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Distal hereditary motor neuropathy, type V

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Description

Distal hereditary motor neuropathy, type V is a progressive disorder that affects nerve cells in the spinal cord. It results in muscle weakness and affects movement of the hands and feet.

Symptoms of distal hereditary motor neuropathy, type V usually begin during adolescence, but onset varies from infancy to the mid-thirties. Cramps in the hand brought on by exposure to cold temperatures are often the initial symptom.

The characteristic features of distal hereditary motor neuropathy, type V are weakness and wasting (atrophy) of muscles of the hand, specifically on the thumb side of the index finger and in the palm at the base of the thumb. Foot abnormalities, such as a high arch (pes cavus), are also common, and some affected individuals eventually develop problems with walking (gait disturbance). People with this disorder have normal life expectancies.

Frequency

The incidence of distal hereditary motor neuropathy, type V is unknown. Only a small number of cases have been reported.

Causes

Mutations in the BSCL2 and GARS1 genes cause distal hereditary motor neuropathy, type V.

The BSCL2 gene provides instructions for making a protein called seipin, whose function is unknown. Mutations in the BSCL2 gene likely alter 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, which is a structure inside the cell that is involved in protein processing and transport. This accumulation likely damages and kills motor neurons (specialized nerve cells in the brain and spinal cord that control muscle movement), leading to muscle weakness in the hands and feet.

The GARS1 gene provides instructions for making an enzyme called glycyl-tRNA synthetase, which is involved in the production (synthesis) of proteins. It is unclear how GARS1 gene mutations lead to distal hereditary motor neuropathy, type V. The mutations probably reduce the activity of glycyl-tRNA synthetase. A reduction in the activity of this enzyme may impair transmission of nerve impulses. As a result, nerve cells slowly lose the ability to communicate with muscles in the hands and feet.

Mutations in other genes may also cause distal hereditary motor neuropathy, type V.

Inheritance

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Some people who have the altered gene never develop the condition, a situation known as reduced penetrance.

Other Names for This Condition

  • DHMN-V
  • distal hereditary motor neuronopathy type 5
  • distal hereditary motor neuronopathy, type V
  • distal spinal muscular atrophy, type V
  • DSMAV
  • HMN V
  • spinal muscular atrophy, distal type V
  • spinal muscular atrophy, distal, with upper limb predominance

Additional Information & Resources

Research Studies from ClinicalTrials.gov

Scientific Articles on PubMed

References

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  • Antonellis A, Lee-Lin SQ, Wasterlain A, Leo P, Quezado M, Goldfarb LG, Myung K, Burgess S, Fischbeck KH, Green ED. Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for tRNA-charging enzymes in peripheral axons. J Neurosci. 2006 Oct 11;26(41):10397-406. Citation on PubMed
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  • Sivakumar K, Kyriakides T, Puls I, Nicholson GA, Funalot B, Antonellis A, Sambuughin N, Christodoulou K, Beggs JL, Zamba-Papanicolaou E, Ionasescu V, Dalakas MC, Green ED, Fischbeck KH, Goldfarb LG. Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. Brain. 2005 Oct;128(Pt 10):2304-14. Epub 2005 Jul 13. Citation on PubMed
  • 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. Citation on PubMed
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