Alternative titles; symbols
SNOMEDCT: 717010007; ORPHA: 99937; DO: 0110182;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.11 | Hereditary motor and sensory neuropathy, type IIc | 606071 | Autosomal dominant | 3 | TRPV4 | 605427 |
A number sign (#) is used with this entry because hereditary motor and sensory neuropathy type IIC (HMSN2C) is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24.
Congenital distal spinal muscular atrophy (HMND8; 600175) and scapuloperoneal spinal muscular atrophy (SPSMA; 181405) are allelic disorders with overlapping phenotypes.
Hereditary motor and sensory neuropathy type IIC (HMSN2C), also known as Charcot-Marie-Tooth disease type 2C (CMT2C), is an autosomal dominant form of peripheral axonal neuropathy with diaphragmatic and vocal cord paresis. Age at onset and severity is variable (Dyck et al., 1994; summary by Klein et al., 2011).
Dyck et al. (1994) described 2 kindreds with an autosomal dominant inherited disorder characterized by a variable degree of muscle weakness of limbs, vocal cords, and intercostal muscles and by asymptomatic sensory loss, beginning in infancy or childhood in severely affected persons. Life expectancy in the patients was shortened because of respiratory failure. Because nerve conduction velocities were normal and the disorder represented an inherited axonal neuropathy, Dyck et al. (1994) classified the condition as a form of hereditary motor and sensory neuropathy type II (HMSN IIC). Klein et al. (2003) reexamined one of the kindreds with CMT2C reported by Dyck et al. (1994) and identified 5 additional affected members.
Chen et al. (2010) reported follow-up of 1 of the families reported by Dyck et al. (1994). The 47-year-old proband developed acute respiratory stridor at age 6 months, requiring a permanent tracheostomy for partial vocal cord paresis at age 3 years. At age 6 years, she had no movement of the right cord and slight movement of the left cord, with a raspy but understandable voice; she developed a slowly progressive peripheral neuropathy at age 7. As an adult, she had weakness and atrophy of intrinsic hand muscles, weakness of the ankle muscles, areflexia, and distal sensory loss in the hands and feet. Her daughter developed severe stridor associated with vocal cord paresis at age 8 months, followed by mild peripheral neuropathy at age 6, and bilateral foot drop at age 26. Both mother and daughter had proportional short stature and used wheelchairs, but could walk short distances with assistance, The daughter also had a congenital strabismus with partial right third nerve deficit and a history of sleep apnea. The father of the mother had no stridor or wheezing, but onset of a peripheral neuropathy at about age 45.
Donaghy and Kennett (1999) described a white British family with axonal HMSN II in which 1 member developed a recurrent laryngeal nerve palsy at the age of 41 years, having had symptomatic polyneuropathy for 4 years and an abducens nerve palsy. McEntagart et al. (2005) provided more clinical details on the family reported by Donaghy and Kennett (1999). The proband presented at age 43 years with a 4-year history of diminished manual dexterity, difficulty walking, and a 2-year history of dysphonia. He had distal amyotrophy, pes cavus, a left lateral rectus palsy, and a left vocal cord paralysis. His mother and older sister were both asymptomatic but showed distal muscle weakness on examination. Electrophysiologic testing on all 3 family members showed an axonal polyneuropathy.
McEntagart et al. (2005) reported a family with 7 affected members spanning 4 generations; 6 were available for examination. The proband presented at birth with sloping shoulders and developed bilateral foot drop in childhood and hoarse voice in adolescence. At age 55 years, he was wheelchair-bound and needed assistance in all activities of daily living due to impaired manual dexterity and gait. He required respiratory assistance for hypercapnic respiratory failure and obstructive sleep apnea. He had severe distal amyotrophy and wasting of the shoulder girdle muscles. Laryngoscopy showed bilateral vocal cord paralysis. Other affected family members were less severely affected. One other member had onset at birth, and the others had onset ranging from 12 to 62 years.
McEntagart et al. (2001) noted that HMSN IIC shows considerable overlap with HMN VII (HMND7; 158580), but is distinguished by the presence of sensory involvement.
Landoure et al. (2010) studied 2 families with HMSN2C, one of which was the family reported by Dyck et al. (1994). There was marked intrafamilial variability of disease onset and severity. One individual had mild late-onset weakness, whereas her daughter had severe quadriparesis and respiratory failure. Axonal neuropathy was more motor than sensory, resulting in progressive weakness of distal limb, diaphragm, and laryngeal muscles. While few affected individuals complained of sensory loss, all had reduced or absent reflexes. Other prominent features included bilateral sensorineural hearing loss, bladder urgency and incontinence, and worsening of hand muscle weakness with cold. Muscle and nerve biopsies in a severely affected individual showed marked neurogenic atrophy of the gastrocnemius muscle, indicating severe loss of muscle innervations, and modest loss of sensory axons.
Chen et al. (2010) reported a 3-generation family in which 6 individuals had autosomal dominant HMSN2C confirmed by genetic analysis (S542Y; 605427.0022). There was phenotypic variability regarding severity of distal muscle weakness and distal sensory loss, but all had peripheral neuropathy, areflexia, and proportional short stature. All except 1 had vocal cord paresis, resulting in difficulty breathing and hoarse voice. Motor nerve conduction velocities were not abnormal, indicating an axonal neuropathy. Radiographic analysis of 1 patient showed reduced height of the vertebral bodies, and another had dolichocephaly. Chen et al. (2010) noted that TRPV4 mutations have also been found in patients with skeletal involvement (see, e.g., brachyolmia type 3; 113500), and suggested that the short stature observed in this family expanded and unified the phenotypic features associated with mutations in this gene.
Aharoni et al. (2011) reported a 3-generation family of Ashkenazi/Sephardic Jewish origin with variable expression of HMSN2C due to a heterozygous TRPV4 mutation (R315W; 605427.0008). Five mutation carriers in 1 family were studied. The proband was a girl who presented at birth with inspiratory stridor, clubfeet, congenital hip dislocation, and knee contractures. She had absent reflexes and bilateral vocal cord paresis requiring tracheostomy. In childhood, she showed delayed motor development, progressive distal amyotrophy and weakness, weakness of the shoulder girdle, scoliosis, and pectus excavatum. Neurophysiologic studies showed an axonal sensorimotor neuropathy. Two of her affected brothers also presented with stridor in infancy and showed a similar phenotype, but without electrophysiologic examination. The mother showed a milder phenotype; she reported being unathletic as a child and having a hoarse voice. In her thirties, she developed slowly progressive fatigue associated with mild distal muscle atrophy in the lower limbs. She had poor reflexes and minimal distal temperature sensitivity. Electrophysiologic studies showed a sensorimotor neuropathy. One mutation carrier in this family was clinically unaffected at age 14 years, although deep tendon reflexes were difficult to elicit.
Landoure et al. (2012) reported a family in which 3 individuals had HMSN2C. This family had previously been reported as family 3 in Landoure et al. (2010). The patients had progressive distal limb muscle weakness and atrophy, hoarse voice, and stridor on exertion. Nerve conduction studies confirmed an axonal neuropathy with phrenic nerve involvement. Two patients had scoliosis and 1 had sensorineural hearing loss, but none had skeletal dysplasia.
In 1 large pedigree with HMSN IIC, Dyck et al. (1994) found no linkage to DNA markers located near the CMT1A (HMSN IA) (118220) locus on 17p (PMP22; 601097) or the CMT1B (HMSN IB) (118200) locus on chromosome 1q (MPZ; 159440).
Using a genomewide scan and multipoint linkage analysis in the large kindred with HMSN IIC reported by Dyck et al. (1994), Klein et al. (2003) found linkage to a region at 12q23-q24 between D12S1645 and D12S1583 (maximum lod = 5.17). Haplotype analysis narrowed the region to approximately 5.0 cM. The authors noted that ataxin-2 (ATX2; 601517), the gene responsible for spinocerebellar ataxia type-2 (SCA2; 183090) localizes to this region, but no triplet repeat expansions or point mutations within the repeat expansion were identified. The same chromosomal region is associated with scapuloperoneal spinal muscular atrophy (SPSMA; 181405) and congenital distal spinal muscular atrophy (600175).
McEntagart et al. (2005) confirmed linkage of CMT2C to 12q23-q24 by combined analysis of 2 unrelated affected families, one of whom was originally reported by Donaghy and Kennett (1999) (multipoint lod score of 2.1 at marker D12S1583). The data refined the disease interval to a 3.9-Mb region between D12S105 and D12S1340. The dHMN2 locus (158590) on chromosome 12q24 was clearly excluded in 1 family, and mutation in the ATX2 gene was excluded in both families.
Landoure et al. (2010) excluded linkage to chromosome 12q24.11 in a family (family 4) with CMT2C, suggesting genetic heterogeneity.
In affected members of the family reported by McEntagart et al. (2005), Auer-Grumbach et al. (2010) identified a heterozygous mutation in the TRPV4 gene (R315W; 605427.0008). Auer-Grumbach et al. (2010) identified the R315W mutation in 4 members of another family with HMSN2C. In that family, the R315W mutation was also identified in another patient with congenital distal spinal muscular atrophy (600175) and in 2 patients with scapuloperoneal spinal muscular atrophy (SPSMA; 181405). A second mutation in the TRPV4 gene (R316C; 605427.0010) was found by Auer-Grumbach et al. (2010) in 3 members of a third family with HMNS2C, and in 1 member of a fourth family with HMSN2C. Again, 2 members of the fourth family with the R316C mutation had a phenotype consistent with SPSMA. The findings indicated that these 3 are allelic disorders with overlapping phenotypes.
In affected members of the family reported by Dyck et al. (1994), Deng et al. (2010) and Landoure et al. (2010) independently identified a heterozygous mutation in the TRPV4 gene (R269H; 605427.0009). Functional studies suggested that the mutation resulted in a gain of function. Landoure et al. (2010) noted that Trpv4-knockout mice (Gevaert et al., 2007) show sensorineural hearing loss and impairment of bladder voiding, suggesting that some clinical manifestations of HMSN2C may be due to loss of TRPV4 function as well as toxic gain of function.
Chen et al. (2010) identified a heterozygous mutation in the TRPV4 gene (R315W; 605427.0008) in a mother and daughter with HMSN2C reported by Dyck et al. (1994).
In affected members of the family reported by Donaghy and Kennett (1999) and in an unrelated patient with HMSN2C, Klein et al. (2011) identified different heterozygous mutations in the TRPV4 gene (R232C, 605427.0025 and R316H, 605247.0026, respectively). Both mutations occurred in conserved residues in the ankyrin-repeat domain. In vitro functional expression studies showed that both mutant proteins had the same subcellular localization as wildtype in HEK293 cells and localized to the plasma membrane similar to wildtype in HeLa cells. In HEK293 cells, the mutant proteins caused increased agonist-induced channel activity and increased basal intracellular calcium concentrations compared to wildtype. HeLa cells expressing the mutant protein showed increased cell death, which could be suppressed by the TRPV antagonist ruthenium red. Klein et al. (2011) concluded that CMT2C-related mutations in this gene cause a dominant gain of function rather than haploinsufficiency.
In 3 members of a family with HMSN2C, Landoure et al. (2012) identified a heterozygous mutation in the TRPV4 gene (R186Q; 605427.0033). The mutation was found by exome sequencing and confirmed by Sanger sequencing. This family had previously been reported as family 3 in Landoure et al. (2010), but the primers used in that study did not identify the TRPV4 mutation. Functional expression studies in HEK293 cells showed that the R186Q mutant protein resulted in increased calcium levels and increased cell death, suggesting abnormal constitutive TRPV4 activity.
Aharoni, S., Harlalka, G., Offiah, A., Shuper, A., Crosby, A. H., McEntagart, M. Striking phenotypic variability in familial TRPV4-axonal neuropathy spectrum disorder. Am. J. Med. Genet. 155A: 3153-3156, 2011. [PubMed: 22065612] [Full Text: https://doi.org/10.1002/ajmg.a.34327]
Auer-Grumbach, M., Olschewski, A., Papic, L., Kremer, H., McEntagart, M. E., Uhrig, S., Fischer, C., Frohlich, E., Balint, Z., Tang, B., Strohmaier, H., Lochmuller, H., and 13 others. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nature Genet. 42: 160-164, 2010. [PubMed: 20037588] [Full Text: https://doi.org/10.1038/ng.508]
Chen, D.-H., Sul, Y., Weiss, M., Hillel, A., Lipe, H., Wolff, J., Matsushita, M., Raskind, W., Bird, T. CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene. Neurology 75: 1968-1975, 2010. [PubMed: 21115951] [Full Text: https://doi.org/10.1212/WNL.0b013e3181ffe4bb]
Deng, H.-X., Klein, C. J., Yan, J., Shi, Y., Wu, Y., Fecto, F., Yau, H.-J., Yang, Y., Zhai, H., Siddique, N., Hedley-Whyte, E. T., Delong, R., Martina, M, Dyck, P. J., Siddique, T. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nature Genet. 42: 165-169, 2010. [PubMed: 20037587] [Full Text: https://doi.org/10.1038/ng.509]
Donaghy, M., Kennett, R. Varying occurrence of vocal cord paralysis in a family with autosomal dominant hereditary motor and sensory neuropathy. J. Neurol. 246: 552-555, 1999. [PubMed: 10463355] [Full Text: https://doi.org/10.1007/s004150050402]
Dyck, P. J., Litchy, W. J., Minnerath, S., Bird, T. D., Chance, P. F., Schaid, D. J., Aronson, A. E. Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann. Neurol. 35: 608-615, 1994. [PubMed: 8179305] [Full Text: https://doi.org/10.1002/ana.410350515]
Gevaert, T., Vriens, J., Segal, A., Everaerts, W., Roskams, T., Talavera, K., Owsianik, G., Liedtke, W., Daelemans, D., Dewachter, I., Van Leuven, F., Voets, T., De Ridder, D., Nilius, B. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J. Clin. Invest. 117: 3453-3462, 2007. [PubMed: 17948126] [Full Text: https://doi.org/10.1172/JCI31766]
Klein, C. J., Cunningham, J. M., Atkinson, E. J., Schaid, D. J., Hebbring, S. J., Anderson, S. A., Klein, D. M., Dyck, P. J. B., Litchy, W. J., Thibodeau, S. N., Dyck, P. J. The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders. Neurology 60: 1151-1156, 2003. [PubMed: 12682323] [Full Text: https://doi.org/10.1212/01.wnl.0000055900.30217.ea]
Klein, C. J., Shi, Y., Fecto, F., Donaghy, M., Nicholson, G., McEntagart, M. E., Crosby, A. H., Wu, Y., Lou, H., McEvoy, K. M., Siddique, T., Deng, H.-X., Dyck, P. J. TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies. Neurology 76: 887-894, 2011. [PubMed: 21288981] [Full Text: https://doi.org/10.1212/WNL.0b013e31820f2de3]
Landoure, G., Sullivan, J. M., Johnson, J. O., Munns, C. H., Shi, Y., Diallo, O., Gibbs, J. R., Gaudet, R., Ludlow, C. L., Fischbeck, K. H., Traynor, B. J., Burnett, B. G., Sumner, C. J. Exome sequencing identifies a novel TRPV4 mutation in a CMT2C family. Neurology 79: 192-194, 2012. [PubMed: 22675077] [Full Text: https://doi.org/10.1212/WNL.0b013e31825f04b2]
Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nature Genet. 42: 170-174, 2010. [PubMed: 20037586] [Full Text: https://doi.org/10.1038/ng.512]
McEntagart, M. E., Reid, S. L., Irrthum, A., Douglas, J. B., Eyre, K. E. D., Donaghy, M. J., Anderson, N. E., Rahman, N. Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24. Ann. Neurol. 57: 293-297, 2005. Note: Erratum: Ann. Neurol. 57: 609 only, 2005. [PubMed: 15668982] [Full Text: https://doi.org/10.1002/ana.20375]
McEntagart, M., Norton, N., Williams, H., Teare, M. D., Dunstan, M., Baker, P., Houlden, H., Reilly, M., Wood, N., Harper, P. S., Futreal, P. A., Williams, N., Rahman, N. Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14. Am. J. Hum. Genet. 68: 1270-1276, 2001. [PubMed: 11294660] [Full Text: https://doi.org/10.1086/320122]