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. 2024 Oct 18;15(10):1338.
doi: 10.3390/genes15101338.

Sleep Abnormalities in SLC13A5 Citrate Transporter Disorder

Raegan M Adams  1 , Can Ozlu  2 , Lauren E Bailey  1 , Rayann M Solidum  3 , Sydney Cooper  4 , Carrie R Best  5   6 , Jennifer Elacio  5 , Brian C Kavanaugh  6 , Tanya L Brown  7 , Kimberly Nye  7 , Judy Liu  8 , Brenda E Porter  3 , Kimberly Goodspeed  2 , Rachel M Bailey  1   2
Affiliations

Sleep Abnormalities in SLC13A5 Citrate Transporter Disorder

Raegan M Adams et al. Genes (Basel). .

Abstract

Background: SLC13A5 Citrate Transporter Disorder is a rare pediatric neurodevelopmental disorder. Patients have epilepsy, developmental disability, and impaired mobility. While sleep disorders are common in children with neurodevelopmental disorders, sleep abnormalities have not been reported in SLC13A5 patients.

Methods: Here, we assessed sleep disturbances in patients through caregiver reported surveys and in a transgenic mouse model of SLC13A5 deficiency. A total of 26 patients were evaluated with the Sleep Disturbance Scale for Children three times over a one-year span. Sleep and wake activities were assessed in the SLC13A5 knock-out (KO) mice using wireless telemetry devices.

Results: A high burden of clinically significant sleep disturbances were reported in the patients, with heterogeneous symptoms that remained stable across time. While sleep disturbances were common, less than 30% of patients were prescribed medications for sleep. Comparatively, in SLC13A5 KO mice using EEG recordings, significant alterations were found during light cycles, when rodents typically sleep. During the sleep period, SLC13A5 mice had increased activity, decreased paradoxical sleep, and changes in absolute power spectral density, indicating altered sleep architecture in the mouse model.

Conclusions: Our results demonstrate a significant component of sleep disturbances in SLC13A5 patients and mice, highlighting a potential gap in patient care. Further investigation of sleep dysfunction and the underlying etiologies of sleep disturbances in SLC13A5 citrate transporter disorder is warranted.

Keywords: EEG; SDSC; SLC13A5; mice; patients; sleep.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Sleep disturbances are prevalent in SLC13A5 patients. (A) Percentage of patients that had clinically significant (T score ≥ 56, shown in green) and non-clinically significant (T score < 56, shown in white) sleep disturbances, as assessed by the overall sleeping score from the SDSC over a one-year span. (B) Individual T scores for each visit. BL = baseline.
Figure 2
Figure 2
Patients had difficulties with sleep transitions and insomnia. (A) Nightly time spent sleeping and (B) time to fall asleep for patients. (C) Percentage of patients with a clinically significant sleep disorder. Affected = T score ≥ 70; unaffected = T score ≥ 70. BL = baseline.
Figure 3
Figure 3
KO mice had decreased paradoxical sleep. (A) Timeline overview of EEG recordings. (B,C) Average EMG activity of WT and KO mice during wake cycles (B) and sleep cycles (C). Student’s t-test, * p < 0.05. (D) Representative EEG, EMG, and activity traces within the four stages of sleep of a WT animal. Each recording window represents one minute. (E–H) Percentage of time spent in active wake (E), quiet wake (F), slow-wave sleep (G), and paradoxical sleep (H). n = 17 WT, n = 22 KO. Two-way ANOVA genotype effect shown, * p < 0.05.
Figure 4
Figure 4
KO mice had altered power spectral densities during sleep. (A,B) Power spectral density (PSD) averaged over two, 60 h recordings during wake cycles (6 PM–6 AM) (A) and sleep cycles (6 AM–6 PM) (B). (C–F). PSD during active wake (C), quiet wake (D), slow-wave sleep (E), and paradoxical sleep (F), divided into delta, theta, alpha, and beta frequencies. n = 17 WT, n = 22 KO. Two-way ANOVA with Sidak’s multiple comparisons test, * p < 0.05.
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References

    1. Thevenon J., Milh M., Feillet F., St-Onge J., Duffourd Y., Juge C., Roubertie A., Heron D., Mignot C., Raffo E., 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. doi: 10.1016/j.ajhg.2014.06.006. - DOI - PMC - PubMed
    1. Goodspeed K., Liu J.S., Nye K.L., Prasad S., Sadhu C., Tavakkoli F., Bilder D.A., Minassian B.A., Bailey R.M. SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy. Genes. 2022;13:1655. doi: 10.3390/genes13091655. - DOI - PMC - PubMed
    1. Matricardi S., De Liso P., Freri E., Costa P., Castellotti B., Magri S., Gellera C., Granata T., Musante L., Lesca G., et al. Neonatal developmental and epileptic encephalopathy due to autosomal recessive variants in SLC13A5 gene. Epilepsia. 2020;61:2474–2485. doi: 10.1111/epi.16699. - DOI - PubMed
    1. Beltran A.S. Novel Approaches to Studying SLC13A5 Disease. Metabolites. 2024;14:84. doi: 10.3390/metabo14020084. - DOI - PMC - PubMed
    1. Gopal E., Miyauchi S., Martin P.M., Ananth S., Srinivas S.R., Smith S.B., Prasad P.D., Ganapathy V. Expression and functional features of NaCT, a sodium-coupled citrate transporter, in human and rat livers and cell lines. Am. J. Physiol. Gastrointest. Liver Physiol. 2007;292:G402–G408. doi: 10.1152/ajpgi.00371.2006. - DOI - PubMed