Das neuropsychiatrische Spektrum des Velokardiofazialen Syndroms (Deletion 22q11.2)

Zusammenfassung

Die Mikrodeletion 22q11.2 (22q11DS) stellt die häufigste interstitielle chromosomale Deletion dar, die beim Menschen bekannt ist. Neben einer Reihe weiterer klinischer Syndrome ist in der Mehrzahl der Fälle das Velokardiofaziale Syndrom auf diese Mikrodeletion zurückzuführen. Erst in den vergangenen Jahren wurde zunehmend über Symptome auch aus dem neuropsychiatrischen Spektrum bei 22q11DS berichtet. In erster Linie sind dabei Psychosen aus dem schizophrenen Formenkreis, das Aufmerksamkeitsdefizit-/Hyperaktivitäts-Syndrom (ADHS), Intelligenzminderung und Lernbehinderung, zerebrale Krampfanfälle und motorische Störungen zu nennen. Vor allem die Assoziation von schizophrenen Psychosen mit Mikrodeletionen 22q11.2 wurde beachtet und wird bezüglich ihrer pathogenetischen Bedeutung für idiopathische Schizophrenien bis heute kontrovers diskutiert. Wir beschreiben zwei klinische Fälle, bei denen erst das Auftreten psychotischer Symptome in Zusammenschau mit den körperlichen Auffälligkeiten Anlass zur molekularzytogenetischen Diagnose einer Mikrodeletion 22q11.2 gab. Zudem gibt diese Arbeit einen systematischen Literaturüberblick über die psychiatrischen Störungen, die neurologischen Symptome und die teilweise korrespondierenden hirnmorphologischen Veränderungen bei 22q11-Deletionssyndromen.

Abstract

Microdeletion 22q11.2 (22q11DS) is the most frequent chromosomal deletion known in man. Velocardiofacial syndrome is one of numerous clinical syndromes that can be attributed to this micro deletion. There is an increasing recognition of associations with neuropsychiatric disorders. Particularly, schizophrenic psychosis, attention-deficit/hyperactivity disorder (ADHD), intellectual impairment and learning disabilities, seizures and motoric abnormalities have been identified in patients with 22q11DS. Recent studies supported the association of schizophrenia and 22q11DS, but the pathogenetic implications for idiopathic schizophrenia are still controversial. We report on two clinical cases in which psychotic symptoms led to the molecularcytogenetic diagnosis of microdeletion 22q11.2. Additionally, this article gives a systematic review of literature regarding psychiatric disorders, neurologic symptoms and partly corresponding morphological brain abnormalities in 22q11 deletion syndromes.

Literatur

• 1 Óskarsdóttir S, Vujic M, Fasth A. Incidence and prevalence of the 22q11 deletion syndrome: a population-based study in Western Sweden.  Arch Dis Child. 2004;  89 148-152
• 2 Carlson C, Papolos D, Pandita R K, Faedda G L, Veit S, Goldberg R, Shprintzen R, Kucherlapati R, Morrow B. Molecular analysis of velo-cardio-facial syndrome patients with psychiatric disorders.  Am J Hum Genet. 1997;  60 851-859
• 3 Adeyinka A, Stockero K J, Flynn H C, Lorentz C P, Ketterling R P, Jalal S M. Familial 22q11.2 deletions in DiGeorge/velocardiofacial syndrome are predominantly smaller than the commonly observed 3Mb.  Genet Med. 2004;  6 517-520
• 4 Dunham I, Shimizu N, Roe B A, Chissoe S, Hunt A R, Collins J E, Bruskiewich R, Beare D M, Clamp M, Smink L J, Ainscough R, Almeida J P, Babbage A, Bagguley C, Bailey J, Barlow K, Bates K N, Beasley O, Bird C P, Blakey S, Bridgeman A M, Buck D, Burgess J, Burrill W D, O'Brien K P. et al . The DNA sequence of human chromosome 22.  Nature. 1999;  402 489-495
• 5 Burn J, Takao A, Wilson D, Cross I, Momma K, Wadey R, Scambler P, Goodship J. Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22q11.  J Med Genet. 1993;  30 822-824
• 6 Scambler P J. The 22q11 deletion syndromes.  Hum Mol Genet. 2000;  9 2421-2426
• 7 Wilson D I, Burn J, Scambler P, Goodship J. DiGeorge syndrome: part of CATCH 22.  J Med Genet. 1993;  10 852-856
• 8 Holder S E, Winter R M, Kamath S, Scambler P J. Velocardiofacial syndrome in a mother and daughter: variability of the clinical phenotype.  J Med Genet. 1993;  30 825-827
• 9 Leyhe T, Haarmeier T, Dufke A, Giedke H. Mikrodeletion 22q11.2 - Eine zu selten diagnostizierte genetische Veränderung bei psychiatrischen Erkrankungen.  Nervenarzt. 2003;  73 452-457
• 10 Ryan A K, Goodship J A, Wilson D I, Philip N, Levy A, Seidel H, Schuffenhauer S, Oechsler H, Belohradsky B, Prieur M, Aurias A, Raymond F L, Clayton-Smith J, Hatchwell E, McKeown C, Beemer F A, Dallapiccola B, Novelli G, Hurst J A, Ignatius J, Green A J, Winter R M, Brueton L, Brondum-Nielsen K, Stewart F, Essen T van, Patton M, Paterson J, Scambler P J. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study.  J Med Genet. 1997;  34 798-804
• 11 Thomas J A, Graham Jr J M. Chromosome 22q11 deletion syndrome: An update and review for the primary pediatrician.  Clin Pediatr (Phila). 1997;  36 253-266
• 12 Bassett A S, Hodgkinson K, Chow E WC, Correia S, Scutt L E, Weksberg R. 22q11 deletion syndrome in adults with schizophrenia.  Am J Med Genet. 1998;  81 328-337
• 13 Driscoll D A, Salvin J, Sellinger B, Budarf M L, McDonald-McGinn D M, Zackai E H, Emanuel B S. Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis.  J Med Genet. 1993;  30 813-817
• 14 Shprintzen R J, Goldberg R, Golding-Kushner K J, Marion R W. Late-onset psychosis in the velo-cardio-facial syndrome.  Am J Med Genet. 1992;  42 141-142
• 15 Endicott J, Spitzer R L, Fleiss J L, Cohen J. The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance.  Arch Gen Psychiatry. 1976;  33 766-771
• 16 DiGeorge A M. Congenital absence of the thymus and its immunological consequences: concurrence with congenital hypothyroidism. In: Good RA, Bergsma D (Hrsg.). Birth defects 1968. New York: March of Dimes, National Foundation Press 1968: 116-121
• 17 Shprintzen R J, Goldberg R B, Lewin M L, Sidoti E J, Berkman M D, Argamaso R V, Young D. A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: velo-cardio-facial syndrome.  Cleft Palate J. 1978;  5 56-62
• 18 Murphy K C, Jones L A, Owen M J. High rates of schizophrenia in adults with velo-cardio-facial syndrome.  Arch Gen Psychiatry. 1999;  56 940-945
• 19 Niklasson L, Rasmussen P, Óskarsdóttir S, Gillberg C. Neuropsychiatric disorders in the 22q11 deletion syndrome.  Genetics in Medicine. 2001;  3 79-84
• 20 Woodin M, Wang P P, Aleman D, McDonald-McGinn D, Zackai E, Moss E. Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion.  Genetics in Medicine. 2001;  3 34-39
• 21 Papolos D F, Faedda G L, Veit S, Goldberg R, Morrow B, Kucherlapati R, Shprintzen R J. Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder?.  Am J Psychiatry. 1996;  153 1541-1547
• 22 Usiskin S I, Nicolson R, Krasnewich D M, Yan W, Lenane M, Wudarsky M, Hamburger S D, Papoport J L. Velocardiofacial syndrome in childhood-onset schizophrenia.  J Am Acad Child Adolesc Psychiatry. 1999;  38 1536-1543
• 23 Bassett A S, Chow E WC, AbdelMalik P, Gheorghiu M, Husted J, Weksberg R. The schizophrenia phenotype in 22q11 deletion syndrome.  Am J Psychiatry. 2003;  160 1580-1586
• 24 Murphy K C. Schizophrenia and velo-cardio-facial syndrome.  Lancet. 2002;  359 426-430
• 25 Karayiourgou M, Morris M A, Morrow B, Shprintzen R J, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyniec P S, Lasseter V K, Eisen H, Childs B, Kazazian H H, Kucherlapati R, Antonarakis S E, Pulver A E, Housman D E. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.  Proc Natl Acad Sci USA. 1995;  92 7612-7616
• 26 Wiehahn G J, Bosch G P, du Preez R R, Pretorius H W, Karayiorgou M, Roos J L. Assessment of the frequency of the 22q11 deletion in Afrikaner schizophrenic patients.  Am J Med Genet. 2004;  129B 20-22
• 27 Horowitz A, Shifman S, Rivalin N, Pisante A, Darvasi A. A survey of the 22q11 microdeletion in a large cohort of schizophrenia patients.  Schizophr Res. 2005;  73 263-267
• 28 Ivanov D, Kirov G, Norton N, Williams H J, Williams N M, Nikolov I, Tzwetkova R, Stambolova S M, Murphy K C, Toncheva D, Thapar A, O'Donovan M C, Owen M J. Chromosome 22q11 deletions, velo-cardio-facial syndrome and early-onset psychosis.  B J Psychiatry. 2003;  183 409-413
• 29 Chow E WC, Bassett A S, Weksberg R. Velo-Cardio-Facial Syndrome and Psychotic Disorders: Implications for Psychiatric Genetics.  Am J Med Genet. 1994;  54 107-112
• 30 Bassett A S, Chow E W, Weksberg R, Brzustowicz L. Schizophrenia and genetics: new insights.  Curr Psychiatry Rep. 2002;  4 307-314
• 31 Mowry B J, Holmans P A, Pulver A E, Gejman P V, Riley B, Williams N M, Laurent C, Schwab S G, Wildenauer D B, Bauche S, Owen M J, Wormley B, Sanders A R, Nestadt G, Liang K Y, Duan J, Ribble R, Norton N, Soubigou S, Maier W, Ewen-White K R, DeMarchi N, Carpenter B, Walsh D, Williams H, Jay M, Albus M, Nertney D A, Papadimitriou G, O'Neill A, O'Donovan M C, Deleuze J F, Lerer F B, Dikeos D, Kendler K S, Mallet J, Silverman J M, Crowe R R, Levinson D F. Multicenter linkage study of schizophrenia loci on chromosome 22q.  Mol Psychiatry. 2004;  9 784-795
• 32 Goldberg R, Motzkin B, Marion R, Scambler P J, Shprintzen R J. Velo-cardio-facial syndrome: a review of 120 patients.  Am J Med Genet. 1993;  45 313-319
• 33 Gothelf D, Presburger G, Levy D, Nahmani A, Burg M, Berant M, Blieden L C, Finkelstein Y, Frisch A, Apter A, Weizman A. Genetic, developmental, and physical factors associated with attention deficit hyperactivity disorder in patients with velocardiofacial syndrome.  Am J Med Genet. 2004;  126B 116-121
• 34 Pulver A E, Nestadt G, Goldberg R, Shprintzen R J, Lamacz M, Wolyniec P S, Morrow B, Karayiorgou M, Antonarakis S E, Housman D, Kucherlapati R. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives.  J Nerv Ment Dis. 1994;  182 476-478
• 35 Golding-Kushner K J, Weller G, Shprintzen R J. Velo-cardio-facial syndrome: Language and psychological profiles.  J Craniofac Genet Dev Biol. 1985;  5 259-266
• 36 Done D J, Crow T J, Johnstone E C, Sacker A. Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11.  BMJ. 1994;  309 699-703
• 37 Baker K D, Skuse D H. Adolescents and young adults with 22q11 deletion syndrome: psychopathology in an at-risk group.  Br J Psychiatry. 2005;  186 115-120
• 38 Swillen A, Devriendt K, Legius E, Eyskens B, Dumoulin M, Gewillig M, Fryns J P. Intelligence and psychosocial adjustment in velocardiofacial syndrome: a study of 37 children and adolescents with VCFS.  J Med Genet. 1997;  34 453-458
• 39 Swillen A, Vogels A, Devriendt K, Fryns J P. Chromosome 22q11 deletion syndrome: update and review of the clinical features, cognitive-behavioral spectrum, and psychiatric complications.  Am J Med Genet (Semin Med Genet). 2000;  97 128-135
• 40 El Tahir M O, Kerr M, Jones R G. Two cases of generalized seizures and the Velocardiofacial syndrome - a clinically significant association?.  J Intellect Disabil Res. 2004;  48 695-698
• 41 Kao A, Mariani J, McDonnald-McGinn D M, Maisenbacher M K, Brooks-Kayal A R, Zackai E H, Lynch D R. Increased prevalence of unprovoked seizures in patients with a 22q11.2 deletion.  Am J Med Genet A. 2004;  1 29-34
• 42 Callenbach P M, Maagdenberg A M van den, Hottenga J J, Boogerd E H van den, Coo R F de, Lindhout D, Frants R R, Sandkuijl L A, Brouwer O F. Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q.  Epilepsia. 2003;  44 1298-1305
• 43 Óskarsdóttir S, Belfrage M, Sandstedt E, Viggedal G, Uvebrant P. Disabilities and cognition in children and adolescents with 22q11 deletion syndrome.  Dev Med Child Neurol. 2005;  47 177-184
• 44 Krahn L E, Maraganore D M, Michels V V. Childhood-onset schizophrenia associated with parkinsonism in a patient with a microdeletion of chromosome 22.  Mayo Clinic Proceedings. 1998;  73 956-959
• 45 Baralle D, Trump D, ffrench-Constant C, Dick D J. Myoclonic movement disorder associated with microdeletion of chromosome 22q11.  J Neurol Neurosurg Psychiatry. 2002;  73 600-601
• 46 Mitnick R J, Bello J A, Shprintzen R J. Brain anomalies in velo-cardio-facial syndrome.  Am J Med Genet. 1994;  54 100-106
• 47 Lynch D R, McDonald-McGinn D M, Zackai E H, Emanuel B S, Driscoll D A, Whitaker L A, Fischbeck K H. Cerebellar atrophy in a patient with velocardiofacial syndrome.  J Med Genet. 1995;  32 561-563
• 48 Chow E WC, Mikulis D J, Zipursky R B, Scutt L E, Weksberg R, Bassett A S. Qualitative MRI findings in adults with 22q11 deletion syndrome and schizophrenia.  Biol Psychiatry. 1999;  46 1436-1442
• 49 Chow E W, Zipursky R B, Mikulis D J, Bassett A S. Structural brain abnormalities in patients with schizophrenia and 22q11 deletion syndrome.  Biol Psychiatry. 2002;  51 208-215
• 50 Amelsvoort T van, Daly E, Henry J, Robertson D, Ng V, Owen M, Murphy K C, Murphy D G. Brain anatomy in adults with velocardiofacial syndrome with and without schizophrenia.  Arch Gen Psychiatry. 2004;  61 1085-1096
• 51 Eliez S, Antonarakis S E, Morris M A, Dahoun S P, Reiss A L. Parental origin of the deletion 22q11.2 and brain development in velocardiofacial syndrome.  Arch Gen Psychiatry. 2001;  58 64-68
• 52 Eliez S, Schmitt J E, White C D, Reiss A L. Children and adolescents with velocardiofacial syndrome: A volumetric MRI study.  Am J Psychiatry. 2000;  157 409-415
• 53 Eliez S, Blasey C M, Schmitt E J, White C D, Hu D, Reiss A L. Velocardiofacial syndrome: Are structural changes in the temporal and mesial temporal regions related to schizophrenia?.  Am J Psychiatry. 2001;  158 447-453
• 54 Barnea-Goraly N, Menon V, Krasnow B, Ko A, Reiss A, Eliez S. Investigation of white matter structures in velocardiofacial syndrome: a diffusion tensor imaging study.  Am J Psychiatry. 2003;  160 1863-1869
• 55 Bish J P, Nguyen V Y, Ding L, Ferrante S, Simon T J. Thalamic reductions in children with chromosome 22q11.2 deletion syndrome.  Neuroreport. 2004;  15 1413-1415
• 56 Eliez S, Barnea-Goraly N, Schmitt J E, Liu Y, Reiss A L. Increased basal ganglia volumes in velo-cardio-facial syndrome (deletion 22q11.2).  Biol Psychiatry. 2002;  52 68-70
• 57 Sugama S, Bingham P M, Wang P P, Moss E M, Kobayashi H, Eto Y. Morphometry of the head of the caudate nucleus in patients with velocardiofacial syndrome (del 22q11.2).  Acta Paediatr. 2000;  89 546-549
• 58 Sciré G, Dallapiccola B, Iannetti P, Bonaiuto F, Galasso C, Migarelli R, Boscherini B. Hypoparathyroidism as the major manifestation in two patients with 22q11 deletions.  Am J Med Genet. 1994;  52 478-482
• 59 Weinzimer S A. Endocrine aspects of the 22q11.2 deletion syndrome.  Genet Med. 2001;  3 19-22
• 60 Sieberer M, Haltenhof H, Haubitz B, Pabst B, Miller K, Garlipp P. Basal ganglia calcification and psychosis in 22q11.2 deletion syndrome. Eur Psychiatry (accepted for publication, 19. 04. 2005)
• 61 Wraith J E, Super M, Watson G H, Phillips M. Velo-cardio-facial syndrome presenting as holoprosencephaly.  Clin Genet. 1985;  27 408-410
• 62 Nickel R E, Pillers D M, Merkens M, Magenis R E, Driscoll D A, Emanuel B S, Zonana J. Velo-cardio-facial syndrome and DiGeorge sequence with meningomyelocele and deletions of the 22q11 region.  Am J Med Genet. 1994;  52 445-449
• 63 MacKenzie-Stepner K, Witzel M A, Stringer D S, Lindsay W K, Munro I R, Hughes H. Abnormal carotid arteries in the velocardiofacial syndrome: report of three cases.  Plast Reconstr Surg. 1987;  80 347-351
• 64 Bird L M, Scambler P. Cortical dysgenesis in 2 patients with chromosome 22q11 deletion.  Clin Genet. 2000;  58 64-68
• 65 Koolen D A, Veltman J A, Renier W O, Droog R P, Kessel A G van. Chromosome 22q11 deletion and pachygyria characterized by array-based comparative genomic hybridisation.  Am J Med Genet. 2004;  131 322-324
• 66 Kawame H, Kurosawa K, Akatsuka A, Ochiai Y, Mizuno K. Polymicrogyria is an uncommon manifestation in 22q11.2 deletion syndrome.  Am J Med Genet. 2000;  94 77-78
• 67 Worthington S, Turner A, Elber J, Andrews P I. 22q11 deletion and polymicrogyria - cause or coincidence?.  Clin Dysmorphol. 2000;  9 193-197
• 68 Ehara H, Maegaki Y, Takeshita K. Pachygyria and polymicrogyria in 22q11 deletion syndrome.  Am J Med Genet A. 2003;  117 80-82
• 69 Simon T J, Ding L, Bish J P, McDonnald-McGinn D M, Zackai E H, Gee J. Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study.  Neuroimage. 2005;  25 169-180
• 70 Shashi V, Muddasani S, Santos C C, Berry M N, Kwapil T R, Lewandowski E, Keshavan M S. Abnormalities of the corpus callosum in nonpsychotic children with chromosome 22q11 deletion syndrome.  Neuroimage. 2004;  21 1399-1406
• 71 Kraynack N C, Hostoffer R W, Robin N H. Agenesis of the corpus callosum associated with DiGeorge-velocardiofacial syndrome: a case report and review of the literature.  J Child Neurol. 1999;  14 754-756
• 72 Vataja R, Elomaa E. Midline brain anomalies and schizophrenia in people with CATCH 22 syndrome.  Br J Psychiatry. 1998;  172 518-520
• 73 Amelsvoort T van, Daly E, Robertson D, Suckling J, Ng V, Critchley H, Owen M J, Henry J, Murphy K C, Murphy D GM. Structural brain abnormalities associated with deletion at chromosome 22q11.  Br J Psychiatry. 2001;  178 412-419
• 74 Murphy K C, Owen M J. Velo-cardio-facial syndrome: a model for understanding the genetics and pathogenesis of schizophrenia.  Br J Psychiatry. 2001;  179 397-402
• 75 Demczuk S, Aurias A. DiGeorge syndrome and related syndromes associated with 22q11.2 deletions.  Ann Genet. 1995;  38 59-76