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Keywords:

  • SPTAN1;
  • Early onset epileptic encephalopathy;
  • West syndrome;
  • Coloboma;
  • Hypomyelination

Summary

  1. Top of page
  2. Summary
  3. Case Report
  4. Discussion
  5. Acknowledgments
  6. Disclosures
  7. References
  8. Supporting Information

Recent study has shown that mutations in the alpha-II-spectrin (SPTAN1) gene cause early onset intractable seizures, severe developmental delay, diffuse hypomyelination, and widespread brain atrophy. We report a Slovene girl with hypotonia, lack of visual attention, early onset epileptic encephalopathy, and severe developmental delay. The patient presented with segmental myoclonic jerks at the age of 6 weeks, and infantile spasms at the age of 3.5 months. Her seizures were resistant to treatment. Multiple electroencephalography recordings showed deterioration of the background activity, followed by multifocal abnormalities before progressing to hypsarrhythmia. Ophthalmologic examination revealed bilateral dysplastic, coloboma-like optic discs. Brain magnetic resonance imaging showed diffusely reduced white matter and brainstem volumes with hypomyelination. A de novo heterozygous in-frame deletion was detected in SPTAN1: c.6619_6621delGAG (p.E2270del). This report supports the causative relationship between SPTAN1 mutations and early onset intractable seizures with severe hypomyelination and widespread brain volume reduction. Coloboma-like optic discs might be an additional feature observed in patients with SPTAN1 mutations.

Mutations in the alpha-II-spectrin (SPTAN1) gene have recently been described in two Japanese children with early onset West syndrome (WS), severe hypomyelination, reduced white matter, and severe developmental delay (Saitsu et al., 2010).

To further support the causative relationship between SPTAN1 gene mutations and WS and to expand the phenotypic spectrum, we report detailed clinical data of a Caucasian girl with SPTAN1 gene mutation.

Case Report

  1. Top of page
  2. Summary
  3. Case Report
  4. Discussion
  5. Acknowledgments
  6. Disclosures
  7. References
  8. Supporting Information

An 8-month-old female infant is the second child of healthy, unrelated, Slovene parents. The mother had one early miscarriage; otherwise family history was unremarkable. The baby was born spontaneously at term after an uneventful pregnancy. Her birth weight was 2,900 g (10th–25th centile), length 48 cm (10th centile), head circumference (HC) 34 cm (25th centile), and Apgar scores 8/8. Dysplastic signs were observed at birth: small anterior fontanel, low set ears, and high arched palate. She had poor spontaneous movement pattern and central hypotonia with brisk tendon reflexes. She responded well to the auditory stimuli, but had no visual contact. Her eye movements were abnormal with slow conjugate oscillations in all directions with no fixation. Ophthalmologic examination revealed bilateral, coloboma-like optic discs (Fig. 1A,B). Flash electroretinography was normal.

image

Figure 1.   Eye and brain abnormalities in the patient with SPTAN1 mutation. (A, B) Fundus photographs of the right (A) and left (B) eye show dysplastic, coloboma-like optic discs with otherwise normal retina and retinal vessels. (CF) Brain MRI images. T1-weighted axial images show hypomyelination in posterior limbs of internal capsule (C), and cortical atrophy of temporopolar regions (D). T1-weighted sagittal image shows a thinned corpus callosum and moderately reduced volume of the brainstem (E). T2-weighted coronal images show widened lateral ventricles and sulci in frontotemporal regions because of reduced deep and subcortical white matter volume and lack of T2 low signal in corticospinal tracts because of hypomyelination (F).

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The first electroencephalography (EEG) study performed on the third day of life revealed monomorphic background activity with superimposed high-frequency beta rhythms and the absence of physiologic patterns. At the age of 6 weeks, the patient was admitted because of repetitive movements: after awakening she would open her mouth and nod her head left to right, as if gasping for air. EEG revealed rare sharp potentials and few spikes, with no clinical correlation (Fig. 2A). Treatment with pyridoxine was started. At 8 weeks she presented with asynchronous myoclonic jerks, predominantly in her hands, fingers, and feet, occasionally more proximal in one extremity. An awake EEG revealed multifocal epileptiform discharges that were either associated with segmental myoclonic jerks or asymptomatic (Fig. 2B). At the age of 3.5 months, series of flexor spasms started on awakening. An EEG displayed typical ictal fast activity superimposed on slow wave during spasms, followed by 2-s attenuation. After 3 weeks, hypsarrhythmia was observed (Fig. 2C). Treatments with levetiracetam, clobazam, vigabatrin, valproate, and hydrocortisone were ineffective. After introduction of topiramate, the frequency of spasms diminished, but complete remission was not achieved. At the age of 7 months, short tonic seizures occurred while the patient was awake. The awake EEG continued to show irregular very slow high-voltage background activity with multifocal epileptiform discharges, whereas the hypsarrhythmia in drowsiness and sleep progressed to suppression-burst–like pattern during hydrocortisone treatment (Fig. 2D).

image

Figure 2.   EEG recordings of the patient with SPTAN1 mutation. At the age of 6 weeks, EEG revealed irregular slow basal activity with rare central spikes and sharp waves (A). At 2 months, slow dysrhythmic background activity with multifocal epileptiform discharges was present (B) and evolved to hypsarrhythmia at 4.5 months of age (C). During the treatment with hydrocortisone, the suppression-burst–like pattern was observed (D).

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The patient’s psychomotor development was severely impaired. Although some response to tactile stimuli was recognized at 3 months of age, eye contact was not achieved. She was fully breast fed until the age of 3 months, and needed nasogastric feeding thereafter. At the age of 8 months, her HC was 42 cm (5th–10th centile) and her weight was 8,850 g (50th–75th centile). Her spontaneous movement was poor and she was completely floppy, with no head control and very brisk proprioceptive reflexes with persistent ankle clonus.

Brain magnetic resonance imaging (MRI) performed at 10 weeks of age revealed hypomyelination, particularly in the posterior limbs of internal capsule and in the central regions (Fig. 1C). The volume of deep and subcortical white matter was reduced and the corpus callosum was thin (Fig. 1E,F). There was also moderate reduction of brainstem volume with widened basal cisterns and cortical atrophy in temporopolar regions (Fig. 1D).

All tests for metabolic disorders and prenatal infections were normal. Standard karyotype and analysis of subtelomeric rearrangements using multiplex ligation-dependent probe amplification technique gave normal result.

The patient’s DNA was analyzed using high-resolution melting curve and confirmatory direct sequencing. A heterozygous c.6619_6621delGAG, p.E2207del mutation was found in the SPTAN1 gene (Fig. S1). The mutation is identical with that of case 2 in the previous report (Saitsu et al., 2010). The mutation was not detected in either parent, suggesting de novo occurrence.

Discussion

  1. Top of page
  2. Summary
  3. Case Report
  4. Discussion
  5. Acknowledgments
  6. Disclosures
  7. References
  8. Supporting Information

To date, SPTAN1 mutations have been reported in only three patients (two Japanese patients and the present case) (Saitsu et al., 2010). All patients had somewhat similar clinical features. The initial symptoms were severe hypotonia (the present case) and lack of visual attention (three of three). Ophthalmologic examination revealed no abnormalities in previously reported patients, whereas the present case had dysplastic, coloboma-like optic discs bilaterally. This raises several hypotheses as to the relationship of this novel SPTAN1 mutation and ocular development. First, because SPTAN1 expression in fetal retina and brain has been shown (BioGPS, http://biogps.org), coloboma might be an additional feature observed in the patients with SPTAN1 mutations. Second, clinical variability may be explained by incomplete penetrance and variable expressivity. Third, SPTAN1 encodes for a filamentous cytoskeletal protein that regulates the stability of axonal structure (Saitsu et al., 2010). Recent experiments have shown that a deficiency of axon guidance molecules like Netrin-1 during development of the mouse nervous system results not only in abnormalities of the central nervous system, but can also lead to defects in optic nerve formation (Oster & Sretavan, 2003). Alternatively, coloboma may arise in our patient through coinheritance of a second, unrelated genetic mutation. Each condition is rare, with coloboma having an incidence of 0.5–7.5 per 10,000 birth (Gregory-Evans et al., 2004) and only four cases of SPTAN1 mutations reported worldwide (Saitsu et al., 2010). Therefore, the possibility of digenic inheritance for these two conditions seems unlikely.

The onset of epilepsy ranged from 2 to 3 months of age. Various types of seizures were displayed, including tonic spasms and seizures (three of three) and myoclonic seizures (the present case) (Tohyama et al., 2008; Saitsu et al., 2010). Epileptic seizures were resistant to treatments in all cases. The EEG in the present patient demonstrated abnormalities of the background activity already in the neonatal period; all patients had hypsarrhythmic pattern after the onset of infantile spasms.

Motor signs described in patients carrying SPTAN1 mutations were severe hypotonia in the first year of life with later evolution to spastic tetraparesis with brisk deep tendon reflexes and clonus, which is a frequent feature of severe encephalopathies of diverse etiologies. No stereotypic behaviors and nonepileptic movement disorders have been noticed in the published cases, whereas head nodding– and gasping for air–like behavior was present in our case before the seizures started. Feeding problems requiring nasogastric tube feeding were present in two patients (the present case and case 3 in Saitsu et al., 2010). All patients had deceleration of the rate of head growth, resulting in microcephaly in two published cases, whereas the head circumference in our case is still between the 5th and 10th centiles at the age of 8 months. All reported patients had profound mental retardation with lack of speech and severely delayed motor development.

Brain MRI in all patients with SPTAN1 mutations showed diffuse hypomyelination and widespread reduction of deep and subcortical white matter with thin corpus callosum. In addition patients presented with significant cortical and brainstem atrophy; however, in the present case the cerebellum was spared. Such severe brain abnormalities have not been described in any patient with West syndrome and mutations in ARX (Kato et al., 2003, 2004; Shoubridge et al., 2010), CDKL5 (Bahi-Buisson et al., 2008), STXBP1 (Deprez et al., 2010; Otsuka et al., 2010), or PLCB1 gene (Kurian et al., 2010).

Regarding molecular data, two different de novo heterozygous in-frame mutations in the SPTAN1 gene have been reported: a 3-bp deletion (6619delGAG) in exon 50 (Case 2 in Saitsu et al., 2010 and present case) and a 6-bp duplication (nucleotides 6,923–6,928) in exon 53 (Case 3 in Saitsu et al., 2010). Alpha-II-spectrin has been shown to be essential for proper myelination in the zebrafish (Voas et al., 2007). In vitro studies showed that pathologic aggregation of alpha/beta spectrin heterodimers and abnormal axon initial segment integrity resulted from SPTAN1 mutation and suggested a dominant negative effect of the mutations (Saitsu et al., 2010).

In conclusion, this report supports the causative relationship between SPTAN1 mutations and early onset intractable seizures with severe hypomyelination and widespread brain atrophy. Coloboma-like optic discs might be an additional feature observed in the patients with SPTAN1 mutations.

Acknowledgments

  1. Top of page
  2. Summary
  3. Case Report
  4. Discussion
  5. Acknowledgments
  6. Disclosures
  7. References
  8. Supporting Information

We thank the patient’s family for their participation in this study. This work was supported by Research Grants from the Ministry of Health, Labour and Welfare (N.M. and H.S.) and a Grant-in-Aid for Young Scientist from Japan Society for the Promotion of Science (H.S.)

Disclosures

  1. Top of page
  2. Summary
  3. Case Report
  4. Discussion
  5. Acknowledgments
  6. Disclosures
  7. References
  8. Supporting Information

None of the authors has any conflict of interest to disclose. 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.

References

  1. Top of page
  2. Summary
  3. Case Report
  4. Discussion
  5. Acknowledgments
  6. Disclosures
  7. References
  8. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Case Report
  4. Discussion
  5. Acknowledgments
  6. Disclosures
  7. References
  8. Supporting Information

Figure S1. Genetic analysis. Direct sequence analysis of SPTAN1 revealed a heterozygous c.6619_6621delGAG (p.E2207del) mutation, which occurred de novo, in the patient.

FilenameFormatSizeDescription
EPI_3437_sm_FigS1.tif650KSupporting info item

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