Report on three additional patients and genotype–phenotype correlation in SLC25A22-related disorders group

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Early infantile epileptic encephalopathy (EIEE) is a heterogeneous group of severe forms of age-related developmental and epileptic encephalopathies with onset during the first weeks or months of life. The interictal electroencephalogram (EEG) shows a “suppression burst” (SB) pattern. The prognosis is usually poor and most children die within the first two years or survive with very severe intellectual disabilities. EIEE type 3 is caused by variants affecting function, in SLC25A22, which is also responsible for epilepsy of infancy with migrating focal seizures (EIMFS). We report a family with a less severe phenotype of EIEE type 3. We performed exome sequencing and identified two unreported variants in SLC25A22 in the compound heterozygous state: NM_024698.4: c.[813_814delTG];[818 G>A] (p.[Ala272Glnfs*144];[Arg273Lys]). Functional studies in cultured skin fibroblasts from a patient showed that glutamate oxidation was strongly defective, based on a literature review. We clustered the 18 published patients (including those from this family) into three groups according to the severity of the SLC25A22-related disorders. In an attempt to identify genotype–phenotype correlations, we compared the variants according to the location depending on the protein domains. We observed that patients with two variants located in helical transmembrane domains presented a severe phenotype, whereas patients with at least one variant outside helical transmembrane domains presented a milder phenotype. These data are suggestive of a continuum of disorders related to SLC25A22 that could be called SLC25A22-related disorders. This might be a first clue to enable geneticists to outline a prognosis based on genetic molecular data regarding the SLC25A22 gene.

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  1. 1.

    Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression-burst. J Clin Neurophysiol. 2003;20:398–407.

  2. 2.

    Molinari F, Raas-Rothschild A, Rio M, Fiermonte G, Encha-Razavi F, Palmieri L, et al. Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclinic epilepsy. Am J Hum Genet. 2005;76:334–9.

  3. 3.

    Molinari F, Kaminska A, Fiermonte G, Boddaert N, Raas-Rothschild A, Plouin P, et al. Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts. Clin Genet. 2009;76:188–94.

  4. 4.

    Fiermonte G, Palmieri L, Todisco S, Agrimi G, Palmieri F, Walker JE. Identification of the mitochondrial glutamate transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. J Biol Chem. 2002;277:19289–94.

  5. 5.

    Cohen R, Basel-Vanagaite L, Goldberg-Stern H, Halevy A, Shuper A, Feingold-Zadok M, et al. Two siblings with early infantile myoclonic encephalopathy due to mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22. Eur J Paediatr Neurol. 2014;18:801–5.

  6. 6.

    Reid ES, Williams H, Anderson G, Benatti M, Chong K, James C, et al. Mutations in SLC25A22: hyperprolinaemia, vacuolated fibroblasts and presentation with developmental delay. J Inherit Metab Dis. 2017;40:385–94.

  7. 7.

    Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:512–21.

  8. 8.

    Poduri A, Heinzen EL, Chitsazzadeh V, Lasorsa FM, Elhosary PC, LaCoursiere CM, et al. SLC25A22 is a novel gene for migrating partial seizures in infancy. Ann Neurol. 2013;74:873–82.

  9. 9.

    Barat-Houari M, Dumont B, Fabre A, Them FT, Alembik Y, Alessandri JLA, et al. The expanding spectrum of COL2A1 gene variants in 136 patients with a skeletal dysplasia phenotype. Eur J Hum Genet. 2016;24:992–1000.

  10. 10.

    Brines ML, Sundaresan S, Spencer DD, de Lanerolle NC. Quantitative autoradiographic analysis of ionotropic glutamate receptor subtypes in human temporal lobe epilepsy: up-regulation in reorganized epileptogenic hippocampus. Eur J Neurosci. 1997;9:2035–44.

  11. 11.

    Ramos M, del Arco A, Pardo B, Martinez-Serrano A, Martinez-Morales JR, Kobayashi K, et al. Developmental changes in the Ca2+-regulated mitochondrial aspartate-glutamate carrier aralar1 in brain and prominent expression in the spinal cord. Brain Res Dev Brain Res. 2003;143:33–46.

  12. 12.

    Bourgeron T, Chretien D, Rotig A, Munnich A, Rustin P. Fate and expression of the deleted mitochondrial DNA differ between human heteroplasmic skin fibroblast and Epstein-Barr virus-transformed lymphocyte cultures. J Biol Chem. 1993;268:19369–76.

  13. 13.

    Rustin P, Chretien D, Bourgeron T, Gérard B, Rötig A, Saudubray JM, et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta. 1994;228:35–51.

  14. 14.

    Aubert S, Bligny R, Douce R, Gout E, Ratcliffe RG, Roberts JK. Contribution of glutamate dehydrogenase to mitochondrial glutamate metabolism studied bu 13C and 31P nuclear magnetic resonance. J Exp Bot. 2001;52:37–45.

  15. 15.

    Berkich DA, Ola MS, Cole J, Sweatt AJ, Hutson SM, LaNoue KF. Mitochondrial transport proteins of the brain. J Neurosci Res. 2007;85:3367–77.

  16. 16.

    Goubert E, Mircheva Y, Lasorsa FM, Melon C, Profilo E, Sutera J, et al. Inhibition of the mitochondrial glutamate carrier SLC25A22 in astrocytes leads to intracellular glutamate accumulation. Front Cell Neurosci. 2017;11:149.

  17. 17.

    Trabelsi Y, Amri M, Becq H, Molinari F, Aniksztejn L. The conversion of glutamate by glutamine synthase in neocortical astrocytes from juvenile rat is important to limit glutamate spillover and peri/extrasynaptic activation of NMDA receptors. Glia. 2017;65:401–15.

  18. 18.

    Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shutoff and cell death pathways. Nat Neurosci. 2002;5:405–14.

  19. 19.

    Ivanov A, Pellegrino C, Rama S, Dumalska I, SalyhaY, Ben-Ari Y, et al. Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons. J Physiol. 2006;572:789–98.

  20. 20.

    Palmieri F. The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol Asp Med. 2013;34:465–84.

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Correspondence to David Geneviève.

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