Neurological Surgery 脳神経外科39巻1号

2011年01月発行

連載 先天奇形シリーズ

（2）小児脳神経外科領域における遺伝子診断

著者： 山崎麻美¹

所属機関： ¹国立病院機構大阪医療センター脳神経外科

ページ範囲：P.65 - P.77

Ⅰ．はじめに

　分子遺伝子学の進歩が，先天性疾患の臨床にもたらした意義は大きい．分子遺伝子学的診断が臨床にもたらす影響の程度から，次のように分けられる．すなわち①遺伝子診断の意義が臨床的に確立し，疾患の確定診断，保因者診断，出生前診断などに寄与しているもの，あるいは疾患の分類が書き換えられつつあるもの，②疾患の一部に原因遺伝子が同定され，病態解明や疾患分類に新しい知見を呈しているものの，臨床的には遺伝子診断の意義は未確立のもの，③まったく研究段階で臨床的な意義は未確立のものである．

　小児脳神経外科領域の疾患で，遺伝子学的研究が進んだ疾患を上記にそって分類すると，①は頭蓋縫合早期癒合症，X連鎖性劣性遺伝性水頭症，滑脳症など，②は全前脳胞症，③はDandy-Walker症候群，脊髄髄膜瘤などである．

　これらの疾患についての研究の成果と臨床上の意義などについて述べていく．平成22年（2010）度の診療報酬改定では，一部の先天性疾患の遺伝子診断や遺伝カウンセリング料は保険収載され，保険診療として認められるようになったが，小児脳神経外科領域の疾患はまだその中には含まれていない．

参考文献

1）Cardoso C, Leventer RJ, Ward HL, Toyo-Oka K, Chung J, Gross A, Martin CL, Allanson J, Pilz DT, Olney AH, Mutchinick OM, Hirotsune S, Wynshaw-Boris A, Dobyns WB, Ledbetter DH：Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 9：18-30, 2003

2）Cohen MM：Achondroplasia, hypochondroplasia and thanatophoric dysplasia：clinically related skeletal dysplasia that are also related at the molecular lebel. Int J Oral Maxillofac Surg 27：451-455, 1998

3）Des Portes V, Pinard JM, Billuart P Vinet MC, Koulakoff A, Carrié A, Gelot A, Dupuis E, Motte J, Berwald-Netter Y, Catala M, Kahn A, Beldjord C, Chelly J：A novel CNS gene required for neuronal migration and involved in X-Linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 92：51-61, 1998

4）Dobyns WB：The clinical patterns and molecular genetic of lissencephaly qnd subcortical band heterotopias. Epilepsia 51：5-9, 2010

5）Dobyns WB, Pagon RA, Armstrong D, Curry CJ, Greenberg F, Grix A, Holmes LB, Laxova R, Michels VV, Robinow M, Zimmerman RL：Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 32：195-210, 1989

6）Dobyns WB, Truwit CL, Ross ME, Matsumoto N, Pilz DT, Ledbetter DH, Gleeson JG, Walsh CA, Barkovich AJ：Differences in the gyral pattern distinguish chromosome 17 linked and X linked lissencephaly. Neurology 53：270-277, 1999

7）Gripp KW, Wotton D, Edwards MC Roessler E, Ades L, Meinecke P, Richieri-Costa A, Zackai EH, Massagué J, Muenke M, Elledge SJ：Mutaions in TGIF cause holoprosencephaly and link NODAL signaling to human neural axis determination. Nat Genet 25：205-208, 2000

8）Hahn JS, Plawner LL：Evaluation and management of children with holoprosencephaly. Pediatr Neurol 31：79-88, 2004

9）Hehr U, Uyanik G, Gross C, Walter MC, Bohring A, Cohen M, Oehl-Jaschkowitz B, Bird LM, Shamdeen GM, Bogdahn U, Schuierer G, Topaloglu H, Aigner L, Lochmüller H, Winkler J：Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease. Neurogenetics 8：279-288, 2007

10）Izumoto S, Yamasaki M, Arita N, Hiraga S, Ohnishi T, Fujitani K, Sakoda S, Hayakawa T：A new mutation of the L1CAM gene in an X-linked hydrocephalus family. Childs Nerv Syst 12：742-747, 1996

11）Kamiguchi H, Hlavin ML, Yamasaki M, Lemmon V：Adhesion molecules and inherited diseases of the human nervous system. Annu Rev Neurosci 21：97-125, 1998

12）Kamiguchi H, Lemmon V：IgCAMs：bidirectional signals underlying neurite growth. Curr Opin Cell Biol 12：598-605, 2000

13）Kaname T, Yanagi K, Chinen Y, Makita Y, Okamoto N, Maehara H, Owan I, Kanaya F, Kubota Y, Oike Y, Yamamoto T, Kurosawa K, Fukushima Y, Bohring A, Opitz JM, Yoshiura K, Niikawa N, Naritomi K：Mutations in CD96, a member of the immunoglobulin superfamily, cause a form of C (Opitz trigonocephaly) syndrome. Am J Hum Genet 81：835-841, 2007

14）Kanemura Y, Okamoto N, Sakamoto H, Shofuda T, Kamiguchi H, Yamasaki M：Molucular mechanisms and neuroimageing criteria for severe L1 syndrome with X-linked hydrocephalus. J Neurosurg (5suppl pediatrics) 105：403-412, 2006

15）Kanemura Y, Takuma Y, Kamiguchi H, Yamasaki M：First case of L1CAM gene mutation identified in MASA syndrome in Asia. Congenit Anom (Kyoto) 45：67-69, 2005

16）Kato M, Das M, Petras K, Sawaishi Y, Dobyn WB：Mutations of ARX are striking pleiotropy and consistent genotype and phenotype correlation. Hum Mutat 23：147-159, 2004

17）Kato M, Das M, Petras K, Sawaishi Y, Dobyn WB：Polyalanine expansion of ARX associated with cryptogenic West syndrome. Neurology 61：267-276, 2003

18）Kato M, Dobyns WB：Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet 12；89-96, 2003

19）Kato M, Saitoh S, Kamei A：A longer polyalanine expansion in the ARX gene causes early infantile epileptic encephalopathy with syndrome. Neurology 61：267-276, 2003

20）Kitamura K, Yanazawa M, Sugiyama N：Mutaion of ARX causes abnormal development of forebrain and testis in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 32：359-369, 2002

21）Lajeunie E, Cameron R, EL Ghouzzi V, Joumeau P, Gonzales M, Delezoide AL, Bonaventure J, Le Merrer M, Renier D：Clinical variability in patients with Apert’s syndrome. J Neurosurg 90：443-447, 1999

22）Lows ASC, Lee SL, Tan ASA, Chan DKL, Chan CLL：Difficulties with prenatal diagnosis of the Walker-Warburg Syndrome. Acta Radiol 6：645-651, 2005

23）Meyers GA, Orlow SJ, Munro IR, Pizylepa KA, Jabs EW：Fibroblast growth factor receptor3 (FGFR3) transmembrane mutation in Crouzon syndromes with acanthosis nigricans. Nature Genet 11：462-464, 1995

24）Ming JE, Kaupas ME, Roessler E Brunner HG, Golabi M, Tekin M, Stratton RF, Sujansky E, Bale SJ, Muenke M：Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associate with holoprosencephaly. Hum Genet 110：297-301, 2002

25）Morriss-Kay GM, Wilkie AOM：Growth of the normal skull vault and its alteration in craniosynostosis：insights from human genetics and experimental studies. J Anat 207：637-653, 2005

26）Okamoto N, Del Maestro R, Valero R, Monros E, Poo P, Kanemura Y, Yamasaki M：Hydrocephalus and Hirschsprung’s disease with a mutation of L1CAM. J Hum Genet 49：334-337, 2004

27）Pineda-Alvarez DE, Dubourg C, David V, Roessler E, Muenke M：Current recommendation for the molecular evaluation of newly diagnoses holoprosencephaly patients. Am J Med Genet 154C：93-101, 2010

28）Renier D, El-Ghouzzi V, Bonaventure J, Le Merrer E, Lajeunie E：Fibroblast growth factor receptor 3 mutation in nonsyndromic coronal synostosis：clinical spectrum, prevalence, and surgical outcome. J Neurosurg 92：631-363, 2000

29）Ribeiro LA, El-Jaick KB, Muenke M, Richieri-Costa A：SIX3 mutations with holoprosencephaly. Am J Med Genet 140A；2577-2588, 2006

30）Ribeiro LA, Quiezi RG, Nascimento A, Bertolacini CP, Richieri-Costa A：Holoprosencephaly and holoprocephaly-like phenotype and GAS1 DNAsequence changes. Am J Med Genet 152A：1688-1694, 2010

31）Roessler E, Bellone E, Gaudentz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M：Mutations in the human sonic hedgehog gene cause holoprosencephaly. Nat Genet 14：357-360, 1996

32）Roessler E, Du Y, Grinka A, Dutra A, Niehrs C, Muenke M：The genomic stracture, chromosome location, and analysis of human DKK head induce gene as a candidate for holoprosencephaly. Cytogenet Cell Genet 89：220-224, 2000

33）Rosenthal A, Jouet M, Kenwrick S：Aberrant splicing of neural cell adhesion molecule L1 messenger RNA in a family with X-linked hydrocephalus. Nat Genet 2：107-112, 1992

34）Ross ME, Swanson K, Dobyns WB Lissencephaly with cerebellar hypoplasia (LCH)：a heterogeneous group of cortical malformations. Neuropediatrics 32：256-263, 2001

35）Solomon BD, Mercier S, Velez JI, Pineda-Alvarez DE, Wyllie A, Zhou N, Dubourg C, David V, Odent S, Roessler E, Muenke M：Analysis of genotype-phenotype correlations in human holprosencephaly. Am J Med Genet 154C：133-141, 2010

36）Thomas GPL, Wilkie AOM, Richards PG, Wall SA：FGFR3 (P250R) mutation increase the risk of reoperation in apparent ‘nonsyndromic’ coronal synostosis. J Craniofac Surg 16：347-354, 2005

37）富和清隆：遺伝子検査と遺伝カウンセリング． pp69-74（山崎麻美編：胎児期水頭症診断と治療ガイドライン第2版Ⅰ部6章，金芳堂，京都，2010）

38）Twigg SRF, Kan R, Babbs C, Bochukova EG, Robertson SP, Wall SA, Morriss-Kay GM, Wilkie AOM：Mutations of ephrin -B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc Natl Acad Sci U S A 101：8652-8657, 2004

39）Vos YJ, de Walle HE, Bos KK, Stegeman JA, Ten Berge AM, Bruining M, van Maarle MC, Elting MW, den Hollander NS, Hamel B, Fortuna AM, Sunde LE, Stolte-Dijkstra I, Schrander-Stumpel CT, Hofstra RM：Genotype-phenotype correlations in L1 syndrome：a guide for genetic counselling and mutation analysis. J Med Genet 47：169-175, 2010

40）Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, Gillessen-Kaesbach G, Zackai EH, Rommens J, Muenke M：Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet 22：196-198, 1999

41）Wilkie AOM, Bochukova EG, Hansen RMS, Taylor IB, Rannan-Eliya SV, Byren JC, Wall SA, Romas L, Venancio M, Hurst JA, O’Rourke AW, Williams LJ, Seller A, Lester T：Clinical dividends from the moleculaer genetic diagnosis of craniosynostosis. Am J Med Genet 143A：1941-1949, 2007

42）Wilkie AOM, Staney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, Hayward RD, David DJ, Pulleyn LJ, Rutland P：Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9：165-172, 1995

43）Wood RH, UI-Haq E, Wilkie AO, Jayamohan J, Richards PG, Johnson D, Lester T, Wall SA：Reoperation for intracranial hypertension in TWIST1-confirmed Saethre-Chotzen syndrome：a 15-year review. Plast Reconstr Surg 123：1801-1810, 2009

44）山崎麻美：先天性奇形の遺伝子検索の意義． pp410-417（松谷雅生，田村　晃：脳神経外科周術期管理のすべて改訂第3版，メジカルビュー社，東京，2009）

45）Yamasaki M, Arita N, Hiraga S, Izumoto S, Morimoto K, Nakatani S, Fujitani K, Sato N, Hayakawa T：A clinical and neuroradiological study of X-linked hydrocephalus in Japan. J Neurosurg 83：50-55, 1995

46）Yamasaki M, Nonaka M, Suzumori N, Nakamura H, Namba A, Kamei Y, Yamada T, Pooh RK, Tanemura M, Sudo N, Nagasaka M, Yoshioka E, Shofuda T, Kanemura Y：Prenatal molecular diagnosis of a severe type of L1CAM syndrome (X-linked hydrocephalus) in submition

47）Yamasaki M, Thompson P, Lemmon V：CRASH Syndrome：Mutations in L1 correlate with severity of the disease. Neuropediatrics 28：175-178, 1997

48）Yoshioka M：Phenotypic spectrum of Fukutinopathy：most severe phenotype of Fukutinopathy. Brain Dev 31 (6)：419-422, 2009