| Congenital distal spinal muscular atrophy | |
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| Other names |
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| Specialty | Paediatrics,medical genetics |
Congenital distal spinal muscular atrophy (cDSMA), also known asdistal hereditary motor neuropathy (orneuronopathy)type VIII (dHMN8), is ahereditary medical condition characterized by muscle wasting (atrophy), particularly ofdistal muscles in legs and hands, and by early-onsetcontractures (permanent shortening of a muscle or joint) of the hip, knee, and ankle. Affected individuals often have shorter lower limbs relative to the trunk and upper limbs. The condition is a result of a loss ofanterior horn cells localized tolumbar andcervical regions of the spinal cord early in infancy, which in turn is caused by a mutation of theTRPV4 gene. The disorder is inherited in anautosomal dominant manner.[1] Arm muscle and function, as well as cardiac and respiratory functions are typically well preserved.[2]
The presentation is as follows:[medical citation needed]
Congenital distal spinal muscular atrophy is caused by a mutation of theTRPV4 gene found on the 12q23-12q24.1.[3] The mutation causes an affected individual to have lower levels ofTRPV4 expression. This deficiency can lead to abnormal osmotic regulation. Congenital dSMA is geneticallyheterogeneous, meaning a mutation on this gene can cause a plethora of otherphenotypically related or phenotypically unrelated diseases depending on the region that is mutated.[citation needed]
TheTRPV4 (transient receptor potential vanilloid 4) gene, located onchromosome 12, encodes for a protein that serves as an ion channel, typically found in theplasma membrane and is permeable to Ca2+. Abnormal regulation of Ca2+ can lead to inefficient muscle contraction.[4]TRPV4 plays a major role inmechanosensation, as well asosmosensory functions innerve endings,endothelia, andalveoli.[5] The TRPV4 protein consists of 871amino acids with itsN- andC- terminals facing intracellularly. The protein also contains sixalpha helices that pass through the plasma membrane. Mutations inTRPV4 can result in the loss of its normal function, or a toxicgain of function. In the latter case, intracellular Ca2+ levels are increased, which results in abnormal regulation.[6]
The ankyrin repeat domain (ARD) is a region located near the intracellular N-terminal of the TRPV4 protein and consists of sixankyrin repeats. Fourmissense mutations have been identified at three specific positions all located within the ARD. All of these mutations are due to the swapping out ofarginine 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]
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 andfibrillation at rest are characteristic of congenital dSMA.[6]The following are useful in diagnosis:[medical citation needed]
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 footorthoses, or wheelchairs.[2] Orthopaedic surgery can be an option for some patients with severely impaired movement.Physical therapy andoccupational 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]