CMT AND NEUROGENIC DISEASE: P.340Distal arthrogryposis, peripheral neuropathy and an autosomal dominant pedigree leading to a diagnosis of TRPV4-pathy

Abstract

Transient receptor potential vanilloid 4 channel (TRPV4) is a calcium permeable cation channel predominantly expressed in bone and peripheral nervous system (PNS). TRPV4 mutations cause a spectrum of skeletal disorders and PNS syndromes, including Charcot-Marie-Tooth disease type 2C, spinal muscular atrophy, arthrogryposis, and scapuloperoneal spinal muscular atrophy. A 6-year-old boy from a non-consanguineous family was referred to our clinic due to arthrogryposis multiplex congenita (AMC) and weakness of lower limbs. He was not able to walk. There were six other members in the family diagnosed with varying degrees of peripheral neuropathy and short stature including his father and uncle. Physical examination showed muscle weakness in lower limbs with predominantly distal involvement and atrophy. Lower limbs were short. There were flexion contractures of knees and ankles. Deep tendon reflexes were absent in lower limbs. There was neither motor deficit in upper limbs nor cranial nerve involvement. Electromyography showed lower motor neuron involvement. Exome sequencing targeted to genes involved in arthrogryposis revealed a heterozygous mutation in TRPV4 (c.805C>T; p.Arg269Cys). This mutation is known to be pathogenic in Clinvar database (rs267607146). The mutation was confirmed by Sanger sequencing and cosegregates with the disease in the family indicating that mutation of this gene is responsible for the disease phenotype. TRPV4-pathies represent a heterogeneous group of diseases presenting with skeletal dysplasias and/or peripheral nervous system involvement. Although our patient is grouped clinically as distal SMA with arthrogryposis, there are patients who present with scapuloperoneal SMA and skeletal dysplasia harbouring the same mutation. Despite significant overlaps in presentations, distal arthrogryposis in combination with short stature, skeletal abnormalities, disproportion of upper and lower extremities and neuropathy should be clinical clues for TRPV4 mutations.