Corneal imaging with optical coherence tomography assisting the diagnosis of mucolipidosis type IV

Mucolipidosis type IV (MPS-IV, OMIM #252650), a lysosomal storage disorder caused by dysfunctional mucolipin-1, is characterized by neurologic and visual impairment, developmental delay, and achlorhydria. MCOLN1 gene mutation identification is diagnostic but requires clinical suspicion. The latter is challenging, however, because most systemic and ocular findings are nonspecific and rarely evolve simultaneously. Bilateral corneal clouding is the earliest hallmark sign of MPS-IV. Unlike in other metabolic causes of corneal opacification, it is owing to preferential accumulation of abnormal material in the corneal epithelium as opposed to other corneal layers. Slit-lamp recognition of isolated epitheliopathy however is difficult owing to limited collaboration in children.

Herein, we report the case of a 12-year-old boy with developmental and intellectual delay, subcortical neurodegeneration, periventricular leukomalacia, and hypoplastic corpus callosum. His ocular findings included progressive bilateral diffuse corneal clouding with normal intraocular pressures, optic atrophy, and retinal degeneration. Anterior segment optical coherence tomography (OCT; Bioptigen Envisu^TM, Leica Microsystems, Wetzlar, Germany; anterior segment probe) revealed increased corneal thickness of 636 µm (normal: 540 µm), increased epithelial thickness of 7 µm (normal: 3–4 µm), and epithelial hyperreflectivity bilaterally (Fig. 1A–B). The stroma and Descemet's membrane/endothelial complex were unremarkable. OCT findings raised our clinical suspicion and helped the medical genetics team orient their diagnostic evaluation toward MPS-IV. Metabolic work-up revealed hypergastrinemia (550 ng/L; normal: 0–115 ng/L), suggesting achlorhydria. Exome sequencing and Sanger confirmation in the trio identified 2 MCOLN1 gene compound heterozygote variants (NM_020533.2:c.694A>C; NM_001008537.2:c.964C>T), consistent with MPS-IV.

Anterior segment OCT is a fast, noninvasive test that can be performed at bedside or in an office to capture cross-sectional images of the cornea, allowing easy visualization and measurement of the different corneal layers. In children with corneal clouding, OCT can facilitate the identification of specific pathologic changes, especially in cases with challenging slit-lamp examination. Corneal epithelial thickening and hyperreflectivity in an overall thickened cornea with normal stroma and endothelium corresponds to the histopathologic findings described in MPS-IV. Their recognition can guide genetic testing, enable timely diagnosis, and prevent unnecessary corneal transplantation. Indeed, these patients’ visual potential is frequently limited by poor retinal and optic nerve function, and corneal clouding tends to rapidly recur in the graft. In other causes of progressive bilateral diffuse corneal opacification in an older child, including mucolipidosis type II and mucopolysaccharidoses types I-H, I-S, IV, and VI, abnormal material predominantly accumulates in stromal keratocytes, with relative sparing of epithelial and endothelial cells. These corneas also appear thickened on OCT but have a normal-appearing epithelium and granular hyperreflectivity confined to the corneal stroma.^, Of note, we previously reported similar corneal OCT findings to those described here in a 2-year-old child with MPS-IV. This suggests that anterior segment OCT can be useful in distinguishing this disease entity from other causes of corneal clouding with normal intraocular pressures in younger children as well. Unlike MPS-IV, these pathologies—including congenital stromal corneal dystrophy, corneal hereditary endothelial dystrophy, posterior polymorphous corneal dystrophy, Peter's anomaly, and forceps injury—all demonstrate normal corneal epithelial thickness and reflectivity.