Diagnostik und Behandlung der hereditären hämorrhagischen Teleangiektasie

Zusammenfassung Die hereditare hamorrhagische Teleangiektasie (HHT; Morbus Osler-Weber-Rendu; Morbus Osler) ist mit einer weltweiten Pravalenz von 1:5000-8000 eine seltene Erkrankung der Kapillaren, bei der sich arteriovenose Shunts bilden. Vorwiegend finden sich diese in der Nasenschleimhaut, im Magen-Darm-Trakt, in der Lunge, in der Leber und im zentralen Nervensystem. Leitsymptom der Erkrankung ist die Epistaxis. Die Therapie besteht aus einem mehrstufigen Behandlungskonzept, das neben Nasenpflege und der Lasertherapie in ortlicher Betaubung auch medikamentose Therapien sowie operative Eingriffe in Vollnarkose umfasst. Zusatzlich erfolgt ein Screening zur Erfassung der Beteiligung innerer Organe in enger interdisziplinarer Zusammenarbeit mit den entsprechenden Fachabteilungen. Eine Behandlung der Lasionen im Bereich der (Schleim-) Haut, des Magen-Darm-Trakts und der Leber erfolgt symptomorientiert, wohingegen Gefa ss malformationen der Lunge und des zentralen Nervensystems aufgrund potenzieller und zum Teil bedrohlicher Komplikationen gelegentlich auch ohne subjektive Beschwerden behandlungsbedurftig sind. Abstract Hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu syndrome; Morbus Osler) represents a syndrome affecting capillary vessels, leading to arteriovenous shunting. With an average worldwide prevalence of 1:5.000-8.000 HHT is considered an orphan disease. Arteriovenous shunts involve predominantly the nasal mucosa, the intestine, lung, liver and central nervous system. Epistaxis is the primary and most bothersome complaint of patients with HHT. A multistage therapeutic concept includes nasal ointment, laser therapy under local anesthesia and surgery under general anesthesia, as well as drug therapies. In addition, screening to determine affection of internal organs is carried out. Lesions that require therapy should be treated in an interdisciplinary setting. Treatment of lesions of the skin, oral and gastrointestinal mucosa and liver is carried out in regard to patients' symptoms, whereas vascular malformations of the lung and brain might need treatment without being symptomatic, due to possible life-threatening complications

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements