intervention. The new treatment is given to patients under very controlled circumstances to make sure that participants are safe and so that any important changes noted among treated patients can be attributed to the treatment and not to external factors. As with every serious disease for which there is no cure, physicians and patients alike strive for effective treatment and are understandably ready to embrace any new hope. This aspect of human nature is well captured in the expression “grasping at straws” and makes it difficult to establish whether a new therapy is helpful or harmful. Everyone wants to take the new treatment and everyone involved wants to believe that it works. The history of medicine, however, has many examples of treatments that were associated with considerable discomfort, cost, or even danger, and that were used on many patients until finally they were proven ineffective or even harmful in controlled clinical trials. Also, so-called “open” trials in which everyone receives the new treatment are prone to providing overly optimistic and inaccurate results concerning treatment benefit because of the so-called “placebo effect”. For this reason, good clinical trial design requires a comparison group that is not receiving the new treatment. Controlled clinical trials are now widely accepted standards in medical research. Most patient advocacy groups, including networks of cancer and HIV patients, support controlled clinical trials. The FDA requires proof of safety and effectiveness in controlled trials before approving any new medication. The National Institutes of Health guidelines for funding of clinical research encourage medical researchers to design rational, controlled trials. One question that families frequently ask is why some participants will receive a placebo (inactive drug) during at least some periods of a trial. They are wondering whether it would not be better for them to be sure to receive the active medication. We understand this reasoning and we try to keep the number of patients on placebo as small as possible without compromising our ability to determine the actual effects of the treatment. However, we feel that it is our responsibility as physicians and researchers to subject new treatments to controlled clinical trials for several reasons. If we were certain that a new treatment would help patients with SMA, we would not have to do a clinical trial. If at any point during the trial it became clear that patients taking a new medication do significantly better or worse than those without the new medication, the trial would be stopped and we would be able to give the appropriate recommendations to SMA patients. Until and unless we have these results, the best way that individual patients with SMA, their family members, and the community of SMA patients can obtain crucial information on the safety and efficacy of a new medication is through a randomized, double-blind (whereby neither the patients nor the clinicians know who is receiving the new treatment), appropriately controlled trial. We strongly believe that participation in controlled clinical trials is in the best interest of patients with SMA and their families. Especially when dealing with relatively rare diseases, it is of crucial importance that potential therapies are investigated at designated research centers and in controlled trials. In doing so, patients and researchers will have the greatest chance to reach their common goal, that is, to improve the situation of patients with SMA as soon as possible. These studies greatly reduce the inconvenience, risk, and expense that many patients and family members encounter when they feel obliged to take suggested treatments without knowing whether the treatment will actually help or when they should stop taking it. Clinical trials allow us to rationally test treatments, eliminate harmful or ineffective treatments rapidly, and, hopefully, find an effective and safe treatment soon.
Outcome Measures in Clinical Trials: “Outcome measures” are the tools we use to try to measure if a new treatment is effective. Outcome measures for clinical trial need to be reliable and sensitive to change. For SMA, we are considering several different outcome measures, each having some advantages and limitations Assessing muscle strength can be difficult in children, because the results depend on the patient’s effort. Also, the standard method of manual strength testing does not allow to grade small differences. Therefore, we are testing a device called a hand-held dynamometer. Using a dynamometer is easy and comfortable and allows for measuring small changes over a continuous range. Muscle strength, which can remain stable over long periods of time in childhood SMA, may not predict the child’s functional status. Motor function testing is conducted by physical and occupational therapists, where they observe the child perform simple movements for about 30 minutes and score these in a standardized fashion. Several different scales are available, depending on the age and developmental status of the child. Examples of these include the Gross Motor Function Scale (GMFM), the Hammersmith SMA Functional Motor Scale (H-SMA-FMS), the Test of Infant Motor Performance (TIMP), and the Children’s’ Hospital of Philadelphia (CHOP) Test of Strength in SMA (CHOP Test). A child’s total muscle mass can be measured using DEXA scanning. This is the same x-ray machine used to measure bone density, and is a painless test which usually lasts 15 minutes. A breathing test can be used in children who can cooperate with the test, typically those over 5 years of age. They simply blow into a tube that measures their breathing function. Motor Unit Number Estimation (MUNE) is a non-invasive test that measures the number of functional motor units using electrophysiological techniques. During this 30 minute test, brief low intensity stimulation is applied to the wrist and a response is recorded. MUNE’s are increasingly used in SMA and offer a measure directly related to the pathophysiology of the disease. Quality of life questionnaires for children with SMA and their parents take 10 minutes to complete and provide information about each child and family’s perceived quality of life.
Importance of Comprehensive Specialist in Clinical Care for SMA Patients: Effective management of a child with SMA requires coordination of several medical specialists. Experts in Neurology, Genetics, Pulmonary Medicine, Gastroenterology, Orthopedics, Physical and Occupational Therapy, Social Work, Rehabilitation Medicine and Nursing work together to address each child’s individual health status and SMA-related issues. Specialized neuromuscular programs at a children’s hospital are designed to provide these services and are available at the New York, Philadelphia and Boston centers of the PNCR SMA network. Providing optimal standards of care for children with SMA types 1, 2 and 3 is one of the goals of the PNCR network. Research in these areas is currently underway at the Philadelphia site. The role of exercise in spinal muscular atrophy is to assist in improving flexibility, function, independence and quality of life. There is no evidence to support traditional strength training. Therefore it is often best for children with SMA to exercise by practicing the movements and tasks they want to perform throughout the day. We call this type of practice functional exercise. It can consist of any movement or position one would like to strengthen in order to improve their activities of daily living, for example rolling, reaching, sitting and maybe even walking. These activities are dependent on age, amount of neuromuscular involvement, and developmental stage. It is extremely important to maintain our range of motion, or the amount of movement each of our joints has. If we do not move our joints throughout their full range of motion, we run the risk of becoming “tight”. This “tightness” can lead to the development of fixed muscles, tendons, or ligaments. We call this fixed tightening contractures. Contractures can be a result of immoblity and inactivity, which puts children with SMA at high risk! Range of motion exercises, positioning techniques and exercise in the form of practicing everyday activities are an important part of the exercise program. Check with your physical and occupational therapists to ensure that you are performing appropriate types and amounts of exercise. Many devices exist to help children with SMA move better, more often, safer and more independently. We call these products adaptive equipment. Adaptive equipment can be in the form of wheelchairs, braces, or communication systems. To find the most appropriate adaptive equipment, see a physical or occupational therapist for an equipment evaluation.
The children with Spinal Muscular Atrophy (SMA) require complete nutrition-but not too much. Each child has a constant need for protein, carbohydrate, fat, minerals, and vitamins. These provide energy and nutrients for growth and physical functions. There are recommended daily allowances of all of these nutrients. However, it is important that the amount of energy that is provided in food for each child is coordinated with the amount of energy that he is able to expend. This will depend on the child’s metabolism and activity level. It is important that the check-up of each child include a weight and height, taking into consideration the muscle mass. This evaluation should look for both under-nutrition and over-nutrition. Over-nutrition or over-weight can become a problematic burden to weakened muscles, especially the respiratory muscles. Routine nutrition support check-ups can help to balance nutritional need.
Data Management Strengths of Muscle Study Group: The Muscle Study Group (MSG), formed in 1997, is a consortium of scientific investigators committed to promoting the cooperative planning, implementation, analysis and reporting of clinical research studies in neuromuscular diseases. The consortium was established to fulfill a specific need within the field. Neuromuscular diseases are rare disorders that require special expertise to evaluate and treat. Consequently, the conduct of any significant clinical studies in these disorders requires the coordinated effort of several specialized centers. The MSG Coordination Center (MSG-CC) helps implement approved studies by providing planning, biostatistical and data management support. Currently, there are 100 active MSG members representing 29 national and international academic institutions. The MSG has completed two multicenter trials, has five ongoing studies as well as several studies in the planning stages. The MSG-CC is part of the University of Rochester’s Neuromuscular Disease Center, which has been involved for more than a 20 years in planning and implementing neuromuscular clinical trials. SMA Foundation: www.smafoundation.org Families of SMA: http://www.fsma.org/ Center Watch: http://www.centerwatch.com/ Muscular Dystrophy Association: http://www.mdausa.org/ National Organization for Rare Disorders: http://www.rarediseases.org/ Washington University Neuromuscular Disease Center: http://www.neuro.wustl.edu/neuromuscular/ SMA Related Publications by PNCR Members Kang PB, Krishnamoorthy KS, Jones RM, Shapiro FD, Darras BT. Atypical presentations of spinal muscular atrophy type III (Kugelberg-Welander disease). Neuromuscul Disord. 2006 Aug;16(8):492-4. Epub 2006 Jun 22. O'Hagen JM, Glanzman AM, McDermott MP, Ryan PA, Flickinger J, Quigley J, Riley S, Sanborn E, Irvine C, Martens WB, Annis C, Tawil R, Oskoui M, Darras BT, Finkel RS, De Vivo DC. An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscul Disord. 2007 Oct;17(9-10):693-7. Epub 2007 Jul 19. Darras BT, Kang PB. Clinical trials in spinal muscular atrophy. Curr Opin Pediatr. 2007 Dec;19(6):675-9. Review. Oskoui M, Levy G, Garland CJ, Gray JM, O'Hagen J, De Vivo DC, Kaufmann P. The changing natural history of spinal muscular atrophy type 1. Neurology. 2007 Nov 13;69(20):1931-6. Kaufmann P, Muntoni F; International Coordinating Committee for SMA Subcommittee on SMA Clinical Trial Design. Issues in SMA clinical trial design. The International Coordinating Committee (ICC) for SMA Subcommittee on SMA Clinical Trial Design. Neuromuscul Disord. 2007 Jun;17(6):499-505. Epub 2007 Feb 14. Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A; Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007 Aug;22(8):1027-49. Last updated: 4/25/2008 |
©Copyright University of Rochester Medical Center, 1999-2006. Disclaimer. For questions or suggestions concerning the content of these pages, contact the URMC Webmaster. |
