SLC25A22 – Early Myoclonic Encephalopathy

Early myoclonic encephalopathy is a severe neonatal epileptic syndrome characterized by suppression-burst electroencephalographic patterns and intractable myoclonic seizures. It presents in the first months of life with profound developmental impairment and high mortality.

SLC25A22 encodes a mitochondrial glutamate/H+ symporter critical for glutamate transport into mitochondria. Pathogenic variants in SLC25A22 disrupt mitochondrial glutamate metabolism, linking metabolic dysfunction to epileptic encephalopathy.

In total, seven affected individuals in three unrelated consanguineous pedigrees were reported (2 siblings [PMID:25033742]; 4 siblings and one unrelated patient [PMID:19780765]). All affected individuals harbored biallelic variants in SLC25A22 consistent with autosomal recessive inheritance.

The variant spectrum includes one recurrent missense change, c.617C>T (p.Pro206Leu), alongside multiple loss-of-function alleles such as frameshift and nonsense mutations. c.617C>T (p.Pro206Leu) is located in a conserved transmembrane domain and segregates with disease in affected families.

Segregation analysis demonstrated cosegregation of SLC25A22 variants with disease in six affected relatives across two pedigrees, supporting pathogenicity. Carrier parents were asymptomatic.

Functional assays in patient fibroblasts revealed markedly reduced glutamate oxidation, and studies in proteoliposomes confirmed defective [14C]glutamate uniport and exchange by mutant protein [PMID:15592994]. Expression profiling showed high SLC25A22 expression in brain regions implicated in seizure generation.

Collectively, genetic and experimental data meet a Strong level of clinical validity. SLC25A22 deficiency underlies early myoclonic encephalopathy through loss of mitochondrial glutamate transport. Genetic testing of SLC25A22 enables definitive diagnosis and informs reproductive counseling.

Key Take-home: Biallelic SLC25A22 variants cause autosomal recessive early myoclonic encephalopathy via a loss-of-function mechanism, supporting clinical testing and inclusion in diagnostic gene panels.

References

• European Journal of Paediatric Neurology • 2014 • Two siblings with early infantile myoclonic encephalopathy due to mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22. PMID:25033742
• 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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