# Ocular Motility Abnormalities in Ehlers-Danlos Syndrome: An Observational Study
## 1 Introduction  
Ehlers-Danlos Syndrome (EDS) is a rare disease that includes a clinically and genetically heterogeneous variety of connective tissue diseases. This hereditary pathology affects predominantly the skin, joints, and the musculoskeletal apparatus. Nowadays, 13 forms of EDS are recognized, and pathogenetic mutations have been identified in 20 different genes. The global incidence and prevalence of the disease is unclear. The incidence of one of the most frequent variants, the classic type (cEDS), has been estimated at around 1:20.00. The vascular one (vEDS) is one of the rarest forms and its incidence is approximated to be between 1:50.00 and 1:200.000. The most frequent mutations concern genes encoding for fibrillary collagen types I, III and IV, enzymes linked to the biosynthetic process of these proteins or other components of the extracellular matrix [1]. Many classifications have been proposed over time, the most famous being the Villerfranche classification, introduced in 1997 [2]. The most recent revision of the EDS classification was introduced in 2017 and includes 13 types with well-characterized genetic features. Moreover, this new classification provides a detailed list of major and minor criteria to help the clinician during the diagnostic process [3]. Thanks to DNA sequencing analysis, for the majorityof EDS variants, a genetic cause has been identified. cEDS is determined by heterozygous pathogenetic variants in COL5A1 or COL5A2, leading to haploinsufficiency in type V procollagen. vEDS is caused by defects in type III procollagen resulting from COL3A1 mutations. Different types of alterations involving type I procollagen are responsible for Arthochalasia EDS, Dermatosparaxis EDS and Cardiac Valvular EDS. Defects of collagen crosslinking or folding are detectable in Kyphoscoliotic EDS forms. Classical-like EDS and Myopathic EDS are attributable to dysfunction in extracellular matrix (ECM) components. Musculonattractual EDS and Spondyloplastic EDS are attributable to defects in glycosaminoglycans' biosynthetic process. In Periodontal EDS, an abnormal interaction between the complement and ECM has been recognized. The brittle cornea syndrome is attributable to the mutation of a zinc finger protein (ZNF469) with unknown function and a transcriptional regulator (PRDM5) leading to dysregulation in many genes, such as COL4A, COL11A1 and genes involved in ECM deposition. Regarding the hypermobile variant, a genetic cause has not been identified [1]. All EDS forms share some pathognonomic clinical characteristics, particularly joint hypermobility, cutaneous hyperlaxity, atrophic scarring, skin fragility and the tendency to develop spontaneous ecchymosis [3]. The classic and hypermobile variants are the most frequently diagnosed, representing around 90% of all forms. The vEDS is one of the rarest, being identified in less than 5% of cases. As a result of the clinical overlapping of EDS with other inheritable connective tissue disorders, a purely clinical diagnosis is often difficult to perform. For this reason, the possibility to confirm the diagnosis with genetic analysis is fundamental [4]. At the same time, for many patients with a clear EDS clinical presentation, a genetic anomaly is not detectable [5]. EDS ophthalmological manifestations involve corneal, conjunctival, orbital and vascular structures. Corneal abnormalities described in the literature are microcornea, megalocornea, corneal thickness and curvature alterations, surface irregularity and decreased corneal sensitivity. The progressive corneal thinning and steepening can lead to spontaneous ruptures with subsequent scarring and to elevated astigmatism and keratoconus [6; 7]. These alterations are linked to an important reduction in type 5 collagen in the corneal stroma and reduced density of collagen fibrils. The finding of larger-diameter fibrils and irregular organization can also affect corneal transparency [8]. The corneal involvement is frequently encountered in cEDS patients, in the presence of type V collagen mutations.