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Download Article (PDF) Schwerpunktthema: Intelligenzminderung medgen 2018 · 30:328–333 Andreas Tzschach https://doi.org/10.1007/s11825-018-0207-1 Institut für Klinische Genetik, Technische Universität Dresden, Dresden, Deutschland Online publiziert: 17. Oktober 2018 © Der/die Autor(en) 2018 X-chromosomale Intelligenzminderung Einleitung Fälle eine X-chromosomale Genverän- mologischen Aspekten insbesondere bei derung nachweisbar [25, 39]. der Bewertung unklarer Varianten und DieungleicheGeschlechterverteilungbei NeueKrankheitsgeneaufdemX-Chro- bei Patienten ohne nachweisbare geneti- Intelligenzminderung („intellectual dis- mosom sind in den letzten Jahren haupt- scheUrsacheauchweiterhineinezentrale ability“, ID) mit ca. 30% höherer Präva- sächlich für X-chromosomal dominante Rolle. lenz bei Knaben und die in den 1940er- Formen identifiziert worden, die über- Jahren beginnende Publikation großer wiegend Mädchen betreffen und meist Fragiles-X-Syndrom Stammbäume mit geschlechtsgebunde- durch De-novo-Mutationen verursacht nem Erbgang ließen das X-Chromosom werden. Diesem Thema ist der Bei- Das Fragile-X-Syndrom (FRAX, Martin- früh in den Mittelpunkt des Interesses trag von Anna Fliedner und Christiane Bell-Syndrom, OMIM 300624) ist die rücken[1,26].ErsteMeilensteinewurden Zweier in diesem Heft gewidmet. Die häufigste monogene Ursache für Intel- mit der zunächst zytogenetischen (1969) Grenze zwischen rezessiver und domi- ligenzminderung. Bei den meisten Pa- und dann molekulargenetischen (1991) nanter XLID ist jedoch unscharf. Fast tienten liegt eine Expansion des CGG- AufklärungdesFragilen-X-Syndromser- alle XLID-Gene sind mit Manifestati- Trinukleotidrepeats in der 5’-UTR des reicht [25]. Die Bündelung von Familien onsformen sowohl im männlichen als FMR1-Gensvor,dieeineHypermethylie- mit vermutetem oder mittels Kopplungs- auch im weiblichen Geschlecht asso- rung und damit fehlende oder stark ver- analyse gesichertem X-chromosomalen ziiert, wobei aber meist Unterschiede minderte Expression des Gens zur Fol- Erbgang im Rahmen großer Konsorti- hinsichtlich Prävalenz und klinischem ge hat. Punktmutationen und Deletionen en (EUROMRX, IGOLD) bildete die Ba- Schweregrad bestehen. von FMR1 sind demgegenüber offenbar sis, auf der schon vor Einführung der Die Unterscheidung von syndroma- sehrseltenundtrotzdesinzwischenweit- Hochdurchsatzsequenzierungzahlreiche ler und nicht syndromaler XLID hat mit verbreiteten Einsatzes von Array-CGH weitere Krankheitsgene für nicht syn- Einführung der parallelen molekularge- und NGS erst bei weniger als zehn Pa- dromale ID identifiziert werden konn- netischen Diagnostik ihre frühere Be- tienten beschrieben worden [33]. Ohne ten [34]. Die X-chromosomale ID nahm deutung eingebüßt. Diese Abgrenzung die instabile CGG-Repeatregion würde damit gegenüber den zwar häufigeren, war ohnehin nie ganz streng gewesen, das Fragile-X-Syndrom zu den seltenen aber aufgrund ihres meist sporadischen weil a) mitunter auch intrafamiliär ei- XLID-Formen zählen. Ob in Analogie Auftretens erst mittels „next generation ne erhebliche klinische Variabilität vor- zu MECP2, wo sowohl Funktionsverlust- sequencing“ (NGS) in größerem Um- liegen kann, b) manche Merkmale erst mutationen als auch Duplikationen mit fang zugänglichen autosomal-dominan- ab einem bestimmtem Alter der Pati- kognitiven Einschränkungen einherge- ten Formen eine Vorreiterrolle ein. In- enten erkennbar werden, c) einige Syn- hen (siehe unten), auch die Überexpres- zwischen konnten XLID-assoziierte Mu- drome erst nach molekularer Aufklärung sion von FMR1 klinische Konsequen- tationeninmehrals100derca.800prote- vonausreichendvielenPatientenklinisch zen hat, ist aktuell noch unklar. Bis jetzt inkodierendenGenedesX-Chromosoms definiert werden konnten (Beispiele da- ist nur ein einziger männlicher Patient identifiziertwerden[29].DerrelativeAn- für sind das Martin-Bell/Fragile-X-Syn- mit FMR1-Duplikation berichtet worden teil ID-assoziierter Gene scheint damit drom sowie die OPHN1-assoziierte ze- [40]. auf dem X-Chromosom deutlich höher rebelläre Hypoplasie) und andererseits Das Genprodukt FMRP ist ein alsaufdenAutosomenzusein.Unterevo- d) vermeintlich klinisch distinkte Enti- mRNA-bindendes Protein mit regu- lutionären Gesichtspunkten könnte diese täten, die nicht selten anhand einer ein- latorischerFunktionbeiderTranslation BeobachtungdurcheinenhöherenSelek- zigen Familie definiert worden waren, insbesondere von Synapsenproteinen. tionsdruck auf das X-Chromosom hin- sich nach Aufklärung der ursächlichen Der Mangel an FMRP hat u.a. die sichtlich kognitiver Merkmale erklärbar Gene als allelische Varianten des gleichen Überexpression postsynaptischer meta- sein [13, 36]. Bei sporadischen männli- Krankheitsbildes herausstellten. Davon botroper Glutamatrezeptoren (mGluR) chen ID-Patienten (also ohne auffällige unbenommen, spielt aber die klinische zurFolge.InFraX-Tiermodellen(Droso- Familienanamnese) ist in ca. 10 % der Beurteilung der Patienten unter syndro- phila und Maus) konnten durch gezielte 328 medizinische genetik 3 · 2018 Hemmung dieser Rezeptoren eindrucks- don-Dudley-Syndrom (OMIM 300523) MED12 (FG/Opitz-Kaveggia-Syndrom, volle phänotypische Korrekturen erzielt assoziiert, einem Krankheitsbild mit OMIM 305450; Lujan-Fryns-Syndrom, werden, die Hoffnungen auf einen the- schwerer ID, Mikrozephalie und Spastik. 309520;Ohdo-Syndrom,OMIM300895), rapeutischen Einsatz beim Menschen Die Unterfunktion dieses Hormontrans- SLC9A6 (Christianson-Syndrom,OMIM geweckt haben [27]. Die daraufhin initi- porters hat erhöhte Werte für T3 bei 300243) und PHF6 (Börjeson-Forssman- ierten klinischen Studien konnten diese erniedrigtem T4 im Serum zur Folge. Lehmann-Syndrom, OMIM 301900) ein. Erwartungen aber leider nicht erfüllen Das Thyreoidea stimulierende Hormon Punktmutationen in MECP2 sind [5]. (TSH) ist allerdings meist im Normbe- nicht nur Ursache des Rett-Syndroms reich, und es liegt auch keine klinisch bei Mädchen, sondern werden auch bei Prävalenz von Mutationen in manifeste Hypothyreose vor. Inzwischen männlichen Patienten beobachtet, wobei einzelnen XLID-Genen sind mehr als 100 Familien mit Allan- der klinische Schweregrad in Abhängig- Herndon-Dudley-Syndrom publiziert keit von der Mutation von Enzepha- Häufige XLID-Gene worden. lopathie mit früher Letalität (OMIM Auch die SLC6A8-assoziierte Kreatin- 300673) bis zu moderater ID reicht Die Mutationshäufigkeiten in den ein- transporter-Defizienz (OMIM 300352) (PPM-X-Syndrom, OMIM 300055). Das zelnen XLID-Genen unterscheiden sich zählt mit mehr als 100 publizierten Fami- häufige MECP2-Duplikations-Syndrom erheblich. Nur für wenige Gene sind Mu- lien zu den häufigen XLID-Syndromen. wird unten im Kapitel Chromosomen- tationen in mehr als 100 Familien be- DieklinischenMerkmaleumfassenne- störungen besprochen. schrieben worden. ben schwerer ID u.a. Kleinwuchs, nied- Missense-Mutationen in IQSEC2 Mutationen in ATRX sind mit schwe- riges Körpergewicht, unterentwickelte (OMIM 309530) waren zunächst in vier rer ID, Mikrozephalie und Hypotonie Muskulatur, Hypotonie, Krampfanfälle Familien mit unspezifischer ID berichtet („X-linked mental retardation-hypoto- und Verhaltensauffälligkeiten. In Blut worden. Später wurden auch Nonsense- nic facies syndrome“, OMIM 309580) und Urin liegt ein erhöhtes Verhältnis Mutationen und Deletionen identifi- sowie in einigen Fällen zusätzlich auch von Kreatin zu Kreatinin vor. Hetero- ziert, die mit schwerer ID, Epilepsie und mit erythrozytären HbH-Einschluss- zygote Anlageträgerinnen für SLC6A8- Mikrozephalie assoziiert sind. De-novo- körpern (Alpha-Thalassämie-Retardie- Mutationen können Auffälligkeiten hin- Mutationen in IQSEC2 wurden inzwi- rungs-Syndrom, OMIM 301040) asso- sichtlich Kognition und Verhalten haben. schen auch mehrfach bei weiblichen ziiert. Es sind mehr als 200 Familien Funktionsverlustmutationen in ARX Patienten nachgewiesen und haben dort mit ATRX-Mutationen berichtet wor- sind mit Hirnfehlbildungen und Genital- u.a. eine dem Rett-Syndrom ähnliche den. ATRX-Mutationen können auch anomalien („X-linked lissencephaly with Symptomatik zur Folge. im weiblichen Geschlecht zu kognitiven ambiguous genitalia“, OMIM 300215) Einschränkungen führen. assoziiert. Bei mehreren großen Familien Seltene XLID-Gene Das Coffin-Lowry-Syndrom (OMIM mit im Vergleich dazu eher unspezifi- 303600) ist klinisch neben schwerer ID scher Symptomatik, die neben ID auch Die Mehrzahl der XLID-Gene scheint durch Kleinwuchs, grobe Gesichtszü- Dystonie und Epilepsie umfassen kann eine niedrige Mutationsrate zu haben, ge, prominente Lippen, Skoliose und (OMIM 300419 und 309510), wurde d.h. es sind sowohl beim Screening von spitz zulaufende Finger gekennzeichnet. eine rekurrente 24-bp-Duplikation in- XLID-Familienalsauchbeisporadischen Es wird durch Mutationen in RPS6KA3 nerhalb des Polyalanin-Trakts von ARX Patienten weniger als 20 Fälle berichtet verursachtundzähltmitüber150berich- nachgewiesen. Da diese Duplikation worden. Diese Beobachtung betrifft kei- teten Familien ebenfalls zu den häufigen bei der NGS-Diagnostik nicht sicher neswegs nur solche Gene, die erst vor XLID-Syndromen. erkannt wird, sind ARX-Mutationen kurzer Zeit aufgeklärt worden sind, wie Das Simpson-Golabi-Behmel-Syn- möglicherweise unterdiagnostiziert. Bis- z. B. ZC4H2 (Wieacker-Wolff-Syndrom, drom (OMIM 312870, Mutationen in lang sind über 100 Familien mit der 24- OMIM 314580; ID und Arthrogrypose) GPC3) ist ein Makrosomie-Syndrom bp-Duplikation beschrieben worden. oder LAS1L (Wilson-Turner-Syndrom, mit charakteristischen fazialen Merk- OMIM 309585; ID mit Kleinwuchs, Gy- malen und variablen
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