TRPV4‐pathy manifesting both skeletal dysplasia and peripheral neuropathy: A report of three patients

Abstract

Heterozygous missense mutations of transient receptor potential vanilloid 4 channel (TRPV4) cause a spectrum of skeletal disorders, including brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, parastremmatic dysplasia, and spondyloepimetaphyseal dysplasia Maroteaux type. Similarly, heterozygous missense mutations of TRPV4 cause a spectrum of peripheral neuropathy, including hereditary motor and sensory neuropathy type IIC, congenital spinal muscular atrophy, and scapuloperoneal spinal muscular atrophy. There are no apparent differences in the amino acid positions affected or type of change predicted by the TRPV4 mutations responsible for the two disease spectrums; nevertheless, no fundamental phenotypic overlap has been shown between the two spectrums. Here, we report on three patients who had both skeletal dysplasia and peripheral neuropathy caused by heterozygous TRPV4 missense mutations. The skeletal and neurologic phenotypes of these patients covered the wide spectrum of reported TRPV4-pathies (disease caused by TRPV4 mutations). The molecular data are complementary, proving that "neuropathic" mutations can cause skeletal dysplasia but also the "skeletopathic" mutations can lead to neuropathies. Our findings suggest that pathogenic mechanisms of TRPV4-pathies in skeletal and nervous systems are not always mutually exclusive and provide further evidence that there is no clear genotype-phenotype correlation for either spectrum. Co-occurrence of skeletal dysplasia and degenerative neuropathy should be kept in mind in clinical practice including diagnostic testing, surgical evaluation, and genetic counseling.

Charcot-Marie-Tooth disease type 2C and scapuloperoneal muscular atrophy overlap syndrome in a patient with the R232C TRPV4 mutation

“…TRPV4 mutations also cause various skeletal dysplasia syndromes, which occasionally overlap with neuropathic phenotypes [4,[6][7][8].…”

Combined Phenotypes of Spondylometaphyseal Dysplasia-Kozlowski Type and Charcot-Marie-Tooth Disease Type 2C Secondary to a TRPV4 Pathogenic Variant

“…[2011] described 4 fetuses (in 3 families) prenatally diagnosed with both metatropic dysplasia and fetal akinesia secondary to pathogenic variants in TRPV4 . Cho et al [2012] described 3 additional patients with combined phenotypes. The first patient had SMD-K and hereditary motor and sensory neuropathy 2.…”

“…al., 2010; Unger et al, 2011;Cho et al, 2012;Evangelista et al, 2015]. TRPV4 mutations are inherited in a dominant/heterozygous manner, and the clinical phenotype tends to be similar in families.…”

Mechanistic and therapeutic insights gained from studying rare skeletal diseases

“…Gain-of-function mutations in transient receptor potential cation channel subfamily V member 4 (TRPV4), a calcium channel, result in distinctive phenotypes: mild brachyolmia, spondylometaphyseal dysplasia, Kozlowski type, and the more severe metatropic dysplasia [2]. Notably, Charcot-Marie-Tooth disease type 2C is also caused by defects in this receptor [4], an observation that led to the identification of a pathological neuromuscular component in the TRPV4 family of disorders [5].…”