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TRPV4-Associated Disorders

, MS, CGC, , MD, and , MD, PhD.

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Summary

Clinical characteristics.

The TRPV4-associated disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within and between both groups is considerable. Bilateral progressive sensorineural hearing loss (SNHL) can occur in both.

The three neuromuscular disorders (mildest to most severe):

  • Charcot-Marie-Tooth disease type 2C (CMT2C)
  • Scapuloperoneal spinal muscular atrophy (SPSMA)
  • Congenital distal spinal muscular atrophy (CDSMA)

The neuromuscular disorders are characterized by a progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures.

The six skeletal dysplasias:

  • Mildest:
    • Familial digital arthropathy-brachydactyly
  • Intermediate:
    • Autosomal dominant brachyolmia
    • Spondylometaphyseal dysplasia, Kozlowski type
    • Spondyloepiphyseal dysplasia, Maroteaux type
  • Most severe:
    • Parastremmatic dysplasia
    • Metatropic dysplasia

The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the TRPV4-associated disorders life span is normal; in the most severe it is shortened.

Diagnosis/testing.

The diagnosis of TRPV4-associated disorders is based on clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and the identification of a heterozygous TRPV4 pathogenic variant on molecular genetic testing.

Management.

Treatment of manifestations: Treatment is symptomatic. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. SNHL is managed by specialists to determine the best habilitation options.

For neuromuscular disorders: Neuropathy and respiratory dysfunction are managed in a routine manner; laryngeal dysfunction requires speech therapy and, in some instances, surgery.

For skeletal dysplasias: Physical therapy/exercise to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present.

Surveillance: For neuromuscular disorders: Routine neurologic examinations, physical therapy assessments, monitoring of laryngeal function, respiratory function, and hearing. For skeletal dysplasias: Annual evaluation for joint pain and scoliosis; assessment for odontoid hypoplasia before a child reaches school age and before surgical procedures involving general anesthesia

Agents/circumstances to avoid: For neuromuscular disorders: Obesity as it makes walking more difficult; medications which are toxic or potentially toxic to persons with a peripheral neuropathy. For skeletal dysplasias: Extreme neck flexion and extension (in those with odontoid hypoplasia); activities that place undue stress on the spine and weight-bearing joints

Pregnancy management: Ideally woman with TRPV4-associated disorder would seek consultation from a high-risk OB/GYN or maternal-fetal-medicine specialist to evaluate risk for pregnancy and delivery.

Genetic counseling.

TRPV4-associated disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with a TRPV4-associated disorder have an affected parent. However, since the most severe skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes likely have a de novo pathogenic variant and unaffected parents. Each child of an individual with a TRPV4-associated disorder has a 50% chance of inheriting the pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be predicted accurately because of incomplete penetrance and variable expressivity. However, in general, a child who inherits a TRPV4 pathogenic variant associated with neuromuscular disease or skeletal dysplasia from an affected parent is likely to have the same phenotype as the parent. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.

GeneReview Scope

TRPV4-Associated Disorders: Included Phenotypes 1
Neuromuscular disorders
  • Charcot-Marie-Tooth neuropathy type 2C
  • Scapuloperoneal spinal muscular atrophy
  • Congenital distal spinal muscular atrophy
Skeletal dysplasias
  • Familial digital arthropathy-brachydactyly
  • Autosomal dominant brachyolmia
  • Spondylometaphyseal dysplasia, Kozlowski type
  • Spondyloepiphyseal dysplasia, Maroteaux type
  • Parastremmatic dysplasia
  • Metatropic dysplasia

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

The phenotypes associated with heterozygous TRPV4 pathogenic variants were considered to be clinically distinct disorders long before their molecular basis was discovered. Now with the current understanding of their molecular basis, these TRPV4-associated disorders have been grouped primarily into neuromuscular disorders and skeletal dysplasias; however, the overlap within the neuromuscular disorders and within the skeletal dysplasias is considerable – as may be the overlap between the neuromuscular disorders and the skeletal dysplasias. Of note, bilateral progressive sensorineural hearing loss (SNHL) that ranges from mild to moderate can occur in both. Thus, TRPV4-associated disorders comprise a continuum that precludes the establishment of clear distinctions within and between phenotypes.

The phenotypes comprising the two groups of TRPV4-associated disorders (listed from mildest to most severe) are:

  • Neuromuscular disorders (see Table 1):
    • Charcot-Marie-Tooth disease type 2C
    • Scapuloperoneal spinal muscular atrophy
    • Congenital distal spinal muscular atrophy
  • Skeletal dysplasias (see Table 2):
    • Familial digital arthropathy-brachydactyly
    • Autosomal dominant brachyolmia
    • Spondylometaphyseal dysplasia, Kozlowski type
    • Spondyloepiphyseal dysplasia, Maroteaux type
    • Parastremmatic dysplasia
    • Metatropic dysplasia

Suggestive Findings

Neuromuscular Disorders

A TRPV4-associated neuromuscular disorder is suspected in individuals with the following range of clinical findings.

Charcot-Marie-Tooth disease type 2C (CMT2C)

  • A progressive peripheral neuronopathy/neuropathy (primarily motor, rather than sensory) associated with pes cavus, distal amyotrophy, and foot drop
    • Nerve conduction studies [Dyck et al 1994, Zimoń et al 2010] show (a) reduced compound motor action potential (CMAP) amplitudes with normal velocities (>40-60 m/s), although occasionally they may be mildly abnormal (36-40 m/s); and (b) normal, decreased, or absent distal sensory nerve action potential (SNAP) amplitudes.
    • Electromyography (EMG) shows predominantly chronic neurogenic changes.
    • Nerve biopsy is infrequently employed as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
  • Laryngeal dysfunction (i.e., vocal fold paresis) that may be bilateral and severe (resulting in inspiratory stridor and/or a raspy (hoarse) voice) or asymmetric (often more severe on the left than the right). Mild paresis may be inferred by presence of flaccid dysphonia [Dyck et al 1994]. Laryngoscopy often shows paresis of one or both vocal folds.
  • Sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate. Onset is from childhood to adulthood [Kannu et al 2007, Landouré et al 2010].
  • Respiratory dysfunction in some cases including intercostal and diaphragm muscle weakness, which may lead to respiratory insufficiency and/or sleep apnea [Chen et al 2010]. Chest radiograph and pulmonary function tests may demonstrate diaphragm weakness with decreased inspiratory and expiratory pressures [Dyck et al 1994, Donaghy & Kennett 1999].
  • Joint contractures (appearing similar to arthrogryposis multiplex congenita [AMC]) and short stature in some cases
  • A family history consistent with autosomal dominant inheritance

Scapuloperoneal spinal muscular atrophy (SPSMA)

  • Slowly progressive lower motor neuron loss associated with muscle weakness and atrophy proximally in the shoulder girdle region (with characteristic scapular winging) and distally in the peroneal (lower leg) muscles. In severe cases, absence of muscle and weakness are evident at birth [DeLong & Siddique 1992, Auer-Grumbach et al 2010, Deng et al 2010].
  • Muscle biopsy (infrequently performed) showing evidence of denervation and renervation [Deng et al 2010, Berciano et al 2011]
  • Laryngeal dysfunction (laryngomalacia and vocal fold anomalies as in CMT2C), vocal cord paresis, and transient dysphonia [Berciano et al 2011]
  • SNHL (as in CMT2C)
  • Sensory deficits (rare)
  • Kyphoscoliosis

Congenital distal spinal muscular atrophy (CDSMA)

  • Congenital-onset, non-progressive or slowly progressive lower motor neuron loss associated with muscle weakness and atrophy, predominantly affecting the lower extremities (distal greater than proximal)
  • Flexion contractures of the knees and hips often present at birth (i.e., arthrogryposis multiplex congenita [AMC])
  • MRI of calf and thigh muscles showing a distinct pattern of fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves [Astrea et al 2012]

Table 1.

Neurologic Findings by TRPV4-Associated Neuromuscular Phenotype

FindingPhenotype
CMT2CScapuloperoneal SMACongenital Distal SMA
Age at onsetBirth–adulthoodBirth–adulthoodPrenatal
NeuropathyPeripheral, progressive (distal)Peripheral, progressive (distal >proximal)Paralysis of the legs at birth 1
Vocal cord
paralysis
++
(transient dysphonia)
±
SNHL++
Respiratory
dysfunction 2
++
Joint
contractures
AMC (involving feet, knee, hips)
OtherSee footnote 3See footnote 4See footnote 5

CMT2C = Charcot-Marie-Tooth disease type 2C

SMA = spinal muscular atrophy

SNHL= sensorineural hearing loss

AMC= arthrogryposis multiplex congenita

1.

More mild manifestation: congenital weakness of the distal part of the lower limbs only. More severe manifestation: weakness of the pelvic girdle and trunk muscles, resulting in scoliosis.

2.

Secondary to diaphragmatic and intercostal muscle involvement

3.

Cold sensitivity (i.e., worsening of hand weakness in the cold)

4.

Rounded shoulders, laterally displaced scapulae

5.

Proximal muscle weakness (shoulder girdle, pelvic girdle) later in the disease course

Skeletal Dysplasias

A TRPV4-associated skeletal dysplasia is suspected in individuals with the following skeletal findings:

  • Familial digital arthropathy-brachydactyly (FDAB) characterized by the following:
    • Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood.
    • Progressive arthropathy of the other joints of the hands and feet with pain and deformity.
    • No clinical overlap with other TRPV4-associated skeletal dysplasias.
  • The other TRPV4-associated skeletal dysplasias (autosomal dominant brachyolmia; spondylometaphyseal dysplasia, Kozlowski type; spondyloepiphyseal dysplasia, Maroteaux type; and parastremmatic dysplasia and metatropic dysplasia) form a phenotypic continuum of overlapping disorders from mild to severe, each with:
    • Short stature
    • Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and over-faced pedicles
    • At least one additional distinctive feature (see Table 2)

Table 2.

Radiographic and Clinical Features of TRPV4-Associated Skeletal Dysplasias

FeaturePhenotype
MildIntermediateSevere
Familial digital arthropathy-brachydactylyAutosomal dominant brachyolmiaSpondylo-metaphyseal dysplasia, Kozlowski typeSpondylo-epiphyseal dysplasia, Maroteaux typeParastremmatic dysplasia 1Metatropic dysplasia
Hands/ feetNormal at birth; progressive swelling & arthropathy (see details)ClinodactylyBrachydactyly; hypoplastic carpal bones w/severe delay in ossificationBrachydactylyJoint contracturesBrachydactyly w/delayed carpal ossification
SpineNormal± Scoliosis, kyphosis; mild platyspondylyPlatyspondyly; over-faced pedicles 2Significant kyphoscoliosis; over-faced pedicles 2Platyspondyly; over-faced pedicles 2
Long bonesN/AMinimal metaphyseal changes; short femoral neck w/irregular proximal femoral metaphyses± Mild metaphyseal changes; genu varumMild to moderate metaphyseal changes; genu varumSevere metaphyseal changes w/severe limb deformity; joint contractures; other 3Dumbbell-shaped long bones w/epiphyseal dysplasia & prominent joints; progressive joint contractures; other 4
PelvisNormalN/ASquare, short, flared iliac wings; flat, irregular acetabulae; coxa vara; ± supra-acetabular notchesChampagne-glass configuration of pelvic inletHalberd-shaped 5 pelvis; supra-acetabular notches
OtherAverage height; early-childhood onsetMild short stature; limbs unaffected; good physical functionShort-trunk short-stature dwarfism; broad chest; early-childhood onset w/waddling gaitShort-trunk short-stature dwarfismSignificant short-trunk short-stature dwarfismMay be lethal prenatally or perinatally; at birth, short-limb short-stature dwarfism 6
1.

Rarest TRPV4-related skeletal dysplasia

2.

Over-faced pedicles = lateral border of the vertebrae appears outside the lateral edge of the pedicles, a characteristic feature of TRPV4-associated skeletal dysplasias best viewed on AP x-ray of the spine. See images in Nemec et al [2012] (full text).

3.

Additional findings: hyperplastic femoral trochanters; severe genu valgum; bowing of long bones; legs twisted along the long axis

4.

Histologic findings: thin seal of bone at the chondroosseous junction; absent primary metaphyseal spongiosa; abnormal metaphyseal vascular invasion; arrest of endochondral ring structures with persistence of circumferential growth

5.

Halberd-shaped pelvis is derived from the shape of a Swedish battle ax.

6.

Progressive kyphoscoliosis and platyspondyly subsequently alter proportions from short-limb to short-trunk dwarfism.

Establishing the Diagnosis

The diagnosis of a TRPV4-associated disorder is established in an individual with a heterozygous TRPV4 pathogenic variant.

One genetic testing strategy is sequence analysis of TRPV4 (Table 3).

Another genetic testing strategy is use of a multi-gene panel that includes TRPV4 and other genes of interest (see Differential Diagnosis). Note that the genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 3.

Summary of Molecular Genetic Testing Used in TRPV4-Associated Neuromuscular and Skeletal Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
TRPV4Sequence analysis 2~99%
Deletion/duplication analysis 3See footnote 4
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis can detect variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice-site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

4.

The authors are unaware of a whole-gene or contiguous gene deletion of TRPV4 causing one of the recognized phenotypes.

Clinical Characteristics

Clinical Description

The two groups of disorders and the phenotypes comprising TRPV4-associated disorders (listed from mildest to most severe) are:

  • Neuromuscular disorders (see Table 1):
    • Charcot-Marie-Tooth disease type 2C
    • Scapuloperoneal spinal muscular atrophy
    • Congenital distal spinal muscular atrophy
  • Skeletal dysplasias (see Table 2):
    • Familial digital arthropathy-brachydactyly
    • Autosomal dominant brachyolmia
    • Spondylometaphyseal dysplasia, Kozlowski type
    • Spondyloepiphyseal dysplasia, Maroteaux type
    • Parastremmatic dysplasia
    • Metatropic dysplasia

The phenotypic spectra within both groups are broad and overlapping, and the phenotypes of both groups often overlap as well [Chen et al 2010, Unger et al 2011, Cho et al 2012].

Of note, sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate, can occur in both phenotypes. Onset is from childhood to adulthood [Kannu et al 2007, Landouré et al 2010].

Neuromuscular Disorders

The TRPV4-associated neuromuscular disorders are peripheral neuropathies/neuronopathies in which motor nerves are more prominently affected than sensory nerves [Delong & Siddique 1992, Dyck et al 1994, Landouré et al 2010].

Clinical findings and age of onset can be extremely variable in TRPV4-associated neuromuscular disorders both between and within families [Dyck et al 1994, Donaghy & Kennett 1999, Zimoń et al 2010]. In some, the disease can be so mild as to go unrecognized by the affected individual and his/her physicians.

Affected individuals usually become symptomatic between early childhood and age 25 years; however, disease onset can range from birth with breathing difficulties and delayed walking to after the eighth decade [Dyck et al 1994].

Affected individuals typically have progressive weakness and atrophy of distal muscles in the feet and/or hands, usually associated with depressed tendon reflexes and mild or no sensory loss. Mild sensory deficits of position, vibration, and pain/temperature may occur in the feet or sensation may be intact.

Laryngeal dysfunction is a hallmark of Charcot-Marie-Tooth disease type 2C (CMT2C) and often observed in individuals with scapuloperoneal spinal muscular atrophy (SPSMA) and those with congenital distal spinal muscular atrophy (CDSMA) [Dyck et al 1994, Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Zimoń et al 2010].

The typical presenting symptoms are difficulty with phonation and breathing (inspiratory stridor) and distal leg weakness and atrophy.

Individuals with TRPV4-associated neuromuscular disorders typically have bilateral foot drop, symmetric atrophy of the muscles below the knee (stork leg appearance), and absent tendon reflexes in the legs. Atrophy of the intrinsic hand muscles is common; tendon reflexes may be intact in the arms.

Proximal limb muscles may be involved in severe cases, particularly in scapuloperoneal spinal muscular atrophy (SPSMA). As the name suggests, the pattern of muscle involvement includes progressive shoulder girdle atrophy and weakness leading to scapular winging (scapula alata) and involvement of the two muscle groups below the knee (peroneal distribution) [Delong & Siddique 1992].

TRPV4-associated neuromuscular disorders are progressive over many years. However, for the congenital forms – SPSMA and CDSMA – affected individuals experience long plateau periods without obvious deterioration [DeLong & Siddique 1992, Vlam et al 2012].

The disease may decrease life span in severe cases, secondary to respiratory complications [Dyck et al 1994, Donaghy & Kennett 1999, Santoro et al 2002, McEntagart et al 2005].

Skeletal Dysplasias

Familial digital arthropathy-brachydactyly is not evident at birth because the hands and feet and skeletal examination (including radiographs) are normal. In early childhood relative shortening of the middle and distal phalanges and swelling and decreased range of motion of the interphalangeal joints become apparent. Later in the first decade and beyond, the other joints of the hands and feet become painful and deformed. No overlap is currently recognized with the manifestations of the other TRPV4-associated skeletal dysplasias.

The remaining TRPV4-associated skeletal disorders are characterized by varying degrees of disproportionate short stature and progressive spinal deformity with scoliosis with or without kyphosis.

Autosomal dominant brachyolmia is the mildest of the short stature TRPV4 skeletal conditions. Its name was derived from the Greek roots brachy-, meaning short and -olmos, meaning trunk or shoulder. Affected individuals have only mild short stature and the limbs are typically unaffected; thus, physical function is unaffected.

Spondylometaphyseal dysplasia, Kozlowski type is marked by short-trunk short stature, although the chest is broader than in some of the more severe TRPV4-associated skeletal dysplasias. Birth length is average. Affected children usually come to medical attention in early childhood when poor growth with disproportionate stature and a waddling gait with genu varum become evident. Premature osteoarthritis of the joints is common.

Spondyloepiphyseal dysplasia, Maroteaux type is marked by short-trunk dwarfism and brachydactyly. Birth length is usually average. Poor growth with a short trunk and overall short stature become evident in childhood. Over time, genu valgum and kyphoscoliosis develop. Osteoporosis has been described.

Parastremmatic dysplasia, probably the rarest of the TRPV4-associated skeletal dysplasias, is characterized by severe limb deformities and joint malalignment, short stature, and kyphoscoliosis which are present at birth and progressively worsen throughout life.

Metatropic dysplasia (from Greek metatropos, meaning with change/changing pattern) was named after the striking reversal of body proportions between birth and childhood. At birth, the limbs are disproportionately short (due the long bone metaphyseal abnormalities) compared to the trunk. In childhood when the platyspondyly and scoliosis and/or kyphosis become more severe, the trunk becomes relatively short compared to the limbs.

Metatropic dysplasia may be lethal in the prenatal or perinatal period, largely due to an extremely narrow chest and hypoplastic lung parenchyma. Infants who survive the perinatal period typically develop severe kyphoscoliosis which eventually compromises pulmonary function. Other skeletal findings in some individuals with severe metatropic dysplasia are poor joint range of motion, joint contractures, and torticollis; these arthrogryposis multiplex congenita-like contractures represent an overlap between the neuromuscular and skeletal phenotypes of TRPV4-associated disorders [Unger et al 2011].

Genotype-Phenotype Correlations

In general, specific sets of TRPV4 pathogenic variants have been associated with either neuromuscular disorders or skeletal dysplasia; overlap may occur, however, making genotype-phenotype correlations difficult [Unger et al 2011, Sullivan & Earley 2013]. See also Table 4.

Of note, the pathogenic variants p.Tyr591Cys, p.Arg594His, p.Glu797Lys, and p.Pro799Leu have been associated with both neuromuscular disease and skeletal dysplasia. In addition, the pathogenic variant p.Ser542Tyr caused both CMT2C and short stature in one family [Chen et al 2010].

Functional studies suggest that TRPV4 pathogenic variants associated with neuromuscular disorders and skeletal dysplasias may cause a gain of channel function [Rock et al 2008, Krakow et al 2009, Nilius & Voets 2013]; whereas the pathogenic variants associated with familial digital arthropathy-brachydactyly (FDAB) may cause a loss of channel function.

TRPV4-associated neuromuscular disorders. Several studies suggest that most TRPV4 pathogenic variants associated with a neuromuscular phenotype cluster on the highly positively charged convex surface of the ankyrin repeats domain and target arginine residues that are strictly conserved throughout 27 available TRPV4 orthologs [Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010]. These surface pathogenic variants are located in three consecutive finger loops of the protein, a distinct region of the TRPV4 ankyrin repeats.

  • At least 13 TRPV4 pathogenic variants cause CMT2C and are predominantly in the N-terminal domain, but others are located in different protein regions.
  • The eight TRPV4 pathogenic variants that cause SPSMA are located in either the N-terminus or the transmembrane region [Nilius & Voets 2013].
  • The six different TRPV4 pathogenic variants that cause congenital distal spinal muscular atrophy are located in the N-terminal cytosolic tail of the TRPV4 proteins [Fiorillo et al 2012].

TRPV4-associated skeletal dysplasias. The familial digital arthropathy-brachydactyly (FDAB)-causing pathogenic variants are restricted to finger 3 of the ankyrin repeats domain (ARD: pathogenic variants p.Gly270Val, p.Arg271Pro, p.Phe273Leu) [Nilius & Voets 2013].

In total, more than 50 pathogenic variants in TRPV4 have been reported to cause brachyolmias. While the pathogenic variants are spread over the whole gene, two hot spots have been observed at residues Pro799 in exon 15 and Arg594 in exon 11 [Nishimura et al 2012], which localize to the channel pore region.

Penetrance

TRPV4-associated neuromuscular disorders. Penetrance is incomplete with the neuromuscular disease-associated pathogenic variants. Non-penetrance has been described for the p.Arg232Cys and p.Arg315Trp variants.

No difference in phenotype is observed between males and females.

Incomplete penetrance is known in the hereditary peripheral neuropathies, and for example has been observed for pathogenic variants in GARS, encoding glycyltRNA synthetase (see GARS-Associated Neuropathies) [Sivakumar et al 2005], MPZ, encoding myelin protein zero (see CMT2) [De Jonghe et al 1999], and BSCL2, encoding seipin (see Berardinelli-Seip Congenital Lipodystrophy and BSCL2-Related Neurologic Disorders/Seipinopathy) [Auer-Grumbach et al 2005]. In TRPV4-associated neuropathy, however, reduced penetrance appears to be a relatively common feature that is not variant specific [Zimoń et al 2010].

TRPV4-associated skeletal dysplasias. In contrast, penetrance of the skeletal dysplasia phenotype appears to be high; however, intra- and interfamilial variability is significant [Dai et al 2010].

Nomenclature

Charcot-Marie-Tooth neuropathy type 2C is also referred to as hereditary motor and sensory neuropathy type 2C.

Spondyloepiphyseal dysplasia, Maroteaux type is also referred to as pseudo-Morquio syndrome type 2.

Prevalence

The prevalence of the TRPV4-associated neuromuscular and skeletal dysplasias has not been well studied.

Fawcett et al [2012] determined that 13 (<1%) of 422 individuals with a CMT2 (axonal CMT) phenotype were heterozygous for a TRPV4 pathogenic variant. Of note, the detection of a TRPV4 pathogenic variant increased to 9% in those with an unusual CMT2 presentation (e.g., vocal fold and diaphragmatic paresis).

Differential Diagnosis

TRPV4-associated neuromuscular disorders (Charcot-Marie-Tooth disease type 2C [CMT2C], scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy) resemble several other disorders (see note):

Note: See Charcot-Marie-Tooth Neuropathy Type 2 for a general overview of CMT2.

TRPV4-associated skeletal dysplasias have a broad phenotypic spectrum and, thus, many skeletal dysplasias to consider in the differential diagnosis.

Mild (familial digital arthropathy-brachydactyly). The differential diagnosis includes reactive arthropathy, diabetic arthropathy, and other forms of brachydactyly [Amor et al 2002].

Intermediate (autosomal dominant brachyolmia; spondylometaphyseal dysplasia, Kozlowski type; and spondyloepiphyseal dysplasia, Maroteaux type). The differential diagnosis includes the following [Krakow et al 2009, Dai et al 2010]:

Severe (parastremmatic dysplasia and metatropic dysplasia). The differential diagnosis includes the following [Maroteaux et al 1966, Beck et al 1983, Hall & Elcioglu 2004]:

  • Weissenbacher Zweymuller syndrome
  • Fibrochondrogenesis (rhizomelic limb shortening, broad dumbbell-shaped metaphyses, pear-shaped vertebral bodies, short and distally cupped ribs)
  • Kniest syndrome (platyspondyly and coronal cleft, shortened tubular bones and metaphyseal flaring, broad and short thorax)
  • Dyssegmental dysplasia

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a TRPV4-associated neuromuscular disorder, the following evaluations are recommended:

  • Physical/neurologic examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
  • Electromyography (EMG) with nerve conduction velocity (NCV)
  • ENT consultation with laryngoscopy, as needed to document the status of the vocal folds
  • Pulmonary function testing and dynamic breathing chest x-ray
  • Hearing assessment (See Deafness and Hereditary Hearing Loss Overview for different types of hearing assessment.)
  • Skeletal x-rays to document any associated skeletal dysplasia
  • Clinical genetics/genetic counseling consultation

To establish the extent of disease and needs in an individual diagnosed with a TRPV4-associated skeletal dysplasia, the following evaluations are recommended:

  • Skeletal radiographs to document involvement of the long bones and spine, which can help determine patient needs as well as provide a baseline for comparison with future studies
  • Flexion/extension cervical spine films to determine if there is atlanto-axial instability secondary to odontoid hypoplasia
  • Pulmonary function tests and/or sleep study if the thorax is particularly narrow and/or kyphoscoliosis is progressive
  • Hearing assessment (See Deafness and Hereditary Hearing Loss Overview for different types of hearing assessment.)

Treatment of Manifestations

Treatment is symptomatic. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Grandis & Shy 2005].

For treatment of findings common to all TRPV4-associated disorders

  • Sensorineural hearing loss. Referral to hearing loss specialists to determine the extent of hearing loss and the best habilitation options for sensorineural hearing loss (See Deafness and Hereditary Hearing Loss Overview for discussion of management issues.)
  • Pain and depression. Symptomatic treatment

For the TRPV4-associated neuromuscular disorders the following are indicated:

  • Neuropathy
    • Special shoes, including those with good ankle support
    • Ankle/foot orthoses (AFO) to correct foot drop and aid walking
    • Orthopedic surgery to correct severe pes cavus deformity as needed [Guyton & Mann 2000]
    • Forearm crutches, canes/walkers for gait stability, and wheelchairs
    • Exercise within the individual's capability (Many individuals remain physically active.)
    • Symptomatic treatment of pain and depression [Gemignani et al 2004, Padua et al 2006]
  • Vocal cord involvement
    • Laryngeal surgery for vocal fold paresis (arytenoidectomy and tracheostomy)
    • Speech therapy
  • Respiratory dysfunction. Respiratory therapy/support (e.g., BiPAP)

For the TRPV4-associated skeletal dysplasias the following treatments may be indicated:

  • Physical therapy/exercise to maintain as much function as possible. Daily heel cord-stretching exercises are helpful in preventing Achilles' tendon shortening.
  • Orthopedic evaluation with consideration of surgical intervention (i.e., spinal fusion) when kyphoscoliosis compromises pulmonary function and/or causes pain
  • Odontoid hypoplasia. When upper cervical spine instability is documented or when clinical findings of cervical myelopathy are present, occipito-cervical or upper cervical decompression and fusion are required to stabilize the upper cervical spine and relieve cervical cord compression. To minimize neurologic injury and maximize function, it is preferred that intervention in children occur when radiographic signs of cervical compression are present, even in the absence of symptoms. Patients undergoing surgical fusion typically do well; minor secondary complications can include pin site infections, pressure sores, and long-term difficulty with endotracheal intubation. Note: It is important for clinicians to be aware that cervical myelopathy from upper cervical instability may result in deteriorating endurance and worsening gait. If myelopathy is suspected, obtain cervical spine radiographs and MRI. The patient should be referred for evaluation by a pediatric orthopedic surgeon or neurosurgeon at a tertiary care facility.
  • Symptomatic treatment of pain and depression (which can influence physical function). Note that chronic pain management preceding or following orthopedic surgery is standard and often required.

Surveillance

TRPV4-associated neuromuscular disorders. Annual:

  • Neurologic examination to determine extent of weakness and atrophy, and sensory loss
  • Physical therapy examination to monitor feet to determine need for bracing, special shoes, and/or surgery
  • ENT consultation with laryngoscopy
  • Dynamic breathing chest x-ray
  • Hearing assessment

TRPV4-associated skeletal dysplasias

  • Annual assessment for the development of joint pain and scoliosis
  • Cervical spinal films to assess for clinically significant odontoid hypoplasia before:
    • A child reaches school age;
    • Surgical procedures involving general anesthesia

Agents/Circumstances to Avoid

No specific data are available for TRPV4-associated neuromuscular or skeletal disorders.

In general, obesity is to be avoided because it makes walking more difficult for individuals with neuropathy, skeletal dysplasia, or both.

For neuromuscular disorders. Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. Click here (pdf) for an up-to-date list.

For skeletal dysplasias

  • In individuals with odontoid hypoplasia, extreme neck flexion and extension
  • Activities and occupations that place undue stress on the spine and weight-bearing joints

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There is no registry or data regarding the frequency or outcome of pregnancies in women with a TRPV4-related disorder; however, the following general information may be reasonable to consider.

Ideally a woman with a TRPV4-associated disorder would seek consultation from a high-risk OB/GYN or maternal-fetal-medicine specialist to evaluate her risks for pregnancy and delivery.

TRPV4-associated neuromuscular disorders. Argov & de Visser [2009] reviewed pregnancy issues in hereditary neuromuscular disorders including CMTs.

About 50% of women with CMT described increased weakness during pregnancy that usually resolved post partum [Rudnik-Schoneborn et al 1993].

Operative deliveries were reported more commonly in women with CMT in Norway [Hoff et al 2005]. Greenwood & Scott [2007] described the obstetric approach to women with mild and severe forms of CMT.

A recent German study reviewed 63 pregnancies in 33 women with CMT [Awater et al 2012] and found no increase in the frequency of Cesarean section, forceps delivery, premature birth, or neonatal problems. About one third of mothers felt a worsening of CMT symptoms during pregnancy; in one fifth of mothers the changes were felt to be persistent.

TRPV4-associated skeletal dysplasias. In TRPV4-associated skeletal dysplasias, the degree of pulmonary compromise (from the short trunk and decreased lung capacity) may affect the ability to carry a pregnancy to term. Thus, it is unlikely a woman with metatropic dysplasia could carry a pregnancy.

A pregnant woman with a TRPV4-assocaited skeletal dysplasia generally undergo cæsarean section delivery because of the small size of the pelvis.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Career and employment choices may be influenced by persistent weakness of hands and/or feet.

Genetic Counseling

Mode of Inheritance

TRPV4-associated disorders (TRPV4-associated neuromuscular and skeletal disorders) are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with a TRPV4-associated disorder have an affected parent. However, since the most severe skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes likely have a de novo pathogenic variant and unaffected parents.
  • A proband with a TRPV4-associated disorder may have the disorder as the result of a de novo pathogenic variant. De novo mutation is likely in children with severe, lethal presentations of TRPV4-associated disorders.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are de novo mutation in the proband or germline mosaicism in a parent. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include TRPV4 molecular genetic testing. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although most individuals diagnosed with a TRPV4-associated disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

  • If a parent of the proband is affected or has a TRPV4 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • The sibs of a proband with clinically unaffected parents are still at increased risk for a TRPV4-associated disorder because of the possibility of reduced penetrance in the parent with the pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with a TRPV4-associated disorder has a 50% chance of inheriting the pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be predicted accurately because of incomplete penetrance and variable expressivity. However, in general, a child who inherits a TRPV4 pathogenic variant associated with neuromuscular disease or skeletal dysplasia from an affected parent is likely to have the same phenotype as the parent.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has a TRPV4 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a TRPV4-associated skeletal disorder may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals may be distinct from those of the parents. When the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has a 25% likelihood of having average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a potentially poor outcome.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant and/or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of at-risk asymptomatic adults. Asymptomatic adults at risk of having inherited a pathogenic variant associated with autosomal dominant with a TRPV4-associated disorder may wish to pursue molecular genetic testing. If identified to have inherited a TRPV4 pathogenic variant, further clinical evaluation, EMG/NCV, and/or skeletal survey may be appropriate. No treatment is available to individuals early in the course of the disease. Thus, such testing is for personal decision making only.

Testing of at-risk asymptomatic individuals during childhood. Testing of at-risk asymptomatic individuals who are younger than age 18 years should be considered on a case-by-case basis to determine if clinically appropriate. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

DNA banking is the storage of DNA [typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the TRPV4 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for a TRPV4-associated disorder are possible options. However, specific phenotype, age of onset, and/or disease severity cannot be reliably predicted based on the results of prenatal testing.

Requests for prenatal testing for conditions which (like TRPV4-associated disorders) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for TRPV4-Associated Disorders have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

TRPV4-Associated Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for TRPV4-Associated Disorders (View All in OMIM)

113500BRACHYOLMIA TYPE 3; BCYM3
156530METATROPIC DYSPLASIA
168400PARASTREMMATIC DWARFISM
181405SCAPULOPERONEAL SPINAL MUSCULAR ATROPHY; SPSMA
184095SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE
184252SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE; SMDK
600175NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE VIII; HMN8
605427TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 4; TRPV4
606071HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC; HMSN2C
606845GOLGI-ASSOCIATED PDZ AND COILED-COIL DOMAINS-CONTAINING PROTEIN; GOPC

Gene structure. TRPV4 comprises 15 exons. Alternative splicing may give rise to ten transcripts ranging from the 3,233-bp full-length transcript variant NM_021625.4 that encodes 871 amino acids to smaller, alternatively spliced transcripts. The functional importance of smaller spliced isoforms of TRPV4 has not been established. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. Variants p.Glu218Lys, p.Tyr567Ter, and p.Trp733Ter were found unlikely to be pathogenic due to lack of familial segregation, lack of protein dysfunction, and lack of segregation and presence in controls, respectively [Fawcett et al 2012].

Pathogenic allelic variants. The authors are not aware of a whole-gene or contiguous-gene deletion of TRPV4 causing any of the recognized phenotypes.

  • TRPV4-associated neuromuscular disorders. Nine pathogenic missense variants have been reported. No frameshift or nonsense pathogenic variants have been reported [Zimoń et al 2010, McEntagart 2012].
  • TRPV4-associated skeletal dysplasias. Over 40 pathogenic variants have been identified scattered throughout the protein. Three have been associated with familial digital arthropathy-brachydactyly (FDAB).

Table 4.

Selected TRPV4 Allelic Variants

Variant ClassificationPredominant PhenotypeDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Benignc.652G>Ap.Glu218LysNM_021625​.4
NP_067638​.3
c.1701C>Ap.Tyr567Ter
c.2198G>Ap.Trp733Ter
PathogenicNeuromuscularc.557G>Ap.Arg186Gln
c.694C>Tp.Arg232Cys 1
c.805C>Tp.Arg269Cys
c.806G>Ap.Arg269His
c.943C>Tp.Arg315Trp
c.946C>Tp.Arg316Cys
c.947G>Ap.Arg316His
c.1625C>Ap.Ser542Tyr 1
c.1858G>Ap.Val620Ile 1
Skeletalc.82A>Gp.Lys276Glu 1
c.232G>Tp.Gly78Trp 1
c.266C>Tp.Thr89Ile
c.547G>Ap.Glu183Lys
c.590A>Gp.Lys197Arg
c.597G>Cp.Leu199Phe
c.649G > Tp.Ala217Ser 1
c.717G>Cp.Gln239His
c.832G>Ap.Glu278Lys 1
c.883A>Gp.Thr295Ala
c.991A>Tp.Ile331Phe
c.992T>Cp.Ile331Thr
c.998A>Gp.Asp333Gly
c.1024G>Tp.Val342Phe
c.1219A>Gp.Lys407Glu
c.1412_1414delTCTp.Phe471del
c.1566_1568dupCCTp.Leu523dup
c.1772A>Gp.Tyr591Cys 1
c.1774T>Cp.Phe592Leu
c.1781G>p.Arg594Ser
c.1781G>Ap.Arg594His 1
c.1787T>Cp.Leu596Pro
c.1798G>Tp.Gly600Trp
c.1805A>Gp.Tyr602Cys
c.1812C>Gp.Ile604Met
c.1847G>Ap.Arg616Gln
c.1851C>Ap.Phe617Leu
c.1853T>Cp Leu618Pro
c.1858G>Ap.Val620Ile
c.1875G>Ap.Met625Ile
c.2125C>Ap.Leu709Met
c.2146G>Tp.Ala716Ser
c.2219C>Tp.Thr740Ile 1
c.2330G>Ap.Cys777Tyr
c.2389G>Ap.Glu797Lys 1
c.2395C>Tp.Pro799Ser
c.2396C > p.Pro799Ala
c.2396C >Gp.Pro799Arg 1
c.2396C>Gp.Pro799Arg 1
c.2396C>Tp.Pro799Leu
c.2396_2412del17p.Pro799LeufsTer63 1
Familial digital arthropathy-brachydactyly (FDAB)c.809G>Tp.Gly270Val
c.812G>Cp.Arg271Pro
c.819C>Gp.Phe273Leu

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Denotes a combined neuromuscular and skeletal phenotype

Normal gene product. TRPV4 encodes a non-selective cation channel modestly permeable to Ca2+ [Liedtke et al 2000, Plant & Strotmann 2007]. TRPV4 was initially identified as a vertebrate osmosensor, but can be activated by a wide variety of stimuli including cell shearing, heat, endogenous agonists (e.g., endocannabinoid anandamide, arachidonic acid), and synthetic agonists like 4_-phorbol-12,13-didecanoate (4_PDD) [Liedtke et al 2000, Nilius et al 2003, Watanabe et al 2003, Plant & Strotmann 2007, Everaerts et al 2010].

TRPV4 is expressed broadly and has diverse physiologic roles, including in osmosensation and flow sensing in the kidney [Pochynyuk et al 2013], mechanosensation and nociception in the sensory nervous system [Suzuki et al 2003, Alessandri-Haber et al 2009], stretch sensation in the bladder [Gevaert et al 2007], skin barrier function [Kida et al 2012], chondrogenesis [Muramatsu et al 2007], bone homeostasis [Masuyama et al 2012], and regulation of adipose oxidative metabolism [Ye et al 2012].

Abnormal gene product. While the exact pathophysiology of TRPV4 pathogenic variants that result in neuromuscular disease is unknown, several hypotheses exist. (Note: The use of various cell systems in the following studies may underlie the differences in results [Nilius & Owsianik 2010].)

  • In one study, three TRPV4 pathogenic variants (p.Arg269His, p.Arg315Trp, and p.Arg316Cys) influenced proper localization of the mutated protein ion channel to the plasma membrane [Auer-Grumbach et al 2010] with the formation of cytoplasmic aggregates. Mutated TRPV4 was shown to cause loss of normal channel function [Auer-Grumbach et al 2010].
  • The results from two other studies differed substantially [Deng et al 2010, Landouré et al 2010]: both showed increased intracellular calcium levels caused by abnormal activity of the TRPV4 ion channel in the presence of the p.Arg269His, p.Arg269Cys, or p.Arg316Cys pathogenic variant.

Similarly the exact pathophysiology of TRPV4 pathogenic variants that result in skeletal dysplasia is not well understood. Based on the lack of a comparable phenotype in the Trpv4 knockout mouse, it is presumed that the mechanism of disease in humans is by dominant gain of function. This mechanism also fits with the vast majority of the known TRPV4 pathogenic variants being missense; however, an insertion which adds an extra leucine in the second transmembrane domain has also been described. Nevertheless, exceptions exist, such as the single frameshift deletion variant shown in Table 4.

The gene is expressed in osteoblasts and osteoclasts at the earliest stages of chondrocyte differentiation – a finding that is consistent with its role in these skeletal disorders. A recent study by Nilius & Voets [2013] showed that the single nucleotide variants p.Arg616Gln and p.Val620Ile result in a gain of function characterized by increased constitutive activity and elevated channel activation.

References

Published Guidelines/Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 5-19-16. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2017. Accessed 5-19-16.

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Chapter Notes

Revision History

  • 15 May 2014 (me) Review posted live
  • 30 July 2013 (as) Original submission
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