DeCure for Distal arthrogryposis type 5D

Distal arthrogryposis type 5D (DA5D) is clinically characterised by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. In a 2024 report of nine affected individuals from eight unrelated Indian families, the authors note that the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, but that fixed knee extension contractures with or without scoliosis could be an early pointer to DA5D. That study identified a possible founder variant in ECEL1 along with four novel variants, expanding the genotypic spectrum.

A 2016 report describes a female DA patient with hand and foot deformities and right-sided torticollis in whom exome sequencing identified a novel TNNI2 mutation (c.485>A, p.Arg162Lys) in the patient and her father. The father had no typical DA but had hip dysplasia, illustrating variable clinical expression. A 2021 case report of a Japanese family with autosomal dominant arthrogryposis found a heterozygous nonsense variant in TNNI1 (c.523A>T, p.K175*) in a 14-year-old boy with proximal joint contractures, elevated serum creatine kinase, and muscle biopsy showing a moth-eaten appearance in some type 1 fibres with Z disk streaming. The authors note that compared with patients with TNNI2 variants, this patient had a milder phenotype and proximal rather than distal arthrogryposis.

Earlier literature on arthrogryposis multiplex congenita, which encompasses distal arthrogryposis, reports that treatment initially consists of stretching and splinting, with significant gains possible in the first years of life. A 1985 series of 95 infants and young children reported that 90% had contractures of all extremities and 40% had multiple congenital anomalies; daily intensive passive stretching and serial splinting substantially increased function in that population. Surgical procedures were used only when persistent deformities required correction. A 2017 review of lower extremity treatment notes that goals range from comfortable seating and shoe wear to independent ambulation, and that treatment of hip and knee contractures has become more interventional while foot deformity treatment has become less surgical. A 2019 review of upper extremity involvement states that despite overall lower functioning scores, quality of life scores in this patient population are comparable to the general age-adjusted population.

What is still missing are large, prospective natural history studies that stratify patients by specific genetic subtype (ECEL1, TNNI2, TNNI1, and others), standardised outcome measures for contracture severity and functional independence, and funding for multicentre trials of early intervention protocols. The genetic heterogeneity and variable expressivity mean that any future trial will need to account for genotype-specific trajectories, which requires both larger cohorts and longer follow-up than currently available.