Advertisement

The neuroimaging spectrum of SLC13A5 related developmental and epileptic encephalopathy

Published:January 23, 2023DOI:https://doi.org/10.1016/j.seizure.2023.01.014

      Highlights

      • Pathogenic variants in SLC13A5 cause an autosomal recessive developmental and epileptic encephalopathy (DEE).
      • Neonatal seizures, fever sensitivity, status epileptics, developmental delay and tooth anomalies occur.
      • Neuroimaging is abnormal in one third of SLC13A5 related DEE cases.
      • White matter abnormalities like punctate white matter lesions appear most common.
      • Periventricular leukomalacia, delayed myelination, atrophy and cortical dysplasia can occur.

      Abstract

      Background

      SLC13A5 related developmental and epileptic encephalopathy (DEE) is an autosomal recessive condition characterized by neonatal seizures, fever sensitivity, status epilepticus, developmental delay and tooth anomalies. The neuroimaging spectrum of SLC13A5 related DEE is not fully known. We present a case of SLC13A5 related DEE with distinct neuroimaging findings and review the neuroimaging findings of all published cases of SLC13A5 related DEE.

      Methods

      A retrospective case review and focused review of the literature was completed.

      Results

      A 16-month-old male with a clinical phenotype consistent with SLC13A5 related DEE and a previously reported pathogenic variant in SLC13A5, c.655G>A, p.Gly219Arg and a novel likely pathogenic variant in SLC13A5, c.202C>T, p.Pro68Ser was identified. MRI at day 5 of life revealed wide spread punctate white matter lesions (PWMLs) affecting the subcortical white matter, periventricular white matter, splenium of the corpus callosum, posterior limb of the internal capsule, corticospinal tracts, midbrain, pons and medulla, mimicking a metabolic/infectious etiology. MRI at one month showed atrophy and evolution of white matter necrosis. One hundred and five cases of SLC13A5 related DEE were identified. Initial MRI was completed in 62 cases (59%). MRI was normal in 41 cases (66%) and abnormal in 21 (34%). White matter abnormalities were most common (n=15, 71%); PWMLs occurred in 8 cases (38%).

      Conclusion

      Neuroimaging abnormalities may exist in a third of SLC13A5 related DEE cases. White matter abnormalities such as PWMLs appear most common. It remains unknown why some are susceptible to these lesions and how they affect long-term neurodevelopmental outcomes in SLC13A5 related DEE.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Seizure - European Journal of Epilepsy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Guerrini R.
        • Balestrini S.
        • Wirrell E.C.
        • et al.
        Monogenic epilepsies: disease mechanisms, clinical phenotypes, and targeted therapies.
        Neurology. 2021; 97: 817-831
        • Morrison-Levy N.
        • Borlot F.
        • Jain P.
        • et al.
        Early-onset developmental and epileptic encephalopathies of infancy: an overview of the genetic basis and clinical features.
        Pediatr Neurol. 2021; 116: 85-94
        • Helbig I.
        • Tayoun AAN.
        Understanding genotypes and phenotypes in epileptic encephalopathies.
        Mol Syndromol. 2016; 7: 172-181
        • McTague A.
        • Howell K.B.
        • Cross J.H.
        • et al.
        The genetic landscape of the epileptic encephalopathies of infancy and childhood.
        Lancet Neurol. 2016; 15: 304-316
        • Mir A.
        • Almudhry M.
        • Alghamadi F.
        • et al.
        SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in Saudi Arabian population.
        Hum Genet. 2022; 141: 81-99
        • Bhutia Y.D.
        • Kopel J.J.
        • Lawrence J.J.
        • et al.
        Plasma membrane Na coupled citrate transporter (SLC13A5) and neonatal epileptic encephalopathy.
        Molecules. 2017; 22: 378
        • Henke C.
        • Tollner K.
        • van Dijk R.M.
        • et al.
        Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuron network excitability in the hippocampus.
        Neurobiol Dis. 2020; 143105018
        • Santalucia R.
        • Vilain C.
        • Soblet J.
        • et al.
        Carbamazepine efficacy in a severe electro-clinical presentation of SLC13A5-epilepsy.
        Ann Clin Trans Neurol. 2022; 9: 1095-1099
        • Bainbridge M.N.
        • Cooney E.
        • Miller M.
        • et al.
        Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle.
        Mol Genet Metab. 2017; 121: 314-319
        • Goodspeed K.
        • Liu J.S.
        • Nye K.L.
        • et al.
        SLC13A5 deficiency disorder: from genetics to gene therapy.
        Genes. 2022; 13: 165
        • Weeke L.C.
        • Brilstra E.
        • Braun K.P.
        • et al.
        Punctate white matter lesions in full-term infants with neonatal seizures associated with SLC13A5 mutations.
        Eur J Paediatr Neurol. 2017; 21: 396-403
        • Thevenon J.
        • Milh M.
        • Feillet F.
        • et al.
        Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life.
        Am J Hum Genet. 2014; 95: 113-120
        • Hardies K.
        • de Kovel C.G.F.
        • Weckhuysen S.
        • et al.
        Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal developmental delay and teeth hypoplasia.
        Brain. 2015; 138: 3238-3250
        • Klotz K.
        • Porter B.E.
        • Colas C.
        • et al.
        Mutations in the Na/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay.
        Mol Med. 2016; : 310-321
        • Matricardi S.
        • De Liso P.
        • Freri E.
        • et al.
        Neonatal developmental and epileptic encephalopathy due to autosomal recessive variants in the SLC13A5 gene.
        Epilepsia. 2020; 61: 2474-2485
        • Yang Q.Z.
        • Spelbrink E.M.
        • Nye K.L.
        • et al.
        Epilepsy and EEG phenotype of SLC13A5 citrate transporter disorder.
        Child Neurol Open. 2020; 7: 1-7
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association of molecular pathology.
        Genet Med. 2015; 17: 405-424
        • Brown T.L.
        • Nye K.
        • Porter B.E.
        • et al.
        Growth and overall health of patients with SLC13A5 citrate transporter disorder.
        Metabolites. 2021; 11: 746
        • Alhakeem A.
        • Alshibani F.
        • Tabarki B.
        Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy.
        Brain Dev. 2018; 40: 827-829
        • Pellegrino F.
        • Tardivo I.
        SLC13A5-related epileptic encephalopathy successfully treated with valproate and acetazolamide.
        Seizure. 2021; 91: 244-245
        • Schossig A.
        • Bloch-Zupan A.
        • Lussi A.
        • et al.
        SLC13A5 is the second gene associated with Kohlschutter–Tonz syndrome.
        J Med Genet. 2017; 54: 54-62
        • Anselm I.
        • MacCuaig M.
        • Prabhu S.
        • et al.
        Disease heterogeneity in Na/citrate cotransporter deficiency.
        JIMD Rep. 2017; 31: 107-111
        • Duan R.
        • Saadi N.W.
        • Grochowski C.M.
        • et al.
        A novel homozygous whole-gene deletion of SLC13A5 mediated by Alu-Alu mediated rearrangement in an Iraqi family with epileptic encephalopathy.
        Am J Med Genet A. 2021; 185: 1972-1980
        • Arvio M.
        • Lahdetie J.
        Adult phenotype of the homogyous missense mutation c.655G>A, p.Gly219Arg in SLC13A5: a case report.
        Am J Med Genet A. 2020; 182a: 2671-2674
        • Pantoja Leao V.H.
        • de Melo Aragao M.
        • Pinho R.S.
        • et al.
        Teaching neuroimages: when the teeth are the clue to the etiology of an epileptic encephalopathy.
        Neurology. 2021; 96: e157-e158
        • Snoeijen-Schouwenaars F.M.
        • van Ool J.S.
        • Verhoeven J.S.
        • et al.
        Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability.
        Epilepsia. 2019; 60: 155-164
        • Hayman M.
        • van Wezel-Meijler G.
        • van Straaten H.
        • et al.
        Punctate white-matter lesions in the full term newborn: underlying aetiology and outcome.
        Eur J Paediatr Neurol. 2019; 23: 280-287
        • Nguyen A.L.A.
        • Ding Y.
        • Suffren S.
        • et al.
        The brain's kryptonite: overview of punctate white matter lesions in neonates.
        Int J Dev Neurosci. 2019; 77: 77-88