Ocular manifestations in a 2 year-old patient with a DYNC1H1 mutation

ABSTRACT Background Mutations in the DYNC1H1 gene have been linked to multiple neurologic syndromes with a multitude of clinical manifestations, both ocular and non-ocular. Previous case reports have outlined various ocular phenotypes, including cataracts of congenital onset, infantile onset, and adult onset with lack of further ophthalmologic detail. Case Presentation Our case report outlines, in more detail, a 24-month-old male with a heterozygous mutation in the DYNC1H1 gene who developed a white, intumescent cataract in his left eye and a posterior subcapsular cataract in his right eye with evidence of progressive axial myopia. Conclusions Based on the findings outlined in our case we suggest eye exams at regular intervals during early childhood in patients with DYNC1H1 mutations to screen for amblyogenic ocular pathology and potential rapidly developing cataracts.


Introduction
DYNC1H1 (Dynein-Cytoplasmic-1-Heavy-Chain-1, OMIM *600112), a highly conserved gene on chromosome 14, encodes for a subunit of the cytoplasmic dynein complex.This gene is believed to play a role in cellular motility, in retrograde axonal transport, and in bipolar spindle formation (1,2).
Ocular manifestations reported secondary to a DYNC1H1 mutation have been limited to cataracts (infantile, congenital and adult-onset) and strabismus (4,5).Two case reports of patients with a DYNC1H1 mutation reported infantile onset bilateral cataracts (4,5).The first describes a girl with congenital cataracts at birth and undefined strabismus requiring surgical correction (4).The second case was discovered to have bilateral cataracts at 4 months of age with the inability to fix and follow (5).After cataract removal the child was described to remain with poor vision, although visual evoked potential was reported as normal.Of note there have also been bilateral cataracts reported in adults with DYNC1H1 (5,6).None of these case reports describe the ophthalmologic characteristics of the patients in further detail.
To our knowledge, this is the first case report in a DYNC1H1 pediatric patient with photographic presentation and a detailed description of the ocular manifestations, including cataract type.

Case presentation
A male infant was born at 39 weeks estimated gestational age (EGA) to a 26-year-old G4P3003 female with a past medical history of anxiety, depression and bipolar, not on medications during pregnancy.In utero the patient was diagnosed with multiple congenital abnormalities including ventriculomegaly and limb anomalies; however, cell-free DNA testing at 28 weeks EGA was unremarkable.Microarray ordered shortly after birth returned unremarkable as well.
A Comprehensive Lissencephaly Panel was performed at 4 months of age (The University of Chicago Genetic Services Laboratory) which identified a de novo likely pathogenic variant (c.4501A>T; p.Ile1510Phe) in the DYNC1H1 gene (NM_001376.4).(E-component supplement provides further genetic details for this patient.) The patient first presented to the Penn State Eye Center, Hershey, Pennsylvania at 3 months of age for a routine genetic evaluation.At this time the patient exhibited many systemic findings similar to those described previously in patients with a DYNC1H1 mutation, as well as a few unique systemic diagnoses (Table 2).On ocular examination the patient was able to fix/follow with either eye individually.He had a 20-prism diopter (pd) right intermittent esotropia.Normal intraocular pressure was measured by iCare tonometry (iCare USA, Raleigh, NC) at 9 mmHg in both eyes.Retinoscopy revealed both right and left eye myopia at −1.50 diopters.The dilated fundus exam was documented as normal aside from a blondeappearing fundus.The patient returned for follow-up at 6 months of age with now a large angle, 50pd, alternating esotropia and mild lagophthalmos.There was no evidence of cataracts documented at this return visit.
Unfortunately the patient was lost to follow-up and presented at age 2 years old for concern of sudden cloudiness in the left eye over the preceding 2 weeks.Visual acuity measured fix/follow/maintain in the right eye and wince-to-light in the left eye.He had an approximate 30pd left esotropia.Anterior segment examination demonstrated a mild to moderate central posterior subcapsular cataract (PSC) in the right eye as well as a white intumescent cataract in the left eye (Figure 1).The remainder of his anterior segment was unremarkable.IOP measured by iCare was 10 mmHg right eye and 9 mmHg left eye.Dilated fundus examination was performed in the right eye showing a blonde retina.There was no direct view to the left posterior segment.B scan ultrasound of the left eye showed a large globe with intact retina.
Cataract extraction with intraocular lens (IOL) implantation to the left eye was scheduled.An exam under anesthesia (EUA) was performed concurrently.Intraocular pressure by Tono-Pen (Reichert, Depew, New York) measured 11 mmHg in the right eye and 7 mmHg in the left eye.Axial lengths by immersion ultrasound were long at 23.58 mm in the right eye and 23.38 mm in the left eye.Central corneal thickness was normal at 520 microns in the right eye and 531 microns in the left eye.Cycloplegic retinoscopy showed high myopia right eye, −7.5 + 1.00×120, unable to be measured in the left.The right lens demonstrated a posterior subcapsular cataract surrounding an area of what appeared to be an indentation of the posterior capsule, reminiscent of a posterior polar cataract.The lens of the left eye showed an intumescent white cataract with upward tenting of the iris and shallowing of the anterior chamber.Cataract surgery was performed without incident to the left eye and IOL implanted within the capsule followed by a pars plana posterior capsulotomy and limited anterior vitrectomy.By post-operative month 1, vision had recovered to fix/follow/maintain in the left eye.Given the size and central location of the right cataract, lens extraction with IOL implant was planned for the right eye as well.EUA at the time of right eye cataract surgery demonstrated a blonde appearing retina in both eyes (Figure 1).

Discussion
Previous case reports have described the ocular manifestations of DYNC1H1 mutations in limited detail.These reports have documented strabismus as well as cataracts at any stage of life, including infantile onset, congenital and adult-onset (4,5).To our knowledge, this is the only case report that presents in detail the specific ocular manifestations of this disorder as well as type of cataract and potential for acute presentation and rapid progression of cataracts in these patients.
A potential mechanism for the pathogenicity of DYNC1H1 mutations is a resultant defect in dyneindependent mitochondrial trafficking resulting in mitochondrial dysfunction and neurodegeneration (3).In particular, it appears DYNC1H1 is involved in dynein function and a mutation here may impair the proper mitochondrial location within the cell and removal of dysfunctional mitochondria via autophagocytic degradation (3).
The complex neurologic sequelae of a DYNC1H1 mutation likely contribute to the presence of strabismus in these patients.As for the natural crystalline lens, DYNC1H1 is expressed in elongating fiber cells of the lens and possibly traffics vesicles along microtubules for reorganization of the fiber cell (7).It has been theorized that mutations in this motor domain disrupt the development of the lens and thus result in cataract formation (5,6).Although the precise mechanism underlying the increase in severity of cataracts in our patient has yet to be determined, we elucidate decreased dynein-dependent vesicular transport in the fiber cells of the lens secondary to a motor domain mutation may contribute to this finding.Another candidate mechanism is dysfunctional and abnormally localized mitochondria due to dysfunctional autophagy.Our patient demonstrated high myopia at a young age as well.Mutations in the DYNC1H1 gene have also been shown in the lab to lead to photoreceptor degeneration in the post-natal retina as cytoplasmic dynein is believed to be essential for retina lamination, nuclear positioning, vesicular trafficking of photoreceptor membrane  proteins, and inner/outer segment elaboration (8).Retinal degeneration has been associated with progressive myopia in other genetic retinal dystrophies including retinitis pigmentosa, Cohen syndrome, and congenital stationary night blindness (7,8).Unfortunately, our patient was not able to undergo an electroretinogram (ERG) due to lack of cooperation and limited availability of alternative ERG testing for pediatric patients at our institution.Further investigation into the potential of retinal degeneration in these patients is warranted as this may help to explain the progressive axial myopia seen in our patient.

Conclusion
Particularly as it applies to the pediatric syndromic patient, the ophthalmologist needs a heightened awareness to screen for potential amblyogenic ocular pathology.Our case report highlights the potential for early onset strabismus, significant refractive error in the form of pathologic myopia as well as progressive and rapid mature cataract formation in patients with a DYNC1H1 mutation.Considering the ocular findings described in previous case reports as well as ours, we recommend close ophthalmology follow-up for patients with a DYNC1H1 mutation in order to avoid the risk for amblyopia and particularly the surgical complications inherent in a mature cataract presentation.

Literature search
This article has been researched to the best of our ability using our institutional access to PubMed MEDLINE, OVID MEDLINE, and Clinical Key for the search terms DYNC1H1, ocular findings in DYNC1H1, retina and DYNC1H1, cataract and DYNC1H1, eye and DYNC1H1 for all years available up until December May 2021.Articles cited in other reference lists of articles were also researched.Foreign literature was considered when applicable to the topic.

Figure 1 .
Figure 1.RetCam (Phoenix Technology Group, California) photographs of a 2-year-old patient with a heterozygous mutation of the DYNC1H1 gene.Top Images: photographs taken of the anterior segment of both eyes during a sedated eye examination performed under anesthesia prior to left eye cataract extraction.A, Right eye posterior subcapsular cataract with posterior capsular indentation centrally.B, Left eye white intumescent cataract.BOTTOM IMAGES: photographs taken of the posterior segment of both eyes during a sedated eye examination performed under anesthesia three months after left eye cataract surgery.C, Right posterior pole retinal image, note the posterior subcapsular cataract blurs the view to the central retina.D, Left posterior pole retinal image, note the intraocular lens and capsular phimosis limit views to the peripheral retinal using the RetCam lens.

Table 1 .
Summary of previously reported systemic clinical findings in patients with a DYNC1H1 mutation.

Table 2 .
Summary of systemic clinical findings in a 2-year-old patient with a heterozygous mutation of the DYNC1H1 gene.