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Gorman et al., 1
Title: Status Dystonicus in Two cases of SOX2-Anophthalmia Syndrome with mutations
resulting in p.Tyr160*
Authors: K Gorman1, SA Lynch 2,3, A Schneider 4, DK Grange 5, KA Williamson 6, DR
FitzPatrick 6, MD King 1,2
1. Department of Neurology and Clinical Neurophysiology, Temple Street Children’s
University Hospital, Dublin 1, Ireland
2. Academic Centre on Rare Diseases, School of Medicine and Medical Science, University
College Dublin, Ireland.
3. Clinical Genetics, Temple Street Children's University Hospital, Temple Street, Dublin 1,
Ireland.
4. Genetics Division, Einstein Medical Center, Philadelphia, Pennsylvania 19141, USA.
5. Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington
University School of Medicine, St. Louis, Missouri, USA.
6. Medical Research Council Human Genetics Unit, MRC Institute of Genetics and
Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
Corresponding Authors:
Kathleen Gorman
Address: Department of Neurology and Clinical Neurophysiology, Temple Street Children’s
University Hospital, Dublin 1, Ireland
E-mail: Kathleen.gorman@cuh.ie
Telephone: +353-1-8784000
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Gorman et al., 2
David R FitzPatrick
Address: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh EH4
2XU, UK
Email: david.fitzpatrick@ed.ac.uk
Telephone: +44 131 651 8569
Word Count: 829
Keywords: SOX2-Anophthalmia Syndrome, Status dystonicus
Financial Disclosure: The authors have indicated they have no financial relationships
relevant to this article to disclose.
Potential conflict of interest: The authors have indicated they have no potential conflicts of
interest to disclose.
Funding Source: No external funding
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To the Editor:
Heterozygous mostly de novo loss-of-function mutations in SRY (Sex Determining Region
Y)-box 2 (SOX2) are responsible for 20-40% of bilateral anophthalmia (Fantes et al. 2003,
Schneider et al., 2009, Gerth-Kahlert et al., 2013). SOX2 (chr3:181,711,924-181,714,436
hg38) encodes a transcription factor critical for early embryogenesis, embryonic stem cell
pluripotency and stem cell maintenance in the central nervous system (Zhang et al., 2014).
SOX2-anophthalmia syndrome is characterized by a spectrum of ocular malformations
(anophthalmia, microphthalmia and, infrequently, coloboma) in association with brain,
pituitary, genitourinary and gastrointestinal anomalies (Ragge et al. 2005, Schneider et al.,
2009, Williamson and FitzPatrick 2014). Status dystonicus is a very rare acute neurological
disorder usually associated with pre-existing dystonia such as cerebral palsy or
neurodegenerative disease. We report two cases with similar mutations in SOX2 presenting
with status dystonicus, an association not previously described.
A male infant with bilateral anophthalmia was born at term of non-consanguineous
parents. A de novo SOX2 mutation, c.479dupA, p.(Tyr160*), was identified by targeted
sequencing. Additionally, array CGH analysis detected a 739 kb deletion (chr1:242,357,208-
243,095,923 GRCh37/hg19), that inactivates a gene that is not known to cause any genetic
disease, PLD5. This deletion was inherited from his phenotypically normal mother and was
thus considered unlikely to be of clinical significance. Auditory brainstem testing detected
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mild bilateral sensorineural hearing loss. At 18 months, there was profound global
development delay (poorly responsive, not rolling or sitting) and axial hypotonia. He
presented aged 20 months with episodes of fever, poor feeding, irritability, arching, stiffening
of all limbs and bruxism lasting several minutes and occurring 10-20 times daily. There was
no preceding illness or drug exposure. Investigations for biochemical, toxic, metabolic
(including CSF neurotransmitters) or infective causes of dystonia were negative. Creatine
kinase (CK) was markedly elevated at 6281 U/L (normal: 20- 155 U/L) with raised
transaminases (AST 190 IU/L [normal: 0-50 IU/L], ALT 135 U/L [normal: 0-45 IU/L]).
Cranial magnetic resonance imaging (MRI) showed features typical of SOX2-anophthalmia
syndrome, with rudimentary right orbit, absent left orbit, malrotated abnormal hippocampi,
underdeveloped splenium of the corpus callosum and a small pons (Figure 1). Over 72 hours
status dystonicus Grade IV (Lumsden et al., 2013) emerged, and treatment was commenced
following guidelines including chloral hydrate, clonidine, trihexyphenidyl, levodopa,
tetrabenazine, gabapentin, baclofen, and midazolam (Allen et al., 2014). There was
resolution of fever, stabilization of CK (829 U/L) and reduction in dystonia while sleeping.
Any decrease in frequency and/or dose of chloral hydrate resulted in reappearance of
continuous dystonia. Due to the severity of the pre-existing neurological disorder, failure to
wean from treatment for four weeks and deteriorating respiratory status, palliative care was
implemented, and the infant died seven weeks after the onset of dystonic symptoms.
Permission for autopsy was declined.
The second case is a girl aged six years with bilateral anophthalmia and a de novo
mutation in SOX2, c.480C>G; p.(Tyr160*). She has profound global developmental delay
with severe axial hypotonia, hearing loss, centrally mediated adrenal and growth hormone
deficiency, insomnia and gastrostomy feeding. Chorea, fluctuating tone and irritability were
noted over the first two years. There are no seizures. She presented acutely at six years with
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an intractable movement disorder (choreoathetosis and dystonia) and fever, requiring
intensive care. CK was 7309 U/l at presentation but returned to normal after four weeks of
treatment. MRI showed bilateral hypoplastic orbits, optic chiasm, and optic tracts, cerebral
and cerebellar atrophy but no acute lesion. MRA and MRS were normal. She requires
multiple medications to control the severe dystonia, which is now more severe than the pre-
extisting choreoathetosis.
As SOX2 is a single exon gene, it is predicted to escape nonsense mediated mRNA
decay. Consequently, both children are predicted to generate the same aberrant peptide from
the mutant allele which truncates at tyrosine 160 (Tyr160) and retains the DNA binding
domain but lacks a significant portion of the transactivation domain. There is no obvious
molecular explanation for the occurrence of the status dytonicus in these children given
our current understanding of role of the transactivation domain and its interactions in
mediating SOX2 function. . It is interesting to note that other adjacent truncating mutations
have been reported in association with dystonic cerebral palsy (Gerth-Kahlert et al., 2013)
and limb contractures (Hagstrom et al., 2005). However, other individual with mutations that
result in p.Tyr160* have been reported without dystonia (see
http://lsdb.hgu.mrc.ac.uk/home.php?select_db=SOX2). It will be important to clinically re-
evaluate such cases to determine the penetrance of dystonia and status dystonicus. In mouse
Sox2 is strongly expressed in the developing ventrolateral thalamus (Sisodiya et al., 2006) and
acute failure in maintenance of cell fate by this extremely dosage sensitive gene may explain
the mechanism of dystonia. This severe movement disorder appears to be a feature of some
types of SOX2-anophthalmia syndrome thus expanding the phenotype. We strongly
recommend that all newborns with bilateral anophthalmia/microphthalmia be screened for
mutations in SOX2. The families of those with Tyr160-truncations or similar mutations
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should be counselled on recognition of the early signs of status dystonicus and personalized
care plans developed for management of this severe but potentially treatable condition.
References
Allen NM, Lin JP, Lynch T, King MD. Status dystonicus: A practice guide. Dev Med Child
Neurol 2014; 56: 105–112
Fantes J, Ragge NK, Lynch SA, McGill NI, Collin JR, Howard-Peebles PN, Hayward C,
Vivian AJ, Williamson K , van Heyningen V, FitzPatick DR. et al. Mutations in SOX2 cause
anophthalmia. Nat. Genet 2003; 33: 461–463
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Figure Legend
Figure 1A and 1B: Coronal T2 MRI Brain showing rudimentary right orbit and absent left
orbit (1A) with malrotated hippocampi (1B)
Figure 1C: Sagittal T1 MRI Brain showing underdeveloped splenium of the corpus callosum
and abnormal midbrain
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