Retinal Changes in Early-Onset cblC Methylmalonic Acidemia Identified Through Expanded Newborn Screening: Highlights from a Case Study and Literature Review

Abstract

Background: Methylmalonic acidemia combined with homocystinuria (cblC) can lead to infantile maculopathy. Although significant visual deterioration is commonly reported in early-onset cblC, we found poor awareness regarding formal assessments of ocular complications, especially in newborns, and of how these complications relate to the timing of therapy initiation. In this work, we present our experience and perform a literature review.

Methods: We performed sequential fundus examinations, optical coherence tomography (OCT) and full-field electroretinography (ERG) under sedation following detection of signs of retinal degeneration. We also assessed visual fields using kinetic attraction perimetry.

Results: We report a newborn who was referred on the eighth day of life, following a diagnosis of cblC through newborn screening (NBS), and who began treatment that same day. Close monitoring of retinal changes through fundus examinations allowed the detection of signs of retinal degeneration at 3 months, which progressed when checked at 5 months. At 7 months, OCT showed retinal thinning with the appearance of bull's eye maculopathy in the corresponding region on fundoscopy; ERG revealed a reduction in the amplitude of both scotopic and photopic components, whereas kinetic attraction perimetry showed no abnormalities. Genetic investigation confirmed the disease, compound heterozygous for a nonsense variant in MMACHC and a splicing one in PRDX1.

Conclusions: In cblC, retinal degeneration occurs in the first months of life despite timely treatment and adequate biochemical control, and it may manifest before any signs of visual deprivation appear. However, there is an early, narrow window during which therapy may slow down retinal degeneration enough to prevent sensory nystagmus. We recommend initiating therapy immediately after biochemical diagnosis, along with close ophthalmological monitoring, before the appearance of any signs.

Keywords: BEM; epi-cblC; infantile maculopathy; motor nystagmus; sensory nystagmus; tandem mass spectrometry biomarkers.

Figure 1

Bilateral bull’s eye maculopathy (BEM) as detected at fundus examination and OCT scans performed in the corresponding region at 7 months. (A). Bilateral BEM is characterized by a round hypopigmented central zone surrounded by a hyperpigmented ring. Top image: right eye (RE); bottom image: left eye (LE). (B). OCT images of the macula. A very thin fovea (total foveal thickness of 72 µm in RE and 78 µm in LE) is visible in both eyes due to the development of foveal atrophy involving only the outer retinal layers. Top image: RE, oblique scan; bottom image: LE, vertical scan. (C). The binocular attraction visual field shows a normal extension for the age. The infrared image of the child’s face during the examination is shown in the top right window and allows us to identify the fixation changes made by both eyes and the head.

Figure 2

Genomic architecture of the epi-cblC gene trio and aberrant antisense transcription leading to MMACHC promoter epimutation. (A). The chromosome location of MMACHC, CCDC163P and PRDX1 is shown along with their transcription orientations (UCSC Genome Browser Genome viewing, hg38). Specifically, CCDC163P is reverse 1 (R1), MMACHC is forward 2 (F2), and PRDX1 is also reverse 3 (R3). (B) The picture depicts the mechanism of formation of the prolonged antisense transcript derived from the PRDX1 splicing variant. Additionally, it highlights the location of the CpG island that is subject to methylation [3].