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Transienter neonataler Diabetes und Hypomethylierungssyndrome

Transient neonatal diabetes and hypomethylation syndromes

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medizinische genetik

Zusammenfassung

Der transiente neonatale Diabetes (TNDM) ist definiert als Manifestation einer diabetogenen Stoffwechsellage in den ersten Lebenswochen und Normalisierung des Glukosestoffwechsels bis zum 18. Lebensmonat. Zu den klinischen Kardinalsymptomen zählen intrauterine Wachstumsverzögerung, Hyperglykämie und Dehydratation bei fehlender Ketoazidose. Die Ätiologie des TNDM ist sehr heterogen. In 70% der Fälle ist die Erkrankung mit Aberrationen in der Chromosomenregion 6q24 assoziiert. Diese Chromosomenregion enthält die genomisch geprägten Gene PLAGL1/ZAC und HYMAI. Durch eine paternale uniparentale Disomie 6 (upd(6)pat), eine paternale Duplikation der geprägten Region in 6q24 oder durch Imprintingdefekte des maternalen Allels kommt es zu einer Überexpression des paternal exprimierten Gens PLAGL1. Imprintingdefekte können isoliert oder im Rahmen eines Hypomethylierungssyndroms mit Beteiligung mehrerer geprägter Loci des Genoms auftreten. Hypomethylierung an multiplen Loci wurde bis jetzt bei Patienten mit TNDM, Silver-Russell-Syndrom (SRS) und Beckwith-Wiedemann-Syndrom (BWS) beobachtet. Das Wiederholungsrisiko hängt wesentlich von der Ursache des TNDM an. Chromosomale Aberrationen der Eltern unter Beteiligung des Chromosoms 6 erhöhen das Risiko sowohl für eine UPD des geprägten Bereichs in 6q24 als auch für eine paternale Duplikation. Jedoch entstehen sowohl UPD als auch Duplikationen zumeist de novo.

Abstract

Transient neonatal diabetes (TNDM) is manifested before the age of 6 weeks and typically resolves within 18 months. Main clinical features include intrauterine growth retardation, hyperglycemia and dehydration with absent ketoacidosis. Causes of TNDM are heterogeneous but 70% are due to a chromosomal aberration in the region 6q24 which contains the imprinted genes PLAGL1/ZAC and HYMAI. Paternal uniparental disomy 6 (upd(6)pat) or paternal duplications of the imprinted region as well as imprinting defects of the maternal allele all result in an overexpression of the paternally expressed gene PLAGL1. Imprinting defects in 6q24 can occur as isolated events or can affect more than one locus (hypomethylation syndrome). Hypomethylation at multiple loci has so far been observed in patients with TNDM, Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS).The risk of recurrence depends on the underlying cause of TNDM. Chromosomal aberrations in the parents affecting chromosome 6 increase the risk for UPD or duplication of the imprinted locus in 6q24. Nevertheless, UPD and duplication 6q24 are mostly de novo occurrences.

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Danksagung

Die eigenen Arbeiten der Autoren zu TNDM und zu Störungen der Methylierung als Ursache von Fehlbildungs-Retardierungs-Syndromen werden gefördert durch das Bundesministerium für Bildung und Forschung (BMBF) im Rahmen des Netzwerks „Imprintingstörungen“ (FKZ: 01GM0886), im Rahmen des Exzellenzclusters „Inflammation at Interfaces“ und durch die Medizinische Fakultät der Christian-Albrechts-Universität zu Kiel. Die Autoren bedanken sich für anregende Hinweise von K. Temple und D. Mackay (University of Southampton, Großbritannien).

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  1. Institut für Humangenetik, Christian-Albrechts-Universität zu Kiel & Universitätsklinikum Schleswig-Holstein, Campus Kiel, Schwanenweg 24, 24105, Kiel, Deutschland

    S. Bens, R. Siebert & A. Caliebe

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  1. S. Bens
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  3. A. Caliebe
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Correspondence to S. Bens.

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Bens, S., Siebert, R. & Caliebe, A. Transienter neonataler Diabetes und Hypomethylierungssyndrome. medgen 22, 411–418 (2010). https://doi.org/10.1007/s11825-010-0246-8

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