Case Reports / Journal of Clinical Neuroscience 21 (2014) 865–867
Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Appendix A. Supplementary material Supplementary material associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.jocn.2013.06.019. References [1] Clemis JD, Mastricola PG, Shuler-Vogler M. Sudden hearing loss in the contralateral ear in postoperative acoustic tumor: three case reports. Laryngoscope 1982;92:76–9.
865
[2] de Keyser J, Bruyland M, Demol P, et al. Sudden hearing loss and facial palsy at the contralateral side following acoustic tumor removal. J Neurol Neurosurg Psychiatry 1983;46:687. [3] Chovanes GI, Buchheit WA. Bilateral hearing loss after unilateral removal of an acoustic neuroma by the suboccipital approach: case report. Neurosurgery 1986;19:452–3. [4] Harada K, Komatsuzaki A, Takahashi H, et al. Acute hearing loss in the contralateral ear after acoustic tumor removal. Nihon Jibiinkoka Gakkai Kaiho 1990;93:1864–8. [5] Lustig LR, Jackler RK, Chen DA. Contralateral hearing loss after neurotologic surgery. Otolaryngol Head Neck Surg 1995;113:276–82. [6] Plans G, Torres A, Ferran E, et al. Contralateral hearing loss after vestibular schwannoma surgery: case report. Neurosurgery 2007;61:E878. [7] Shuto T, Matsunaga S, Suenaga J. Contralateral hearing disturbance following posterior fossa surgery – case report. Neurol Med Chir (Tokyo) 2011;51:434–7. [8] Walsted A. Effects of cerebrospinal fluid loss on hearing. Acta Otolaryngol Suppl 2000;543:95–8. [9] Gharabaghi A, Koerbel A, Samii A, et al. The impact of hypotension due to the trigeminocardiac reflex on auditory function in vestibular schwannoma surgery. J Neurosurg 2006;104:369–75.
http://dx.doi.org/10.1016/j.jocn.2013.08.005
Giant axonal neuropathy diagnosed on skin biopsy Shekeeb S. Mohammad a,b, Chiyan Lau c, Christopher Burke a,d, Naomi McCallum d, Thomas Robertson d,⇑ a
Department of Neurosciences, Royal Children’s Hospital, Herston, QLD, Australia School of Medicine, University of Queensland, Herston Campus, Herston, QLD, Australia Molecular Genetics Laboratory, Pathology Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia d Department of Anatomical Pathology, Pathology Queensland, Level 2, Block 7, Royal Brisbane and Women’s Hospital and Royal Children’s Hospital, Herston, QLD 4029, Australia b c
a r t i c l e
i n f o
Article history: Received 28 March 2013 Accepted 10 June 2013
Keywords: Giant axonal neuropathy HMSN Microarray Skin biopsy
a b s t r a c t Evaluation of hereditary axonal neuropathy in childhood is complex. Often, the child has to be subjected to general anaesthesia for a nerve biopsy to guide further genetic testing, which may or may not be readily available. We describe a toddler with clinical features suggesting giant axonal neuropathy (GAN), whose diagnosis was confirmed by minimally invasive skin biopsy and corroborated by the finding of compound heterozygous mutations involving the GAN gene, including a novel interstitial microdeletion at 16q23.2 detected by microarray and a point mutation detected by direct sequencing. Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
1. Case report Giant axonal neuropathy (GAN) is an autosomal recessive inherited progressive motor and sensory neuropathy with typical onset in early childhood. We report a 2-year-old girl with inability to walk independently. She was born to non-consanguineous Caucasian parents following a normal pregnancy with normal foetal movements and no polyhydramnios. She often tripped and fell while cruising. Other aspects of her development were satisfactory. She had areflexia of all four limbs, small feet, hyperextensible knees and slender, tapered legs. Bilateral upper limb power was normal proximally and 4/5 Medical Research Council (MRC) scale distally. Bilateral lower limb power was 2–3+ MRC in all muscle groups. The peripheral nerves were impalpable. The plantar responses were flexor. Peripheral sensation was intact and the plantar arches were normal. Other aspects of her neurological and systemic examination were normal. Nerve conduction studies were consistent with an axonal sensori-motor neuropathy, which was more severe in the legs than
⇑ Corresponding author. Tel.: +61 7 3646 0299. E-mail address: [email protected] (T. Robertson).
the arms. The left ulnar nerve had a conduction velocity of 58 m/s with the abductor digitus minimus showing a distal compound muscle action potential (CMAP) of 0.7 mV (normal range, 7.66 ± 2.23 mV) [1] and distal latency of 2.8 ms while the left common peroneal nerve had a conduction velocity of 63 m/s with the extensor digitorum brevis showing a distal CMAP of 0.5 mV (normal range, 6.42 ± 1.92 mV) and distal latency of 4 ms [1]. Sensory nerve action potentials were absent in both the ulnar and sural nerves. MRI of the brain and spine were normal. Cerebrospinal fluid protein was normal. Other investigations ruled out an infective or toxic cause for the neuropathy. The child was noted to have prominent curly hair, raising a clinical suspicion of GAN [2]. A skin biopsy was performed. Examination by light and electron microscope revealed dermal nerves showing segmental myelinated axon swellings containing inclusions of densely packed intermediate filaments (Fig. 1). Abnormal aggregates of intermediate filaments were also found in unmyelinated axons, Schwann cells, dermal fibroblasts, mast cells and vascular endothelium. Light and scanning electron microscopic examination of hair shafts revealed a variety of abnormalities including pili torti, shallow longitudinal grooves and an irregular roughened cuticle (Fig. 2). These findings are consistent with GAN [3].
866
Case Reports / Journal of Clinical Neuroscience 21 (2014) 865–867
ico analysis predicted that this will likely result in mis-splicing of the GAN transcript, leading to loss of production of normal gigaxonin protein.
3. Discussion
Fig. 1. Transmission electron micrograph of dermal myelinated axon showing an aggregate of intermediate filaments (arrow) between the layers of the dark myelin sheath (original magnification 15000).
Fig. 2. Scanning electron micrograph of a hair showing pili torti with twisting of the hair associated with flattening of shaft (original magnification 140).
2. Genetic testing Single nucleotide polymorphism (SNP) microarray testing performed on genomic DNA extracted from the patient’s peripheral blood (Illumina HumanCytoSNP-12 v2.1, 0.20 Mb resolution; San Diego, CA, USA) revealed a novel interstitial microdeletion of approximately 0.72 megabases on the long arm of one chromosome 16 (16q23.2) with genomic coordinates chr16:7927395879992177 (NCBI36/hg18) [4]. The deleted segment contains nine known genes including GAN, which codes for gigaxonin. This deletion was not detected in either of the patient’s parents by microarray analysis, suggesting that the microdeletion in the proband was either de novo or inherited from a balanced insertional translocation in a parent, which cannot be detected by microarray analysis. Since GAN is an autosomal recessive disorder we undertook sequencing of the GAN gene in the proband to look for another pathogenic mutation in the remaining allele. Sequencing revealed a single base substitution in intron 2, close to the exon2/intron2 boundary – NM_022041.3(GAN):c.282+3A>G. Although this sequence variant has not been previously reported to our knowledge, either as a benign polymorphism or as a causative mutation, in sil-
Hereditary motor and sensory neuropathies in childhood are a heterogeneous group of disorders which can be either demyelinating or axonal [5]. Axonal neuropathies are difficult to delineate and classify in many cases. Infants with an axonal neuropathy may have reduced nerve conduction velocities due to a relative paucity of large diameter fibres and this may mislead investigators towards a demyelinating neuropathy. On the other hand, axonal pathology does not always result in a measurable abnormality in the nerve conduction studies. Electromyography in GAN would be expected to show evidence of denervation. However, this was not able to be satisfactorily performed in our patient where the nerve conduction was done under sedation. In situations suggesting an axonal degeneration neuropathy, genetic testing is usually performed after a nerve biopsy has been performed. In our patient, nerve conduction results did suggest an axonal neuropathy and the patient’s prominent curly hair raised the clinical suspicion of GAN. Other than nerve biopsy, investigators have noted that gingival and skin biopsies can show pathognomonic features in GAN [3,6]. Since nerve biopsies in children requires general anaesthesia and concerns have been raised about the use of general anaesthesia in patients with GAN [7], we performed a skin biopsy under local anaesthesia and examined several shafts of the patient’s hair by light and electron microscopy. Clinical presentation in GAN has been reported from birth up to 10 years of age. The usual picture is of a progressive neuropathy in the first decade of life. Cranial nerves, particularly the third and seventh, can also be affected. Some patients can have central nervous system involvement. Many but not all patients have tightly curled hair. Most patients are wheelchair bound and many die in the second or third decade of life. Brain MRI may reveal white matter abnormalities but these were not detected in our patient. Our patient has slowly progressive weakness now affecting both hands at 1 year from diagnosis but ambulation has improved significantly with the aid of a walker. There have been no concerns with her intellectual performance, speech or cognition, which are age appropriate based on parental, paediatrician and kindergarten reports. In several case series the diagnostic yield from microarray testing has been shown to be 10–15% or higher for various neurological conditions including developmental delay and autism spectrum disorder [8,9]. Although similar yields have not been demonstrated in neuropathies, previous patients with GAN have been reported with genetic abnormalities detected on microarray [3]. Therefore SNP array was performed as the first stage of genetic testing in our patient following confirmation of the diagnosis by skin biopsy. The majority of GAN gene mutations reported in the literature are point mutations, although copy number changes have also been reported [2]. The combination of microarray testing and subsequent direct gene sequencing in this patient revealed compound heterozygous mutations including a novel interstitial microdeletion involving the GAN gene and a novel point mutation predicted to cause transcriptional mis-splicing and loss of protein function. To clarify the origin of the mutations and the recurrence risks in this family, several further genetic tests are planned. These include metaphase fluorescence in situ hybridisation analysis to exclude a balanced insertional translocation involving the GAN gene region in either parent [10], sequencing of the GAN gene in the parents to determine if either is a carrier of the c.282+3A>G sequence
Case Reports / Journal of Clinical Neuroscience 21 (2014) 867–869
variant and RNA studies to confirm the effect of the c.282+3A>G sequence variant on transcriptional splicing. This patient highlights the potential role of skin biopsy in the diagnosis of hereditary peripheral neuropathy. Used judiciously, this is a minimally invasive test that may reduce the need for general anaesthesia and nerve biopsy, and can help direct more expensive genetic investigations such as microarray analysis and sequencing of candidate genes. Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements We thank the Cytogenetics laboratory at the Victorian Clinical Genetics Service (VCGS) for performing the microarray analyses. GAN gene sequencing was performed at the Diagenos laboratories (Osnabrueck, Germany). We thank the patient’s family for consent to share the patient’s case.
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References [1] Cai F, Zhang J. Study of nerve conduction and late responses in normal Chinese infants, children, and adults. J Child Neurol 1997;12:13–8. [2] Ouvrier RA. Giant axonal neuropathy. A review. Brain Dev 1989;11:207–14. [3] Buysse K, Vergult S, Mussche S, et al. Giant axonal neuropathy caused by compound heterozygosity for a maternally inherited microdeletion and a paternal mutation within the GAN gene. Am J Med Genet A 2010;152A:2802–4. [4] Kent WJ, Sugnet CW, Furey TS, et al. The human genome browser at UCSC. Genome Res 2002;12:996–1006. [5] Wilmshurst JM, Ouvrier R. Hereditary peripheral neuropathies of childhood: an overview for clinicians. Neuromuscul Disord 2011;21:763–75. [6] Bonnaure-Mallet M, Tricot-Doleux S, Le Berre C. Gingival biopsy in the diagnosis of giant axonal neuropathy. J Oral Pathol Med 1995;24:89–92. [7] Diagos P, Bos JA, Verrips A, et al. Giant axonal neuropathy and anaesthesia. Anaesthesia 2003;58:723–4. [8] Dale RC, Grattan-Smith P, Nicholson M, et al. Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single-centre study. Dev Med Child Neurol 2012;54:618–23. [9] Kurian MA. The clinical utility of chromosomal microarray in childhood neurological disorders. Dev Med Child Neurol 2012;54:582–3. [10] Nowakowska BA, de Leeuw N, Ruivenkamp CA, et al. Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies. Eur J Hum Genet 2012;20:166–70.
http://dx.doi.org/10.1016/j.jocn.2013.06.017
Psychosis with obsessive-compulsive symptoms in tuberous sclerosis Islam K. Hassan a,⇑, Jeffrey C.L. Looi b, Dennis Velakoulis a, Frank Gaillard c, Elaine H. Lui c, Terence J. O’Brien d,e, Chris French d, Campbell Le Heron d, Sophia J. Adams a a
Melbourne Neuropsychiatry Centre, University of Melbourne, Level 2, John Cade Building, Royal Melbourne Hospital, Grattan Street, Parkville, Melbourne, VIC 3050, Australia Academic Unit of Psychological and Addiction Medicine, Australian National University Medical School, Canberra Hospital, Canberra, ACT, Australia c Department of Radiology, Royal Melbourne Hospital, Melbourne, VIC, Australia d Department of Neurology, Melbourne Brain Centre, University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia e Department of Medicine, University of Melbourne, Melbourne, VIC, Australia b
a r t i c l e
i n f o
Article history: Received 29 July 2013 Accepted 13 August 2013
Keywords: Epilepsy Neuropsychiatry Obsessive compulsive disorder Psychosis Tuberous sclerosis
a b s t r a c t We present a case of tuberous sclerosis complex (TSC) diagnosed in adulthood in a man initially referred for specialist neuropsychiatric assessment with psychosis and obsessive-compulsive symptoms (OCS) on a background of epilepsy and intellectual disability. To our knowledge, this is the first reported patient with TSC featuring both psychosis and OCS. This patient highlights the importance of comprehensive re-evaluation of atypical presentations of intellectual disability, epilepsy and associated neuropsychiatric symptoms, even in adulthood. This is particularly relevant in the context of significant advances in genetics, neuroscience, imaging and treatments for heritable neurogenetic disorders. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Tuberous sclerosis complex (TSC) is a disabling multisystem condition of autosomal dominant inheritance with variable expression [1]. Making the diagnosis is challenging because of the variability of manifestations and because it can arise sporadically with no family history in two-thirds of patients and can test negatively on genotyping in 10–15% of patients [1]. Given that over 80% of patients are diagnosed by the age of 10 years, TSC might not be readily considered as a potential diagnosis by specialists in adult psychiatry and neurology [2]. Both psychosis and obsessive-compulsive disorder (OCD) have been separately described as neuropsychiatric comor-
⇑ Corresponding author. Tel.: +61 3 9342 8750; fax: +61 3 9342 8483. E-mail address: [email protected] (I.K. Hassan).
bidities in TSC [3,4]. However, to our knowledge there have been no reports of patients with TSC with a combination of psychosis and obsessive-compulsive symptoms (OCS) resulting in diagnosis in adulthood. This combination of psychiatric features, occasionally referred to – when arising independently of another organic syndrome – as schizo-obsessive syndrome, has been gaining interest as a proposed distinct syndrome carrying specific implications regarding diagnosis and management [5]. 2. Case report A 28-year-old single unemployed man with known history of intellectual disability, epilepsy and psychosis was referred to our prolonged inpatient video-electroencephalography monitoring unit to explore whether recent staring episodes were epileptic, and to explore the possibility of TSC suggested on recent brain
Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Appendix A. Supplementary material Supplementary material associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.jocn.2013.06.019. References [1] Clemis JD, Mastricola PG, Shuler-Vogler M. Sudden hearing loss in the contralateral ear in postoperative acoustic tumor: three case reports. Laryngoscope 1982;92:76–9.
865
[2] de Keyser J, Bruyland M, Demol P, et al. Sudden hearing loss and facial palsy at the contralateral side following acoustic tumor removal. J Neurol Neurosurg Psychiatry 1983;46:687. [3] Chovanes GI, Buchheit WA. Bilateral hearing loss after unilateral removal of an acoustic neuroma by the suboccipital approach: case report. Neurosurgery 1986;19:452–3. [4] Harada K, Komatsuzaki A, Takahashi H, et al. Acute hearing loss in the contralateral ear after acoustic tumor removal. Nihon Jibiinkoka Gakkai Kaiho 1990;93:1864–8. [5] Lustig LR, Jackler RK, Chen DA. Contralateral hearing loss after neurotologic surgery. Otolaryngol Head Neck Surg 1995;113:276–82. [6] Plans G, Torres A, Ferran E, et al. Contralateral hearing loss after vestibular schwannoma surgery: case report. Neurosurgery 2007;61:E878. [7] Shuto T, Matsunaga S, Suenaga J. Contralateral hearing disturbance following posterior fossa surgery – case report. Neurol Med Chir (Tokyo) 2011;51:434–7. [8] Walsted A. Effects of cerebrospinal fluid loss on hearing. Acta Otolaryngol Suppl 2000;543:95–8. [9] Gharabaghi A, Koerbel A, Samii A, et al. The impact of hypotension due to the trigeminocardiac reflex on auditory function in vestibular schwannoma surgery. J Neurosurg 2006;104:369–75.
http://dx.doi.org/10.1016/j.jocn.2013.08.005
Giant axonal neuropathy diagnosed on skin biopsy Shekeeb S. Mohammad a,b, Chiyan Lau c, Christopher Burke a,d, Naomi McCallum d, Thomas Robertson d,⇑ a
Department of Neurosciences, Royal Children’s Hospital, Herston, QLD, Australia School of Medicine, University of Queensland, Herston Campus, Herston, QLD, Australia Molecular Genetics Laboratory, Pathology Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia d Department of Anatomical Pathology, Pathology Queensland, Level 2, Block 7, Royal Brisbane and Women’s Hospital and Royal Children’s Hospital, Herston, QLD 4029, Australia b c
a r t i c l e
i n f o
Article history: Received 28 March 2013 Accepted 10 June 2013
Keywords: Giant axonal neuropathy HMSN Microarray Skin biopsy
a b s t r a c t Evaluation of hereditary axonal neuropathy in childhood is complex. Often, the child has to be subjected to general anaesthesia for a nerve biopsy to guide further genetic testing, which may or may not be readily available. We describe a toddler with clinical features suggesting giant axonal neuropathy (GAN), whose diagnosis was confirmed by minimally invasive skin biopsy and corroborated by the finding of compound heterozygous mutations involving the GAN gene, including a novel interstitial microdeletion at 16q23.2 detected by microarray and a point mutation detected by direct sequencing. Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
1. Case report Giant axonal neuropathy (GAN) is an autosomal recessive inherited progressive motor and sensory neuropathy with typical onset in early childhood. We report a 2-year-old girl with inability to walk independently. She was born to non-consanguineous Caucasian parents following a normal pregnancy with normal foetal movements and no polyhydramnios. She often tripped and fell while cruising. Other aspects of her development were satisfactory. She had areflexia of all four limbs, small feet, hyperextensible knees and slender, tapered legs. Bilateral upper limb power was normal proximally and 4/5 Medical Research Council (MRC) scale distally. Bilateral lower limb power was 2–3+ MRC in all muscle groups. The peripheral nerves were impalpable. The plantar responses were flexor. Peripheral sensation was intact and the plantar arches were normal. Other aspects of her neurological and systemic examination were normal. Nerve conduction studies were consistent with an axonal sensori-motor neuropathy, which was more severe in the legs than
⇑ Corresponding author. Tel.: +61 7 3646 0299. E-mail address: [email protected] (T. Robertson).
the arms. The left ulnar nerve had a conduction velocity of 58 m/s with the abductor digitus minimus showing a distal compound muscle action potential (CMAP) of 0.7 mV (normal range, 7.66 ± 2.23 mV) [1] and distal latency of 2.8 ms while the left common peroneal nerve had a conduction velocity of 63 m/s with the extensor digitorum brevis showing a distal CMAP of 0.5 mV (normal range, 6.42 ± 1.92 mV) and distal latency of 4 ms [1]. Sensory nerve action potentials were absent in both the ulnar and sural nerves. MRI of the brain and spine were normal. Cerebrospinal fluid protein was normal. Other investigations ruled out an infective or toxic cause for the neuropathy. The child was noted to have prominent curly hair, raising a clinical suspicion of GAN [2]. A skin biopsy was performed. Examination by light and electron microscope revealed dermal nerves showing segmental myelinated axon swellings containing inclusions of densely packed intermediate filaments (Fig. 1). Abnormal aggregates of intermediate filaments were also found in unmyelinated axons, Schwann cells, dermal fibroblasts, mast cells and vascular endothelium. Light and scanning electron microscopic examination of hair shafts revealed a variety of abnormalities including pili torti, shallow longitudinal grooves and an irregular roughened cuticle (Fig. 2). These findings are consistent with GAN [3].
866
Case Reports / Journal of Clinical Neuroscience 21 (2014) 865–867
ico analysis predicted that this will likely result in mis-splicing of the GAN transcript, leading to loss of production of normal gigaxonin protein.
3. Discussion
Fig. 1. Transmission electron micrograph of dermal myelinated axon showing an aggregate of intermediate filaments (arrow) between the layers of the dark myelin sheath (original magnification 15000).
Fig. 2. Scanning electron micrograph of a hair showing pili torti with twisting of the hair associated with flattening of shaft (original magnification 140).
2. Genetic testing Single nucleotide polymorphism (SNP) microarray testing performed on genomic DNA extracted from the patient’s peripheral blood (Illumina HumanCytoSNP-12 v2.1, 0.20 Mb resolution; San Diego, CA, USA) revealed a novel interstitial microdeletion of approximately 0.72 megabases on the long arm of one chromosome 16 (16q23.2) with genomic coordinates chr16:7927395879992177 (NCBI36/hg18) [4]. The deleted segment contains nine known genes including GAN, which codes for gigaxonin. This deletion was not detected in either of the patient’s parents by microarray analysis, suggesting that the microdeletion in the proband was either de novo or inherited from a balanced insertional translocation in a parent, which cannot be detected by microarray analysis. Since GAN is an autosomal recessive disorder we undertook sequencing of the GAN gene in the proband to look for another pathogenic mutation in the remaining allele. Sequencing revealed a single base substitution in intron 2, close to the exon2/intron2 boundary – NM_022041.3(GAN):c.282+3A>G. Although this sequence variant has not been previously reported to our knowledge, either as a benign polymorphism or as a causative mutation, in sil-
Hereditary motor and sensory neuropathies in childhood are a heterogeneous group of disorders which can be either demyelinating or axonal [5]. Axonal neuropathies are difficult to delineate and classify in many cases. Infants with an axonal neuropathy may have reduced nerve conduction velocities due to a relative paucity of large diameter fibres and this may mislead investigators towards a demyelinating neuropathy. On the other hand, axonal pathology does not always result in a measurable abnormality in the nerve conduction studies. Electromyography in GAN would be expected to show evidence of denervation. However, this was not able to be satisfactorily performed in our patient where the nerve conduction was done under sedation. In situations suggesting an axonal degeneration neuropathy, genetic testing is usually performed after a nerve biopsy has been performed. In our patient, nerve conduction results did suggest an axonal neuropathy and the patient’s prominent curly hair raised the clinical suspicion of GAN. Other than nerve biopsy, investigators have noted that gingival and skin biopsies can show pathognomonic features in GAN [3,6]. Since nerve biopsies in children requires general anaesthesia and concerns have been raised about the use of general anaesthesia in patients with GAN [7], we performed a skin biopsy under local anaesthesia and examined several shafts of the patient’s hair by light and electron microscopy. Clinical presentation in GAN has been reported from birth up to 10 years of age. The usual picture is of a progressive neuropathy in the first decade of life. Cranial nerves, particularly the third and seventh, can also be affected. Some patients can have central nervous system involvement. Many but not all patients have tightly curled hair. Most patients are wheelchair bound and many die in the second or third decade of life. Brain MRI may reveal white matter abnormalities but these were not detected in our patient. Our patient has slowly progressive weakness now affecting both hands at 1 year from diagnosis but ambulation has improved significantly with the aid of a walker. There have been no concerns with her intellectual performance, speech or cognition, which are age appropriate based on parental, paediatrician and kindergarten reports. In several case series the diagnostic yield from microarray testing has been shown to be 10–15% or higher for various neurological conditions including developmental delay and autism spectrum disorder [8,9]. Although similar yields have not been demonstrated in neuropathies, previous patients with GAN have been reported with genetic abnormalities detected on microarray [3]. Therefore SNP array was performed as the first stage of genetic testing in our patient following confirmation of the diagnosis by skin biopsy. The majority of GAN gene mutations reported in the literature are point mutations, although copy number changes have also been reported [2]. The combination of microarray testing and subsequent direct gene sequencing in this patient revealed compound heterozygous mutations including a novel interstitial microdeletion involving the GAN gene and a novel point mutation predicted to cause transcriptional mis-splicing and loss of protein function. To clarify the origin of the mutations and the recurrence risks in this family, several further genetic tests are planned. These include metaphase fluorescence in situ hybridisation analysis to exclude a balanced insertional translocation involving the GAN gene region in either parent [10], sequencing of the GAN gene in the parents to determine if either is a carrier of the c.282+3A>G sequence
Case Reports / Journal of Clinical Neuroscience 21 (2014) 867–869
variant and RNA studies to confirm the effect of the c.282+3A>G sequence variant on transcriptional splicing. This patient highlights the potential role of skin biopsy in the diagnosis of hereditary peripheral neuropathy. Used judiciously, this is a minimally invasive test that may reduce the need for general anaesthesia and nerve biopsy, and can help direct more expensive genetic investigations such as microarray analysis and sequencing of candidate genes. Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements We thank the Cytogenetics laboratory at the Victorian Clinical Genetics Service (VCGS) for performing the microarray analyses. GAN gene sequencing was performed at the Diagenos laboratories (Osnabrueck, Germany). We thank the patient’s family for consent to share the patient’s case.
867
References [1] Cai F, Zhang J. Study of nerve conduction and late responses in normal Chinese infants, children, and adults. J Child Neurol 1997;12:13–8. [2] Ouvrier RA. Giant axonal neuropathy. A review. Brain Dev 1989;11:207–14. [3] Buysse K, Vergult S, Mussche S, et al. Giant axonal neuropathy caused by compound heterozygosity for a maternally inherited microdeletion and a paternal mutation within the GAN gene. Am J Med Genet A 2010;152A:2802–4. [4] Kent WJ, Sugnet CW, Furey TS, et al. The human genome browser at UCSC. Genome Res 2002;12:996–1006. [5] Wilmshurst JM, Ouvrier R. Hereditary peripheral neuropathies of childhood: an overview for clinicians. Neuromuscul Disord 2011;21:763–75. [6] Bonnaure-Mallet M, Tricot-Doleux S, Le Berre C. Gingival biopsy in the diagnosis of giant axonal neuropathy. J Oral Pathol Med 1995;24:89–92. [7] Diagos P, Bos JA, Verrips A, et al. Giant axonal neuropathy and anaesthesia. Anaesthesia 2003;58:723–4. [8] Dale RC, Grattan-Smith P, Nicholson M, et al. Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single-centre study. Dev Med Child Neurol 2012;54:618–23. [9] Kurian MA. The clinical utility of chromosomal microarray in childhood neurological disorders. Dev Med Child Neurol 2012;54:582–3. [10] Nowakowska BA, de Leeuw N, Ruivenkamp CA, et al. Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies. Eur J Hum Genet 2012;20:166–70.
http://dx.doi.org/10.1016/j.jocn.2013.06.017
Psychosis with obsessive-compulsive symptoms in tuberous sclerosis Islam K. Hassan a,⇑, Jeffrey C.L. Looi b, Dennis Velakoulis a, Frank Gaillard c, Elaine H. Lui c, Terence J. O’Brien d,e, Chris French d, Campbell Le Heron d, Sophia J. Adams a a
Melbourne Neuropsychiatry Centre, University of Melbourne, Level 2, John Cade Building, Royal Melbourne Hospital, Grattan Street, Parkville, Melbourne, VIC 3050, Australia Academic Unit of Psychological and Addiction Medicine, Australian National University Medical School, Canberra Hospital, Canberra, ACT, Australia c Department of Radiology, Royal Melbourne Hospital, Melbourne, VIC, Australia d Department of Neurology, Melbourne Brain Centre, University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia e Department of Medicine, University of Melbourne, Melbourne, VIC, Australia b
a r t i c l e
i n f o
Article history: Received 29 July 2013 Accepted 13 August 2013
Keywords: Epilepsy Neuropsychiatry Obsessive compulsive disorder Psychosis Tuberous sclerosis
a b s t r a c t We present a case of tuberous sclerosis complex (TSC) diagnosed in adulthood in a man initially referred for specialist neuropsychiatric assessment with psychosis and obsessive-compulsive symptoms (OCS) on a background of epilepsy and intellectual disability. To our knowledge, this is the first reported patient with TSC featuring both psychosis and OCS. This patient highlights the importance of comprehensive re-evaluation of atypical presentations of intellectual disability, epilepsy and associated neuropsychiatric symptoms, even in adulthood. This is particularly relevant in the context of significant advances in genetics, neuroscience, imaging and treatments for heritable neurogenetic disorders. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Tuberous sclerosis complex (TSC) is a disabling multisystem condition of autosomal dominant inheritance with variable expression [1]. Making the diagnosis is challenging because of the variability of manifestations and because it can arise sporadically with no family history in two-thirds of patients and can test negatively on genotyping in 10–15% of patients [1]. Given that over 80% of patients are diagnosed by the age of 10 years, TSC might not be readily considered as a potential diagnosis by specialists in adult psychiatry and neurology [2]. Both psychosis and obsessive-compulsive disorder (OCD) have been separately described as neuropsychiatric comor-
⇑ Corresponding author. Tel.: +61 3 9342 8750; fax: +61 3 9342 8483. E-mail address: [email protected] (I.K. Hassan).
bidities in TSC [3,4]. However, to our knowledge there have been no reports of patients with TSC with a combination of psychosis and obsessive-compulsive symptoms (OCS) resulting in diagnosis in adulthood. This combination of psychiatric features, occasionally referred to – when arising independently of another organic syndrome – as schizo-obsessive syndrome, has been gaining interest as a proposed distinct syndrome carrying specific implications regarding diagnosis and management [5]. 2. Case report A 28-year-old single unemployed man with known history of intellectual disability, epilepsy and psychosis was referred to our prolonged inpatient video-electroencephalography monitoring unit to explore whether recent staring episodes were epileptic, and to explore the possibility of TSC suggested on recent brain
