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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
E-mail: [email protected]
Telephone: +353-1-8784000
David R FitzPatrick
Address: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK
Word Count: 829
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
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 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 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 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
Gerth-Kahlert C, Williamson K, Ansari M, Rainger J, Hingst V, Zimmermann T, Tech S, Guthoff RF, van Heyningen V, FitzPatick DR. Clinical and mutation analysis of 51 probands with anophthalmia and/or severe microphthalmia from a single center. Mol Genet Genomic Med 2013; 1: 15-31
Hagstron SA, PAuer GJ, Reid J, Simpson E, Crowe S, Maumenee IH,Traboulsi EI. SOX2 mutation causes anophthalmia, hearing loss, and brain anomalies. Am J Med Genet A 2005; 138: 95-8
Lumsden DE, Lundy C, Fairhurst C, Lin JP. Dystonia Severity Action Plan: a simple grading system for medical severity of status dystonicus and life-threatening dystonia. Dev Med Child Neurol 2013; 55: 671-672
Ragge NK, Lorenz B, Schneider A, Bushby K, de Sanctis L, de Sanctis U, Salt A, Collin JR, Vivian AJ, Free SL, Thompson P, Williamson KA, Sisodiya SM, van Heyningen V, Fitzpatrick DR. SOX2anophthalmia syndrome. Am J Med Genet A. 2005 May 15;135(1):1-7. PMID:15812812
Schneider A, Bardakjian T, Reis LM, Tyler RC, Semina EV. Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia. Am J Med Genet A. 2009; 149A: 2706–2715
Sisodiya SM, Ragge NK, Cavalleri GL, Hever A, Lorenz B, Schneider A, Williamson KA, Stevens JM, Free SL, Thompson PJ, van Heyningen V, Fitzpatrick DR. Role of SOX2 mutations in human hippocampal malformations and epilepsy. Epilepsia 2006; 47: 534-542
Williamson KA, FitzPatrick DR. The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014 Aug;57(8):369-80. PMID:24859618
Zhang S, Cui W. Sox2, a key factor in the regulation of pluripotency and neural differentiation. World J Stem Cells 2014; 6: 305–311.
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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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
E-mail: [email protected]
Telephone: +353-1-8784000
David R FitzPatrick
Address: MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK
Word Count: 829
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
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 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 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 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
Gerth-Kahlert C, Williamson K, Ansari M, Rainger J, Hingst V, Zimmermann T, Tech S, Guthoff RF, van Heyningen V, FitzPatick DR. Clinical and mutation analysis of 51 probands with anophthalmia and/or severe microphthalmia from a single center. Mol Genet Genomic Med 2013; 1: 15-31
Hagstron SA, PAuer GJ, Reid J, Simpson E, Crowe S, Maumenee IH,Traboulsi EI. SOX2 mutation causes anophthalmia, hearing loss, and brain anomalies. Am J Med Genet A 2005; 138: 95-8
Lumsden DE, Lundy C, Fairhurst C, Lin JP. Dystonia Severity Action Plan: a simple grading system for medical severity of status dystonicus and life-threatening dystonia. Dev Med Child Neurol 2013; 55: 671-672
Ragge NK, Lorenz B, Schneider A, Bushby K, de Sanctis L, de Sanctis U, Salt A, Collin JR, Vivian AJ, Free SL, Thompson P, Williamson KA, Sisodiya SM, van Heyningen V, Fitzpatrick DR. SOX2anophthalmia syndrome. Am J Med Genet A. 2005 May 15;135(1):1-7. PMID:15812812
Schneider A, Bardakjian T, Reis LM, Tyler RC, Semina EV. Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia. Am J Med Genet A. 2009; 149A: 2706–2715
Sisodiya SM, Ragge NK, Cavalleri GL, Hever A, Lorenz B, Schneider A, Williamson KA, Stevens JM, Free SL, Thompson PJ, van Heyningen V, Fitzpatrick DR. Role of SOX2 mutations in human hippocampal malformations and epilepsy. Epilepsia 2006; 47: 534-542
Williamson KA, FitzPatrick DR. The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014 Aug;57(8):369-80. PMID:24859618
Zhang S, Cui W. Sox2, a key factor in the regulation of pluripotency and neural differentiation. World J Stem Cells 2014; 6: 305–311.
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
8