Congenital distal spinal muscular atrophy

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This article is about a genetic disorder associated with a defect in the TRPV4 gene. For a list of other conditions with a broadly similar name, see Spinal muscular atrophies.
Congenital distal spinal muscular atrophy
Other names
  • congenital dSMA;
  • distal hereditary motor neuropathy type VIII;
  • distal hereditary motor neuronopathy type VIII;
  • dHMN8;
  • congenital benign spinal muscular atrophy with contractures
Paediatrics, medical genetics

Congenital distal spinal muscular atrophy (cDSMA), also known as distal hereditary motor neuropathy (or neuronopathy) type VIII (dHMN8), is a

autosomal dominant manner.[1] Arm muscle and function, as well as cardiac and respiratory functions are typically well preserved.[2]

Signs and symptoms

The presentation is as follows:[medical citation needed]

Causes

Congenital distal spinal muscular atrophy is caused by a mutation of the TRPV4 gene found on the 12q23-12q24.1.[3] The mutation causes an affected individual to have lower levels of TRPV4 expression. This deficiency can lead to abnormal osmotic regulation. Congenital dSMA is genetically heterogeneous, meaning a mutation on this gene can cause a plethora of other phenotypically related or phenotypically unrelated diseases depending on the region that is mutated.[citation needed]

Pathophysiology

The TRPV4 (transient receptor potential vanilloid 4) gene, located on

nerve endings, endothelia, and alveoli.[5] The TRPV4 protein consists of 871 amino acids with its N- and C- terminals facing intracellularly. The protein also contains six alpha helices that pass through the plasma membrane. Mutations in TRPV4 can result in the loss of its normal function, or a toxic gain of function. In the latter case, intracellular Ca2+ levels are increased, which results in abnormal regulation.[6]

Mechanism

The ankyrin repeat domain (ARD) is a region located near the intracellular N-terminal of the TRPV4 protein and consists of six ankyrin repeats. Four missense mutations have been identified at three specific positions all located within the ARD. All of these mutations are due to the swapping out of arginine with a different amino acid.[7] Arginine is highly polar and positively charged, while its replacements are less polar or nonpolar. Some of these identified amino acid substitutions are:[medical citation needed]

  • R296H, arginine to histidine substitution
  • R315W, arginine to tryptophan substitution
  • R316C, arginine to cysteine substitution
  • R594H, arginine to histidine substitution

Diagnosis

Denervation atrophy

Electrophysiological evidence of denervation with intact motor and sensory nerve conduction findings must be made by using nerve conduction studies, usually in conjunction with EMG. The presence of polyphasic potentials and fibrillation at rest are characteristic of congenital dSMA.[6] The following are useful in diagnosis:[medical citation needed]

Management

Congenital dSMA has a relatively stable disease course, with disability mainly attributed to increased contractures rather than loss of muscle strength. Individuals frequently use crutches, knee, ankle, and/or foot orthoses, or wheelchairs.[2] Orthopaedic surgery can be an option for some patients with severely impaired movement. Physical therapy and occupational therapy can help prevent further contractures from occurring, though they do not reverse the effects of preexisting ones. Some literature suggests the use of electrical stimulation or botulinum toxin to halt the progression of contractures.[8]

See also

References

  1. PMID 22628388
    .
  2. ^
    S2CID 34825353
    .
  3. PMID 19835908
    .
  4. PMID 22050238
    .
  5. PMID 20037588
    .
  6. ^
    S2CID 14428057
    .
  7. PMID 20505684
    .
  8. S2CID 22732753
    .

External links
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