Alternative titles; symbols
SNOMEDCT: 763067000; ORPHA: 1216; DO: 0111215;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.11 | Neuronopathy, distal hereditary motor, autosomal dominant 8 | 600175 | Autosomal dominant | 3 | TRPV4 | 605427 |
A number sign (#) is used with this entry because of evidence that autosomal dominant distal hereditary motor neuronopathy-8 (HMND8) is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24.
See also hereditary motor and sensory neuropathy 2C (HMSN2C; 606071) and scapuloperoneal spinal muscular atrophy (SPSMA; 181405), allelic disorders with overlapping phenotypes.
For a discussion of genetic heterogeneity of autosomal dominant distal hereditary motor neuronopathy, see HMND1 (182960).
Fleury and Hageman (1985) reported a large 4-generation Dutch family in which 21 individuals had a nonprogressive congenital lower motor neuron disorder restricted to the lower part of the body. Fifteen patients had arthrogryposis, indicative of antenatal onset. At birth, the proband showed bilateral talipes equinovarus and flexion contractures of the knees and hips. She later had marked lordosis and slight scoliosis with restricted joint movement. There was a severe flaccid paralysis of the upper part of the legs and paralysis of the distal legs associated with muscle atrophy and areflexia. Other family members were less affected, with paresis of dorsiflexors of the ankles and only distal leg muscle weakness. One skeletal muscle biopsy showed large groups of small angulated fibers with pyknotic nuclei without fiber type grouping, and another showed predominance of type II fibers. The mode of inheritance was autosomal dominant with varied expression. Van der Vleuten et al. (1998) provided further details of the disorder in this family. Mildly affected individuals had congenital weakness of the distal part of the lower limbs only. More severely affected individuals had weakness of the pelvic girdle and trunk muscles, resulting in scoliosis. Reflexes were decreased or absent; there were no sensory abnormalities.
Astrea et al. (2012) reported 2 unrelated children with genetically confirmed congenital distal spinal muscular atrophy. Both had proximal and distal muscle weakness, atrophy of distal leg muscles, and clubfoot. MRI of the thigh and calf muscles showed extensive fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves. This pattern was distinct when compared to a patient with non-TRPV4 SMA.
Echaniz-Laguna et al. (2014) reported 10 patients from 7 families with a clinical diagnosis of DHMN and 2 additional unrelated patients with congenital spinal muscle atrophy and arthrogryposis associated with heterozygous TRPV4 mutations. The patients had onset in childhood of distal muscle weakness of the upper and lower limbs; some also had proximal muscle weakness. Additional features included scoliosis, pes cavus, and vocal cord paresis. Some patients had scapular winging, and most patients tested had increased serum creatine kinase. Muscle biopsies were consistent with chronic denervation. In 2 families, there was evidence of incomplete penetrance.
Clinical Variability
Reddel et al. (2008) reported a woman with congenital nonprogressive distal spinal muscular atrophy. She had talipes equinovarus and congenital hip contractures at birth, and did not walk until 19 months of age. Bowel and bladder dysfunction was noted early in life. She had a waddling gait, lumbar lordosis, weakness of the hip girdle muscles, weakness of ankle dorsiflexion, and areflexia of the lower limbs. Serum creatine kinase was mildly increased. Skeletal muscle biopsy showed type I fiber predominance. Examination at age 24 years showed no apparent progression of the disorder and mild distal weakness and atrophy of the upper and lower limbs. Nerve conduction studies were normal. Her daughter was also affected. Reddel et al. (2008) noted that dominant congenital spinal muscular atrophy predominantly affecting the lower limbs is rarely described, and suggested that the disorder may be due to a congenital deficiency of motor neurons.
Berciano et al. (2011) reported a family in which 2 of 5 individuals carrying the same heterozygous mutation in the TRPV4 gene (R269C; 605427.0011) had different phenotypes: a 44-year-old woman had scapuloperoneal spinal muscular atrophy (181405) and her 7-year-old daughter had congenital distal spinal muscular atrophy. The 3 other individuals with the mutation were clinically and electrophysiologically asymptomatic 9, 40, and 70 years of age, respectively, consistent with incomplete penetrance. The mother had sloped shoulders since childhood and later developed progressive lower leg muscle weakness and atrophy. She also had transient dysphonia. Muscle biopsy showed evidence of chronic denervation and renervation, and electrophysiologic studies showed reduced compound muscle action potentials with normal nerve conduction velocities, consistent with a motor axonal neuropathy. The daughter was born with congenital arthrogryposis and showed delayed motor development and laryngomalacia with stridor and vocal cord paresis necessitating intermittent tracheostomy placement. She was wheelchair-bound at age 7 due to limited joint mobility and lower limb muscle weakness, and also had weakness and atrophy of the shoulder girdle muscles.
By linkage analysis of the Dutch family reported by Fleury and Hageman (1985), van Ravenswaaij et al. (1997) and van der Vleuten et al. (1998) found linkage to an 11-cM interval between markers D12S78 and D12S1646 on chromosome 12q23-q24. Linkage to chromosome 5q was excluded. Van der Vleuten et al. (1998) noted that scapuloperoneal spinal muscular atrophy (SPSMA; 181405) maps to the same region (12q24.1-q24.31). However, van Ravenswaaij et al. (1997) suggested that these 2 forms of SMA are not allelic. Scapuloperoneal SMA is characterized by stridorous breathing in the newborn due to laryngeal palsy, while lower limb weakness, which is progressive, and contractures appear only in the first or second decade.
In affected members of the Dutch family reported by Fleury and Hageman (1985) and van der Vleuten et al. (1998), Auer-Grumbach et al. (2010) identified a heterozygous mutation in the TRPV4 gene (R269H; 605427.0009). Auer-Grumbach et al. (2010) identified a different heterozygous mutation in the TRPV4 gene (R315W; 605427.0008) in a patient with congenital distal SMA whose other family members with the same mutation had phenotypes consistent with hereditary motor and sensory neuropathy-2 (HMSN2; 606071) or scapuloperoneal spinal muscular atrophy (SPSMA; 181405), thus proving that these are allelic disorders with overlapping phenotypes.
Astrea, G., Brisca, G., Fiorillo, C., Valle, M., Tosetti, M., Bruno, C., Santorelli, F. M., Battini, R. Muscle MRI in TRPV4-related congenital distal SMA. Neurology 78: 364-365, 2012. [PubMed: 22291064] [Full Text: https://doi.org/10.1212/WNL.0b013e318245295a]
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]
Berciano, J., Baets, J., Gallardo, E., Zimon, M., Garcia, A., Lopez-Laso, E., Combarros, O., Infante, J., Timmerman, V., Jordanova, A., De Jonghe, P. Reduced penetrance in hereditary motor neuropathy caused by TRPV4 arg269-to-cys mutation. J. Neurol. 258: 1413-1421, 2011. [PubMed: 21336783] [Full Text: https://doi.org/10.1007/s00415-011-5947-7]
Echaniz-Laguna, A., Dubourg, O., Carlier, P., Carlier, R.-Y., Sabouraud, P., Pereon, Y., Chapon, F., Thauvin-Robinet, C., Laforet, P., Eymard, B., Latour, P., Stojkovic, T. Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy. Neurology 82: 1919-1926, 2014. [PubMed: 24789864] [Full Text: https://doi.org/10.1212/WNL.0000000000000450]
Fleury, P., Hageman, G. A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis. J. Neurol. Neurosurg. Psychiat. 48: 1037-1048, 1985. [PubMed: 4056805] [Full Text: https://doi.org/10.1136/jnnp.48.10.1037]
Reddel, S., Ouvrier, R. A., Nicholson, G., Dierick, I., Irobi, J., Timmerman, V., Ryan, M. M. Autosomal dominant congenital spinal muscular atrophy--a possible developmental deficiency of motor neurones? Neuromusc. Disord. 18: 530-535, 2008. [PubMed: 18579380] [Full Text: https://doi.org/10.1016/j.nmd.2008.04.016]
van der Vleuten, A. J. W., van Ravenswaaij-Arts, C. M. A., Frijns, C. J. M., Smits, A. P. T., Hageman, G., Padberg, G. W., Kremer, H. Localisation of the gene for a dominant congenital spinal muscular atrophy predominantly affecting the lower limbs to chromosome 12q23-q24. Europ. J. Hum. Genet. 6: 376-382, 1998. [PubMed: 9781046] [Full Text: https://doi.org/10.1038/sj.ejhg.5200229]
van Ravenswaaij, C. M. A., van der Vleuten, A. J. W., Smits, A. P. T, Padberg, G. W., Kremer, H. Localization of the gene for a congenital non-progressive spinal muscular atrophy affecting the lower limbs to chromosome 12q23-q24. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A299 only, 1997.