KIF21A Mutations Research Articles

Clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles

ObjectiveThis study aimed to describe the clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles (CFEOM), and to evaluate the phenotype–genotype correlations in these patients.MethodsThis was a retrospective study. Patients with CFEOM underwent detailed ophthalmic examinations and magnetic resonance imaging (MRI). Panel-based next-generation sequencing was performed to identify pathogenic variants of disease-causing genes.ResultsSixty-two patients with CFEOM were recruited into this study. Thirty-nine patients were diagnosed with CFEOM1 and 23 with CFEOM3. Forty-nine of the 62 patients with CFEOM carried either KIF21A (41/49) or TUBB3 variants (8/49). Six known missense variants in the KIF21A and TUBB3 genes, and a novel variant (c.3906T > A, p.D1302E) in the KIF21A gene were detected. Most patients with CFEOM1 carrying the KIF21A mutation displayed isolated CFEOM, whereas patients with CFEOM3 carrying the TUBB3 mutation had a wide range of clinical manifestations, either CFEOM alone or syndromes. Nystagmus was also present in 12 patients with CFEOM. Furthermore, the MRI findings varied, ranging from attenuation of the extraocular muscles to dysgenesis of the cranial nerves and brain structure.ConclusionsThe novel variants identified in this study will further expand the spectrum of pathogenic variants in CFEOM-related genes. However, no phenotype–genotype correlations were established because of the diversity of the clinical characteristics of these patients.

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

PurposeCongenital 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.MethodsThe 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.ResultsAffected 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.ConclusionInstead 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.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Outcomes of strabismus surgery in genetically confirmed congenital fibrosis of the extraocular muscles

To detail surgical strategy and strabismus outcomes in a genetically defined cohort of patients with congenital fibrosis of the extraocular muscles (CFEOM). A total of 13 patients with genetically confirmed CFEOM (via genetic testing for mutations in KIF21A, PHOX2A, and TUBB3) were retrospectively identified after undergoing strabismus surgery at Boston Children's Hospital and surgical outcomes were compared. Age at first surgery ranged from 11months to 63years, with an average of 3 strabismus procedures per patient. Ten patients had CFEOM1, of whom 9 had the KIF21A R954W amino acid substitution and 1 had the M947T amino acid substitution. Of the 3 with CFEOM3, 2 had the TUBB3 E410K amino acid substitution, and 1 had a previously unreported E410V amino acid substitution. CFEOM1 patients all underwent at least 1 procedure to address chin-up posture. Chin-up posture improved from 24° ± 8° before surgery to 10.0° ± 8° postoperatively (P<0.001). Three CFEOM1 patients developed exotropia after vertical muscle surgery alone; all had the R954W amino acid substitution. Postoperatively, 1 CFEOM1 patient developed a corneal ulcer. All CFEOM3 patients appeared to have underlying exposure keratopathy, successfully treated with prosthetic replacement of the ocular surface ecosystem (PROSE) lens in 2 patients. CFEOM is a complex strabismus disorder for which surgical management is difficult. Despite an aggressive surgical approach, multiple procedures may be necessary to achieve a desirable surgical effect. Knowledge of the underlying genetic diagnosis may help to inform surgical management.

KIF21A mutation in two Chinese families with congenital fibrosis of the extraocular muscles type 1 and 3.

Congenital fibrosis of the extraocular muscles (CFEOM) is a hereditary ocular disease and can be classified into three subtypes. The aim of the present study was to determine the genetic basis and describe the clinical phenotype of CFEOM type 1 and 3. Two Chinese families with CFEOM type 1 and 3 were identified. The patients and their family members were subjected to comprehensive ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, assessment of palpebral fissure size, levator function, ocular motility, and cover and forced duction tests. Genomic DNA was extracted from the leukocytes of venous blood samples collected from the two families and from 200 unrelated control subjects from the same population. Coding exons of the KIF21A gene were amplified using polymerase chain reaction analysis and sequenced directly in the two probands. The detected mutations were further analyzed in all available family members and the unrelated control subjects. A heterozygous mutation, c.2860C>T (p.R954W), in KIF21A was identified in the two families, and this was cosegregated with the presence of the diseases in the two families, however, it was absent in the 200 normal control subjects. Among the three affected family members with CFEOM1, differences were observed with regard to the presence of aberrant eye movement. The results indicated that, in the patients with CFEOM1 and CFEOM3, the disease was caused by the same KIF21A gene mutation. The KIF21A gene may be a major disease-causing gene for Chinese patients with CFEOM3. Phenotypic heterogeneity was observed in the patients with CFEOM1.

Genetics of strabismus and lid diseases.

The prevalence of congenital ocular malformations has been described to vary from 0.04 to 6.8 per 10,000 live births. The nuclear mutations identified in chronic progressive external ophthalmoplegia harbor multiple mtDNA deletions that include POLG mutations, PEO1 mutations, OPA1 mutations and RRM2B mutations. In Kearns-Sayre syndrome, the spontaneous mitochondrial deletions vary from 1.3 to 8.0 kb subunits of the oxidative phosphorylation enzymes and several t-RNA genes are affected. Oculopharyngeal muscle dystrophy is both autosomal dominant and recessive form. Congenital fibrosis of extraocular muscles (CFEOM) 1 has mutations in KIF21A on chromosome 12 with TUBB3 mutation also being seen. CFEOM 2 is an autosomal recessive, genetically distinct entity with homozygous mutations in PHOX2A. CFEOM 3 is autosomal dominant heterozygous missense mutations in TUBB3. Most cases of Mobius syndrome are sporadic with familial cases being autosomal dominant, autosomal recessive or X-linked recessive inheritance. Genetic testing has shown abnormalities involving chromosome 1 and 13. Presynaptic congenital myasthenic syndrome is caused by ChAT (choline acetyltransferase) mutation. Two loci have been found for myotonic dystrophy (DM). DM1, which is associated with trinucleotide expansion on chromosome 19q13.3 and DM2 which is associated with CCTG tetranucleotide expansion at 3q21. Blepharophimosis is caused by mutations in the FOXL2 gene 49 located at chromosome 3q23. Lymphedema-distichiasis is an autosomal dominant disorder caused by mutations in the FOXC2 gene.

A rare case of congenital fibrosis of extraocular muscle type 1A due to KIF21A mutation with Marcus Gunn jaw-winking phenomenon

Congenital fibrosis of the extraocular muscles (CFEOM1) is classically a congenital, non-progressive, restrictive strabismus syndrome characterized by bilateral ptosis and ophthalmoplegia with an infraducted position of the globes. This autosomal dominant syndrome is caused by mutations in the KIF21A gene. In this report we describe a 5-year-old boy, and his mother, both of whom have a mutation in the KIF21A gene, who possesses typical features of CFEOM1 syndrome. Besides displaying typical features of CFEOM1, he demonstrated Marcus Gunn jaw-winking phenomenon. The patient additionally had a positive family history of such features. This is first report of the coexistence of CFEOM and Marcus Gunn jaw-winking phenomenon in a patient with a KIF21A mutation from Turkey. We explain the phenotypic findings associated with mutations in KIF21A including CFEOM1A and Marcus Gunn jaw-winking phenomenon.

CFEOM1-Associated Kinesin KIF21A Is a Cortical Microtubule Growth Inhibitor

Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.

Inherited KIF21A and PAX6 gene mutations in a boy with congenital Fibrosis of extraocular muscles and aniridia

BackgroundMutations in the KIF21A gene are detected in the patients with congenital fibrosis of the extraocular muscles. Mutations in the PAX6 gene are detected in the patients with congenital aniridia.Case presentationHerein we report a boy with both congenital fibrosis of extraocular muscles and aniridia. Sequence analysis of his KIF21A and PAX6 genes reveals a 1-bp deletion (c.745delC) in the PAX6 gene and a missense mutation of c.2860C > T (p.Arg954Trp) in KIF21A.ConclusionsThis study demonstrates that the occurrence of independent mutations in more than a single gene in a patient may lead to a complex phenotype.

R954 mutations in KIF21A gene in Chinese patients with congenital fibrosis of extraocular muscles

Screening KIF21A gene mutation in 9 families with congenital fibrosis of extraocular muscles and 7 sporadic cases. Families were ascertained and patients underwent complete ophthalmological examinations. The probands of 9 families with CFEOM and 7 sporadic patients were recruited for this study after informed consent. Genomic DNA was isolated from 5 ml peripheral blood samples according to the standard methods. Direct sequencing was performed after PCR amplification to genomic DNA for detection of KIF21A gene mutation. We identified heterozygous KIF21A mutations in 14 of sixteen patients. Twelve of them harbor the most common mutation, c.2860C > T (p.R954W) and two of them harbor the second most common mutation, c2861G > A(p.R954Q). The R954 mutations account for 87.5% (14/16), in which 75% (12/16) are R954W, 12.5% (2/16) are R954Q. The R954 mutations are also hotspots in Chinese patients with CFEOM.

Spatiotemporal expression pattern of KIF21A during normal embryonic development and in congenital fibrosis of the extraocular muscles type 1 (CFEOM1)

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is a rare inherited strabismus syndrome characterized by non-progressive ophthalmoplegia. We previously identified that CFEOM1 results from heterozygous missense mutations in KIF21A, which encodes a kinesin motor protein. Here we evaluate the expression pattern of KIF21A in human brain and muscles of control and CFEOM1 patients, and during human and mouse embryonic development. KIF21A is expressed in the cell bodies, axons, and dendrites of many neuronal populations including those in the hippocampus, cerebral cortex, cerebellum, striatum, and motor neurons of the oculomotor, trochlear, and abducens nuclei from early development into maturity, and its spatial distribution is not altered in the CFEOM1 tissues available for study. Multiple splice isoforms of KIF21A are identified in human fetal brain, but none of the reported CFEOM1 mutations are located in or near the alternatively spliced exons. KIF21A immunoreactivity is also observed in extraocular and skeletal muscle biopsies of control and CFEOM1 patients, where it co-localizes with triadin, a marker of the excitation–contractile coupling system. The diffuse and widespread expression of KIF21A in the developing human and mouse central and peripheral nervous system as well as in extraocular muscle does not account for the restricted ocular phenotype observed in CFEOM1, nor does it permit the formal exclusion of a myogenic etiology based on expression patterns alone.

The Optic Nerve Head in Congenital Fibrosis of the Extraocular Muscles

Objective: Optic nerve head abnormalities have been reported in some patients with congenital fibrosis of the extraocular muscles (CFEOM). This study prospectively assesses optic nerve head appearance in a consecutive CFEOM cohort.Methods: All patients with CFEOM referred between 2006 and 2010 and who were mature enough to cooperate with fundus photography were included. Fundus photographs were reviewed with attention to optic nerve head features (eg, cupping >0.6, asymmetric cupping >0.3, optic nerve hypoplasia). Interested participants had CFEOM candidate gene analysis (KIF21A, TUBB3, PHOX2A) for genetic counseling purposes.Results: Ten CFEOM patients (five CFEOM1, five CFEOM3, age range 5–23 years) from eight families (all consanguineous but one) participated. All 10 patients had notable disc excavation (5) or optic nerve hypoplasia (5). CFEOM candidate gene analysis was performed in all patients and revealed a heterozygous p.R954W KIF21A mutation only in the patient who was not from a consanguineous family.Conclusions: Our observations suggest the optic nerve head can be affected by the orbital dysinnervation that occurs in CFEOM. Because careful clinical optic nerve head assessment is difficult in young patients with CFEOM and associated large angle incomitant strabismus, optic nerve head abnormalities may be under-diagnosed. The absence of mutations in known CFEOM genes in our cohort of consanguineous families suggests further genetic heterogeneity of this group of conditions.

Germline Mosaicism for KIF21A Mutation (p.R954L) Mimicking Recessive Inheritance for Congenital Fibrosis of the Extraocular Muscles

To document the genotype for familial congenital fibrosis of the extraocular muscles (CFEOM) with apparent autosomal recessive inheritance. Interventional family study. Two affected siblings, 3 asymptomatic siblings, and their 2 asymptomatic parents. Ophthalmologic examination and candidate gene analysis (KIF21A and PHOX2A from venous blood samples) of the 2 affected siblings and their parents; confirmatory testing for 3 available asymptomatic siblings. Significant clinical observations and results of gene testing. The 2 affected siblings had large-angle exotropia, moderate bilateral hypotropia, moderate bilateral ptosis, sluggish pupils, and almost complete ophthalmoloplegia with some abnormal synkinesis. The asymptomatic parents were not related and had unremarkable ophthalmic examinations. Four other siblings were normal by history; 3 underwent venous blood sampling for confirmatory testing. Candidate gene testing of PHOX2A, the gene for recessive CFEOM (CFEOM2), did not reveal mutation in the 2 patients or their parents. Sequencing of KIF21A, the gene for dominant CFEOM (CFEOM1), revealed heterozygous p.R954L in both affected individuals but in not in their parents or 3 asymptomatic siblings, consistent with parental germline mosaicism. Haplotype analysis suggested paternal inheritance but was not conclusive. Parental germline mosaicism can mimic recessive inheritance in CFEOM and likely is underrecognized. Ophthalmologists should be aware of this phenomenon when counseling parents of children with apparent recessive (or de novo) hereditary eye disease. Unlike other reported KIF21A mutations that cause CFEOM1, the p.R954L variant seems to be associated with abnormal pupils. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Synergistic divergence: a distinct ocular motility dysinnervation pattern.

To summarize the clinical, neuroradiologic, and genetic observations in a group of patients with unilateral synergistic divergence (SD). Five unrelated patients with unilateral SD underwent ophthalmic and orthoptic examinations; three of them also had magnetic resonance imaging of the brain and orbits. Three patients underwent genetic evaluation of genes known to affect ocular motility: KIF21A, PHOX2A, HOXA1, and ROBO3. The patients did not meet the clinical criteria for CFEOM types 1, 2, or 3. Each patient had severe adduction weakness on the affected side and large-angle exotropia in primary gaze that increased on attempted contralateral gaze because of anomalous abduction. Magnetic resonance imaging revealed a much smaller medial rectus muscle in the involved SD orbit. Oculomotor cranial nerves were present in the one patient imaged appropriately. Genetic sequencing in three patients revealed no mutations in KIF21A, PHOX2A, HOXA1, or ROBO3. SD should be classified as a distinct congenital ocular motility pattern within congenital cranial dysinnervation disorders. It may be caused by denervation of the medial rectus with dysinnervation of the ipsilateral lateral rectus by the oculomotor nerve precipitated by genetic abnormalities (some currently identified) or by local environmental, teratogenic, or epigenetic disturbances.

A major mutation of KIF21A associated with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) enhances translocation of Kank1 to the membrane

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is associated with heterozygous mutations in the KIF21A gene, including a major (R954W) and a minor (M947T) mutation. Kank1, which regulates actin polymerization, cell migration and neurite outgrowth, interacted with the third and fourth coiled-coil domains of KIF21A protein at its ankyrin-repeat domain. While both KIF21AR954W and KIF21AM947T enhanced the formation of a heterodimer with the wild type, KIF21AWT, these mutants also enhanced the interaction with Kank1. Knockdown of KIF21A resulted in Kank1 predominantly occurring in the cytosolic fraction, while KIF21AWT slightly enhanced the translocation of Kank1 to the membrane fraction. Moreover, KIF21AR954W significantly enhanced the translocation of Kank1 to the membrane fraction. These results suggest that KIF21A regulates the distribution of Kank1 and that KIF21A mutations associated with CFEOM1 enhanced the accumulation of Kank1 in the membrane fraction. This might cause an abrogation of neuronal development in cases of CFEOM1 through over-regulation of actin polymerization by Kank1.

Novel and Recurrent KIF21A Mutations in Congenital Fibrosis of the Extraocular Muscles Type 1 and 3

To characterize the disease-causing mutations and associated clinical phenotypes in 5 Chinese families with congenital fibrosis of the extraocular muscles (CFEOM). Ophthalmic investigations included visual acuity, levator function, documentation of compensatory head position, ocular motility, and slitlamp and fundus examinations. The kinesin family member 21A gene (KIF21A) was sequenced for mutation detection. Genotyping and linkage analysis were performed for the KIF21A/FEOM1 and FEOM3 loci. Four families were clinically classified as having CFEOM type 1 (CFEOM1) with full expression of severe ptosis and ophthalmoplegia. One family had CFEOM type 3 (CFEOM3) with typically varying expression of phenotypes between individuals. Recurrent heterozygous KIF21A mutations were identified in 2 CFEOM1 families (2860C>T) and the CFEOM3 family (2861G>A). In another CFEOM1 family, a novel missense mutation (84C>G, C28W) was revealed. The novel KIF21A mutation 84C>G demonstrated in a CFEOM1 family affects the kinesin motor domain, supporting that mutations may also occur outside the commonly involved coiled-coil domain. The 2861G>A mutation found in a CFEOM3 family has been previously reported in CFEOM1, further supporting that different phenotypes can arise from identical mutations. Clinical Relevance Clinical and genetic characterization are complementary tools for diagnostic, prognostic, and treatment purposes in CFEOM.

Congential Fibrosis of the Extraocular Muscles Type I (CFEOM1) on the Arabian Peninsula

Purpose: To assess for KIF21A mutation in the first two reported Saudi Arabian families with the classic phenotype of congenital fibrosis of the extraocular muscles type I (CFEOM1). Methods: Clinical examination and genetic testing by amplification refractory mutation system (ARMS) assay for KIF21A R954W, the most common KIF21A mutation worldwide. Results: Clinical examination was consistent with classic CFEOM1 in both Family A and Family B. All participating patients (one child from Family A and four adults from Family B) were heterozygous for KIF21A R954W mutation. Conclusions: CFEOM1 is rare is Saudi Arabia as it is in the rest of the world. The finding of R954W mutation in the historically isolated population of the Arabian Peninsula confirms that R954 is a “hotspot” for KIF21A mutation.

Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1

BackgroundCongenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in KIF21A. KIF21A encodes a kinesin motor involved in anterograde axonal transport, and the familial and de novo mutations reported to date predictably alter one of only a few KIF21A amino acids – three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of KIF21A mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in KIF21A.ResultsSixteen CFEOM1 and 29 CFEOM3 probands were studied. Three previously unreported de novo KIF21A mutations were identified in three CFEOM1 probands, all located in the same coiled-coil region of the stalk that contains all but one of the previously reported mutations. Eight additional CFEOM1 probands harbored three of the mutations previously reported in KIF21A; seven had one of the two most common mutations, while one harbored the mutation in the distal motor domain. No mutation was detected in 5 CFEOM1 or any CFEOM3 probands.ConclusionAnalysis of sixteen CFEOM1 probands revealed three novel KIF21A mutations and confirmed three reported mutations, bringing the total number of reported KIF21A mutations in CFEOM1 to 11 mutations among 70 mutation positive probands. All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, further highlighting the importance of alterations in this domain in the etiology of CFEOM1.

A Novel kif21a Mutation in a Patient With Congenital Fibrosis of the Extraocular Muscles and Marcus Gunn Jaw-Winking Phenomenon

To determine whether congenital fibrosis of the extraocular muscles (CFEOM) with Marcus Gunn jaw-winking phenomenon (MG) can result from mutations in the KIF21A gene encoding a kinesin motor protein. An individual with CFEOM1 (classic autosomal dominant CFEOM) and MG underwent a comprehensive ophthalmic examination. He and his healthy parents underwent screening for mutations in the KIF21A gene by direct DNA sequencing. The clinical records of our previously described patients with CFEOM and KIF21A mutations were reviewed for evidence of more extensive dysinnervation. A de novo and novel KIF21A mutation 2840T-->C (M947T) was present in the proband. In addition, among our previously described patients with CFEOM and KIF21A mutations, 3 individuals had MG and 1 had hypertropia during toothbrushing. This report introduces a new CFEOM1 KIF21A mutation and is, to our knowledge, the first report of a genetic defect associated with MG. The combination of CFEOM1 with MG supports a primary neurogenic etiology of CFEOM resulting from KIF21A mutations. These findings will increase understanding of the etiology of CFEOM and increase awareness of the affiliation of CFEOM with MG.

Magnetic Resonance Imaging Evidence For Widespread Orbital Dysinnervation in Congenital Fibrosis of Extraocular Muscles Due to Mutations inKIF21A

High-resolution orbital magnetic resonance imaging (MRI) was used to investigate the structural basis of ocular motility abnormalities in humans with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) due to missense mutations in the developmental kinesin KIF21A. Clinical ophthalmic and motility findings in 19 volunteers from six unrelated CFEOM1 pedigrees harboring four of the six reported KIF21A mutations and 23 normal control subjects were correlated with MRI studies demonstrating extraocular muscle (EOM) size, location, contractility, and innervation. Subjects with CFEOM1 had severe bilateral blepharoptosis, limited supraduction, and variable ophthalmoplegia. In affected subjects, MRI demonstrated atrophy of the levator palpebrae superioris and superior rectus EOMs and small or absent orbital motor nerves. The oculomotor nerve was most severely hypoplastic, but the abducens was also affected. EOMs exhibited variable atrophy and an abnormally bright T1 signal. Subjects with the R954W and R954Q substitutions frequently exhibited A-pattern strabismus, with misinnervation of the lateral rectus muscle by an oculomotor nerve branch. Rectus pulley locations were generally normal. Subjects with CFEOM1 exhibited subclinical but highly significant reduction from normal in mean optic nerve size (P < 0.001). Comparing clinical and MRI phenotypes did not reveal distinguishing features among KIF21A mutations. Orbital imaging in CFEOM1 due to various amino acid substitutions in the kinesin KIF21A demonstrates consistent abnormalities of motor and sensory innervation in the orbit. These findings suggest that neuronal disease is primary in CFEOM1, with myopathy arising secondary to abnormal innervation and minimal rectus pulley abnormality secondary to reduced EOM forces.