Clinical Guidance

In general, specific sets of TRPV4 pathogenic variants have been associated with either neuromuscular disorders or skeletal dysplasias. However, overlap phenotypes may occur , making genotype-phenotype correlations difficult . Moreover, pathogenic variants associated with TRPV4-related neuromuscular disease can cause any of the recognized subtypes, with different presentations even within families. Functional studies suggest that TRPV4 pathogenic variants associated with neuromuscular disorders and short-stature skeletal dysplasias cause a gain of channel function [, , , , , , ], whereas there are reports of both loss-of-function and gain-of-function features in pathogenic variants associated with familial digital arthropathy with brachydactyly . TRPV4-related neuromuscular disorders.

Source: GeneReviews — "Autosomal Dominant TRPV4-Related Disorders"

Penetrance

Autosomal dominant

TRPV4-related neuromuscular disorders. Penetrance is reduced with the neuromuscular disease-associated pathogenic variants. Autosomal dominant TRPV4-related skeletal dysplasias. In contrast, penetrance of the skeletal dysplasia phenotype appears to be high; however, intra- and interfamilial variability is significant .

Source: GeneReviews — "Autosomal Dominant TRPV4-Related Disorders"

Diagnostic Criteria

Suggestive Findings

Neuromuscular Disorders

An autosomal dominant TRPV4-related neuromuscular disease should be suspected in individuals with the following clinical findings based on phenotype and family history.

Charcot-Marie-Tooth disease type 2, TRPV4-related (CMT2C)

Source: GeneReviews — "Autosomal Dominant TRPV4-Related Disorders"

Differential Diagnosis

Autosomal Dominant TRPV4-Related Neuromuscular Disorders

Autosomal dominant TRPV4-related neuromuscular disorders resemble several other disorders . Note: See Charcot-Marie-Tooth Hereditary Neuropathy Overview for a general overview of CMT2.

Table 4.

Autosomal Dominant TRPV4-Related Neuromuscular Disorders: Differential Diagnosis

Gene | MOI | Phenotype(s)

ATP7A

| XL | Adult-onset distal motor neuropathy resembling CMT (See ATP7A-Related Copper Transport Disorders.)

BICD2

| AD | Lower extremity-predominant SMA (OMIM 615290)

BSCL2

| AD | Variants of CMT2; dHMN (See BSCL2-Related Neurologic Disorders/ Seipinopathy.)

DCTN1

| AD | Distal HMN characterized by bilateral vocal cord palsy progressive atrophy weakness of facial distal limb muscles (See DCTN1-Related Neurodegeneration.)

DYNC1H1

| AD | Motor axonal...

Source: GeneReviews — "Autosomal Dominant TRPV4-Related Disorders"

Management Guidelines

No clinical practice guidelines for autosomal dominant TRPV4-related disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an autosomal dominant TRPV4-related neuromuscular disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6a.

TRPV4-Related Neuromuscular Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurology

| Physical/neurologic exam | To determine extent of weakness atrophy, pes cavus, gait stability, sensory loss

EMG w/NCV | As needed to document status of neuropathy

Referral to physiatry, PT, OT, speech therapy |

Laryngology

| Video laryngoscopy | As needed to document status of vocal folds

Respiratory

| • Pulmonary function testing dynamic breathing chest radiograph

• Sleep study

| As needed to assess pulmonary respiratory function presence of sleep apnea

Audiology

| Hearing assessment | See Genetic Hearing Loss Overview for different types of hearing assessment.

Skeletal

| Skeletal radiographs | To identify any associated scoliosis or skeletal dysplasia features

Growth/

Nutrition

| Assess weight, height, weight-for-height. |

Genetic

Source: GeneReviews — "Autosomal Dominant TRPV4-Related Disorders"

Clinical Guidance

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

For neuromuscular disorders

• Preventive health care to avoid diabetes-related complications is recommended.

• Neurotoxic medications should be avoided. Medications that are toxic or potentially toxic to persons with Charcot-Marie-Tooth disease (CMT) comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list. See also the Inherited Neuropathy Consortium website for additional information.

• Upper respiratory tract infections can cause vocal fold swelling and worsen upper airway obstruction.

For skeletal dysplasias

• In individuals with odontoid hypoplasia, avoid extreme neck flexion and extension.

• Avoid activities and occupations that place undue stress on the spine and weight-bearing joints.

Source: GeneReviews — "Autosomal Dominant TRPV4-Related Disorders"

Therapies Under Investigation

have reviewed the future of therapeutic options in CMT. Preclinical studies in knock-in mouse models of TRPV4-related neuromuscular disease have shown that small-molecule TRPV4 (transient receptor potential cation channel subfamily V member 4) ion channel antagonists result in improvement in disease phenotypes . Based on these studies and the known mechanism of disease, TRPV4-specific ion channel antagonists are under study as a potential therapy for TRPV4-related neuromuscular disease. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Autosomal Dominant TRPV4-Related Disorders"

Surveillance Guidelines

Table 8a. Autosomal Dominant TRPV4-Related Neuromuscular Disorder: Recommended Surveillance

Source: GeneReviews — "Autosomal Dominant TRPV4-Related Disorders"