Recessive variants in COL25A1 gene as novel cause of arthrogryposis multiplex congenita with ocular congenital cranial dysinnervation disorder

Abstract

A proper interaction between muscle-derived collagen XXV and its motor neuron-derived receptors protein tyrosine phosphatases σ and δ (PTP σ/δ) is indispensable for intramuscular motor innervation. Despite this, thus far, pathogenic recessive variants in the COL25A1 gene had only been detected in a few patients with isolated ocular congenital cranial dysinnervation disorders. Here we describe five patients from three unrelated families with recessive missense and splice site COL25A1 variants presenting with a recognizable phenotype characterized by arthrogryposis multiplex congenita with or without an ocular congenital cranial dysinnervation disorder phenotype. The clinical features of the older patients remained stable over time, without central nervous system involvement. This study extends the phenotypic and genotypic spectrum of COL25A1 related conditions, and further adds to our knowledge of the complex process of intramuscular motor innervation. Our observations indicate a role for collagen XXV in regulating the appropriate innervation not only of extraocular muscles, but also of bulbar, axial, and limb muscles in the human.

Keywords: COL25A1; arthrogryposis; axon guidance; congenital cranial dysinnervation disorders; distal arthrogryposis.

Figure 1.. Clinical images of individuals with COL25A1 variants

(a-i) Individual A1. Note ocular findings in individual A1 at age 3 months (a) and age 9 years (d and g), with asymmetric ptosis and limitation of upwards gaze in left eye, and bulbous tip of the nose. Note finger contractures at age 3 years 11 months (b) and 9 years (c, e and f). In (h) and (i) note ankle and toe contractures, in particular of first toe, at age 3 months and 3 years 11 months, respectively. (j-n) Individual C1. Note marked compensatory head position in individual C1 at age 14 months, which changed depending on fixation preference (j: patient is fixing right eye; k: patient is fixing left eye) and how it was dramatically improved after two surgical procedures at age 27 and 37 months (l, n). Also, note bulbous tip of the nose (l, n). (o,p) Individual C2. Note clasped thumb (o).

Figure 2.. Muscle MRI images of an individual with COL25A1 variants

T1-weighted MRI sequences of lower limb muscles in patient A1 at 8 years old showing diffuse reduction in volume of muscles, more marked in thighs (a) than in calves (b), especially in the posterior compartment, possibly suggestive of disuse atrophy. Fatty infiltration in muscles is not observed.

Figure 3.. Muscle pathology from individual A1 with COL25A1 variants

Muscle biopsy (site unknown) of individual A1 at 5 years 8 months of age. (a) Haematoxylin & Eosin; (b) NADH-TR; (c) COX-SDH; (d) slow myosin; (e) fast myosin. There is mild fibre size variation (a).Oxidative stains (b, c) show mild overall type I fibre predominance, and ill-defined core-like lesions in several fibres, more often type I (b, c, arrows). Immunolabeling with slow (d) and fast (e) myosins confirms mild slow fibre predominance. Scale bar: a,d,e: 250 µm; b,c: 100 µm

Figure 4.. Schematic COL25A1 protein structure and location of COL25A1 gene variants

Location of here-reported COL25A1 variants is indicated with red (homozygous) and orange (compound heterozygous) arrows, while previously reported changes are indicated with black (homozygous) and grey (compound heterozygous) arrows and horizontal grey bar.