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 malateaspartate 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.

Amino Acid Transport Defects in Human Inherited Metabolic Disorders

“…One patient improved psychomotor functioning and resumed myelination by following a ketogenic diet [162]. In the oldest patient, who had MRI results from multiples ages, the clinical presentation was consistent with leukodystrophy of the leuko-axonopathy category instead of with a primary hypo-myelinating disorder [163].…”

“…Currently, there are a total of five patients with pathogenic SLC25A12 variants described in the literature. They presented with a clinical phenotype consisting of arrested progressive encephalopathy, profound developmental delay, hypotonia, microcephaly, and myoclonic epilepsy [160][161][162][163]. In terms of neural abnormalities, two siblings described in the literature had cerebral atrophy, fluctuating basal ganglia changes, abnormal myelination, and decreased N-acetylaspartate levels, as indicated by magnetic resonance spectroscopy [160].…”

Inborn disorders of the malate aspartate shuttle

“…Lactate was reported normal to mildly elevated in these four patients. A fifth patient was identified with compound heterozygous variants at the age of 12 12 . The clinical phenotype of this patient was characterized by small stature, microcephaly, dysmorphic features, early‐onset global developmental delay, severe intellectual disability (non‐verbal), hypotonia, epilepsy, nonambulatory spastic quadriplegia albeit a happy disposition.…”

“… 5 The fact that patients with a deficiency in one of the components of the MAS present with predominant neurological signs and symptoms emphasizes the importance of the MAS for neurological functioning. 6 , 7 , 8 , 9 , 10 , 11 , 12 Early infantile epileptic encephalopathy is a common phenotype observed in patients with a defect in the MAS but is currently attributed to over 80 different genetic diseases in the OMIM database 13 and over 30 in the IEMbase. 14 Since these clinical phenotypes are aspecific, insights into the clinical and biochemical phenotypes of MAS deficiencies could help narrowing down the differential diagnosis.…”

βOHB Protective Pathways in Aralar-KO Neurons and Brain: An Alternative to Ketogenic Diet

“…In humans, Aralar/AGC1 deficiency causes the rare disease "global cerebral hypomyelination" (OMIM #612949, also named early infantile epileptic encephalopathy 39), a neurodevelopmental disease that matches aralar-KO mice phenotype, as it is characterized by severe hypomyelination, hypotonia, neurodevelopmental arrest, and seizures (Wibom et al, 2009;Falk et al, 2014;Kavanaugh et al, 2019;Pfeiffer et al, 2020). The first patient described for Aralar/AGC1 deficiency initiated a treatment with ketogenic diet (KD) at the age of 6 and for at least 19 months.…”