Longitudinal MRI findings in patient with SLC25A12 pathogenic variants inform disease progression and classification

Abstract

Aspartate-glutamate carrier 1 (AGC1) is one of two exchangers within the malate-aspartate shuttle. AGC1 is encoded by the SLC25A12 gene. Three patients with pathogenic variants in SLC25A12 have been reported in the literature. These patients were clinically characterized by neurodevelopmental delay, epilepsy, hypotonia, cerebral atrophy, and hypomyelination; however, there has been discussion in the literature as to whether this hypomyelination is primary or secondary to a neuronal defect. Here we report a 12-year-old patient with variants in SLC25A12 and magnetic resonance imaging (MRI) at multiple ages. Novel compound heterozygous, recessive variants in SLC25A12 were identified: c.1295C>T (p.A432V) and c.1447-2_1447-1delAG. Clinical presentation is characterized by severe intellectual disability, nonambulatory, nonverbal status, hypotonia, epilepsy, spastic quadriplegia, and a happy disposition. The serial neuroimaging findings are notable for cerebral atrophy with white matter involvement, namely, early hypomyelination yet subsequent progression of myelination. The longitudinal MRI findings are most consistent with a leukodystrophy of the leuko-axonopathy category, that is, white matter abnormalities that are most suggestive of mechanisms that result from primary neuronal defects. We present here the first case of a patient with compound heterozygous variants in SLC25A12, including brain MRI findings, in the oldest individual reported to date with this neurogenetic condition.

Keywords: AGC1; MRI; SLC25A12; genetics; intellectual disability.

Figure 1

MRI and MRS findings in male patient with compound heterozygous SLC25A12 pathogenic variants. (a-c) T₂-weighted images at 7 months of age, with axial images shown in (a) and (b) and a coronal image in (c). Images reveal diffusely accentuated signal in the bilateral frontal and parietal deep white matter (a,b, arrows) that contrasts with myelinating periventricular and corticospinal tract white matter (b, *). The corpus callosum (a, white arrowheads) is abnormally thin for age, which is also reflective of white matter volume loss. Images also reveal diffuse panlobar sulcal prominence and white matter volume loss that results in contraction of the gyri, most conspicuously in the bilateral superior frontal gyri (b, red arrowheads). Thin membranes in the bilateral lateral ventricles that may outline intraventricular cysts (b,c, black arrowheads) can also be seen. (d,e) Axial HASTE images at 10 years 5 months of age suggest further contraction of the gyri and white matter, yet also reveal interval myelination on the T₂-weighted images. (f) Results of MRS performed over the left basal ganglia at 7 months of age. The spectrum acquired at intermediate echo time (TE 135 ms) shows an inverted lactate peak at 1.3 ppm (white arrow), which may reflect sequela of seizures. (g) Pedigree showing heterozygous parents, each of which is a carrier of a distinct SLC25A12 variant, and the affected male patient with compound heterozygous variants in SLC25A12. Note, information regarding siblings of the patient is not shown to aid in protecting the anonymity and privacy of the family. (h) Sanger DNA sequencing chromatograms showing SLC25A12 variants in the father, mother, and patient, as indicated in (g). References for variant coordinates are based on GenBank transcript ID NM_003705 and Ensembl transcript ID ENST00000422440.

Figure 2

In silico structural modeling of SLC25A12 and of the A432V pathogenic variant. (a) The in silico model of the transmembrane region of SLC25A12. N- and C-termini have been excluded to facilitate modeling and for clarity. (b) The model of SLC25A12 (gray) overlaid on the structure of bovine SLC25A4 (aqua). (c) The model of SLC25A12 (gray) overlaid on the structure of yeast SLC25A4 (green). (d) The model of SLC25A12 (gray) overlaid on the structure of mouse SLC25A8 (magenta). (e) A view of transmembrane helices 2 (bottom) and 3 (top) of the consensus sequence model. A432 is highlighted in green. (f) The same region of the variant-containing sequence model. V432 is highlighted in red. (g) The consensus sequence (gray) and variant sequence (yellow) model overlaid. (h) An overlay of A432V, with the position shifts of residues 414–417 in the consensus sequence and variant-containing sequence highlighted.