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Genetics Home Reference: your guide to understanding genetic conditions
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Silver syndrome

Reviewed February 2012

What is Silver syndrome?

Silver syndrome belongs to a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by progressive muscle stiffness (spasticity) and, frequently, development of paralysis of the lower limbs (paraplegia). Hereditary spastic paraplegias are divided into two types: pure and complex. Both types involve the lower limbs; the complex types may also involve the upper limbs, although to a lesser degree. In addition, the complex types may affect the brain and parts of the nervous system involved in muscle movement and sensations. Silver syndrome is a complex hereditary spastic paraplegia.

The first sign of Silver syndrome is usually weakness in the muscles of the hands. These muscles waste away (amyotrophy), resulting in abnormal positioning of the thumbs and difficulty using the fingers and hands for tasks such as handwriting. People with Silver syndrome often have high-arched feet (pes cavus) and spasticity in the legs. The signs and symptoms of Silver syndrome typically begin in late childhood but can start anytime from early childhood to late adulthood. The muscle problems associated with Silver syndrome slowly worsen with age, but affected individuals can remain active throughout life.

How common is Silver syndrome?

Although Silver syndrome appears to be a rare condition, its exact prevalence is unknown.

What genes are related to Silver syndrome?

Mutations in the BSCL2 gene cause Silver syndrome. The BSCL2 gene provides instructions for making a protein called seipin, whose function is unknown. The BSCL2 gene is active (expressed) in cells throughout the body, particularly in nerve cells that control muscle movement (motor neurons) and in brain cells. Within cells, seipin is found in the membrane of a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport.

BSCL2 gene mutations that cause Silver syndrome likely lead to an alteration in the structure of seipin, causing it to fold into an incorrect 3-dimensional shape. Research findings indicate that misfolded seipin proteins accumulate in the endoplasmic reticulum. This accumulation likely damages and kills motor neurons, which leads to muscle weakness and spasticity. In Silver syndrome, only specific motor neurons are involved, resulting in the hand and leg muscles being solely affected.

Some people with Silver syndrome do not have an identified mutation in the BSCL2 gene. The cause of the condition in these individuals is unknown.

Related Gene(s)

Changes in this gene are associated with Silver syndrome.

  • BSCL2

How do people inherit Silver syndrome?

Silver syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In these cases, the affected person inherits the mutation from one affected parent. However, some people who inherit the altered gene never develop features of Silver syndrome. (This situation is known as reduced penetrance.) It is unclear why some people with a mutated gene develop the disease and other people with a mutated gene do not.

Rarely, Silver syndrome is caused by new mutations in the gene and occurs in people with no history of the disorder in their family.

Where can I find information about diagnosis or management of Silver syndrome?

These resources address the diagnosis or management of Silver syndrome and may include treatment providers.

  • Gene Review: BSCL2-Related Neurologic Disorders/Seipinopathy (http://www.ncbi.nlm.nih.gov/books/NBK1307)
  • Gene Review: Hereditary Spastic Paraplegia Overview (http://www.ncbi.nlm.nih.gov/books/NBK1509)
  • Genetic Testing Registry: Spastic paraplegia 17 (http://www.ncbi.nlm.nih.gov/gtr/conditions/CN074197)
  • Spastic Paraplegia Foundation, Inc.: Treatments and Therapies (http://sp-foundation.org/understanding-hsp-pls/treatments-and-therapies/)

You might also find information on the diagnosis or management of Silver syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/silver-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/silver-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Silver syndrome?

You may find the following resources about Silver syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Silver syndrome?

  • Silver spastic paraplegia syndrome
  • spastic paraplegia 17
  • spastic paraplegia with amyotrophy of hands and feet
  • SPG17

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Silver syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding Silver syndrome?

autosomal ; autosomal dominant ; cell ; endoplasmic reticulum ; expressed ; gene ; hereditary ; inherit ; inherited ; motor ; mutation ; nervous system ; paraplegia ; penetrance ; pes cavus ; prevalence ; protein ; sign ; spasticity ; syndrome

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Cafforio G, Calabrese R, Morelli N, Mancuso M, Piazza S, Martinuzzi A, Bassi MT, Crippa F, Siciliano G. The first Italian family with evidence of pyramidal impairment as phenotypic manifestation of Silver syndrome BSCL2 gene mutation. Neurol Sci. 2008 Jun;29(3):189-91. doi: 10.1007/s10072-008-0937-y. Epub 2008 Jul 9. (http://www.ncbi.nlm.nih.gov/pubmed/18612770?dopt=Abstract)
  • Rowland LP, Bird TD. Silver syndrome: The complexity of complicated hereditary spastic paraplegia. Neurology. 2008 May 20;70(21):1948-9. doi: 10.1212/01.wnl.0000312519.62351.5b. (http://www.ncbi.nlm.nih.gov/pubmed/18490616?dopt=Abstract)
  • Silver JR. Silver syndrome. BMJ. 2007 Sep 1;335(7617):422-3. (http://www.ncbi.nlm.nih.gov/pubmed/17762032?dopt=Abstract)
  • van de Warrenburg BP, Scheffer H, van Eijk JJ, Versteeg MH, Kremer H, Zwarts MJ, Schelhaas HJ, van Engelen BG. BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy. Neuromuscul Disord. 2006 Feb;16(2):122-5. Epub 2006 Jan 19. (http://www.ncbi.nlm.nih.gov/pubmed/16427281?dopt=Abstract)
  • Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Hörl G, Malli R, Reed JA, Dierick I, Verpoorten N, Warner TT, Proukakis C, Van den Bergh P, Verellen C, Van Maldergem L, Merlini L, De Jonghe P, Timmerman V, Crosby AH, Wagner K. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004 Mar;36(3):271-6. Epub 2004 Feb 22. (http://www.ncbi.nlm.nih.gov/pubmed/14981520?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: February 2012
Published: September 15, 2014