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.

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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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