Expanding the Phenotypic Spectrum of ECEL1-Associated Distal Arthrogryposis

Abstract

Distal arthrogryposis type 5D (DA5D), a rare autosomal recessive disorder, is caused by mutations in ECEL1. We describe two consanguineous families (three patients) with novel ECEL1 gene mutations detected by next-generation sequencing (NGS). A 12-year-old boy (patient 1) presented with birth asphyxia, motor developmental delay, multiple joint contractures, pes planus, kyphoscoliosis, undescended testis, hypophonic speech with a nasal twang, asymmetric ptosis, facial weakness, absent abductor pollicis brevis, bifacial, and distal lower limb weakness. Muscle MRI revealed asymmetric fatty infiltration of tensor fascia lata, hamstring, lateral compartment of the leg, and gastrocnemius. In addition, 17-year-old monozygotic twins (patients 2 and 3) presented with motor development delay, white hairlock, hypertelorism, tented upper lip, bulbous nose, tongue furrowing, small low set ears, multiple contractures, pes cavus, prominent hyperextensibility at the knee, hypotonia of lower limbs, wasting and weakness of all limbs (distal > proximal), areflexia, and high steppage gait. One had perinatal insult, seizures, mild intellectual disability, unconjugated eye movements, and primary optic atrophy. In the twins, MRI revealed extensive fatty infiltration of the gluteus maximus, quadriceps, hamstrings, and anterior and posterior compartment of the leg. Electrophysiology showed prominent motor axonopathy. NGS revealed rare homozygous missense variants c.602T > C (p.Met201Thr) in patient 1 and c.83C > T (p.Ala28Val) in patients 2 and 3, both localized in exon 2 of ECEL1 gene. Our three cases expand the clinical, imaging, and molecular spectrum of the ECEL1-mutation-related DA5D.

A Novel ECEL1 Variant Associated with a Congenital Contracture Disorder

“…The affected individuals in family RDHR-01 showed the characteristic clinical features of distal arthrogryposis type 5D. The 48 variants have been identified in a total of 59 individuals with distal arthrogryposis type 5D in several families (Barnett et al, 2014;Bayram et al, 2016;Dieterich et al, 2013;Dohrn et al, 2015;Hamzeh et al, 2017;McMillin et al, 2013;Patil et al, 2014;Rai et al, 2018;Shaaban et al, 2014;Shaheen et al, 2014;Stattin et al, 2018;Ullmann et al, 2018;Umair et al, 2019;Gowda et al, 2021;Huddar et al, 2021;Jin et al, 2020;Alesi et al, 2021). Pronounced unilateral ptosis more severe on the right side, adducted thumbs, and the limbs contracture presented by RDHR01 are consistent with features observed in reported patients of distal arthrogryposis, type 5D (Table I).…”

A novel compound heterozygous variant of ECEL1 induced joint dysfunction and cartilage degradation: a case report and literature review

“…ECEL1 cleaves neuropeptides at a specific site within the C-terminal region, and this cleavage is regulated by zinc binding to the protein. This study provides insight into the substrate specificity and regulation of ECEL1 (24). Dysfunction of the ECEL1 molecule can be caused by impairments in each domain and transmembranous part.…”

“…Unfortunately, the two patients reported by Cohen were diagnosed in middle age and focused on the description and treatment of eye muscle related symptoms. Mutations in multiple exons and introns of the ECEL1 gene have been reported to induce DA5D, while mutations in exon 2, such as c.716dupA, c.344_355 del, c.590G>A, c.589G>A, c.158C>A, c.69C>A, c.602 T>C, c.83C>T, c.633G>C, and c.110_155del, were primarily recorded in DA5D patients, suggesting that impairment of exon 2 transcription significantly contributes to DA5D ( 3 , 19–21 , 24 , 25 ).…”

“…At present, this disease is considered to be a congenital non-progressive disease. For children with early detection and diagnosis, rehabilitation training can significantly improve related joint symptoms in the critical period of their development, and later surgical treatment is more of a supplementary (3,8,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). This characteristic is considered congenital and myogenic and results from the lack of an eyelid crease and dysfunction of the levator muscle (27).…”

Congenital Fibrosis of the Extraocular Muscles: An Overview from Genetics to Management

“…It is associated with neuronal development and neuromuscular junction formation [ 60 ]. A series of autosomal recessive mutations in ECEL1 have been documented to cause arthrogryposis multiplex congenita (AMC), a common type of congenital contracture disorder [ 61 ]. Additionally, some sporadic cases were recorded with ocular phenotypes in addition to limb phenotypes, including ophthalmoplegia, strabismus, and ptosis, in accordance with a definition of CFEOM [ 62 , 63 ].…”