Hereditary condition characterized by muscle wasting
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
.
Medical condition
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
|
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Specialty
| Paediatrics
,
medical genetics
|
---|
Congenital distal spinal muscular atrophy
(
cDSMA
), also known as
distal hereditary motor neuropathy
(or
neuronopathy
)
type VIII
(
dHMN8
), is a
hereditary
medical condition characterized by muscle wasting (
atrophy
), particularly of
distal
muscles in legs and hands, and by early-onset
contractures
(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 of
anterior horn cells
localized to
lumbar
and
cervical
regions of the spinal cord early in infancy, which in turn is caused by a mutation of the
TRPV4
gene. The disorder is inherited in an
autosomal dominant
manner.
[1]
Arm muscle and function, as well as cardiac and respiratory functions are typically well preserved.
[2]
Signs and symptoms
[
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]
The presentation is as follows:
[
medical citation needed
]
Causes
[
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]
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
[
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]
The
TRPV4
(transient receptor potential vanilloid 4) gene, located on
chromosome 12
, encodes for a protein that serves as an ion channel, typically found in the
plasma membrane
and is permeable to Ca
2+
. Abnormal regulation of Ca
2+
can lead to inefficient muscle contraction.
[4]
TRPV4
plays a major role in
mechanosensation
, as well as
osmosensory
functions in
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 Ca
2+
levels are increased, which results in abnormal regulation.
[6]
Mechanism
[
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]
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
[
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]
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
[
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]
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
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]
References
[
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]
- ^
Oates EC, Reddel S, Rodriguez ML, et al. (June 2012). "Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cells".
Brain
.
135
(Pt 6): 1714?23.
doi
:
10.1093/brain/aws108
.
PMID
22628388
.
- ^
a
b
Mercuri E, Messina S, Kinali M, et al. (February 2004). "Congenital form of spinal muscular atrophy predominantly affecting the lower limbs: a clinical and muscle MRI study".
Neuromuscul. Disord
.
14
(2): 125?9.
doi
:
10.1016/j.nmd.2003.09.005
.
PMID
14733958
.
S2CID
34825353
.
- ^
Everaerts W, Nilius B, Owsianik G (September 2010). "The vanilloid transient receptor potential channel
TRPV4
: from structure to disease".
Prog. Biophys. Mol. Biol
.
103
(1): 2?17.
doi
:
10.1016/j.pbiomolbio.2009.10.002
.
PMID
19835908
.
- ^
Menezes MP, North KN (June 2012).
"Inherited neuromuscular disorders: pathway to diagnosis"
.
J Paediatr Child Health
.
48
(6): 458?65.
doi
:
10.1111/j.1440-1754.2011.02210.x
.
PMID
22050238
.
- ^
Auer-Grumbach M, Olschewski A, Papi? L, et al. (February 2010).
"Alterations in the ankyrin domain of
TRPV4
cause congenital distal SMA, scapuloperoneal SMA and HMSN2C"
.
Nat. Genet
.
42
(2): 160?4.
doi
:
10.1038/ng.508
.
PMC
3272392
.
PMID
20037588
.
- ^
a
b
Fiorillo C, Moro F, Brisca G, et al. (August 2012). "
TRPV4
mutations in children with congenital distal spinal muscular atrophy".
Neurogenetics
.
13
(3): 195?203.
doi
:
10.1007/s10048-012-0328-7
.
PMID
22526352
.
S2CID
14428057
.
- ^
Dai J, Cho TJ, Unger S, et al. (July 2010).
"
TRPV4
-pathy, a novel channelopathy affecting diverse systems"
.
J. Hum. Genet
.
55
(7): 400?2.
doi
:
10.1038/jhg.2010.37
.
PMID
20505684
.
- ^
Farmer SE, James M (September 2001). "Contractures in orthopaedic and neurological conditions: a review of causes and treatment".
Disabil Rehabil
.
23
(13): 549?58.
doi
:
10.1080/09638280010029930
.
PMID
11451189
.
S2CID
22732753
.
External links
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]