Congenital distal spinal muscular atrophy: Difference between revisions
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'''Congenital distal spinal muscular atrophy''' (congenital dSMA) is a [[Heredity | hereditary]] genetic condition characterized by muscle wasting ([[atrophy]]), particularly of [[Anatomical terms of location#Proximal and distal|distal]] muscles in legs and hands, and by early - onset [[contracture | contractures]] 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 [[Neck | 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. |
'''Congenital distal spinal muscular atrophy''' (congenital dSMA) is a [[Heredity | hereditary]] genetic condition characterized by muscle wasting ([[atrophy]]), particularly of [[Anatomical terms of location#Proximal and distal|distal]] muscles in legs and hands, and by early - onset [[contracture | contractures]] 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 [[Neck | 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. {{cite journal |author=Oates EC, Reddel S, Rodriguez ML, ''et al.'' |title=Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cells |journal=Brain |volume=135 |issue=Pt 6 |pages=1714–23 |year=2012 |month=June |pmid=22628388 |doi=10.1093/brain/aws108 |url=}} Arm muscle and function, as well as cardiac and respiratory functions are typically well preserved. {{cite journal |author=Mercuri E, Messina S, Kinali M, ''et al.'' |title=Congenital form of spinal muscular atrophy predominantly affecting the lower limbs: a clinical and muscle MRI study |journal=Neuromuscul. Disord. |volume=14 |issue=2 |pages=125–9 |year=2004 |month=February |pmid=14733958 |doi= |url=}} [[File:Stuve-wiedemann3.JPG|thumb|Radiograph showing dysplasia in lower limbs]] |
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==Signs and Symptoms== |
==Signs and Symptoms== |
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==Causes== |
==Causes== |
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[[File:Autosomal dominant - en.svg|thumb|Autosomal dominant - en]] |
[[File:Autosomal dominant - en.svg|thumb|Autosomal dominant - en]] |
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Congenital distal spinal muscular atrophy is caused by a mutation of the TRPV4 gene found on the 12q23- |
Congenital distal spinal muscular atrophy is caused by a mutation of the TRPV4 gene found on the 12q23-12q24.1. {{cite journal |author=Everaerts W, Nilius B, Owsianik G |title=The vanilloid transient receptor potential channel TRPV4: from structure to disease |journal=Prog. Biophys. Mol. Biol. |volume=103 |issue=1 |pages=2–17 |year=2010 |month=September |pmid=19835908 |doi=10.1016/j.pbiomolbio.2009.10.002 |url=}} 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 [[Genetic_heterogeneity | heterogeneous]], meaning a mutation on this gene can cause a plethora of other [[Phenotype | phenotypically]] related or phenotypically unrelated diseases depending on the region that is mutated. |
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===Pathophysiology=== |
===Pathophysiology=== |
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The TRPV4 (transient receptor potential vanilloid 4) gene, located on [[Chromosome_12_(human) | chromosome 12]], encodes for a protein that serves as an ion channel, typically found in the [[Cell_membrane | plasma membrane]] and is permeable to Ca<sup>2+</sup>. TRPV4 plays a major role in [[Mechanosensation | mechanosensation]], as well as [[Osmosensory | osmosensory]] functions in endothelia and alveoli, as well as nerve endings. |
The TRPV4 (transient receptor potential vanilloid 4) gene, located on [[Chromosome_12_(human) | chromosome 12]], encodes for a protein that serves as an ion channel, typically found in the [[Cell_membrane | plasma membrane]] and is permeable to Ca<sup>2+</sup>. TRPV4 plays a major role in [[Mechanosensation | mechanosensation]], as well as [[Osmosensory | osmosensory]] functions in endothelia and alveoli, as well as nerve endings. {{cite journal |author=Auer-Grumbach M, Olschewski A, Papić L, ''et al.'' |title=Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C |journal=Nat. Genet. |volume=42 |issue=2 |pages=160–4 |year=2010 |month=February |pmid=20037588 |pmc=3272392 |doi=10.1038/ng.508 |url=}}The TRPV4 protein consists of 871 [[Amino_acid | amino acids]] with it's [[N-terminus | N-]] and [[C-terminus | C-]] terminals facing intracellularly. The protein is also comprised of six [[Alpha_helix | alpha helices]] that pass through the plasma membrane. Mutations in TRPV4 can result in the loss of it's normal function, or a toxic gain of function. In the latter case, intracellular Ca<sup>2+</sup> levels are increased, which result in abnormal regulation. {{cite journal |author=Fiorillo C, Moro F, Brisca G, ''et al.'' |title=TRPV4 mutations in children with congenital distal spinal muscular atrophy |journal=Neurogenetics |volume=13 |issue=3 |pages=195–203 |year=2012 |month=August |pmid=22526352 |doi=10.1007/s10048-012-0328-7 |url=}} |
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====Mechanism==== |
====Mechanism==== |
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The ankyrin repeat domain (ARD) is located near the intracellular N-terminal of the TRPV4 protein and consists of six [[Ankyrin_repeat | ankyrin repeats]]. Four [[Missense_mutation | missense mutations]] have been identified at three specific positions all located within the ARD. All of these mutations are due to the substitution of [[Arginine | arginine]], which is an amino acid. |
The ankyrin repeat domain (ARD) is located near the intracellular N-terminal of the TRPV4 protein and consists of six [[Ankyrin_repeat | ankyrin repeats]]. Four [[Missense_mutation | missense mutations]] have been identified at three specific positions all located within the ARD. All of these mutations are due to the substitution of [[Arginine | arginine]], which is an amino acid. {{cite journal |author=Dai J, Cho TJ, Unger S, ''et al.'' |title=TRPV4-pathy, a novel channelopathy affecting diverse systems |journal=J. Hum. Genet. |volume=55 |issue=7 |pages=400–2 |year=2010 |month=July |pmid=20505684 |doi=10.1038/jhg.2010.37 |url=}} Arginine is highly polar and positively charged, while it's replacements are less polar or nonpolar. Some of these identified amino acid substitutions have been listed below. |
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=====Identified Mutations===== |
=====Identified Mutations===== |
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==Diagnosis== |
==Diagnosis== |
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A diagnosis is made after specific criteria have been satisfied. Electrophysiological evidence of denervation with intact motor and sensory nerve conduction findings must be made by using NCSs, usually in conjunction with EMG. The presence of polyphasic potentials and [[Fibrillation | fibrillation]] at rest are characteristic of congenital dSMA. |
A diagnosis is made after specific criteria have been satisfied. Electrophysiological evidence of denervation with intact motor and sensory nerve conduction findings must be made by using NCSs, usually in conjunction with EMG. The presence of polyphasic potentials and [[Fibrillation | fibrillation]] at rest are characteristic of congenital dSMA.5. {{cite journal |author=Fiorillo C, Moro F, Brisca G, ''et al.'' |title=TRPV4 mutations in children with congenital distal spinal muscular atrophy |journal=Neurogenetics |volume=13 |issue=3 |pages=195–203 |year=2012 |month=August |pmid=22526352 |doi=10.1007/s10048-012-0328-7 |url=}} An x-ray of an individual will also show abnormal bone growth Histologic evidence from muscle biopsy samples of denervation must also be present. {{cite journal |author=Russman BS |title=Spinal muscular atrophy: clinical classification and disease heterogeneity |journal=J. Child Neurol. |volume=22 |issue=8 |pages=946–51 |year=2007 |month=August |pmid=17761648 |doi=10.1177/0883073807305673 |url=}} |
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==Management== |
==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 foot [[Orthotics | orthoses]], callipers, or wheelchairs. |
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 foot [[Orthotics | orthoses]], callipers, or wheelchairs. {{cite journal |author=Mercuri E, Messina S, Kinali M, ''et al.'' |title=Congenital form of spinal muscular atrophy predominantly affecting the lower limbs: a clinical and muscle MRI study |journal=Neuromuscul. Disord. |volume=14 |issue=2 |pages=125–9 |year=2004 |month=February |pmid=14733958 |doi= |url=}} Orthopaedic surgery can be an option for some patients. [[Physical_therapy | Physical therapy]] and [[Occupational_therapy | occupational therapy]] can help prevent further contractures from occuring, 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. {{cite journal |author=Farmer SE, James M |title=Contractures in orthopaedic and neurological conditions: a review of causes and treatment |journal=Disabil Rehabil |volume=23 |issue=13 |pages=549–58 |year=2001 |month=September |pmid=11451189 |doi= |url=}} |
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==Prognosis== |
==Prognosis== |
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Some researchers have concluded that prognosis is mainly dependent on maximum function achieved by an affected individual. Patients who can not sit alone typically have a life expectancy of less than 4 years. Patients who can sit, but could never walk live for at least 20 to 30 years. And patients who have the ability to walk at some point in their lives have a lifespan that is indefinite. However, all patients lose function over time. |
Some researchers have concluded that prognosis is mainly dependent on maximum function achieved by an affected individual. Patients who can not sit alone typically have a life expectancy of less than 4 years. Patients who can sit, but could never walk live for at least 20 to 30 years. And patients who have the ability to walk at some point in their lives have a lifespan that is indefinite. However, all patients lose function over time. |
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==Related Disorders Involving the TRPV4 Gene== |
==Related Disorders Involving the TRPV4 Gene== |
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Mutations on the TRPV4 gene can cause different, but very similar spinal muscular atrophies (SMA) of the peripheral nervous system. Other skeletal dysplasias can also be the result of a mutation on the TRPV4 gene. |
Mutations on the TRPV4 gene can cause different, but very similar spinal muscular atrophies (SMA) of the peripheral nervous system. Other skeletal dysplasias can also be the result of a mutation on the TRPV4 gene. {{cite journal |author=Krakow D, Vriens J, Camacho N, ''et al.'' |title=Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia |journal=Am. J. Hum. Genet. |volume=84 |issue=3 |pages=307–15 |year=2009 |month=March |pmid=19232556 |pmc=2667978 |doi=10.1016/j.ajhg.2009.01.021 |url=}} The mutations can occur at different [[Allele | alleles]] that have been linked to [[Scapuloperoneal_spinal_muscular_atrophy | scapuloperoneal spinal muscular atrophy]] (SPSMA) and [[Hereditary_motor_and_sensory_neuropathy | hereditary motor and sensory neuropathy 2C]] (HMSN2C), which are forms of SMAs. The related skeletal dysplasias include [[Brachyolmia | brachyolmia]], [[Spondylometaphyseal dysplasia Kozlowski type | spondylometaphyseal dysplasia Kozlowski type]], and nonlethal [[Metatropic_dysplasia | metatropic dysplasia]]. {{cite journal |author=Camacho N, Krakow D, Johnykutty S, ''et al.'' |title=Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia |journal=Am. J. Med. Genet. A |volume=152A |issue=5 |pages=1169–77 |year=2010 |month=May |pmid=20425821 |doi=10.1002/ajmg.a.33392 |url=}} All of these disorders exhibit overlapping symptoms, as well as unique ones that set them apart from the others. |
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===Scapuloperoneal Spinal Muscular Atrophy (SPSMA)=== |
===Scapuloperoneal Spinal Muscular Atrophy (SPSMA)=== |
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Scapuloperoneal weakness and atrophy, vocal cord paralysis, laryngeal palsy, along with absence of some muscle groups are all typical features of SPSMA. Males are more affected than females, and later generations have increased disease expression, suggesting [[Anticipation_(genetics) | genetic anticipation]]. |
Scapuloperoneal weakness and atrophy, vocal cord paralysis, laryngeal palsy, along with absence of some muscle groups are all typical features of SPSMA. Males are more affected than females, and later generations have increased disease expression, suggesting [[Anticipation_(genetics) | genetic anticipation]]. {{cite journal |author=Isozumi K, DeLong R, Kaplan J, ''et al.'' |title=Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31 |journal=Hum. Mol. Genet. |volume=5 |issue=9 |pages=1377–82 |year=1996 |month=September |pmid=8872481 |doi= |url=}} |
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===Hereditary Motor and Sensory Neuropathy 2C (HMSN2C)=== |
===Hereditary Motor and Sensory Neuropathy 2C (HMSN2C)=== |
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Hereditary motor and sensory neuropathy 2C, or commonly known as [[Charcot–Marie–Tooth_disease | Charcot - Marie - Tooth disease]] is also a result of a mutation of the TRPV4 gene. Signs and symptoms include distal muscle weakness and wasting in the limbs, distal sensory loss, vocal cord paralysis, and weakness of the diaphragm and intercostal muscles. Onset varies greatly from childhood to 30 years of age, with prognosis mainly due to respiratory complications. |
Hereditary motor and sensory neuropathy 2C, or commonly known as [[Charcot–Marie–Tooth_disease | Charcot - Marie - Tooth disease]] is also a result of a mutation of the TRPV4 gene. Signs and symptoms include distal muscle weakness and wasting in the limbs, distal sensory loss, vocal cord paralysis, and weakness of the diaphragm and intercostal muscles. Onset varies greatly from childhood to 30 years of age, with prognosis mainly due to respiratory complications. {{cite journal |author=Zimoń M, Baets J, Auer-Grumbach M, ''et al.'' |title=Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies |journal=Brain |volume=133 |issue=Pt 6 |pages=1798–809 |year=2010 |month=June |pmid=20460441 |pmc=2912694 |doi=10.1093/brain/awq109 |url=}} |
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===Brachyolmia=== |
===Brachyolmia=== |
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Features of brachyolmia include short trunk, scoliosis, and mild short stature. The autosomal dominant form of brachyolmia is also linked to a mutation on the TRPV4 gene located on chromosome 12q24.1-12q24.2. |
Features of brachyolmia include short trunk, scoliosis, and mild short stature. The autosomal dominant form of brachyolmia is also linked to a mutation on the TRPV4 gene located on chromosome 12q24.1-12q24.2. {{cite journal |author=Rock MJ, Prenen J, Funari VA, ''et al.'' |title=Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia |journal=Nat. Genet. |volume=40 |issue=8 |pages=999–1003 |year=2008 |month=August |pmid=18587396 |pmc=3525077 |doi=10.1038/ng.166 |url=}} |
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===Spondylometaphyseal dysplasia Kozlowski type (SMDK)=== |
===Spondylometaphyseal dysplasia Kozlowski type (SMDK)=== |
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Affected individuals typically have short trunk and short stature, in addition to bowlegs and a waddling gait. [[Kyphoscoliosis | Kyphoscoliosis]] is common and the thorax is generally short and broad. Further features include severe platyspondyly, and [[Metaphyseal_dysplasia | metaphyseal dysplasia]]. |
Affected individuals typically have short trunk and short stature, in addition to bowlegs and a waddling gait. [[Kyphoscoliosis | Kyphoscoliosis]] is common and the thorax is generally short and broad. Further features include severe platyspondyly, and [[Metaphyseal_dysplasia | metaphyseal dysplasia]]. {{cite journal |author=Nishimura G, Lausch E, Savarirayan R, ''et al.'' |title=TRPV4-associated skeletal dysplasias |journal=Am J Med Genet C Semin Med Genet |volume=160C |issue=3 |pages=190–204 |year=2012 |month=August |pmid=22791502 |doi=10.1002/ajmg.c.31335 |url=}} |
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===Nonlethal metatropic dysplasia (MD)=== |
===Nonlethal metatropic dysplasia (MD)=== |
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The course of the disease is very unique in that it evolves from individuals being short-limbed at birth to instead possessing a short-trunk phenotype over the first decade, as a result of rapidly progressing kyphoscoliosis. At birth, a prominent forehead and squared jaw are present. Occasionally, an individual may be born with an elongated [[Coccyx | coccyx]], sometimes referred to as a tail-like appendage. |
The course of the disease is very unique in that it evolves from individuals being short-limbed at birth to instead possessing a short-trunk phenotype over the first decade, as a result of rapidly progressing kyphoscoliosis. At birth, a prominent forehead and squared jaw are present. Occasionally, an individual may be born with an elongated [[Coccyx | coccyx]], sometimes referred to as a tail-like appendage. |
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== See also == |
== See also == |
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Revision as of 15:47, 19 November 2013
| Congenital distal spinal muscular atrophy |
|---|
Congenital distal spinal muscular atrophy (congenital dSMA) is a hereditary genetic condition characterized by muscle wasting (atrophy), particularly of distal muscles in legs and hands, and by early - onset contractures 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. Oates EC, Reddel S, Rodriguez ML; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Arm muscle and function, as well as cardiac and respiratory functions are typically well preserved. Mercuri E, Messina S, Kinali M; et al. (2004). "Congenital form of spinal muscular atrophy predominantly affecting the lower limbs: a clinical and muscle MRI study". Neuromuscul. Disord. 14 (2): 125–9. PMID 14733958. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
Signs and Symptoms
- Neurogenic muscle weakness
- Atrophy (of lower and upper limbs)
- Club_foot
- Arthrogryposis
- Scoliosis
- Platyspondyly
- Pes cavus
- Vocal cord paralysis
Causes
Congenital distal spinal muscular atrophy is caused by a mutation of the TRPV4 gene found on the 12q23-12q24.1. Everaerts W, Nilius B, Owsianik G (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) 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.
Pathophysiology
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 Ca2+. TRPV4 plays a major role in mechanosensation, as well as osmosensory functions in endothelia and alveoli, as well as nerve endings. Auer-Grumbach M, Olschewski A, Papić L; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)The TRPV4 protein consists of 871 amino acids with it's N- and C- terminals facing intracellularly. The protein is also comprised of six alpha helices that pass through the plasma membrane. Mutations in TRPV4 can result in the loss of it's normal function, or a toxic gain of function. In the latter case, intracellular Ca2+ levels are increased, which result in abnormal regulation. Fiorillo C, Moro F, Brisca G; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
Mechanism
The ankyrin repeat domain (ARD) is 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 substitution of arginine, which is an amino acid. Dai J, Cho TJ, Unger S; et al. (2010). "TRPV4-pathy, a novel channelopathy affecting diverse systems". J. Hum. Genet. 55 (7): 400–2. doi:10.1038/jhg.2010.37. PMID 20505684. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Arginine is highly polar and positively charged, while it's replacements are less polar or nonpolar. Some of these identified amino acid substitutions have been listed below.
Identified Mutations
- R296H, arginine to histidine substitution
- R315W, arginine to tryptophan substitution
- R316C, arginine to cysteine substitution
- R594H, arginine to histidine substitution
Screening
- Nerve conduction studies (NCS), to test for denervation
- Electromyography (EMG), also to detect denervation
- X-ray, to look for bone abnormalities
- Magnetic Resonance Imaging (MRI)
- Skeletel muscle biopsy examination
- Serum creatine kinase (CK) level in blood, usually elevated in affected individuals
- Pulmonary function test
Diagnosis
A diagnosis is made after specific criteria have been satisfied. Electrophysiological evidence of denervation with intact motor and sensory nerve conduction findings must be made by using NCSs, usually in conjunction with EMG. The presence of polyphasic potentials and fibrillation at rest are characteristic of congenital dSMA.5. Fiorillo C, Moro F, Brisca G; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) An x-ray of an individual will also show abnormal bone growth Histologic evidence from muscle biopsy samples of denervation must also be present. Russman BS (2007). "Spinal muscular atrophy: clinical classification and disease heterogeneity". J. Child Neurol. 22 (8): 946–51. doi:10.1177/0883073807305673. PMID 17761648. {{cite journal}}: Unknown parameter |month= ignored (help)
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 foot orthoses, callipers, or wheelchairs. Mercuri E, Messina S, Kinali M; et al. (2004). "Congenital form of spinal muscular atrophy predominantly affecting the lower limbs: a clinical and muscle MRI study". Neuromuscul. Disord. 14 (2): 125–9. PMID 14733958. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Orthopaedic surgery can be an option for some patients. Physical therapy and occupational therapy can help prevent further contractures from occuring, 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. Farmer SE, James M (2001). "Contractures in orthopaedic and neurological conditions: a review of causes and treatment". Disabil Rehabil. 23 (13): 549–58. PMID 11451189. {{cite journal}}: Unknown parameter |month= ignored (help)
Prognosis
Some researchers have concluded that prognosis is mainly dependent on maximum function achieved by an affected individual. Patients who can not sit alone typically have a life expectancy of less than 4 years. Patients who can sit, but could never walk live for at least 20 to 30 years. And patients who have the ability to walk at some point in their lives have a lifespan that is indefinite. However, all patients lose function over time.
Related Disorders Involving the TRPV4 Gene
Mutations on the TRPV4 gene can cause different, but very similar spinal muscular atrophies (SMA) of the peripheral nervous system. Other skeletal dysplasias can also be the result of a mutation on the TRPV4 gene. Krakow D, Vriens J, Camacho N; et al. (2009). "Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia". Am. J. Hum. Genet. 84 (3): 307–15. doi:10.1016/j.ajhg.2009.01.021. PMC 2667978. PMID 19232556. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) The mutations can occur at different alleles that have been linked to scapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy 2C (HMSN2C), which are forms of SMAs. The related skeletal dysplasias include brachyolmia, spondylometaphyseal dysplasia Kozlowski type, and nonlethal metatropic dysplasia. Camacho N, Krakow D, Johnykutty S; et al. (2010). "Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia". Am. J. Med. Genet. A. 152A (5): 1169–77. doi:10.1002/ajmg.a.33392. PMID 20425821. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) All of these disorders exhibit overlapping symptoms, as well as unique ones that set them apart from the others.
Scapuloperoneal Spinal Muscular Atrophy (SPSMA)
Scapuloperoneal weakness and atrophy, vocal cord paralysis, laryngeal palsy, along with absence of some muscle groups are all typical features of SPSMA. Males are more affected than females, and later generations have increased disease expression, suggesting genetic anticipation. Isozumi K, DeLong R, Kaplan J; et al. (1996). "Linkage of scapuloperoneal spinal muscular atrophy to chromosome 12q24.1-q24.31". Hum. Mol. Genet. 5 (9): 1377–82. PMID 8872481. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
Hereditary Motor and Sensory Neuropathy 2C (HMSN2C)
Hereditary motor and sensory neuropathy 2C, or commonly known as Charcot - Marie - Tooth disease is also a result of a mutation of the TRPV4 gene. Signs and symptoms include distal muscle weakness and wasting in the limbs, distal sensory loss, vocal cord paralysis, and weakness of the diaphragm and intercostal muscles. Onset varies greatly from childhood to 30 years of age, with prognosis mainly due to respiratory complications. Zimoń M, Baets J, Auer-Grumbach M; et al. (2010). "Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies". Brain. 133 (Pt 6): 1798–809. doi:10.1093/brain/awq109. PMC 2912694. PMID 20460441. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
Brachyolmia
Features of brachyolmia include short trunk, scoliosis, and mild short stature. The autosomal dominant form of brachyolmia is also linked to a mutation on the TRPV4 gene located on chromosome 12q24.1-12q24.2. Rock MJ, Prenen J, Funari VA; et al. (2008). "Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia". Nat. Genet. 40 (8): 999–1003. doi:10.1038/ng.166. PMC 3525077. PMID 18587396. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
Spondylometaphyseal dysplasia Kozlowski type (SMDK)
Affected individuals typically have short trunk and short stature, in addition to bowlegs and a waddling gait. Kyphoscoliosis is common and the thorax is generally short and broad. Further features include severe platyspondyly, and metaphyseal dysplasia. Nishimura G, Lausch E, Savarirayan R; et al. (2012). "TRPV4-associated skeletal dysplasias". Am J Med Genet C Semin Med Genet. 160C (3): 190–204. doi:10.1002/ajmg.c.31335. PMID 22791502. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
Nonlethal metatropic dysplasia (MD)
The course of the disease is very unique in that it evolves from individuals being short-limbed at birth to instead possessing a short-trunk phenotype over the first decade, as a result of rapidly progressing kyphoscoliosis. At birth, a prominent forehead and squared jaw are present. Occasionally, an individual may be born with an elongated coccyx, sometimes referred to as a tail-like appendage.
See also
References
External Links
Congenital dSMA Online Mendelian Inheritance in Man (OMIM)
Connective Tissue Gene Tests (CTGT)
Info on EMG recordings
Brachyolmia