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Epilepsy, status epilepticus, and hemiplegic migraine coexisting with a novel SLC4A4 mutation

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Abstract

Background

Recessive mutations in the SLC4A4 gene cause a syndrome characterised by proximal renal tubular acidosis (pRTA), mental retardation, dental and ocular abnormalities, and hemiplegic migraine. Rare cases involving the development of epilepsy or its severe complication—status epilepticus—have been described.

Methods

The clinical and genetic status of four affected members in a Spanish family was studied. The SLC4A4 gene mutation was detected with a next-generation sequencing (NGS) panel in the proband, and Sanger confirmed the putative mutations in affected relatives. In silico analysis was performed to elucidate the putative effect of mutation on the splicing process.

Results

A novel mutation, c.2562+2T>G, was identified in the homozygous state in all diseased members of the family. This mutation affected a canonical splice site and is predicted to abolish the wild-type donor site, which predicts a premature truncated NBCe1 protein with cotransport activity. The resulting protein lacks the 190 amino acids of the carboxyl-terminus, and the effect is likely to be a loss of function. All patients suffered from severe pRTA and ocular abnormalities, and the adults also suffered from neurological complications, such as hemiplegic migraine and/or epilepsy. Two developed life-threatening status epilepticus, although they fully recovered and remained free of seizures with valproate.

Conclusion

These results expand the clinical and mutational spectra of SLC4A4-related disease and have implications for understanding the potential role of NBCe1 in the pathophysiologic processes of hemiplegic migraine and epilepsy/status epilepticus associated with the mutation.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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Funding

This study was supported by the Health Institute Carlos III–Ministry of Health of Spain ISCIII (Rio Hortega Fellowship CM12/00014).

Author information

Author notes

  1. Sara Gil-Perotín and Teresa Jaijo contributed equally to this work.

Authors and Affiliations

  1. Neurology Department, University and Polytechnic Hospital La Fe, Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain

    Sara Gil-Perotín & Samuel Díaz

  2. Neuroimmunology Unit, Health Research Institute La Fe (IISLAFE), Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain

    Sara Gil-Perotín & Raquel Gasqué-Rubio

  3. Genetic Unit, University and Polytechnic Hospital La Fe, Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain

    Teresa Jaijo

  4. Molecular, Cellular and Genomics Biomedicine Research Group, Health Research Institute La Fe (IISLAFE), Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain

    Teresa Jaijo

  5. CIBER de Enfermedades Raras (CIBERER), Madrid, Spain

    Teresa Jaijo

  6. Neurophysiology Department, University and Polytechnic Hospital La Fe, Avda. Fernando Abril Martorell 106, 46026, Valencia, Spain

    Andrés G. Verdú & Pilar Rubio

  7. Radiology Department, Hospital Arnau de Vilanova, C/San Clemente, 12, 46025, Valencia, Spain

    Miguel Mazón

Authors
  1. Sara Gil-Perotín
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  2. Teresa Jaijo
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  3. Andrés G. Verdú
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  4. Pilar Rubio
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  5. Miguel Mazón
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  6. Raquel Gasqué-Rubio
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  7. Samuel Díaz
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Contributions

SGP and TJ designed the study and wrote the manuscript. RGR helped collect data and design figures. MM was the neuroradiologist that analysed CT and MRI data. AGV and PR performed and interpreted EEG data. SGP and SD were the attending physicians of the proband during admittance and follow-up, and SD is the head of the Headache Unit and helped revise the final manuscript. All authors read and approved of the final manuscript.

Corresponding author

Correspondence to Sara Gil-Perotín.

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Conflict of interest

The authors have no conflicts of interest to disclose.

Ethical approval

The institutional review board at the Health Institute in Hospital La Fe approved this study.

Informed consent statement

All studies were undertaken with the understanding and written consent of all subjects or next-of-kin involved and conformed with the World Medical Association Declaration of Helsinki.

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Gil-Perotín, S., Jaijo, T., Verdú, A.G. et al. Epilepsy, status epilepticus, and hemiplegic migraine coexisting with a novel SLC4A4 mutation. Neurol Sci 42, 3647–3654 (2021). https://doi.org/10.1007/s10072-020-04961-x

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  • DOI: https://doi.org/10.1007/s10072-020-04961-x

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