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NORD is very grateful to 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.
Kugelberg Welander syndrome is a milder type of spinal muscular atrophy. It is a rare inherited neuromuscular disorder characterized by wasting and weakness in the muscles of the arms and legs, leading to walking difficulties in, and eventual loss of ambulation. Symptoms of Kugelberg Welander syndrome occur after 12 months of age. Patients learn to walk, may fall frequently and may have trouble walking up and down stairs at 2-3 years of age; some patients will not show functional changes until the teens. The legs are more severely affected than the arms. The long-term prognosis depends on the degree of motor function attained as a child.
Kugelberg Welander syndrome is inherited as an autosomal recessive trait. Molecular genetic testing has revealed that all types of autosomal recessive SMA (Werndnig-Hoffman disease, juvenile SMA and Kugelberg-Welander disease) are caused by mutations in the SMN (survival motor neuron) gene on chromosome 5. Deletion of the NAIP (neuronal apoptosis inhibitory protein) gene that is close to the SMN gene is also associated with SMA. More patients with Werdnig Hoffman disease (SMA1) than other types of SMA have NAIP deletions. The relationship between specific mutations in the SMN gene and nearby genes and the severity of SMA is still being investigated so classification of SMA subdivisions is based on age of onset of symptoms and maximum function achieved as opposed to the genetic profile.
People with Kugelberg Welander syndrome experience muscle wasting, difficulty in walking or climbing stairs, and trouble rising from lying on one's back. Breathing may be affected, but very late in the course of disease. Approximately 50% of patients with Kugelberg Welander syndrome develop spinal curvature (scoliosis).
All types of proximal spinal muscular atrophy (SMA) including Kugelberg Welander syndrome are caused by mutations in the SMN (survival motor neuron) gene at chromosomal locus 5q11-q13. Deletion of the NAIP (neuronal apoptosis inhibitory protein) gene that is close to the SMN gene is also associated with SMA. More patients with Werdnig Hoffman disease (SMA1) than other types of SMA have NAIP deletions.
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 area where the SMA gene sits. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Spinal muscular atrophy is 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.
The birth prevalence of all types of spinal muscular atrophy has been estimated to be 7.8 per 100,000 live births. An estimate of the prevalence of Kugelberg-Welander syndrome (SMA3) is not available.
Symptoms of the following disorders can be similar to those of Kugelberg Welander syndrome. Comparisons may be useful for a differential diagnosis:
Duchenne muscular dystrophy (DMD), a hereditary degenerative disease of skeletal (voluntary) muscles, is considered the most prevalent form of childhood muscular dystrophy. The disorder typically is recognized from approximately age three to five years; the patients with DMD usually lose ambulatory abilities by 12 years of age. Duchenne muscular dystrophy is initially characterized by muscle weakness within the pelvic area that may be followed by involvement of the shoulder muscles. With disease progression, muscle weakness and atrophy affect the trunk and forearms and gradually progress to involve most major muscles of the body. For more information about this disorder, choose "muscular dystrophy, Duchenne" as your search in the Rare Disease Database.
Myotubular myopathy is a rare muscle wasting disorder that occurs in three forms. The most severe form is present at birth, inherited as an X- Linked genetic trait, and presents with severe respiratory muscle weakness. A less severe form is present at birth or early childhood, progresses slowly and is inherited as an autosomal recessive genetic trait. The least severe of the three forms of is inherited as an autosomal dominant genetic trait, presents between the first and third decades of life and is slowly progressive. For more information on this disorder, choose "myotubular myopathy" as your search term in the Rare Disease Database.
Nemaline myopathy is a rare inherited neuromuscular disease that is usually apparent at birth (congenital) and characterized by extreme muscle weakness (hypotonia) but may manifest itself after age 1 year. . Laboratory examination of muscle tissue samples from people with nemaline myopathy reveal the presence of fine fibrous threads known as nemaline rods that interfere with the muscle function. For more information on this disorder, choose "nemaline myopathy" as your search term in the Rare Disease Database.
Glycogen storage diseases are a group of hereditary disorders caused by a lack of one or more enzymes involved in glycogen synthesis or breakdown and characterized by deposition of abnormal amounts or types of glycogen in tissues. The gait disorder secondary to glycogen accumulation in the muscles may start after age 1 year.
Molecular genetic testing is used to determine if a mutation is present in the SMN gene. SMA is caused by a partial or complete loss of the SMN gene and about 95% of those affected will show a deletion of both copies of a specific portion (exon 7 or exon 8) of the gene. About 5% 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, neurophysiologic studies and muscle biopsy were used for diagnosis, but 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 of Kugelberg-Welander syndrome is aimed at alleviating the symptoms. In most cases physical therapy and orthopedic devices may be prescribed. Ventilation support may be used to assist breathing. An orthopedic appliance may be used to allow the patient to be upright when scoliosis becomes a major problem. Surgery is necessary when spinal curvature becomes severe (more than 50 degrees).
Genetic counseling may be of benefit for patients 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 under gone 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
For information about clinical trials sponsored by private sources, contact:
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
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Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Spinal Muscular Atrophy, Type III; SMA3. Entry No: 253400. Last Edited November 15, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 22, 2012.
Report last updated: 2012/03/26 00:00:00 GMT+0