Kugelberg Welander Syndrome

Kugelberg Welander Syndrome

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Kugelberg Welander Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • KWS
  • SMA3
  • spinal muscular atrophy type 3

Disorder Subdivisions

  • None

General Discussion

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.

Symptoms

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).

Causes

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.

Affected Populations

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.

Standard Therapies

Diagnosis

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

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.

Investigational Therapies

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

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

References

TEXTBOOKS

Russman BS. Spinal Muscular Atrophy. In: The NORD Guide to Rare Disorders, Philadelphia, PA: Lippincott, Williams and Wilkins; 2993:637.



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.



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, et al., Progressive spinal muscular atrophies. J Child Neurol. 1999;14:691-95.



Andersson PB, et al., Neuromuscular disorders of childhood. Curr Opin Pediatr. 1999;11:497-503.



Liu YB, et al., Atrial standstill in a case of Kugelberg-Welander syndrome with cardiac involvement: an electrophysiologic study. Int J Cardiol. 1999;70:207-10.



Zerres K, Rudnick-Schoneborn S, Forrest E, et al. A collaborative study on the natural history of childhood and juvenile onset proximal SMA (type II and III SMA):569 patients. J Neurol Sci 1997;146:67-72.



Cunha MC, et al., Spinal muscular atrophy type II (intermediary) and III (Kugelberg-Welander). Evolution of 50 patients with physiotherapy and hydrotherapy in a swimming pool. Arq Neuropsiquiatr. 1996;54:402-06.



Brzustowicz LM, et al., Assessment of non-allelic genetic heterogeneity of chronic (type II and III) spinal muscular atrophy. Hum Hered. 1993;43:380-87.



Miles JM, et al., Pathological case of the month. Type 3 spinal muscular atrophy (Kugelberg-Welander disease). Am J Dis Child. 1993;147:793-94.



Iannaccone ST, Browne RH, Samaha FL, et al. 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. New observations on the

natural history of SMA. J Child Neurol 1992;7:347-353.



Brzustowicz LM, et al., Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature. 1990;344:540-41.



Urbanek K et al., ACTH and steroids in Kugelberg-Welander disease. Acta Univ Palacki Olomuc Fac Med. 1990;126:147-50.



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 III; SMA3. Entry No: 253400. Last Edited November 15, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 22, 2012.

Resources

March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



Families of Spinal Muscular Atrophy

925 Busse Road

Elk Grove Village, IL 60007

Tel: (847)367-7620

Tel: (800)886-1762

Email: sma@fsma.org

Internet: http://www.fsma.org/



Muscular Dystrophy Association

3300 East Sunrise Drive

Tucson, AZ 85718-3208

USA

Tel: (520)529-2000

Fax: (520)529-5300

Tel: (800)572-1717

Email: mda@mdausa.org

Internet: http://www.mda.org/



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Jennifer Trust for Spinal Muscular Atrophy

40 Cygnet Court

Timothy's Bridge Road

Stratford upon Avon

Warwickshire, CV37 9NW

United Kingdom

Tel: 4401789267520

Fax: 4401789268371

Tel: 8009753100

Email: office@jtsma.org.uk

Internet: http://www.jtsma.org.uk



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Fight SMA/Spinal Muscular Atrophy

1807 Libbie Avenue

Suite 104

Richmond, VA 23226

Tel: (804)515-0080

Fax: (804)515-0080

Email: CarolineGibson@fightsma.com

Internet: http://www.fightsma.org



For a Complete Report

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