Clinical Guidance

The two groups of disorders and the phenotypes comprising autosomal dominant TRPV4-related disorders are the following:

• Neuromuscular disorders (See .)

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

• Scapuloperoneal spinal muscular atrophy, TRPV4-related (TRPV4-SPSMA)

• Congenital distal spinal muscular atrophy, TRPV4-related (TRPV4-CDSMA)

• Skeletal dysplasias, listed from mildest to most severe (See .)

• Familial digital arthropathy with brachydactyly, TRPV4-related

• Brachyolmia, TRPV4-related

• Spondylometaphyseal dysplasia, TRPV4-related (Kozlowski type)

• Spondyloepimetaphyseal dysplasia, TRPV4-related (Maroteaux type)

• Metatropic dysplasia, TRPV4-related

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"

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"

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"