NORD gratefully acknowledges Barry S. Russman, MD, Professor of Pediatrics and Neurology, Oregon Health Sciences University and Shriners Hospital for Children-Portland, for assistance in the preparation of this report.
The spinal muscular atrophies (SMAs), are characterized by degeneration of nerve cells (motor nuclei) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells) leading to muscle weakness of the truncal, and extremity muscles initially, followed by chewing, swallowing and breathing difficulties. Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue.
Approximately 80 percent of individuals with SMA fall into the severe category (Werdnig-Hoffmann disease or SMA1). Infants with SMA1 experience severe weakness before 6 months of age, and the patient never achieves the ability to sit independently when placed. Muscle weakness, lack of motor development and poor muscle tone are the major clinical manifestations of SMA1. Infants with the gravest prognosis have problems sucking or swallowing. Some show abdominal breathing in the first few months of life. Abdominal breathing is noted when the abdomen protrudes during inspiration. Normally, the chest expands during inspiration as the intercostal muscles (the muscles between the ribs) expand during inspiration. Abdominal breathing occurs when the intercostal muscles are weak and the diaphragm muscle is responsible for inspiration. Movement of the diaphragm (the muscle between the chest and abdomen) expands causing the abdomen to move during the inspiration cycle. Twitching of the tongue is often seen (fasciculations). Cognitive development is normal. Most affected children die before 2 years of age but survival may be dependent on the degree of respiratory function and respiratory support.
The different subtypes, SMA 0-4 are based on the age of onset of symptoms and the course and progression of the disease. SMA represents a continuum or spectrum of disease with a mild end and a severe end. SMA0 patients are extremely weak at birth, require immediate artificial ventilation and will never breathe independently. Werdnig-Hoffmann disease, which is also known as spinal muscular atrophy type 1 (SMA1) or acute spinal muscular atrophy, refers to individuals who have symptom onset prior to 6 months of age. SMA 2 patients will show symptoms prior to age 1 year, will sit but never walk. SMA 3 patients (Kugelberg-Welander disease) will show symptoms after age 1, and will walk for a period of time prior to loss of motor abilities. SMA 4 patients will not develop symptoms much before age 10 years.
All the SMAs are inherited as an autosomal recessive trait. Molecular genetic testing has revealed that all types of autosomal recessive SMA are caused by disruptions or errors (mutations) in the SMN1 (survival motor neuron 1) gene on chromosome 5.
The symptoms and progression of SMA1 or Werdnig-Hoffmann disease varies among affected individuals. Affected infants are weak before 6 months of age. The early signs include a generalized muscle weakness, diminished muscle tone (hypotonia) resulting in “floppiness,” abnormal flexibility (hypermobility) of the joints, absent tendon reflexes, twitching (fasciculation) of the tongue, a frog-like position with the hips moved apart (abducted) and knees bent or flexed, and an alert appearance. Muscles of the face are not affected initially. Mental development is usually normal. Typically, the child does not gain head control, cannot turn over and is unable to sit or stand. In addition, children with SMA may develop difficulties sucking, swallowing, and breathing; have an increased susceptibility to respiratory infections, or develop other complications that may lead to potentially life-threatening abnormalities within the first months or years of life.
For infants who appear to have normal development for several months prior to the onset of muscle weakness, the disorder may tend to have a more slowly progressive course. Muscles of the lower extremities appear to be disproportionately affected. With disease progression, diminished muscle tone and weakness may gradually spread to affect almost all voluntary muscles, with the exception of certain muscles controlling movements of the eyes.
The rate of progression of Werdnig-Hoffmann disease varies. Within a few months, breathing (respiratory) and bowel (constipation) difficulties may develop. The infant may be unable to swallow. Respiratory failure may occur or food inhaled into the lungs (aspiration) may cause choking. Most affected children die before 2 years of age but survival may be dependent on the degree of respiratory function.
All forms of spinal muscular atrophy are caused by mutations in the SMN1 (survival motor neuron 1) gene at chromosomal locus 5q11-q13. A second gene, known as the SMN2 (survival motor neuron 2) gene, plays a role in the development of SMA. The SMN2 gene is next to (adjacent) to the SMN1 gene on chromosome 5. While the mutations of the SMN1 cause SMA, evidence has been developed that SMN2 influences disease severity; individuals with more copies of the SMN2 gene tend to have a milder form of SMA.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosomal locus 5q11-q13” refers to bands 11-13 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. All SMAs are inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Parents of several individuals with Werdnig-Hoffmann disease have been closely related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are consanguineous have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
The specific underlying cause of Werdnig-Hoffmann disease is unknown. In SMA, it appears that the SMN1 and SMN2 genes produce (encode) a protein, which is essential for the proper function of motor neurons. Mutation of the SMN1 causes the gene to produce a defective protein that cannot perform its intended function. It is believed that SMN2 gene produces a partially-effective protein required by motor neurons to function. This is why individuals with more copies of SMN2 have a milder form of SMA.
Additional genes may influence the development of SMA. Deletion of the NAIP (neuronal apoptosis inhibitory protein) gene that is close to the SMN gene may also be associated with SMA. More patients with Werdnig-Hoffmann disease (SMA1) than other types of SMA have NAIP deletions. Some researchers suggest that loss of the NAIP gene and/or different mutations of the SMN gene may play a role in affecting the disorder’s severity. Some investigators also indicate that other genetic factors may contribute to the variable clinical expression of the disorder.
Werdnig-Hoffmann disease is a rare disorder that affects males and females in equal numbers. The prevalence of all types of spinal muscular atrophy has been estimated to be 4-7.8 per 100,000 live births. Approximately 80% of SMA patients have the Werdnig-Hoffmann form.
A diagnosis of SMA may be suspected based upon a detailed patient history, a thorough clinical examination and identification of characteristic findings. A diagnosis may be confirmed through molecular genetic testing, which can determine whether a mutation is present in the SMN gene. SMA is caused by a partial or complete loss of the SMN gene and about 95 percent of those affected will show a deletion of both copies of a specific portion (exon 7 or exon 8) of the gene. About 5 percent of those affected will show a deletion of exon 7 in one copy of the SMN gene and a different mutation in the other copy of the SMN gene.
Prior to the availability of molecular testing, electromyogram testing (neurophysiologic study of muscles) and microscopic study of samples of affected muscle tissue (biopsy) were used for diagnosis. These tests are no longer necessary unless SMN gene testing is normal.
Carrier testing for SMA is a molecular genetic test in which the number of copies of the SMN gene in which exons 7 and 8 are present is determined.
Treatment
No curative treatment exists for infants with Werdnig-Hoffmann disease. Treatment is aimed at the specific symptoms that are present in each individual. Treatment may require a team of specialists.
Feeding difficulties may cause nutritional concerns and may require a gastrostomy, a procedure in which a feeding tube is inserted directly into the stomach through a surgical opening.
Breathing (respiratory) function declines in individuals with Werdnig-Hoffmann disease. Treatment options range from offering no respiratory support to using noninvasive procedures or long-term invasive procedures such as a tracheotomy. A tracheotomy is a procedure in which a tube is inserted through a surgical opening in the windpipe (trachea). A non-invasive option is intermittent positive pressure ventilation (NIPPV), in which breathing is mechanically assisted without the creation of an artificial airway as is done with a tracheotomy. The specific treatment for the life-threatening respiratory complications of Werdnig-Hoffman disease is controversial. Any decisions for treatment should be made after consultation between the parents and the entire medical team and taken on an individual case basis.
Physical and occupational therapy is helpful to minimize contractures and help the patient/caretakers develop compensatory strategies; muscle strengthening is not a reason for therapy. Orthopedic devices (e.g., braces) and surgery to correct scoliosis may become necessary.
In 2017, Spinraza (nusinersen) was FDA approved as the first drug to treat children and adults with SMA. Spinraza is manufactured by Biogen.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Several trials of different medications have been conducted, none of which have shown a significant difference between the placebo and the study medication. The study medications have included: Gabapentin, Phenylbutyrate, Albuterol, Riluzole, Histone deacetylase inhibitors, including, Valproate Acid and Aclarubicin. Hydroxyurea has also undergone a clinical trial without success. Finally Myostatin, a transforming growth factor-beta family member that inhibits muscle growth, has not been effective in ameliorating the findings in the SMA mouse model
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com.
Contact for additional information about Kugelberg Welander syndrome:
Barry S. Russman, MD
Professor of Pediatrics and Neurology
Oregon Health Sciences University
Shriners Hospital for Children
Portland, OR
BRUSSMAN@shrinenet.org
TEXTBOOKS
Russman BS. Spinal Muscular Atrophy. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins; 2003:637.
Zerres K, Rudnik-Schoneborn S. Spinal Muscular Atrophies. IN: Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 4th ed. New York, NY: Churchill Livingstone; 2002:3349-3372.
JOURNAL ARTICLES
Sumner CJ, Wee CD, Warsing LC, et al. Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice. Hum Mol Genet. 2009;18(17):3145-52.
Petrone A, Pavone M, Testa MB, et al. Noninvasive ventilation in children with spinal muscular atrophy types 1 and 2. Am J Phys Med Rehabil. 2007;86:222-4.
Bush A, Fraser J, Jardine E, et al. Respiratory management of the infant with type I spinal muscular atrophy. Arch Dis Child. 2005;90:709-11.
Chung BY, Wong VC, Ip P. Spinal muscular atrophy: survival pattern and functional status. Pediatrics. 2004;114:e548-53.
Hardart MKM, Truog RD. Spinal muscular atrophy-type I. Arch Dis Child. 2003;88-848-50.
Russman, BS, Iannaconne ST, Samaha FJ. A phase 1 trial of riluzole in spinal muscular atrophy. Arch Neurol. 2003;60:1601-3.
Gozal D. Pulmonary manifestations of neuromuscular disease with special reference to Duchenne muscular dystrophy and spinal muscular atrophy. Pediatr Pulmonol. 2000;29:141-50.
Strober JB, Tennekoon GI. Progressive spinal muscular atrophies. J Child Neurol. 1999;14:691-95.
Andersson PB, Rando TA. Neuromuscular disorders of childhood. Curr Opin Pediatr. 1999;11:497-503.
Iannaccone ST, Browne RH, Samaha FL, Buncher CR. DCN/SMA group: A prospective study of SMA before age six years. Pediatr Neurol. 1993;9:187-193.
Russman BS, Iannaccone ST, Buncher CR, et al. Spinal muscular atrophy: new thoughts on the pathogenesis and classification of schema. J Child Neurol. 1992;7:347-353.
INTERNET
Prior TW, Russman BS. (Updated January 27, 2011). Spinal Muscular Atrophy. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed March 22, 2012.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Spinal Muscular Atrophy, Type I; SMA1. Entry No: 253300. Last Edited March 21, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 22, 2012.
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