Points of View

The British Journal of Developmental Disabilities Vol. 53, Part 2, JULY 2007, No. 105, pp. 153-156

POINTS OF VIEW

RING CHROMOSOME 22, MOOD DISORDER AND SODIUM VALPROATE (A CASE REPORT)

Introduction aware of his environment, but cannot talk. His basic presentation that required psychiatric in- Ring chromosome, also known as ring 22, put was cyclic changes in his behaviour over a or r (22), was first reported by Weleber and con- three year period. firmed by Magenis (Weleber et al., 1968). So Detailed history revealed that he displays far, only a few cases have been described. Its in- mood swings regularly when he can change be- cidence is considered to be one per million in tween manic stages and depression. He presents the UK. It arises from terminal breaks on both with the following: arms of chromosome 22 followed by fusion. Al- though familial cases have been described, it is Elated phase mainly considered to be caused by spontaneous • Makes noises, shouts at staff and has bouts or de novo errors very early in the development of inappropriate laughter of the embryo (Battini et al., 2004). • Becomes overactive, quite fidgety in bed, The physical phenotype is not very distinct moving his hands, while moving rapidly with mild and variable dysmorphic features. from place to place whilst in his wheelchair Cognitive aspects are of moderate to severe • Pulls staff at every possible opportunity learning disability. Behavioural aspects are ab- • Sleep disturbance and on some nights has sence of speech and autistic behaviour. Bipolar one hour maximum sleep while shouting affective disorder has been described in ring at night chromosome 22 (Sovner et al., 1996; MacLean • Shows very poor concentration especially et al., 2000). while eating and becomes unable to put a spoon in his mouth during that time

Depressed phase Case history • Is tired and finds it difficult to stay awake • Shows no interest in any of the routine tasks Mr A is a 35 years old immobile (wheelchair that he usually enjoys bound) service user with severe learning disabil- • Does not eat properly ity who is in a residential setting. He was first • Looks tired diagnosed with ring chromosome 22 at 5 years • Avoids social situations of age. He has been in long term residential care • Noticeable motor retardation since he was ten years of age. He is able to un- derstand simple commands, recognises faces, is All these symptoms go in cycles of

153 variable duration. Sometimes symptoms can oc- Discussion cur in mixed state also or can change on a daily basis. Symptoms were first noticed when he was Clinical findings in ring twenty-three but may predate that as initially chromosome 22 the symptoms were considered as attention seek- ing. The symptoms have become more intense The following associations have been de- during the last two years and the cycles have scribed in various studies: become more frequent. Background information: There is no his- Mental retardation, general hypotonia, tory of obstetric complications or asphyxia at hydronephrosis, urinary tract infection, birth. During the first week his unusual appear- downward slanting palpebral fissure, ance was noted by his mother. He was noted to epicanthus, undescended testes, dysphagia, be hypotonic and slow in reflexes. Global devel- lack of development of speech, unsteady opmental delay with delayed speech resulted in gait, large low set ears, puffy feet, cardiac him attending the paediatrician regularly. He defects, gum hyperplasia and seizures was considered as a probable learning disability (MacLean et al., 2000; Ishmael et al., case at three years of age and this was confirmed 2003; Hunter et al., 1977). It should be when he was five years old. There is no family noted, however, that it is not necessary history of any learning disability or psychiatric for symptoms to be present in every illness. His physical disability has deteriorated person - they are not diagnostic and many in the last few years. He has a past history of symptoms are noted only in case reports. undescended testis and recurrent urinary tract infection. Chromosome 22 related disorders include: Treatment: He was initially started on Ha- • Chromosome 22 Central loperidol by his GP for presumed challenging • 22q11 Deletion Syndrome (DiGeorge behaviour. This resulted in no benefit except Syndrome, Velocardiofacial Syndrome) some improvement in sleep. Later on, after • The 11/22 Translocation (Emanuel review by the psychiatrist, he was started on Syndrome, partial trisomy 11/22) Carbamezapine that resulted in some improve- • 22q13 Deletion Syndrome (Phelan- ment for a short while in that the cycles changed McDermid Syndrome) to become much longer in duration. This im- • Cat Eye Syndrome provement was subsequently strengthened by • Complete or Full Trisomy 22 Quetiapine but the effects were short lived. • Mosaic Trisomy 22 Olanzapine was then used as an alternative to • Chromosome 22 Ring achieve further improvement but this made no • Microduplication 22q11 Syndrome major difference either. (taken from Chromosome 22 central Inc., USA After this, he was started on sodium val- (http://www.nt.net/a815/learn.htm)). proate and showed a marked improvement. He did not exhibit mood swings for the next six The symptoms represented in this service months (note that lithium has been avoided be- user fulfil the DC-LD (Diagnostic criteria for cause of disturbed renal function). psychiatric disorders for use with adults with learning disabilities/mental retardation) criteria of bipolar affective disorder in learning disability. The diagnosis is strengthened by the good response to sodium valproate. Bipolar disorder is often considered a condition that reflects ge-

154 netic influence. If one identical twin develops compared to ethnically matched controls, while bipolar disorder, the likelihood of the other twin alleles at the other three loci did not show any developing the condition is 85 to 89%. Only such difference. 15% of instances of bipolar disorder can be at- tributed to factors specific to individuals or to their unique life experiences outside the family of origin (Tsuang and Faraone, 1990; Bertelsen Conclusion et al., 1977; Mendlewicz and Rainer, 1977). Occasional families may exist in which a single • Bipolar affective disorder appears to be as- gene plays a major role in determining sus- sociated with ring chromosome 22. ceptibility, but the majority of bipolar disorder • Bipolar affective disorder in ring chromo- involves more complex genetic mechanisms such some 22 can present with more atypical as the interaction of multiple genes and envi- symptoms and in rapid cycling fashion. ronmental factors. Molecular genetic positional • This patient’s bipolar disorder showed a bet- and candidate gene approaches are being used ter response to sodium valproate than it did for the genetic dissection of bipolar disorder. No to other mood stabilisers. gene has yet been identified but promising findings are emerging. Regions of interest include chromosomes 4p16, 12q23—q24, 16p13, 21q22, and Xq24—q26 (Kelsoe, 2001). A genome sur- Summary vey of bipolar disorder using 443 micro-satellite markers in a set of 20 families from the general The case of a 35 year old man with severe North American population to identify possible learning disability, ring chromosome 22, rapid susceptibility loci was conducted. A maximum cycling bipolar illness and the effectiveness of so- logarithm of odds score of 3.8 was obtained at dium valproate is reported. We were led to write D22S278 on 22q (Craddock and Jones, 2001). this case report because of the limited research Chromosome 22 is involved in catechol-o-meth- on both ring chromosome 22 and its unusual yltransferase (COMT). This is the enzyme, manifestation with rapid cycling bipolar illness which is responsible for postsynaptic dopamine in severe learning disability. Although velo- and norepinephrine degradation. Alteration in cardiofacial syndrome and its association with the gene responsible for “COMT” formation psychotic illness is well documented, there has can be implicated in mood alteration. Contrary not been much work on bipolar disorder in as- findings, however, have been reported in an in- sociation with this genetic abnormality. vestigation by Rice et al., (1984), who showed that there was no difference in control in those *Dr Khalid Nawab, M.B.B.S, D.C.P. with mood disorder in these monoamines levels Locum Consultant Psychiatrist (Rice et al., 1984). Kirklands Hospital Fallside Road Chromosome 22 has been implicated in Bothwell G71 8BB UK schizophrenia and bipolar disorder in a number Tel: 00441698855629 of linkage, association and cytogenetic stud- Email: [email protected] ies (Kelsoe, 2001; Coon et al. 1994; Vallada et al.,1995). Recent evidence has also implicated CAG repeat tract expansion in these diseases Dr Ijaz Hussain, M.B.B.S., MRCPsych, (Saleem et al., 2001). The 8-repeat allele at this D.C.P. locus was significantly over represented in both Registrar in General Adult Psychiatry schizophrenia and bipolar patient groups when University College Hospital Galway

155 Republic of Ireland Hunter, A., Ray, M., Wang, H. and Thomp- Tel: 00353-91-741730 son D. (1977). Phenotypic correlations in Email: [email protected] patients with ring chromosome 22. Clinical Genetics, 12, 239-249. Ishmael, H., Cataldi, D., Begleiter, M., Pasztor, Dr Linda Findlay, MBChB, MRCPsych, L., Dasouki, M. and Butler M. (2003). Five L.L.M. new subjects with ring chromosome 22. Clin- Consultant Psychiatrist ical Genetics, 63, 410-414. Kirklands Hospital Kelsoe, J. (2001). A genome survey indicates a Fallside Road possible susceptibility locus for bipolar dis- Bothwell G71 8BB UK order on chromosome 22. Proceedings of the Tel: 00441698855629 National Academy of Sciences (USA), 98, 585- Email: 590. [email protected] MacLean, J., Teshima, I., Szatmari, P., and Now- aczyk M. (2000). Ring chromosome 22 and * For Correspondence autism: Report and review. American Journal of Medical Genetics, 90, 382 – 385. Mendlewicz, J. and Rainer J. (1977). Adop- tion study supporting genetic transmission References in manic-depressive illness. Nature, 268, 327-329. Battini, R., Battaglia, A., Bertini, V., Cioni, G., Rice, J., McGuffin, P., Goldin, L., Shaskan, E. Parrini, B., Rapalini, E., Simi, P., Tinelli, F. and Gershon E. (1984). (platelet monoamine and Valetto A. (2004). Characterization of oxidase (MAO) activity: evidence for single the phenotype and definition of the dele- major locus. American Journal of Human Ge- tion in a new patient with ring chromosome netics, 36, 36-43. 22. American Journal of Medical Genetics, 130, Saleem, Q., Dash, D., Gandhi, C., Kishore, A., 196-9. Benegal, V., Sherrin, T., Mukherjee, O., Bertelsen, A., Harvald, B. and Hauge M. (1977). Jain, S. and Brahmachari K. (2001). Asso- A Danish twin study of manic-depres- ciation of CAG repeat loci on chromosome sive illness. British Journal of Psychiatry, 130, 22 with schizophrenia and bipolar disorder. 330-351. Molecular Psychiatry, 6, 694-700. Chromosome 22 central inc USA, http://www. Sovner, R., Stone, A. and Fox C. (1996). Ring nt.net/a815/learn.htm. chromosome 22 and mood disorders. Journal Coon, H., Holick, J., Hoff, M., Reimherr, F. and of Intellectual Disability Research, 40, 82-86. Wender P. (1994). Analysis of chromosome Tsuang, M and Faraone S. (1990). The genetics 22 markers in nine schizophrenia pedigrees. of mood disorders. Baltimore: The Johns Hop- American Journal of Medical Genetics, 54, 72- kins University Press, 79. Vallada, H., Gill, M., Sham, P., Lim, L., Nan- Craddock, N. and Jones I. (2001). Molecular ge- ko, S., Asherson, P., Murray, R., McGuffin, netics of bipolar disorder. The British Journal P., Owen, M. and Collier D. (1995). Linkage of Psychiatry, 178, 128-133. studies on chromosome 22 in familial schizo- DC-LD: Diagnostic criteria for psychiatric dis- phrenia. American Journal of Medical Genetics, orders for use with adults with learning 60, 139-146. disabilities/mental retardation, 2001: Lon- Weleber, R., Hecht, F. and Giblett E. (1968). Ring don. Royal College of Psychiatrists. G chromosome a new G deletion syndrome? Gibbons, B., Tan, S. and Tam P. (1999). American Journal of Diseases of Children, 115, Ring chromosome 22 resulting in partial 489-493. monosomy in a mentally retarded boy. Sin- gapore Medical Journal, 40.

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