G.P.239: Expanding phenotype of TRPV4 related neuropathies with notable intrafamilial variability

Abstract

TRPV4 gene mutations are known to cause 5 skeletal dysplasias, 1 arthropathy and 3 forms of neuropathies: congenital distal spinal muscular atrophy (CDSMA), scapuloperoneal spinal muscular atrophy (SPSMA) and Charcot-Marie-Tooth disease type 2C (CMT2C). We report 5 patients with TRPV4 related neuropathies, three of whom have positive family histories. Three patients share the common p.Arg269His mutation but have varied phenotypes. Patients 1 and 2 presented with arthrogryposis multiplex congenital (AMC), hip dysplasia, scoliosis, distal > proximal weakness in lower extremities (LE) with limited walking, and weakness of proximal upper extremities (UE). Patient 3 with the p.Arg269His has CMT2 with pure axonal neuropathy, which she inherited from her subclinically affected mother with evidence of mild chronic denervation on EMG. Her maternal uncle and cousin, also with p.Arg269His, had AMC, motor axonal neuropathy and severe course: uncle lost ambulation in his 40s; her cousin never walked. Patient 4 has AMC with limited walking since 2.5 years, distal > proximal weakness in LE, mild proximal UE weakness and prominent scapulae. He has 2 mutations: p.Val620Ile – seen in CMT2C and brachyolmia type 3, but not in CDSMA; and p.Arg151Trp seen with low frequency in dbSNP. Patient 5 is a 3 y/o with gait abnormalities and axonal neuropathy with a similarly affected father and grandmother. His p.Arg186Gln is a known CMT2C mutation. All 5 patients reported have pure motor axonal neuropathy. Muscle ultrasound in all showed a neurogenic pattern and fasciculations. The broad spectrum of TRPV4 neuropathies presents diagnostic and management dilemmas without a genotype: phenotype correlation, as demonstrated by CMT2C and CDSMA phenotypes in patient 3 family. Patients with AMC had proximal UE weakness and scapular winging, showing an overlap between CDSMA and SPSMA. TRPV4 gene mutations should be considered in all cases of AMC presentation with evidence of axonal neuropathy.