Congenital cranial dysinnervation disorder with homozygous KIF26A variant.

Congenital fibrosis of the extraocular muscles (CFEOM) type 1 is associated with heterozygous missense variants in KIF21A, which encodes a kinesin-like motor protein. Individuals with CFEOM1 have severe paralysis of upgaze and ptosis, resulting in a pronounced chin-up head posture. There can also be limitations of horizontal eye movements. Loss of function of KIF26A, an unconventional kinesin motor protein that lacks ATP-dependent motor activity, has been recently reported to cause a spectrum of congenital brain malformations associated with defects in migration, localization, and growth of excitatory neurons. It has also been associated with megacolon resembling Hirschsprung's disease. We report the case of a boy with homozygous loss of function of KIF26A with restricted eye movements, specifically restricted upgaze and downgaze with variable nystagmus and dissociated vertical eye movements. This case represents a congenital cranial dysinnervation disorder, most similar to CFEOM, and is the first report of a congenital cranial dysinnervation disorder caused by a kinesin other than KIF21A.

Neuromuscular Junction Development Differs Between Extraocular and Skeletal Muscles and Between Different Extraocular Muscles.

Purpose: To determine whether development of neuromuscular junctions (NMJs) differs between extraocular muscles (EOMs) and other skeletal muscles. Methods: Mouse EOMs, diaphragm, and tibialis anterior (TA) were collected at postnatal day (P)0, P3, P7, P10, P14, and P21, and 12 weeks. Whole muscles were stained with α-bungarotoxin, anti-neurofilament antibody, and slow or fast myosin heavy chain antibody, and imaged with a confocal microscope. Images were quantified using Imaris software. Results: NMJs in the EOMs show a unique pattern of morphological development compared to diaphragm and TA. At P0, diaphragm and TA NMJs were oval plaques; EOM single NMJs were long, thin rods. NMJs in the three muscle types progress to mature morphology at different rates. At all ages, EOM single NMJs were larger, especially relative to myofiber size. The inferior oblique and inferior rectus muscles show delayed single NMJ development compared to other EOMs. NMJs on multiply-innervated fibers in the EOMs vary widely in size, and there were no consistent differences between muscles or over time. Incoming motor nerves formed complex branching patterns, dividing first into superficial and deep branches, each of which branched extensively over the full width of the muscle. Motor axons that innervate multiply-innervated fibers entered the muscle with the axons that innervate singly-innervated fibers, then extended both proximally and distally. EOM NMJs had more subsynaptic nuclei than skeletal muscle NMJs throughout development. Conclusions: EOMs show a unique pattern of NMJ development and have more subsynaptic nuclei than other muscles, which may contribute to the exquisite control of eye movements.

Distinct transcriptomic profile of satellite cells contributes to preservation of neuromuscular junctions in extraocular muscles of ALS mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive weakness of almost all skeletal muscles, whereas extraocular muscles (EOMs) are comparatively spared. While hindlimb and diaphragm muscles of end-stage SOD1G93A (G93A) mice (a familial ALS mouse model) exhibit severe denervation and depletion of Pax7+satellite cells (SCs), we found that the pool of SCs and the integrity of neuromuscular junctions (NMJs) are maintained in EOMs. In cell sorting profiles, SCs derived from hindlimb and diaphragm muscles of G93A mice exhibit denervation-related activation, whereas SCs from EOMs of G93A mice display spontaneous (non-denervation-related) activation, similar to SCs from wild-type mice. Specifically, cultured EOM SCs contain more abundant transcripts of axon guidance molecules, including Cxcl12, along with more sustainable renewability than the diaphragm and hindlimb counterparts under differentiation pressure. In neuromuscular co-culture assays, AAV-delivery of Cxcl12 to G93A-hindlimb SC-derived myotubes enhances motor neuron axon extension and innervation, recapitulating the innervation capacity of EOM SC-derived myotubes. G93A mice fed with sodium butyrate (NaBu) supplementation exhibited less NMJ loss in hindlimb and diaphragm muscles. Additionally, SCs derived from G93A hindlimb and diaphragm muscles displayed elevated expression of Cxcl12 and improved renewability following NaBu treatment in vitro. Thus, the NaBu-induced transcriptomic changes resembling the patterns of EOM SCs may contribute to the beneficial effects observed in G93A mice. More broadly, the distinct transcriptomic profile of EOM SCs may offer novel therapeutic targets to slow progressive neuromuscular functional decay in ALS and provide possible 'response biomarkers' in pre-clinical and clinical studies.

Developmental, Physiological and Phylogenetic Perspectives on the Expression and Regulation of Myosin Heavy Chains in Craniofacial Muscles.

This review deals with the developmental origins of extraocular, jaw and laryngeal muscles, the expression, regulation and functional significance of sarcomeric myosin heavy chains (MyHCs) that they express and changes in MyHC expression during phylogeny. Myogenic progenitors from the mesoderm in the prechordal plate and branchial arches specify craniofacial muscle allotypes with different repertoires for MyHC expression. To cope with very complex eye movements, extraocular muscles (EOMs) express 11 MyHCs, ranging from the superfast extraocular MyHC to the slowest, non-muscle MyHC IIB (nmMyH IIB). They have distinct global and orbital layers, singly- and multiply-innervated fibres, longitudinal MyHC variations, and palisade endings that mediate axon reflexes. Jaw-closing muscles express the high-force masticatory MyHC and cardiac or limb MyHCs depending on the appropriateness for the acquisition and mastication of food. Laryngeal muscles express extraocular and limb muscle MyHCs but shift toward expressing slower MyHCs in large animals. During postnatal development, MyHC expression of craniofacial muscles is subject to neural and hormonal modulation. The primary and secondary myotubes of developing EOMs are postulated to induce, via different retrogradely transported neurotrophins, the rich diversity of neural impulse patterns that regulate the specific MyHCs that they express. Thyroid hormone shifts MyHC 2A toward 2B in jaw muscles, laryngeal muscles and possibly extraocular muscles. This review highlights the fact that the pattern of myosin expression in mammalian craniofacial muscles is principally influenced by the complex interplay of cell lineages, neural impulse patterns, thyroid and other hormones, functional demands and body mass. In these respects, craniofacial muscles are similar to limb muscles, but they differ radically in the types of cell lineage and the nature of their functional demands.

Two cases of Duane retraction syndrome with abnormal orbital structures.

Duane retraction syndrome (DRS) is a rare congenital nonprogressive restrictive strabismus. The absence/hypoplasia of the abducens nerve and the aberrant innervation of the lateral rectus muscle by the oculomotor nerve have been hypothesized as causes of DRS, although the phenomenon of globe retraction can also occur in the setting of mechanical factors, such as congenital abnormal orbital structures or orbital trauma. We present the cases of 2 DRS patients with absent abducens nerve and abnormal muscular bands connecting the superior rectus and inferior rectus muscles on the temporal side of the optic nerve.

Evolution and development of extraocular motor neurons, nerves and muscles in vertebrates.

The purpose of this review is to analyze the origin of ocular motor neurons, define the pattern of innervation of nerve fibers that project to the extraocular eye muscles (EOMs), describe congenital disorders that alter the development of ocular motor neurons, and provide an overview of vestibular pathway inputs to ocular motor nuclei. Six eye muscles are innervated by axons of three ocular motor neurons, the oculomotor (CNIII), trochlear (CNIV), and abducens (CNVI) neurons. Ocular motor neurons (CNIII) originate in the midbrain and innervate the ipsilateral orbit, except for the superior rectus and the levator palpebrae, which are contralaterally innervated. Trochlear motor neurons (CNIV) originate at the midbrain-hindbrain junction and innervate the contralateral superior oblique muscle. Abducens motor neurons (CNVI) originate variously in the hindbrain of rhombomeres r4-6 that innervate the posterior (or lateral) rectus muscle and innervate the retractor bulbi. Genes allow a distinction between special somatic (CNIII, IV) and somatic (CNVI) ocular motor neurons. Development of ocular motor neurons and their axonal projections to the EOMs may be derailed by various genetic causes, resulting in the congenital cranial dysinnervation disorders. The ocular motor neurons innervate EOMs while the vestibular nuclei connect with the midbrain-brainstem motor neurons.

Understanding Visual Disorders through Correlation of Clinical and Radiologic Findings.

Patients presenting with visual disturbances often require a neuroimaging approach. The spectrum of visual disturbances includes three main categories: vision impairment, ocular motility dysfunction, and abnormal pupillary response. Decreased vision is usually due to an eye abnormality. However, it can also be related to other disorders affecting the visual pathway, from the retina to the occipital lobe. Ocular motility dysfunction may follow disorders of the cranial nerves responsible for eye movements (ie, oculomotor, trochlear, and abducens nerves); may be due to any abnormality that directly affects the extraocular muscles, such as tumor or inflammation; or may result from any orbital disease that can alter the anatomy or function of these muscles, leading to diplopia and strabismus. Given that pupillary response depends on the normal function of the sympathetic and parasympathetic pathways, an abnormality affecting these neuronal systems manifests, respectively, as pupillary miosis or mydriasis, with other related symptoms. In some cases, neuroimaging studies must complement the clinical ophthalmologic examination to better assess the anatomic and pathologic conditions that could explain the symptoms. US has a major role in the assessment of diseases of the eye and anterior orbit. CT is usually the first-line imaging modality because of its attainability, especially in trauma settings. MRI offers further information for inflammatory and tumoral cases. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Magnetic Resonance Imaging Findings in Patients With Duane Retraction Syndrome.

BACKGROUND: Duane retraction syndrome (DRS) is known to relate to the absence of the abducens nucleus, with abnormal innervation of the lateral rectus (LR) muscle by branchesof the oculomotor nerve (CN III). The purposes of this study were to investigate the morphological characteristics of the oculomotor nerve (CN III), the abducens nerve (CN VI), and the extraocular muscles in patients with clinically diagnosed Duane retraction syndrome (DRS) using MRI. In addition, we assessed the association between ocular motility, horizontal rectus muscle volumes, and CN III/VI in patients with Duane retraction syndrome (DRS). METHODS: The study comprised 20 orthotropic control subjects (40 eyes) and 42 patients with Duane syndrome (48 eyes), including 20 patients with DRS Type I (24 eyes), 5 patients with DRS Type II (6 eyes), and 17 patients with DRS Type III (18 eyes). Three-dimensional (3D) T1/2 images of the brainstem and orbit were obtained to visualize the cranial nerves, especially the abducens (VI) and oculomotor (III) nerves, as well as extraocular muscles. RESULTS: Based on the clinical classification, among 42 patients, MRI showed that the abducens nerves (CN VI) on the affected side were absent in 24 of 24 eyes (100%; 20 patients) with Type I DRS and in 16 of 18 eyes (88%; 16 patients) with Type III DRS. However, CN VI was observed in 6 of 6 eyes (100%; 5 patients) with Type II DRS and in 2 of 18 eyes (11%) with Type III DRS. CN III was observed in all patients. The oculomotor nerves on the affected side were thicker than those on the nonaffected contralateral side in DRS Type I ( P < 0.05) and Type III ( P < 0.05), but not in DRS Type II. Smaller LR and larger MR volumes were shown in the affected eye than that in the nonaffected eye in DRS Types I and III. Based on the presence or absence of CN VI, there was a tendency for thicker oculomotor nerves in the affected eye than in the nonaffected eye in the absence groups ( P < 0.05). However, no significant difference was found in the present group. In the CN VI absence groups, similar results were found in the affected eyes than in the nonaffected eyes as in DRS Types I and III. In addition, the presence of CN VI was correlated with better abduction ( P = 0.008). The LR and MR volumes have positive correlations with the oculomotor nerve diameter in the affected eye. However, there was no correlation between the range of adduction/abduction and the LR/MR ratio in patients with or without an abducens nerve. CONCLUSIONS: Different types of DRS have different characteristic appearances of CN VI and CN III on MRI. Horizontal rectus muscles have morphological changes to adapt to dysinnervation of CN VI and aberrant innervation of CN III. Thus, these neuroimaging findings may provide a new diagnostic criterion for the classification of DRS, improving the comprehension of the physiopathogenics of this disease.

Proprioceptors in extraocular muscles.

Proprioception is the sense that lets us perceive the location, movement and action of the body parts. The proprioceptive apparatus includes specialized sense organs (proprioceptors) which are embedded in the skeletal muscles. The eyeballs are moved by six pairs of eye muscles and binocular vision depends on fine-tuned coordination of the optical axes of both eyes. Although experimental studies indicate that the brain has access to eye position information, both classical proprioceptors (muscle spindles and Golgi tendon organ) are absent in the extraocular muscles of most mammalian species. This paradox of monitoring extraocular muscle activity in the absence of typical proprioceptors seemed to be resolved when a particular nerve specialization (the palisade ending) was detected in the extraocular muscles of mammals. In fact, for decades there was consensus that palisade endings were sensory structures that provide eye position information. The sensory function was called into question when recent studies revealed the molecular phenotype and the origin of palisade endings. Today we are faced with the fact that palisade endings exhibit sensory as well as motor features. This review aims to evaluate the literature on extraocular muscle proprioceptors and palisade endings and to reconsider current knowledge of their structure and function.

[Central trochlear nerve palsy treated with inferior oblique muscle weakening]. / Parálisis central del nervio troclear tratada con debilitamiento del músculo oblicuo inferior.

TITLE: Parálisis central del nervio troclear tratada con debilitamiento del músculo oblicuo inferior.

Müller's Muscle as a Sensory Proprioceptive Organ: Histological and Histochemical Analysis.

Purpose: The purpose of this study was to determine whether proprioceptive nerves are present in Müller's muscle. Methods: This was a prospective cohort study in which histologic and immunofluorescence analyses of excised Müller's muscle specimens were performed. Twenty fresh Müller's muscle's specimens from patients undergoing posterior approach ptosis surgery in one center between 2017 and 2018 were evaluated by histologic and immunofluorescent analysis. Axonal types were determined by measuring axon diameter in methylene blue stained plastic sections and by immunofluorescence of frozen sections. Results: We identified large (greater than 10 microns) and small myelinated fibers in the Müller's muscle, with 6.4% of these fibers being large. Immunofluorescent labeling with choline acetyltransferase showed no evidence of skeletal motor axons in the samples, indicating large axons are likely to be sensory and proprioceptive. In addition, we identified C-fibers using double labeling with peripherin and neural cell adhesion molecules. Conclusions: Overall, large myelinated sensory fibers are present in the Müller's muscle, likely serving proprioceptive innervation. This suggests that proprioception signals from Müller's muscle may have a role in eyelid spatial positioning and retracting, in addition to visual deprivation. This finding sheds new light on our understanding of this complex mechanism.

Investigation of Selective Innervation of Extraocular Muscle Compartments.

Purpose: Recent magnetic resonance imaging studies have suggested that extraocular muscles (EOM) are further divided into transverse compartments that behave differentially and often unexpectedly during eye movements. Selective innervation of EOM compartments may explain the observation that certain horizontal recti compartments contribute to specific vertical eye movements and that some cyclovertical EOM compartments do not contribute to vertical vergence. We investigated the discharge characteristics of extraocular motoneurons during these eye movement tasks where EOM compartments behaved differentially for evidence of selective innervation. Methods: We recorded from all six extraocular motoneuron populations in the abducens, oculomotor, and trochlear nuclei as two non-human primates performed vertical vergence and vertical smooth-pursuit. The relationship between motoneuron firing rate, horizontal and vertical eye parameters of the innervated eye during each task was determined using multiple linear regression. Results: All 26 medial rectus motoneurons recorded showed no significant modulation during vertical smooth-pursuit and vertical vergence. Twenty-eight of 30 abducens motoneurons showed no significant modulation during vertical vergence, and all 30 cells did not modulate during vertical smooth-pursuit. For the cyclovertical motoneurons, 147 of the 149 cells (44/46 inferior rectus, 27/27 superior oblique, 41/41 superior rectus and 35/35 inferior oblique) modulated significantly during vertical vergence. Conclusions: Extraocular motoneuron activity during vertical vergence and vertical smooth-pursuit does not support the theory that EOM compartments are selectively innervated. The observed differential behavior of EOM compartments is likely not driven by oculomotor control and could be due to passive change in EOM cross-sectional area.

Minimally invasive extraocular cranial nerve electromyography.

OBJECTIVE: A reluctance to monitor extraocular cranial nerve (EOCN) function has restricted skull base surgery worldwide. Spontaneous and triggered electromyography (EMG) monitoring can be recorded intraoperatively to identify and assess potential cranial nerve injury. Determining the conductive function of EOCNs requires the collection of clear, reliable, and repeatable compound muscle action potentials (CMAPs) secondary to stimulation. EOCN EMG needle electrodes can, although infrequently, cause ocular morbidity including hematoma, edema, and scleral laceration. The aim of this study was to ascertain if minimally invasive 7-mm superficial needle electrodes would record CMAPs as well as standard 13-mm intraorbital electrodes. METHODS: Conventionally, the authors have monitored EOCN function with intraorbital placement of paired 13-mm needle electrodes into three extraocular muscles: medial rectus, superior oblique, and lateral rectus. A prospective case-control study was performed using shorter (7-mm) needle electrodes. A single minimally invasive electrode was placed superficially near each extraocular muscle and coupled with a common reference. CMAPs were recorded from the minimally invasive electrodes and compared with CMAPs recorded from the paired intraorbital electrodes. The presence or absence of CMAPs was analyzed and compared among EMG recording techniques. RESULTS: A total of 429 CMAPs were analyzed from 71 EOCNs in 25 patients. The experimental setup yielded 167 true-positive (39%), 106 false-positive (25%), 17 false-negative (4%), and 139 true-negative (32%) responses. These values were used to calculate the sensitivity (91%), specificity (57%), positive predictive value (61%), and negative predictive value (89%). EOCN electrodes were placed in 82 total eyes in 58 patients (CMAPs were obtained in 25 patients). Twenty-six eyes showed some degree of edema, bruising, or bleeding, which was transient and self-resolving. Three eyes in different patients had complications from needle placement or extraction including conjunctival hemorrhage, periorbital ecchymosis, and corneal abrasion, ptosis, and upper eyelid edema. CONCLUSIONS: Because of artifact contamination, 106 false-positive responses (25%), and 17 false-negative responses (4%), the minimally invasive EMG technique cannot reliably record CMAP responses intraoperatively as well as the intraorbital technique. Less-invasive techniques can lead to an inaccurate EOCN assessment and potential postoperative morbidity. EOCN palsies can be debilitating and lifelong; therefore, the benefits of preserving EOCN function outweigh the potential risks of morbidity from electrode placement. EMG monitoring with intraorbital electrodes remains the most reliable method of intraoperative EOCN assessment.

Phenotype, genotype, and management of congenital fibrosis of extraocular muscles type 1 in 16 Chinese families.

PURPOSE: Congenital fibrosis of extraocular muscles type 1 (CFEOM1), a classical subtype of CFEOM, is characterized by restrictive ophthalmoplegia and ptosis. It is mainly caused by aberrant neural innervation of the extraocular muscles. This study aimed to investigate the genetic characteristics and clinical manifestations of CFEOM1 in Chinese families. METHODS: The clinical data, including ocular examinations, magnetic resonance imaging (MRI), and surgical procedures of affected individuals from 16 Chinese CFEOM1 families, were collected. The genomic DNA of 16 probands and their family members were sequenced for causative KIF21A gene mutations. Linkage analysis using microsatellite markers across KIF21A was also conducted. RESULTS: Affected individuals were presented with bilateral non-progressive ptosis, restricted horizontal eye movement, fixed infraduction of both eyes, compensatory chin-up head position, and neuromuscular abnormalities. Three heterozygous KIF21A mutations, c.2860C > T (p.R954W) (in eight families), c.2861G > T (p.R954L) (in two families), and c.2861G > A (p.R954Q) (in two families) were identified, which implied that hotspot mutations were common in Chinese CFEOM1 families. Germline Mosaicism was likely to be the cause of affected individuals with asymptomatic parents without KIF21A mutations presented in the eight families. Two affected individuals underwent modified levator muscle complex suspension surgery and achieved a good result without any complications. CONCLUSION: Instead of evaluating the whole CFEOM1 gene variant, hotspot mutations could be given priority for screening. The occurrence of germline mosaicism has to be taken into account in genetic counseling. Patients with CFEOM1 who have ptosis may benefit from an innovative surgical procedure called modified levator muscle complex suspension.

Extraocular Motoneurons and Neurotrophism.

Extraocular motoneurons are located in three brainstem nuclei: the abducens, trochlear and oculomotor. They control all types of eye movements by innervating three pairs of agonistic/antagonistic extraocular muscles. They exhibit a tonic-phasic discharge pattern, demonstrating sensitivity to eye position and sensitivity to eye velocity. According to their innervation pattern, extraocular muscle fibers can be classified as singly innervated muscle fiber (SIF), or the peculiar multiply innervated muscle fiber (MIF). SIF motoneurons show anatomical and physiological differences with MIF motoneurons. The latter are smaller and display lower eye position and velocity sensitivities as compared with SIF motoneurons.

The use of lyophilized bovine pericardium (Tutopatch®) in the management of third nerve palsy following prior conventional strabismus surgery - a case series.

To study the secondary management of strabismus due to third nerve palsy using bovine pericardium (Tutopatch®) when previous conventional surgical therapy had failed. Review of our clinic records of selected patients with third nerve palsy, in whom residual deviation had been managed using Tutopatch® after previous surgical correction. The squint angle was measured preoperatively, and at 1 day, 3 months, and if possible 6 months postoperatively. Nine patients were enrolled in this study. One patient had mainly residual vertical deviation and was corrected with tendon elongation of the contralateral superior rectus. Three patients were operated on with tendon elongation of the lateral rectus muscle with or without medial rectus muscle resection and/or advancement (Group 1). Lateral rectus splitting after tendon elongation in addition to the resection and/or advancement of the medial rectus was performed in five patients with complete third nerve palsy (Group 2). In Group 1, the preoperative median squint angle was -20° (range -17° to -25°), which improved postoperatively to -4.5° (range -12° to +3°). In Group 2, the preoperative horizontal and vertical median squint angles were -27° (range -20° to -40°) and 0.5° (range 0° and 20°), respectively. Postoperatively, they had improved to -12.5° (range-2° to -25°), and 1.5° (range 0° to 7°), respectively. Two patients of Group 2 were re-operated due to residual exotropia. No postoperative complications were observed in any patient. In this small series several complex re-do situations of patients with third nerve palsy were evaluated in which Tutopatch® markedly improved outcomes after an initially ineffective surgical management. For better evaluation of its usefulness a study with more patients is recommended.

Oculomotor nerve root split: incidental finding on MRI-case report and literature review.

BACKGROUND: The oculomotor nerve (OMN) innervates the pupil, ciliary body, upper eyelid, and extraocular muscles through two divisions: a superior division that innervates the levator palpebrae superioris (LPS) and superior rectus (SR), and an inferior division that supplies the medial rectus (MR), inferior rectus (IR), inferior oblique (IO), and parasympathetic fibers to the pupil and ciliary body. We present a case of complete splitting of the cisternal segment of bilateral OMNs that was discovered incidentally on magnetic resonance imaging (MRI) in a patient who had no ocular complaints. CASE REPORT: A 69-year-old patient was found to have bilateral splitting of the cisternal segments of OMNs during an MRI for trigeminal neuralgia workup. Both nerves sprang from the midbrain as distinct roots. They were symmetric on the right and minimally asymmetric on the left. On both sides, the medial root was slightly inferiorly situated. The patient had no visual problems and continued to function normally. A review of the literature for similar cases identified no such variants; however, it did identify eight examples of OMN fenestrations produced by aneurysms (AN), six of which had no OMN palsy symptoms. CONCLUSION: An anatomic variant of split bilateral OMN cisternal segments is described. The superior and inferior divisions may have different brainstem origins. Although this variant is an anatomic curiosity, it may have clinical significance and explain the various presentation of compressive OMN palsies.

The Oculomotor Nerve: Anatomy and Pathology.

The oculomotor nerve is the third cranial nerve, exiting the brainstem in the medial border of the cerebral peduncle, from where it crosses straight to the superior orbital fissure. It is a purely motor nerve responsible for the innervation of all the extraocular muscles, except the superior oblique and lateral rectus muscles. It also has parasympathetic pre-ganglionic fibers, responsible for the innervation of sphincter pupillae and ciliary muscles. Magnetic resonance imaging (MRI) is the best imaging exam to evaluate patients with clinical signs of third cranial nerve palsy. The oculomotor nerve can be affected by several diseases, such as congenital malformations, trauma, inflammatory or infectious diseases, vascular disorders, and neoplasms. This article aims to review the oculomotor nerve anatomy, discuss the best MRI techniques to evaluate each nerve segment, and demonstrate the imaging aspect of the diseases that most commonly affect it.