SLC25A22 – malignant migrating partial seizures of infancy

SLC25A22 encodes a mitochondrial glutamate transporter highly expressed in brain regions implicated in seizure genesis. Autosomal recessive biallelic loss‐of‐function in SLC25A22 causes malignant migrating partial seizures of infancy (MPSI), an early‐onset epileptic encephalopathy characterized by refractory focal seizures, hypotonia, and global developmental delay.

Whole exome sequencing in three unrelated families identified six children with biallelic SLC25A22 variants presenting with refractory neonatal or early infantile seizures, hypotonia, and developmental delay ([PMID:28255779]). A consanguineous pedigree yielded two affected siblings homozygous for c.328G>C (p.Gly110Arg), demonstrating segregation with disease ([PMID:24596948]). A separate Arab Muslim consanguineous family contributed four additional affected individuals homozygous for p.Gly236Trp, all with neonatal seizures and suppression‐burst EEG pattern ([PMID:19780765]).

The variant spectrum includes recurrent missense changes (p.Glu79Lys, p.Gly110Arg, p.Pro206Leu, p.Gly236Trp), multiple nonsense alleles (p.Ser151Ter, p.Gln132Ter, p.Gln147Ter, p.Gln140Ter, p.Gln254Ter), splice‐site variants (c.743-2A>C, c.202+1G>A), frameshifts (p.Ala2fs, p.Arg141fs, p.Pro245_Cys246insTer), and multi‐exon deletions (c.568_587+6del), consistent with loss of transporter function.

Functional studies in patient fibroblasts and reconstituted proteoliposomes for p.Pro206Leu and p.Gly110Arg demonstrated severely impaired glutamate uniport and exchange activity, confirming a loss‐of‐function mechanism ([PMID:15592994]). Expression analyses show SLC25A22 localized to mitochondria in brain and liver, implicating disrupted glutamate metabolism and secondary proline shuttle defects in disease pathogenesis.

Collectively, twelve probands across four families, robust segregation, and concordant functional deficits support a Strong ClinGen gene‐disease association. The autosomal recessive inheritance, clear genotype–phenotype correlations, and mechanistic insights into mitochondrial glutamate transport underscore the diagnostic utility of SLC25A22 sequencing in early‐onset epileptic encephalopathies.

Key Take‐home: Biallelic SLC25A22 loss‐of‐function variants are a strong cause of malignant migrating partial seizures of infancy, guiding genetic diagnosis and counseling.

References

• Journal of inherited metabolic disease | 2017 | Mutations in SLC25A22: hyperprolinaemia, vacuolated fibroblasts and presentation with developmental delay. PMID:28255779
• Annals of neurology | 2013 | SLC25A22 is a novel gene for migrating partial seizures in infancy. PMID:24596948
• Clinical genetics | 2009 | Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts. PMID:19780765
• American journal of human genetics | 2005 | Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy. PMID:15592994

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