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SDHB-linked Paraganglioma

Rijken, J.A.

2020

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Rijken, J. A. (2020). SDHB-linked Paraganglioma.

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Addendum

Samenvatting en conclusie

List of publications

Curriculum vitae

Dankwoord

10

10.1

SAMENVATTING EN CONCLUSIE

Samenvatting

,ŽŽĨĚƐƚƵŬϭďĞƐƚĂĂƚƵŝƚĞĞŶŽǀĞƌnjŝĐŚƚǀĂŶĚĞŚƵŝĚŝŐĞŝŶnjŝĐŚƚĞŶŵĞƚďĞƚƌĞŬŬŝŶŐ ƚŽƚĚĞŬůŝŶŝƐĐŚĞŬĞŶŵĞƌŬĞŶ͕ŐĞŶĞƟĐĂ͕ĚŝĂŐŶŽƐƟĞŬĞŶďĞŚĂŶĚĞůŝŶŐƐƐƚƌĂƚĞŐŝĞģŶǀĂŶ ƉĂƟģŶƚĞŶŵĞƚĞĞŶƉĂƌĂŐĂŶŐůŝŽŽŵĞŶĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵ͘ InŚŽŽĨĚƐƚƵŬϮǁŽƌĚĞŶĚĞŬůŝŶŝƐĐŚĞŬĞŶŵĞƌŬĞŶĞŶďĞŚĂŶĚĞůŝŶŐƐƐƚƌĂƚĞŐŝĞģŶǀĂŶ ϭϰϳ ŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŽŵ ƉĂƟģŶƚĞŶͲ ŵĞƚ ŝŶ ƚŽƚĂĂů Ϯϴϵ ƚƵŵŽƌĞŶ ʹ ŐĞģǀĂͲ ůƵĞĞƌĚ͘sĞƌƐĐŚŝůůĞŶĚĞŬůŝŶŝƐĐŚĞŵĂŶŝĨĞƐƚĂƟĞƐnjŝũŶǁĂĂƌŐĞŶŽŵĞŶ͕njŽĂůƐŵƵůƟĨŽĐĂͲ ůŝƚĞŝƚ ;ϱϰйͿ͕ ĞĞŶ ƐLJŶĐŚƌŽŽŶ ƐLJŵƉĂƚŚŝƐĐŚ ƉĂƌĂŐĂŶŐůŝŽŽŵ ;ϭйͿ ŽĨ ĨĞŽĐŚƌŽŵŽĐLJ-ƚŽŽŵ ;ϯйͿ͕ ŚLJƉĞƌƐĞĐƌĞƟĞ ǀĂŶ ĐĂƚĞĐŚŽůĂŵŝŶĞƐ ;ϯϬйͿ ŽĨ ŐĞŵĞƚĂƐƚĂƐĞĞƌĚĞ njŝĞŬƚĞ ;ϮйͿ͘sĂŶĚĞƉĂƟģŶƚĞŶĚŝĞĞĞŶEͲƚĞƐƚŚĞďďĞŶŽŶĚĞƌŐĂĂŶŝƐϲϱйĚƌĂŐĞƌǀĂŶ ĞĞŶŵƵƚĂƟĞŝŶSDHD͕ϭϬйǀĂŶĞĞŶŵƵƚĂƟĞŝŶSDHBĞŶϭйǀĂŶĞĞŶŵƵƚĂƟĞŝŶ SDHAF2͘'ĞĞŶǀĂŶĚĞSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐŚĞĞŌĞĞŶĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵ͕ƐLJŵ-ƉĂƚŚŝƐĐŚƉĂƌĂŐĂŶŐůŝŽŽŵŽĨŐĞŵĞƚĂƐƚĂƐĞĞƌĚĞnjŝĞŬƚĞ͘/ŶĚĞĂĨŐĞůŽƉĞŶϲϬũĂĂƌŝƐŚĞƚ ƉĞƌĐĞŶƚĂŐĞŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŵĞŶĚĂƚŽƉĞƌĂƟĞĨǁĞƌĚǀĞƌǁŝũĚĞƌĚĂĂŶnjŝĞŶůŝũŬ ŐĞĚĂĂůĚ͘^ƚĞĞĚƐǀĂŬĞƌǁĞƌĚŐĞŬŽnjĞŶǀŽŽƌĞĞŶ͚ĂĐƟǀĞƐƵƌǀĞŝůůĂŶĐĞ͛ďĞŚĂŶĚĞůŝŶŐƐ-ƐƚƌĂƚĞŐŝĞ͘DĞĞƌŬĞŶŶŝƐǀĂŶ;/ͿĚĞŐĞŶĞƟƐĐŚĞƉƌĞĚŝƐƉŽƐŝƟĞ͕;//ͿĚĞŐĞĂƐƐŽĐŝĞĞƌĚĞ ŬůŝŶŝƐĐŚĞƌŝƐŝĐŽƉƌŽĮĞůĞŶ;ĨĞŶŽƚLJƉĞͿ͕ĞŶ;///ͿŚĞƚŶĂƚƵƵƌůŝũŬĞďĞůŽŽƉǀĂŶĚĞnjĞƚƵŵŽ-ƌĞŶŚĞĞŌŐĞƌĞƐƵůƚĞĞƌĚŝŶĞĞŶŵĞĞƌĐŽŶƐĞƌǀĂƟĞǀĞĂĂŶƉĂŬǀĂŶƉĂƟģŶƚĞŶŵĞƚĞĞŶ ŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŽŵ͘ In ŚŽŽĨĚƐƚƵŬϯǁŽƌĚƚĞĞŶŶŝĞƵǁĞSDHBͲŵƵƚĂƟĞďĞƐĐŚƌĞǀĞŶĚŝĞƐĂŵĞŶŚĂŶŐƚŵĞƚ ĚĞŽŶƚǁŝŬŬĞůŝŶŐǀĂŶĞĞŶŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŽŵ͘/ŶĚĞnjĞƐƚƵĚŝĞŝƐŚĞƚEǀĂŶ ϭϴůĞĚĞŶǀĂŶĠĠŶĨĂŵŝůŝĞŐĞƚĞƐƚ͘'ĞďůĞŬĞŶŝƐĚĂƚϭϬůĞĚĞŶĚƌĂŐĞƌnjŝũŶǀĂŶĞĞŶĞdžŽŶ ϭͲϯĚĞůĞƟĞŝŶŚĞƚSDHBͲŐĞŶ͘ĠŶĨĂŵŝůŝĞůŝĚŚĂĚĞĞŶ;ƉƌĞƐLJŵƉƚŽŵĂƟƐĐŚͿƉĂƌĂŐĂŶ-ŐůŝŽŽŵ ƚĞƌ ƉůĂĂƚƐĞ ǀĂŶ ĚĞ ĐĂƌŽƟƐďŝĨƵƌĐĂƟĞ͕ ĞĞŶ ŚŽŐĞ ďůŽĞĚĚƌƵŬ ĞŶ ǀĞƌŚŽŽŐĚĞ ĐĂƚĞĐŚŽůĂŵŝŶĞǁĂĂƌĚĞŶ͕ĚŝĞďĞŝĚĞŶŶŽƌŵĂůŝƐĞĞƌĚĞŶŶĂŽƉĞƌĂƟĞǀĞǀĞƌǁŝũĚĞƌŝŶŐ ǀĂŶĚĞƚƵŵŽƌ͘ĞŶŶĞŐĂƟĞǀĞSDHBͲŝŵŵƵŶŽŬůĞƵƌŝŶŐŽƉŚĞƚƚƵŵŽƌǁĞĞĨƐĞůŚĞĞŌ ďĞǀĞƐƟŐĚ ĚĂƚ ĚĞnjĞ ƚƵŵŽƌ ǁŽƌĚƚ ǀĞƌŽŽƌnjĂĂŬƚ ĚŽŽƌ ĚĞ SDHBͲŵƵƚĂƟĞ͘ ĞnjĞ ŶŝĞƚ ĞĞƌĚĞƌďĞƐĐŚƌĞǀĞŶĚĞůĞƟĞǀĂŶĞdžŽŶϭͲϯŝŶŚĞƚSDHBͲŐĞŶŝƐĞĞŶŶŝĞƵǁĞĞƌĨĞůŝũŬĞ ǀĂƌŝĂŶƚ͕ĚŝĞŐĞĂƐƐŽĐŝĞĞƌĚǁŽƌĚƚŵĞƚĚĞŽŶƚǁŝŬŬĞůŝŶŐǀĂŶƉĂƌĂŐĂŶŐůŝŽŵĞŶ͘ In ŚŽŽĨĚƐƚƵŬϰǁŽƌĚƚĞĞŶŐƌŽƚĞĨĂŵŝůŝĞďĞƐĐŚƌĞǀĞŶŵĞƚĞĞŶĞdžŽŶϯĚĞůĞƟĞŝŶŚĞƚ SDHBͲŐĞŶ͘ĞƐǀĂŶĚĞϭϳŐĞŢĚĞŶƟĮĐĞĞƌĚĞŵƵƚĂƟĞĚƌĂŐĞƌƐŚĞďďĞŶĞĞŶƉĂƌĂŐĂŶ-ŐůŝŽŽŵ͘ĞŐĞƐĐŚĂƩĞƉĞŶĞƚƌĂŶƟĞǀĂŶĚĞnjĞŵƵƚĂƟĞŽƉĚĞůĞĞŌŝũĚǀĂŶϰϬ͕ϱϬ͕ϲϬ ĞŶϳϬũĂĂƌŝƐƌĞƐƉĞĐƟĞǀĞůŝũŬϰй͕ϵй͕ϭϱйĞŶϮϭй͘ĞnjĞůĂŐĞƉĞŶĞƚƌĂŶƟĞnjŽƵĞĞŶ ŬůŝŶŝƐĐŚŬĞŶŵĞƌŬǀĂŶĚĞnjĞĞdžŽŶϯĚĞůĞƟĞŬƵŶŶĞŶnjŝũŶ͘ĞŶĂŶĚĞƌĞŵŽŐĞůŝũŬŚĞŝĚŝƐ 170 Addendum

ĚĂƚĚĞnjĞǁŽƌĚƚǀĞƌŽŽƌnjĂĂŬƚĚŽŽƌĞĞŶŐĞĚĞĞůĚĞŐĞŶĞƟƐĐŚĞͲŽĨŽŵŐĞǀŝŶŐƐĨĂĐƚŽƌ ďŝŶŶĞŶĚĞnjĞĨĂŵŝůŝĞ͕ĚŝĞǀĂŶŝŶǀůŽĞĚŝƐŽƉĚĞƉĞŶĞƚƌĂŶƟĞ͘ĞƌĚĞƌĞƐƚƵĚŝĞƐďĞƐĐŚƌŝũ-ǀĞŶ ĞĞŶ ŚŽŐĞƌĞ ƉĞŶĞƚƌĂŶƟĞ ǀĂŶ SDHBͲŵƵƚĂƟĞƐ͕ ǀĞƌŵŽĞĚĞůŝũŬ ƚĞŶ ŐĞǀŽůŐĞ ǀĂŶ ǀĞƌƐĐŚŝůůĞŶĚĞǀŽƌŵĞŶǀĂŶďŝĂƐ͘ĞnjĞĞĞƌĚĞƌĞďĞƌĞŬĞŶŝŶŐĞŶǀĂŶƉĞŶĞƚƌĂŶƟĞnjŝũŶ ǀĂƚďĂĂƌǀŽŽƌŽǀĞƌƐĐŚĂƫŶŐǀĂŶǁĞŐĞ;/ͿĚĞďĞƉĞƌŬƚĞŝŶĐůƵƐŝĞǀĂŶŶŝĞƚͲĂĂŶŐĞĚĂŶĞ ŵƵƚĂƟĞĚƌĂŐĞƌƐĞŶ;//ͿĚĞŝĚĞŶƟĮĐĂƟĞǀĂŶŵƵƚĂƟĞĚƌĂŐĞƌƐǀŝĂŝŶĚĞdžƉĂƟģŶƚĞŶ͘ŝƚ ƌĞƐƵůƚĞĞƌƚŝŶĞĞŶǀĞƌŚŽŽŐĚĞŬĂŶƐŽƉĚĞƐĞůĞĐƟĞǀĂŶĂĂŶŐĞĚĂŶĞŵƵƚĂƟĞĚƌĂŐĞƌƐ ;ĂƐĐĞƌƚĂŝŶŵĞŶƚ ďŝĂƐͿ͘ /Ŷ ĚĞ ŚƵŝĚŝŐĞ ƐƚƵĚŝĞ ŚĞďďĞŶ ǁĞ ĞĞŶ ƌĞůĂƟĞĨ ŐƌŽŽƚ ĂĂŶƚĂů ŶŝĞƚͲĂĂŶŐĞĚĂŶĞ ŵƵƚĂƟĞĚƌĂŐĞƌƐ ŐĞŢŶĐůƵĚĞĞƌĚ ĞŶ ŝƐ ŐĞĐŽƌƌŝŐĞĞƌĚ ǀŽŽƌ ĂƐĐĞƌƚĂŝŶ-ŵĞŶƚ ďŝĂƐ͘ sŽŽƌŐĂĂŶĚĞ ŚĞĞŌ ŐĞůĞŝĚ ƚŽƚ ĞĞŶ ŐĞƌĞĚƵĐĞĞƌĚĞ ƐĐŚĂƫŶŐǀĂŶ SDHB-ŐĞĂƐƐŽĐŝĞĞƌĚĞƉĞŶĞƚƌĂŶƟĞ͕ŚĞƚŐĞĞŶďĞůĂŶŐƌŝũŬŝƐǀŽŽƌĞĞŶĂĚĞƋƵĂƚĞ;ŐĞŶĞƟƐĐŚĞͿ ĐŽƵŶƐĞůŝŶŐǀĂŶSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐ͘ In ŚŽŽĨĚƐƚƵŬϱŬŽŵĞŶĚĞŬůŝŶŝƐĐŚĞŬĞŶŵĞƌŬĞŶǀĂŶSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐŝŶĞĞŶ ůĂŶĚĞůŝũŬĐŽŚŽƌƚĂĂŶĚĞŽƌĚĞ͘/ŶĚĞnjĞƌĞƚƌŽƐƉĞĐƟĞǀĞ͕ďĞƐĐŚƌŝũǀĞŶĚĞƐƚƵĚŝĞnjŝũŶϭϵϰ SDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐŐĞŢŶĐůƵĚĞĞƌĚǀĂŶƵŝƚnjĞǀĞŶŬůŝŶŝƐĐŚͲŐĞŶĞƟƐĐŚĞĐĞŶƚƌĂ͘,Ğƚ ĐŽŚŽƌƚ ďĞƐƚĂĂƚ Ƶŝƚ ϴϯ ;ϰϮ͘ϴйͿ ĂĂŶŐĞĚĂŶĞ ŵƵƚĂƟĞĚƌĂŐĞƌƐ ĞŶ ϭϭϭ ;ϱϳ͘ϮйͿ ŶŝĞƚͲ ĂĂŶŐĞĚĂŶĞŵƵƚĂƟĞĚƌĂŐĞƌƐ͘sŝĞƌĞŶǀŝũŌŝŐŵƵƚĂƟĞĚƌĂŐĞƌƐ;Ϯϳ͘ϴйͿŚĞďďĞŶĠĠŶŽĨ ŵĞĞƌ ŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŵĞŶ͘ ^ůĞĐŚƚƐ ϰ ƉĂƟģŶƚĞŶ ;Ϯ͘ϭйͿ ŚĞďďĞŶ ĞĞŶ ĨĞŽ-ĐŚƌŽŵŽĐLJƚŽŽŵ ĞŶ Ϯϲ ;ϭϯ͘ϰйͿ ĠĠŶ ŽĨ ŵĞĞƌ ƐLJŵƉĂƚŚŝƐĐŚĞ ƉĂƌĂŐĂŶŐůŝŽŵĞŶ͖ ĞĞŶ ĂĂŶnjŝĞŶůŝũŬ ůĂŐĞƌ ƌŝƐŝĐŽ ĚĂŶ ƐƚĂĂƚ ďĞƐĐŚƌĞǀĞŶ ŝŶ ĞĞƌĚĞƌĞ ƐƚƵĚŝĞƐ ŽǀĞƌ SDHBͲŵƵ-ƚĂƟĞĚƌĂŐĞƌƐ͘,ĞƚĂĂŶƚĂůƉĂƟģŶƚĞŶŵĞƚƚĞŶŵŝŶƐƚĞĠĠŶŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŽŵ ŝƐƌĞůĂƟĞĨŚŽŽŐ;Ϯϳ͘ϴйͿŝŶǀĞƌŐĞůŝũŬŝŶŐŵĞƚĂŶĚĞƌĞƐƚƵĚŝĞƐ;ϯͲϯϭйͿ͘KŵĚĂƚŝŶĚĞ ŽŶĚĞƌŚĂǀŝŐĞ ƐƚƵĚŝĞ ĞĞŶ ŐƌŽŽƚ ĂĂŶƚĂů ŶŝĞƚͲĂĂŶŐĞĚĂŶĞ ŵƵƚĂƟĞĚƌĂŐĞƌƐ ŝƐ ŐĞŢŶĐůƵ-ĚĞĞƌĚ͕ ďůŝũŌ ĚĞ ĂƐĐĞƌƚĂŝŶŵĞŶƚ ďŝĂƐ ďĞƉĞƌŬƚ͘ /Ŷ EĞĚĞƌůĂŶĚ ǁŽƌĚƚ ĂĂŶ ĨĂŵŝůŝĞůĞ-den van SDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐ ƐƚƌƵĐƚƵƌĞĞů ŐĞŶĞƟƐĐŚ ŽŶĚĞƌnjŽĞŬ ĂĂŶŐĞďŽĚĞŶ͘ /ŶĚŝĞŶ ĞĞŶ ĨĂŵŝůŝĞůŝĚ ĚƌĂŐĞƌ ďůŝũŬƚ ƚĞ njŝũŶ ǀĂŶ ĚĞ ŵƵƚĂƟĞ ǁŽƌĚƚ Ğƌ ǀŽůŐĞŶƐ ĞĞŶ ǀĂƐƚƉƌŽƚŽĐŽůǀĞƌǀŽůŐŽŶĚĞƌnjŽĞŬĂĂŶŐĞďŽĚĞŶ͘,ŝĞƌĚŽŽƌǁŽƌĚƚĞĞŶƌĞůĂƟĞĨŐƌŽŽƚ ĂĂŶƚĂůĂƐLJŵƉƚŽŵĂƟƐĐŚĞŵƵƚĂƟĞĚƌĂŐĞƌƐͲŵĞƚŽĨnjŽŶĚĞƌŐĞĂƐƐŽĐŝĞĞƌĚĞƚƵŵŽƌĞŶ ʹ ŐĞŢĚĞŶƟĮĐĞĞƌĚ͘ ĞnjĞ ĂĂŶƉĂŬ njŽƌŐƚ ǀŽŽƌ ĞĞŶ ŶĂƵǁŬĞƵƌŝŐĞ ǁĞĞƌŐĂǀĞ ǀĂŶ ŚĞƚ ĨĞŶŽƚLJƉĞ ǀĂŶ SDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐ͘ ^ůĞĐŚƚƐ ϭϱ ƉĂƟģŶƚĞŶ ;ϳ͘ϳйͿ ŚĞďďĞŶ ŐĞŵĞ-ƚĂƐƚĂƐĞĞƌĚĞ njŝĞŬƚĞ ĞŶ ϭϳ ƉĂƟģŶƚĞŶ ;ϴ͘ϴйͿ ĞĞŶ ŶŝĞƚͲƉĂƌĂŐĂŶŐůŝŽŶ ŐĞƌĞůĂƚĞĞƌĚĞ ƚƵŵŽƌ͕ ǁĂĂƌŽŶĚĞƌ ϱ ŶŝĞƌĐĞůĐĂƌĐŝŶŽŵĞŶ ĞŶ Ϯ ŐĂƐƚƌŽͲŝŶƚĞƐƟŶĂůĞ ƐƚƌŽŵĂůĞ ƚƵŵŽ-ƌĞŶ͘ ^ƚĂƟƐƟƐĐŚĞ ĂŶĂůLJƐĞƐ ƚŽŶĞŶ ŐĞĞŶ ƐŝŐŶŝĮĐĂŶƚĞ ǀĞƌƐĐŚŝůůĞŶ ƚƵƐƐĞŶ ĚĞ ĚƌĂŐĞƌƐ ǀĂŶ ĚĞ ƚǁĞĞ ŵĞĞƐƚ ǀŽŽƌŬŽŵĞŶĚĞ ŵƵƚĂƟĞƐ ŝŶSDHB ;ĞdžŽŶ ϯ ĚĞůĞƟĞ ĞŶ Đ͘ϰϮϯ н ϭ'х Ϳ ďĞƚƌĞīĞŶĚĞ ŚĞƚ ĂĂŶƚĂů ĞŶ ĚĞ ůŽĐĂƟĞ ǀĂŶ ŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŵĞŶ͕ ƐLJŵƉĂƚŚŝƐĐŚĞ ƉĂƌĂŐĂŶŐůŝŽŵĞŶ ŽĨ ĨĞŽĐŚƌŽŵŽĐLJƚŽŵĞŶ͘ ƌ njŝũŶ ŽŽŬ ŐĞĞŶ ƐŝŐŶŝĮ-ĐĂŶƚĞǀĞƌƐĐŚŝůůĞŶnjŝĐŚƚďĂĂƌŝŶŚĞƚǀŽŽƌŬŽŵĞŶǀĂŶŐĞŵĞƚĂƐƚĂƐĞĞƌĚĞnjŝĞŬƚĞŽĨĚĞ ĂĂŶǁĞnjŝŐŚĞŝĚ ǀĂŶ ŶŝĞƚͲƉĂƌĂŐĂŶŐůŝŽŶ ŐĞƌĞůĂƚĞĞƌĚĞ ƚƵŵŽƌĞŶ ǀŽŽƌ ĚĞnjĞ ŵƵƚĂƟĞƐ͘ /ŶĚŝƚŚŽŽĨĚƐƚƵŬǁŽƌĚƚŚĞƚďĞůĂŶŐŽŶĚĞƌƐƚƌĞĞƉƚǀĂŶŚĞƚŝŶĐůƵĚĞƌĞŶǀĂŶŶŝĞƚͲĂĂŶ-Addendum 171

ŐĞĚĂŶĞŵƵƚĂƟĞĚƌĂŐĞƌƐŝŶƐƚƵĚŝĞƐǁĂĂƌŚĞƚĨĞŶŽƚLJƉĞǀĂŶĞĞŶƉĂƚŚŽŐĞŶĞŵƵƚĂƟĞ ǁŽƌĚƚ ďĞŽŽƌĚĞĞůĚ͘ Ğ ŝŶĐůƵƐŝĞ ǀĂŶ ĂƐLJŵƉƚŽŵĂƟƐĐŚĞ ŵƵƚĂƟĞĚƌĂŐĞƌƐ ŐĞĞŌ ĞĞŶ ďĞƚĞƌ njŝĐŚƚ ŽƉ ŚĞƚ ǁĂƌĞ ƐƉĞĐƚƌƵŵ ǀĂŶ ĚĞ njŝĞŬƚĞ͘ Ğ ďĞƐĐŚƌĞǀĞŶ ƌĞƐƵůƚĂƚĞŶ njŝũŶ ǀĂŶďĞůĂŶŐǀŽŽƌĚĞŐĞŶĞƟƐĐŚĞĐŽƵŶƐĞůŝŶŐĞŶďĞŚĂŶĚĞůŝŶŐǀĂŶĨĂŵŝůŝĞƐ͕ĚŝĞnjŝũŶ aangedaan door SDHB-geassocieerde ziekte.

,ŽŽĨĚƐƚƵŬ ϲ ƌŝĐŚƚ njŝĐŚ ŽƉ ĚĞ ŬůŝŶŝƐĐŚĞ ŬĞŶŵĞƌŬĞŶ ĞŶ ďĞŚĂŶĚĞůŝŶŐƐƐƚƌĂƚĞŐŝĞģŶ ǀĂŶ ϱϰ ĚƌĂŐĞƌƐ ǀĂŶ ĞĞŶ ƉĂƚŚŽŐĞŶĞ ŵƵƚĂƟĞ ŝŶ SDHB ŵĞƚ ĞĞŶ ŚŽŽĨĚͲŚĂůƐƉĂƌĂ-ŐĂŶŐůŝŽŽŵ ;ŐĞƐĞůĞĐƚĞĞƌĚ Ƶŝƚ ŚĞƚ ůĂŶĚĞůŝũŬĞ ĐŽŚŽƌƚ ďĞƐĐŚƌĞǀĞŶ ŝŶ ŚŽŽĨĚƐƚƵŬ ϱͿ͘ ^ůĞĐŚƚƐ ϴ ƉĂƟģŶƚĞŶ ;ϭϱйͿ ŚĞďďĞŶ ŵĞĞƌĚĞƌĞ ƉĂƌĂŐĂŶŐůŝŽŵĞŶ͕ ŝŶ ƚĞŐĞŶƐƚĞů-ůŝŶŐ ƚŽƚ SDHD ŵƵƚĂƟĞĚƌĂŐĞƌƐ͕ ĚŝĞ ǀĂĂŬ ŵĞĞƌĚĞƌĞ ƉĂƌĂŐĂŶŐůŝŽŵĞŶ ŚĞďďĞŶ ;ϲϬͲ ϳϵйͿ͘ ĠŶ ƉĂƟģŶƚ ;ϮйͿ ŚĞĞŌ ƚĞǀĞŶƐ ĞĞŶ ĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵ ĞŶ ϯ ƉĂƟģŶƚĞŶ ;ϲйͿ ŚĞďďĞŶ ŐĞŵĞƚĂƐƚĂƐĞĞƌĚĞ njŝĞŬƚĞ͘ ĞǀĞŶĞŶƚǁŝŶƟŐ ƉĂƟģŶƚĞŶ ;ϱϬйͿ njŝũŶ ŐĞ-ŽƉĞƌĞĞƌĚ ǀĂŶǁĞŐĞ ŚĞƚ ŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŽŵ ĞŶ ϭϱ ƉĂƟģŶƚĞŶ ;ϮϴйͿ njŝũŶ ƌĂĚŝŽƚŚĞƌĂƉĞƵƟƐĐŚ ďĞŚĂŶĚĞůĚ͘ ,ŽĞǁĞů ĚĞ ůĞĞŌŝũĚ ǁĂĂƌŽƉ ĚĞ ĚŝĂŐŶŽƐĞ ŚŽŽĨĚͲ ŚĂůƐƉĂƌĂŐĂŶŐůŝŽŽŵ ŝŶ Ěŝƚ ĐŽŚŽƌƚ ŐĞƐƚĞůĚ ǁĞƌĚ ƌĞůĂƟĞĨ ŚŽŽŐ ŝƐ ;ϰϱ͘ϵ ũĂĂƌͿ͕ ŚĂĚ ĚĞ ũŽŶŐƐƚĞ ƉĂƟģŶƚ ŽƉ ϭϭͲũĂƌŝŐĞ ůĞĞŌŝũĚ ĞĞŶ ŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŽŵ ĞŶ ĞĞŶ ϭϴͲũĂƌŝŐĞ ƉĂƟģŶƚ ďůĞĞŬ ƌĞĞĚƐ ŐĞŵĞƚĂƐƚĂƐĞĞƌĚĞ njŝĞŬƚĞ ƚĞ ŚĞďďĞŶ͘ KǀĞƌĞĞŶŬŽŵ-ƐƟŐ ĚĞnjĞ ŽŶĚĞƌnjŽĞŬƐƌĞƐƵůƚĂƚĞŶ ƐƚĂƌƚ ƐĐƌĞĞŶŝŶŐ ŽƉ ƉĂƌĂŐĂŶŐůŝŽŵĞŶ ŝŶ SDHB-ŐĞĂƐƐŽĐŝĞĞƌĚĞ ĨĂŵŝůŝĞƐ ƚĞŐĞŶǁŽŽƌĚŝŐ ŽƉ ĚĞ ůĞĞŌŝũĚ ǀĂŶ ϭϬ ũĂĂƌ ŝŶ EĞĚĞƌůĂŶĚ͘ /ŶĚŝĞŶ ĞĞŶ ƉĂƟģŶƚ ŵĞƚ ĞĞŶ ŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŽŵ ĚƌĂŐĞƌ ŝƐ ǀĂŶ ĞĞŶ SHDB- ŵƵƚĂƟĞŵŽĞƚĚĞďĞŚĂŶĚĞůĞŶĚĂƌƚƐŽƉĚĞŚŽŽŐƚĞnjŝũŶǀĂŶĚĞǀĞƌƐĐŚŝůůĞŶĚĞŵĂŶŝ-ĨĞƐƚĂƟĞƐĚŝĞŚĞƚSDHBͲŐĞĂƐƐŽĐŝĞĞƌĚĞƚƵŵŽƌƐLJŶĚƌŽŽŵŵĞƚnjŝĐŚŵĞĞŬĂŶďƌĞŶŐĞŶ͗ ŚLJƉĞƌƐĞĐƌĞƟĞǀĂŶĐĂƚĞĐŚŽůĂŵŝŶĞƐ͕ĂĂŶǁĞnjŝŐŚĞŝĚǀĂŶĞĞŶƐLJŵƉĂƚŚŝƐĐŚƉĂƌĂŐĂŶ-ŐůŝŽŽŵŽĨĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵĞŶĚĞĂƐƐŽĐŝĂƟĞŵĞƚŶŝĞƚͲƉĂƌĂŐĂŶŐůŝŽŶŐĞƌĞůĂƚĞĞƌĚĞ ƚƵŵŽƌĞŶ͘ĚĞƋƵĂƚĞƐƵƌǀĞŝůůĂŶĐĞǀĂŶSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐǁŽƌĚƚƐƚĞƌŬĂĂŶďĞǀŽ-ůĞŶĞŶŽŵǀĂƚƐĐƌĞĞŶŝŶŐŽƉĐĂƚĞĐŚŽůĂŵŝŶĞƐŽĨ ŚƵŶŵĞƚĂďŽůŝĞƚĞŶ͕ŝŶĐŽŵďŝŶĂƟĞ ŵĞƚ ƉĞƌŝŽĚŝĞŬ ƌĂĚŝŽůŽŐŝƐĐŚ ŽŶĚĞƌnjŽĞŬ ǀĂŶ ĚĞ ďƵŝŬ͕ ďĞŬŬĞŶƌĞŐŝŽ͕ ƚŚŽƌĂdž ĞŶ ŚĞƚ ŚŽŽĨĚͲŚĂůƐŐĞďŝĞĚ͘ In ŚŽŽĨĚƐƚƵŬϳǁŽƌĚƚĚĞƉĞŶĞƚƌĂŶƟĞďĞƌĞŬĞŶĚŝŶŚĞƚůĂŶĚĞůŝũŬĞĐŽŚŽƌƚSDHBͲŵƵ-ƚĂƟĞĚƌĂŐĞƌƐ;njŝĞŚŽŽĨĚƐƚƵŬϱͿŵŝĚĚĞůƐĞĞŶŶŝĞƵǁĞŵĂdžŝŵƵŵͲůŝŬĞůŝŚŽŽĚͲƐĐŚĂƩĞƌ͘ ĞnjĞƐĐŚĂƩĞƌŚŽƵĚƚƌĞŬĞŶŝŶŐŵĞƚŽŶƚďƌĞŬĞŶĚĞŐĞŐĞǀĞŶƐŽǀĞƌƐƚĂŵŵŐƌŽŽƩĞ ĞŶʹƐƚƌƵĐƚƵƵƌĞŶĂƐĐĞƌƚĂŝŶŵĞŶƚďŝĂƐ͘/ŶƚŽƚĂĂůnjŝũŶϭϵϱSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐŐĞ- ŝŶĐůƵĚĞĞƌĚ͕ĚŝĞϮϳǀĞƌƐĐŚŝůůĞŶĚĞSDHBͲŵƵƚĂƟĞƐĚƌĂŐĞŶ͘ĞƚǁĞĞŵĞĞƐƚǀŽŽƌŬŽ-mende SDHBͲŵƵƚĂƟĞƐ njŝũŶ ďĞŬĞŶĚĞ EĞĚĞƌůĂŶĚƐĞ ĨŽƵŶĚĞƌŵƵƚĂƟĞƐ͗ ĞĞŶ ĞdžŽŶ ϯ ĚĞůĞƟĞ;ϯϭйǀĂŶĚĞŵƵƚĂƟĞĚƌĂŐĞƌƐͿĞŶĞĞŶĐ͘ϰϮϯнϭ'хŵƵƚĂƟĞ;ϮϰйǀĂŶĚĞ ŵƵƚĂƟĞĚƌĂŐĞƌƐͿ͘ŝũϭϭϮĚƌĂŐĞƌƐ;ϱϳйͿnjŝũŶĞƌŐĞĞŶĂĂŶǁŝũnjŝŶŐĞŶǀŽŽƌĚĞĂĂŶǁĞ-njŝŐŚĞŝĚǀĂŶĞĞŶƉĂƌĂŐĂŶŐůŝŽŽŵŽĨĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵďŝũůŝĐŚĂŵĞůŝũŬ͕ƌĂĚŝŽůŽŐŝƐĐŚ ŽĨ ďŝŽĐŚĞŵŝƐĐŚ ŽŶĚĞƌnjŽĞŬ͘ sŝĞƌĞŶǀŝũŌŝŐ ƉĂƟģŶƚĞŶ ŚĞďďĞŶ ĞĞŶ ŚŽŽĨĚͲŚĂůƐƉĂƌĂ-172 Addendum

ŐĂŶŐůŝŽŽŵ;ϮϴйͿ͕ϰƉĂƟģŶƚĞŶĞĞŶĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵ;ϮйͿĞŶϮϲƉĂƟģŶƚĞŶĞĞŶ ƐLJŵƉĂƚŚŝƐĐŚƉĂƌĂŐĂŶŐůŝŽŽŵ;ϭϯйͿ͘DĞƚďĞŚƵůƉǀĂŶĚĞŶŝĞƵǁĞƐĐŚĂƩĞƌǁŽƌĚƚĚĞ ƉĞŶĞƚƌĂŶƟĞǀĂŶSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐŐĞƐĐŚĂƚŽƉϮϭйŽƉĚĞůĞĞŌŝũĚǀĂŶϱϬũĂĂƌ ĞŶϰϮйŽƉĚĞůĞĞŌŝũĚǀĂŶϳϬũĂĂƌ͘ĞnjĞƐĐŚĂƫŶŐůŝŐƚůĂŐĞƌĚĂŶĞĞƌĚĞƌŐĞƌĂƉƉŽƌ-ƚĞĞƌĚĞƉĞŶĞƚƌĂŶƟĞƐĐŚĂƫŶŐĞŶǀĂŶSDHBͲŐĞƌĞůĂƚĞĞƌĚĞĐŽŚŽƌƚĞŶĞŶďĞǀĞƐƟŐƚĚĞ ƐĐŚĂƫŶŐǀĂŶƉĞŶĞƚƌĂŶƟĞǀĂŶSDHBŝŶŚŽŽĨĚƐƚƵŬϰ͘^ŽŽƌƚŐĞůŝũŬĞnjŝĞŬƚĞƌŝƐŝĐŽ͛ƐǁŽƌ-ĚĞŶŐĞǀŽŶĚĞŶďŝũǀĞƌƐĐŚŝůůĞŶĚĞSDHBͲŵƵƚĂƟĞƐĞŶǀŽŽƌŵĂŶŶĞůŝũŬĞĞŶǀƌŽƵǁĞůŝũŬĞ SDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐ͘ ĞŵŽƌƚĂůŝƚĞŝƚǀĂŶĞĞŶůĂŶĚĞůŝũŬĐŽŚŽƌƚSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐĞŶĚŝĞǀĂŶĞĞŶŐƌŽŽƚ cohort SDHDͲŵƵƚĂƟĞĚƌĂŐĞƌƐǁŽƌĚĞŶŐĞƐĐŚĂƚŝŶŚŽŽĨĚƐƚƵŬϴĞŶǀĞƌŐĞůĞŬĞŶŵĞƚ ĚĞŵŽƌƚĂůŝƚĞŝƚǀĂŶĞĞŶŐĞŵĂƚĐŚƚĐŽŚŽƌƚǀĂŶĚĞĚŽŽƌƐŶĞĞEĞĚĞƌůĂŶĚƐĞďĞǀŽůŬŝŶŐ͘ /ŶƚŽƚĂĂůnjŝũŶϭϵϮSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐĞŶϮϯϮSDHDͲŵƵƚĂƟĞĚƌĂŐĞƌƐŐĞŢŶĐůƵĚĞĞƌĚ ŝŶĚĞnjĞƐƚƵĚŝĞ͘ĞƐƚĂŶĚĂĂƌĚŵŽƌƚĂůŝƚĞŝƚƐƌĂƟŽ;^DZͿǀĂŶSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐŝƐ ϭ͘ϴϵ͕ŽƉůŽƉĞŶĚƚŽƚϮ͘ϴϴǀĂŶŵƵƚĂƟĞĚƌĂŐĞƌƐŵĞƚĞĞŶƉĂƌĂŐĂŶŐůŝŽŽŵŽĨĨĞŽĐŚƌŽ- ŵŽĐLJƚŽŽŵ͘Ğ^DZǀĂŶSDHDͲŵƵƚĂƟĞĚƌĂŐĞƌƐŝƐϬ͘ϵϯĞŶǀĂŶĂĂŶŐĞĚĂŶĞŵƵƚĂƟĞ-ĚƌĂŐĞƌƐϭ͘Ϭϲ͘sĞƌŐĞůĞŬĞŶŵĞƚĚĞĚŽŽƌƐŶĞĞďĞǀŽůŬŝŶŐůŝũŬƚĚĞŵŽƌƚĂůŝƚĞŝƚǀĞƌŚŽŽŐĚ te zijn van SDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐ͕ŵĞƚŶĂŵĞǀĂŶĚŝĞŐĞŶĞŶŵĞƚĞĞŶƉĂƌĂŐĂŶŐůŝŽŽŵ ŽĨ ĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵ͘ sĂŶ SDHDͲŵƵƚĂƟĞĚƌĂŐĞƌƐ ŝƐ ĚĞ ŵŽƌƚĂůŝƚĞŝƚ ǀĞƌŐĞůŝũŬďĂĂƌ ŵĞƚĚŝĞǀĂŶĚĞĚŽŽƌƐŶĞĞEĞĚĞƌůĂŶĚƐĞďĞǀŽůŬŝŶŐ͕njĞůĨƐĂůƐĚĞŵƵƚĂƟĞĚƌĂŐĞƌĞĞŶ ƉĂƌĂŐĂŶŐůŝŽŽŵŽĨĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵŚĞĞŌ͘ŝƚƌĞƐƵůƚĂĂƚŝƐĞĞŶƐĂŝůůĂŶƚǀŽŽƌďĞĞůĚ ǀĂŶŚĞƚǀĞƌƐĐŚŝůŝŶŬůŝŶŝƐĐŚƌŝƐŝĐŽĚĂƚǁŽƌĚƚǀĞƌŽŽƌnjĂĂŬƚĚŽŽƌǀĞƌƐĐŚŝůůĞŶĚĞSDHx-ŐĞŶĞŶ͘,ŝĞƌĚŽŽƌǁŽƌĚƚŚĞƚďĞůĂŶŐǀĂŶEͲŽŶĚĞƌnjŽĞŬǀŽŽƌĂůůĞƉĂƟģŶƚĞŶŵĞƚ ĞĞŶ ƉĂƌĂŐĂŶŐůŝŽŽŵ ŽĨ ĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵ ŽŶĚĞƌƐĐŚƌĞǀĞŶ ĞŶ ĚĞnjĞ ďĞǀŝŶĚŝŶŐĞŶ ŬƵŶŶĞŶĞĞŶŐĞŶͲƐƉĞĐŝĮĞŬĞďĞŚĂŶĚĞůŝŶŐƐƐƚƌĂƚĞŐŝĞƌĞĐŚƚǀĂĂƌĚŝŐĞŶ͘

Conclusie

ĞnjŽƌŐǀŽŽƌƉĂƟģŶƚĞŶŵĞƚĞĞŶƉĂƌĂŐĂŶŐůŝŽŽŵŽĨĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵŚĞĞŌƐŝŶĚƐ ŚĞƚũĂĂƌϮϬϬϬĞĞŶŐƌŽƚĞŽŶƚǁŝŬŬĞůŝŶŐĚŽŽƌŐĞŵĂĂŬƚ͘dĞŐĞŶǁŽŽƌĚŝŐŝƐĞĞŶŐƌŽĞŝĞŶĚ ĂĂŶƚĂůŐĞŶŵƵƚĂƟĞƐŐĞĂƐƐŽĐŝĞĞƌĚŵĞƚĚĞŽŶƚǁŝŬŬĞůŝŶŐǀĂŶĚĞnjĞƚƵŵŽƌĞŶĞŶĚĞnjĞ ŐĞŶĞƟƐĐŚĞŚĞƚĞƌŽŐĞŶŝƚĞŝƚŝƐŽŶŐĞģǀĞŶĂĂƌĚĚŽŽƌĞŶŝŐĂŶĚĞƌŵĞŶƐĞůŝũŬŶĞŽƉůĂƐŵĂ͘ DƵƚĂƟĞƐ ŝŶ ǀĞƌƐĐŚŝůůĞŶĚĞ ŐĞŶĞŶ ǀĞƌŽŽƌnjĂŬĞŶ ŝĚĞŶƟĞŬĞ ƉĂƌĂŐĂŶŐůŝŽŵĞŶ͕ ĞĐŚƚĞƌ ĚĞnjĞďƌĞŶŐĞŶĞĞŶǀĞƌƐĐŚŝůůĞŶĚŬůŝŶŝƐĐŚĞƌŝƐŝĐŽ;ĨĞŶŽƚLJƉĞͿŵĞƚnjŝĐŚŵĞĞ͘DĞĞƌŬĞŶ-ŶŝƐǀĂŶĚĞŐĞŶŽƚLJƉĞͲĨĞŶŽƚLJƉĞͲƌĞůĂƟĞǀĞƌďĞƚĞƌƚĚĞŶĂƵǁŬĞƵƌŝŐŚĞŝĚǀĂŶŬůŝŶŝƐĐŚĞ ǀŽŽƌƐƉĞůůŝŶŐĞŶ͕ ǀĞƌŐĞŵĂŬŬĞůŝũŬƚ ŚĞƚ ŵĂŬĞŶ ǀĂŶ ŽƉƟŵĂůĞ ƐƵƌǀĞŝůůĂŶĐĞ ƉƌŽŐƌĂŵ-ŵĂ͛ƐǀŽŽƌĂƐLJŵƉƚŽŵĂƟƐĐŚĞŵƵƚĂƟĞĚƌĂŐĞƌƐĞŶŝƐďĞŚƵůƉnjĂĂŵďŝũŚĞƚŵĂŬĞŶǀĂŶ ŽƉŵĂĂƚŐĞŵĂĂŬƚĞŬůŝŶŝƐĐŚĞďĞƐůŝƐƐŝŶŐĞŶ͘,ĞƚŽŶĚĞƌŚĂǀŝŐĞƉƌŽĞĨƐĐŚƌŝŌďĞƐĐŚƌŝũŌ ĚĞŬůŝŶŝƐĐŚĞŬĞŶŵĞƌŬĞŶǀĂŶSDHB-geassocieerde ziekte in twee SDHB-geassoci-ĞĞƌĚĞĨĂŵŝůŝĞƐĞŶŝŶĞĞŶůĂŶĚĞůŝũŬEĞĚĞƌůĂŶĚƐĐŽŚŽƌƚǀĂŶSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐ͘

Addendum

/ŶŚĞƚŽŶĚĞƌnjŽĞŬǀĂŶĞĞŶĨĂŵŝůŝĞǀĂŶǀŝĞƌŐĞŶĞƌĂƟĞƐŝƐĞĞŶŶŝĞƵǁĞSDHBͲŵƵƚĂƟĞ ;ĞĞŶ ĞdžŽŶ ϭͲϯ ĚĞůĞƟĞ ŝŶ ŚĞƚ SDHBͲŐĞŶͿ ŐĞĂƐƐŽĐŝĞĞƌĚ ŵĞƚ ĚĞ ŽŶƚǁŝŬŬĞůŝŶŐ ǀĂŶ ĞĞŶŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŽŵ͘/ŶĞĞŶĂŶĚĞƌĞ͕ŐƌŽƚĞĨĂŵŝůŝĞŵĞƚĚƌĂŐĞƌƐǀĂŶĞĞŶ ďĞŬĞŶĚĞ EĞĚĞƌůĂŶĚƐĞ ĨŽƵŶĚĞƌŵƵƚĂƟĞ ;ĞĞŶ ĞdžŽŶ ϯ ĚĞůĞƟĞ ŝŶ ŚĞƚ SDHBͲŐĞŶͿ ŝƐ ĚĞƉĞŶĞƚƌĂŶƟĞďĞƌĞŬĞŶĚ͘KƉĚĞůĞĞŌŝũĚǀĂŶƌĞƐƉĞĐƟĞǀĞůŝũŬϰϬ͕ϱϬ͕ϲϬĞŶϳϬũĂĂƌ ŝƐĚĞƉĞŶĞƚƌĂŶƟĞϰй͕ϵй͕ϭϱйĞŶϮϭйǀĂŶĚĞnjĞƐƉĞĐŝĮĞŬĞŵƵƚĂƟĞ͘ĞnjĞƐĐŚĂƚ-ƟŶŐ ůŝŐƚ ĂĂŶnjŝĞŶůŝũŬ ůĂŐĞƌ ĚĂŶ ĞĞƌĚĞƌĞ ƐĐŚĂƫŶŐĞŶ ǀĂŶ SDHB-geassocieerde pe-ŶĞƚƌĂŶƟĞ͘ĞďŝũŐĞƐƚĞůĚĞƐĐŚĂƫŶŐǀĂŶƉĞŶĞƚƌĂŶƟĞŝƐŚĞƚŐĞǀŽůŐǀĂŶĚĞŝŶĐůƵƐŝĞ ǀĂŶ ĞĞŶ ƌĞůĂƟĞĨ ŐƌŽŽƚ ĂĂŶƚĂů ŶŝĞƚͲĂĂŶŐĞĚĂŶĞ ŵƵƚĂƟĞĚƌĂŐĞƌƐ ŝŶ ĚĞ ďĞƌĞŬĞŶŝŶŐ͘ /ŶĞĞŶůĂŶĚĞůŝũŬĞƐƚƵĚŝĞǁŽƌĚƚŐĞƐƚĞůĚĚĂƚSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐĞĞŶŐĞŵŝĚĚĞůĚƌŝ-ƐŝĐŽŚĞďďĞŶŽƉĚĞŽŶƚǁŝŬŬĞůŝŶŐǀĂŶĞĞŶŚŽŽĨĚͲŚĂůƐƉĂƌĂŐĂŶŐůŝŽŽŵ;ϮϴйͿ͕ĞĞŶůĂĂŐ ƌŝƐŝĐŽŽƉĚĞŽŶƚǁŝŬŬĞůŝŶŐǀĂŶĞĞŶĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵ;ϮйͿ͕ĞĞŶŐĞŵŝĚĚĞůĚƌŝƐŝĐŽ ŽƉĚĞŽŶƚǁŝŬŬĞůŝŶŐǀĂŶĞĞŶƐLJŵƉĂƚŚŝƐĐŚĞƉĂƌĂŐĂŶŐůŝŽŽŵ;ϭϯйͿĞŶĞĞŶƌĞůĂƟĞĨ ůĂĂŐƌŝƐŝĐŽŽƉŚĞƚŽŶƚǁŝŬŬĞůĞŶǀĂŶŐĞŵĞƚĂƐƚĂƐĞĞƌĚĞnjŝĞŬƚĞ;ϴйͿ͘ŽŽƌĞĞŶŶŝĞƵǁĞ ŵĂdžŝŵƵŵͲůŝŬĞůŝŚŽŽĚͲƐĐŚĂƩĞƌ ƚĞ ŐĞďƌƵŝŬĞŶ ǀŽŽƌ ĚĞ ďĞƌĞŬĞŶŝŶŐ ǀĂŶ ƉĞŶĞƚƌĂŶƟĞ ǁŽƌĚƚĚĞƉĞŶĞƚƌĂŶƟĞǀĂŶSDHBͲŵƵƚĂƟĞƐŐĞƐĐŚĂƚŽƉϮϭйŽƉϱϬͲũĂƌŝŐĞůĞĞŌŝũĚĞŶ ϰϮйŽƉϳϬͲũĂƌŝŐĞůĞĞŌŝũĚ͕ŚĞƚŐĞĞŶďĞǀĞƐƟŐƚĚĂƚĚĞSDHB-geassocieerde penetran-ƟĞ ůĂŐĞƌ ůŝŐƚ ĚĂŶ ĞĞƌĚĞƌ ŝƐ ďĞƐĐŚƌĞǀĞŶ͘ ^ŽŽƌƚŐĞůŝũŬĞ njŝĞŬƚĞƌŝƐŝĐŽ͛Ɛ njŝũŶ ŐĞǀŽŶĚĞŶ ǀŽŽƌǀĞƌƐĐŚŝůůĞŶĚĞƚLJƉĞŶSDHBͲŵƵƚĂƟĞƐĞǀĞŶĂůƐǀŽŽƌŵĂŶŶĞůŝũŬĞŽĨǀƌŽƵǁĞůŝũŬĞ SDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐ͘ sĞƌŐĞůĞŬĞŶŵĞƚĞĞŶŐĞŵĂƚĐŚƚĐŽŚŽƌƚǀĂŶĚĞĚŽŽƌƐŶĞĞďĞǀŽůŬŝŶŐŝƐĚĞŵŽƌƚĂůŝƚĞŝƚ van SDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐǀĞƌŚŽŽŐĚ͕ŵĂĂƌĚŝƚŝƐŶŝĞƚŚĞƚŐĞǀĂůďŝũSDHDͲŵƵƚĂƟĞ-ĚƌĂŐĞƌƐ͘ƌƐĐŚƵŝůƚĞĞŶŝŶƚĞƌĞƐƐĂŶƚĞƉĂƌĂĚŽdžĂĐŚƚĞƌĚŝƚŽŶĚĞƌnjŽĞŬƐƌĞƐƵůƚĂĂƚ͕ĚŝĞ ŚĞƚǀĞƌƐĐŚŝůŝŶŬůŝŶŝƐĐŚƌŝƐŝĐŽƚƵƐƐĞŶĚƌĂŐĞƌƐǀĂŶƉĂƚŚŽŐĞŶĞSDHB- en SDHDͲŵƵ-ƚĂƟĞƐŝůůƵƐƚƌĞĞƌƚ͘dĞƌǁŝũůSDHDͲŵƵƚĂƟĞƐĚƌĂŐĞƌƐŝŶĚĞŵĞĞƐƚĞŐĞǀĂůůĞŶ;ϴϴͲϭϬϬйͿ ĠĠŶŽĨŵĞĞƌ;ŚŽŽĨĚͲŚĂůƐͿƉĂƌĂŐĂŶŐůŝŽŵĞŶŽŶƚǁŝŬŬĞůĞŶ͕ŶĞĞŵƚĚĞŵŽƌƚĂůŝƚĞŝƚǀĂŶ ĚĞŐƌŽĞƉĂůƐŐĞŚĞĞůŶŝĞƚƚŽĞ͘ĂĂƌĞŶƚĞŐĞŶnjĂůƐůĞĐŚƚƐĞĞŶŵŝŶĚĞƌŚĞŝĚǀĂŶSDHB-ŵƵƚĂƟĞĚƌĂŐĞƌƐ ĞĞŶ ƉĂƌĂŐĂŶŐůŝŽŽŵ ŽĨ ĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵ ŽŶƚǁŝŬŬĞůĞŶ ;ϰϯйͿ͕ ŵĂĂƌ ŝƐ ĚĞ ŵŽƌƚĂůŝƚĞŝƚ ǀĞƌŚŽŽŐĚͲ ĞĞŶ ĞīĞĐƚ ĚĂƚ ƚŽĞŐĞƐĐŚƌĞǀĞŶ ůŝũŬƚ ƚĞ ŬƵŶŶĞŶ ǁŽƌĚĞŶĂĂŶĚĞŬůŝŶŝƐĐŚĂĂŶŐĞĚĂŶĞSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐ͘ ^ĂŵĞŶǀĂƩĞŶĚǀĞƌŐƌŽŽƚĚŝƚƉƌŽĞĨƐĐŚƌŝŌŽŶnjĞŬĞŶŶŝƐǀĂŶSDHBͲŵƵƚĂƟĞƐĞŶŚĞƚŐĞ-ĂƐƐŽĐŝĞĞƌĚĞŬůŝŶŝƐĐŚĞďĞĞůĚŝŶEĞĚĞƌůĂŶĚ͘KŽŬǁŽƌĚĞŶŶŝĞƵǁĞŝŶnjŝĐŚƚĞŶŽŶƚŚƵůĚ͕ ŵĞƚŶĂŵĞŝŶĚĞƉĞŶĞƚƌĂŶƟĞĞŶŵŽƌƚĂůŝƚĞŝƚǀĂŶSDHB-geassocieerde ziekte.

Toekomstperspectieven

,ĞƚŝƐŝŶƚƌŝŐĞƌĞŶĚĚĂƚŚĞƚŽŽƌnjĂŬĞůŝũŬĞŐĞŶďĞƉĂůĞŶĚŝƐǀŽŽƌĞĞŶǀĂƌŝĂƟĞŝŶĨĞŶŽ-ƚLJƉĞ ĞŶ ƉƌŽŐŶŽƐĞ ǀĂŶ ƉĂƟģŶƚĞŶ ŵĞƚ ĞĞŶ ƉĂƌĂŐĂŶŐůŝŽŽŵ ŽĨ ĨĞŽĐŚƌŽŵŽĐLJƚŽŽŵ͕ 174 Addendum

ŽŶĚĂŶŬƐ ŚĞƚ ĨĞŝƚ ĚĂƚ ŵƵƚĂƟĞƐ ŝŶ ǀĞƌƐĐŚŝůůĞŶĚĞ SDHͲŐĞŶĞŶ ĞĞŶ ƉĂƌĂŐĂŶŐůŝŽŽŵ-ƐLJŶĚƌŽŽŵ ŬƵŶŶĞŶ ǀĞƌŽŽƌnjĂŬĞŶ ĚŽŽƌ ĚĞĨĞĐƚĞŶ ŝŶ ŚĞƚnjĞůĨĚĞ ĞŝǁŝƚĐŽŵƉůĞdž ;SDHͿ͘ ŽǀĞŶĚŝĞŶůŝũŬƚĞƌďĞǁŝũƐƚĞnjŝũŶĚĂƚĚĞnjĞĚŝǀĞƌŐĞŶƟĞŝŶĨĞŶŽƚLJƉĞŶŝĞƚĂůůĞĞŶĂĬĂŶ-ŬĞůŝũŬŝƐǀĂŶŚĞƚŐĞŶ͕ŵĂĂƌŽŽŬǀĂŶŚĞƚƚLJƉĞŵƵƚĂƟĞ;ŽŌĞǁĞůŵŝƐƐĞŶƐĞͬŶŽŶƐĞŶƐĞͿ͘ ĞǀĞƌĚĞƌĞŽŶƚůĞĚŝŶŐĞŶǀĞƌĮũŶŝŶŐǀĂŶŵƵƚĂƟĞͲƐƉĞĐŝĮĞŬĞĨĞŶŽƚLJƉĞƐnjĂůŵŽŐĞůŝũŬ ŵĞĞƌĚƵŝĚĞůŝũŬŚĞŝĚŐĂĂŶŐĞǀĞŶŽǀĞƌĚĞŵĂŶŝĞƌǁĂĂƌŽƉĚĞǀĞƌƐƚŽƌŝŶŐǀĂŶŚĞƚŐĞŶ ĞĞŶ ƉĂƌĂŐĂŶŐůŝŽŽŵ ǀĞƌŽŽƌnjĂĂŬƚ͘ ĞnjĞ ĂĂŶƉĂŬ njĂů ŽŶƐ ďĞŐƌŝƉ ŽǀĞƌ ŐĞŶŽƚLJƉĞͲĨĞ- ŶŽƚLJƉĞͲĐŽƌƌĞůĂƟĞƐĂĂŶŶĞŵĞůŝũŬďĞǀŽƌĚĞƌĞŶ͕ŚĞƚŐĞĞŶƚŽƚĞĞŶŵĞĞƌŐĞƉĞƌƐŽŶĂůŝ-ƐĞĞƌĚĞƌŝƐŝĐŽƐĐŚĂƫŶŐ͕ĐŽƵŶƐĞůŝŶŐĞŶƚŚĞƌĂƉŝĞnjĂůůĞŝĚĞŶ͘ ĞŶďĞƚĞƌŝŶnjŝĐŚƚŝŶĚĞƚƵŵŽƌďŝŽůŽŐŝĞŬĂŶŽŽŬĚĞďĞƐĐŚŝŬďĂƌĞďĞŚĂŶĚĞůŝŶŐƐƐƚƌĂ- ƚĞŐŝĞģŶǀŽŽƌƉĂƟģŶƚĞŶŵĞƚƉĂƌĂŐĂŶŐůŝŽŵĞŶĞŶĨĞŽĐŚƌŽŵŽĐLJƚŽŵĞŶĚŽĞŶƚŽĞŶĞ- ŵĞŶ͕ŵĞƚŶĂŵĞǀŽŽƌƉĂƟģŶƚĞŶŵĞƚŵĞĞƌǀŽƵĚŝŐĞŽĨŐĞŵĞƚĂƐƚĂƐĞĞƌĚĞƉĂƌĂŐĂŶ-ŐůŝŽŵĞŶ͘ dŽƚ ŶƵ ƚŽĞ njŝũŶ Ğƌ ŐĞĞŶ ĐƵƌĂƟĞǀĞ ďĞŚĂŶĚĞůŽƉƟĞƐ ǀŽŽƌ ƉĂƟģŶƚĞŶ ŵĞƚ ŐĞŵĞƚĂƐƚĂƐĞĞƌĚĞnjŝĞŬƚĞ͘sĞƌĚĞƌŽŶĚĞƌnjŽĞŬŝƐŶŽĚŝŐŽŵƚŚĞƌĂƉŝĞģŶŵĞƚŶŝĞƵǁĞ ǁĞƌŬŝŶŐƐŵĞĐŚĂŶŝƐŵĞŶƚĞĞǀĂůƵĞƌĞŶ͘,ĞƚŐĞďƌƵŝŬǀĂŶƚLJƌŽƐŝŶĞŬŝŶĂƐĞƌĞŵŵĞƌƐ͕ƌĂ-ĚŝŽŶƵĐůŝĚĞŶĞŶŐĞƌŝĐŚƚĞŝŵŵƵŶŽƚŚĞƌĂƉŝĞnjŽƵŚĞƚďĞŚĂŶĚĞůƌĞƐƵůƚĂĂƚǀĂŶƉĂƟģŶͲ ƚĞŶŵĞƚŵĞĞƌǀŽƵĚŝŐĞŽĨŐĞŵĞƚĂƐƚĂƐĞĞƌĚĞƉĂƌĂŐĂŶŐůŝŽŵĞŶŝŶĚĞƚŽĞŬŽŵƐƚŬƵŶ-ŶĞŶǀĞƌďĞƚĞƌĞŶ͘ Pathogene SDHBͲŵƵƚĂƟĞƐůŝũŬĞŶŐƌŽƚĞƌĞƌŝƐŝĐŽ͛ƐǀŽŽƌƉĂƟģŶƚĞŶŵĞƚnjŝĐŚŵĞĞƚĞ ďƌĞŶŐĞŶ͕ŝŶƚĞŐĞŶƐƚĞůůŝŶŐƚŽƚďŝũǀŽŽƌďĞĞůĚSDHDͲŵƵƚĂƟĞƐ͘ŝƚǁŽƌĚƚǁĞĞƌƐƉŝĞŐĞůĚ ŝŶĚĞǀĞƌŚŽŽŐĚĞŵŽƌƚĂůŝƚĞŝƚǀĂŶSDHBͲŵƵƚĂƟĞĚƌĂŐĞƌƐnjŽĂůƐǁŽƌĚƚďĞƐĐŚƌĞǀĞŶŝŶ ĚŝƚƉƌŽĞĨƐĐŚƌŝŌ͘ĞnjĞďĞǀŝŶĚŝŶŐnjŽƵĞĞŶŵĞĞƌĂŐƌĞƐƐŝĞǀĞďĞŚĂŶĚĞůŝŶŐƐƐƚƌĂƚĞŐŝĞ ǀŽŽƌƉĂƟģŶƚĞŶ met een SDHBͲŵƵƚĂƟĞƌĞĐŚƚǀĂĂƌĚŝŐĞŶ͘,ĞƚĞīĞĐƚǀĂŶĞĞŶǀƌŽĞŐĞ ŽĨĂŐƌĞƐƐŝĞǀĞƌĞŝŶƚĞƌǀĞŶƟĞŽƉŬǁĂĂĚĂĂƌĚŝŐĞƚƌĂŶƐĨŽƌŵĂƟĞŽĨŵŽƌƚĂůŝƚĞŝƚŝƐĞĐŚƚĞƌ ŶŽŐŽŶďĞŬĞŶĚǀŽŽƌSDHBͲŐĞĂƐƐŽĐŝĞĞƌĚĞƉĂƟģŶƚĞŶ͘ĞŚƵŝĚŝŐĞďĞŚĂŶĚĞůŝŶŐƐƐƚƌĂ-ƚĞŐŝĞģŶ͕njŽĂůƐĐŚŝƌƵƌŐŝĞĞŶƌĂĚŝŽƚŚĞƌĂƉŝĞ͕ďƌĞŶŐĞŶŝŶŚĞƌĞŶƚĞƌŝƐŝĐŽ͛ƐŵĞƚnjŝĐŚŵĞĞ͘ ŽǀĞŶĚŝĞŶǀĂƌŝĞĞƌƚŚĞƚŬůŝŶŝƐĐŚĞďĞůŽŽƉƐƚĞƌŬďŝŶŶĞŶĚĞŐƌŽĞƉƉĂƟģŶƚĞŶŵĞƚĞĞŶ SDHBͲŵƵƚĂƟĞ͕ ǁĂĂƌĚŽŽƌ ŵŽŐĞůŝũŬ ŶŝĞƚ ĂůůĞ ƉĂƟģŶƚĞŶ njƵůůĞŶ ƉƌŽĮƚĞƌĞŶ ǀĂŶ ĞĞŶ ĚĞƌŐĞůŝũŬĞǀĞƌƐĐŚƵŝǀŝŶŐǀĂŶĚĞďĞŚĂŶĚĞůŝŶŐƐƐƚƌĂƚĞŐŝĞ͘,ŽƉĞůŝũŬnjĂůǀĞƌĚĞƌŽŶĚĞƌ-njŽĞŬďĞŚƵůƉnjĂĂŵnjŝũŶŝŶŚĞƚĚŝīĞƌĞŶƟģƌĞŶǀĂŶƉĂƟģŶƚĞŶŵĞƚŽĨnjŽŶĚĞƌďĂĂƚďŝũ ƐƉĞĐŝĮĞŬĞŝŶƚĞƌǀĞŶƟĞƐ͘KƉĚĞnjĞŵĂŶŝĞƌŬĂŶŚĞƚƌĞƐƵůƚĂĂƚǀĂŶĚĞďĞŚĂŶĚĞůŝŶŐďŝũ ƉĂƟģŶƚĞŶŵĞƚĞĞŶƉĂƌĂŐĂŶŐůŝŽŽŵǁŽƌĚĞŶǀĞƌďĞƚĞƌĚ͕njŽŶĚĞƌnjĞŽŶŶŽĚŝŐďůŽŽƚƚĞ ƐƚĞůůĞŶĂĂŶƚŚĞƌĂƉŝĞͲŐĞƌĞůĂƚĞĞƌĚĞƌŝƐŝĐŽ͛Ɛ͘ /ŶŚĞƚǀĞƌůĞĚĞŶŝƐŚĞƚƉĂƌĂŐĂŶŐůŝŽŵĞŶŽŶĚĞƌnjŽĞŬĞĞŶƉƌĂĐŚƟŐǀŽŽƌďĞĞůĚŐĞďůĞ- ŬĞŶǀĂŶŚŽĞŚĞƚďĞƐƚƵĚĞƌĞŶǀĂŶĞĞŶnjĞůĚnjĂŵĞĐŽŶĚŝƟĞŽƉŚĞůĚĞƌŝŶŐŬĂŶǀĞƌƐĐŚĂĨ-ĨĞŶ ŝŶ ďĂƐĂůĞ͕ ĂůŐĞŵĞĞŶ ŐĞůĚĞŶĚĞ ďŝŽůŽŐŝƐĐŚĞ ĞŶ ƉĂƚŚŽŐĞŶĞ ŵĞĐŚĂŶŝƐŵĞŶ͘ KƉ ĚĞnjĞŵĂŶŝĞƌnjŝũŶŽŶƚĚĞŬŬŝŶŐĞŶŐĞĚĂĂŶĚŝĞŝŶĞĞŶďƌĞĚĞƌĞĐŽŶƚĞdžƚƚŽĞŐĞƉĂƐƚŬƵŶ-Addendum 175

ŶĞŶǁŽƌĚĞŶ͘,ĞƚŽŶĚĞƌnjŽĞŬĚƌĂĂŐƚďŝũĂĂŶĞĞŶďĞƚĞƌďĞŐƌŝƉĞŶŚĞƌŬĞŶŶŝŶŐǀĂŶ ŚĞƚŵĞƚĂďŽůŝƐŵĞŝŶƚƵŵŽƌŐĞŶĞƐĞ͘KŽŬǁŽƌĚĞŶŚŝĞƌŝŶĚĞĞŝŐĞŶĂĂƌĚŝŐĞǁŝũnjĞŶǀĂŶ ŽǀĞƌĞƌǀŝŶŐĞŶĚĞŐĞŶĞƟƐĐŚĞŚĞƚĞƌŽŐĞŶŝƚĞŝƚĂĂŶŐĞƚŽŽŶĚ͕ĚŝĞĂĂŶĞĞŶƐƉĞĐŝĮĞŬĞ njŝĞŬƚĞƚĞŶŐƌŽŶĚƐůĂŐŬƵŶŶĞŶůŝŐŐĞŶ͘hŝƚŐĞĚĂĂŐĚĚŽŽƌĚĞǀƌĂŐĞŶďŝũŚĞƚSDHB-geas- ƐŽĐŝĞĞƌĚĞƉĂƌĂŐĂŶŐůŝŽŽŵƐLJŶĚƌŽŽŵŝƐŝŶĚŝƚƉƌŽĞĨƐĐŚƌŝŌĞĞŶŶŝĞƵǁĞŵĞƚŚŽĚĞŽŶƚ- ǁŝŬŬĞůĚǀŽŽƌŚĞƚďĞƌĞŬĞŶĞŶǀĂŶƉĞŶĞƚƌĂŶƟĞ͘,ŝĞƌĚŽŽƌŝƐĞĞŶĚƵŝĚĞůŝũŬĞŵĞƚŚŽĚŽ-ůŽŐŝĞďĞƐĐŚŝŬďĂĂƌǀŽŽƌƉĞŶĞƚƌĂŶƟĞďĞƌĞŬĞŶŝŶŐĞŶ͕ĚŝĞŶŝĞƚĂůůĞĞŶŐĞƐĐŚŝŬƚŝƐǀŽŽƌ ďĞƌĞŬĞŶŝŶŐĞŶ ǀĂŶ ƉĂƌĂŐĂŶŐůŝŽŵĞŶ͕ ŵĂĂƌ ŽŽŬ ǀŽŽƌ ƉĞŶĞƚƌĂŶƟĞďĞƌĞŬĞŶŝŶŐĞŶ ŝŶ ŚĞƚĂůŐĞŵĞĞŶ͘ĂƚŝƐǀŽŽƌĂůŶƵƫŐďŝũnjĞůĚnjĂŵĞĞŶůĂĂŐͲƉĞŶĞƚƌĂŶƚĞĞƌĨĞůŝũŬĞnjŝĞŬ-ƚĞƐǁĂŶŶĞĞƌŐĞŐĞǀĞŶƐŽǀĞƌƐƚĂŵŵŐƌŽŽƩĞĞŶͲƐƚƌƵĐƚƵƵƌŽŶƚďƌĞŬĞŶ͘,ŽƉĞůŝũŬ njĂůƚŽĞŬŽŵƐƟŐƉĂƌĂŐĂŶŐůŝŽŵĞŶŽŶĚĞƌnjŽĞŬŶŝĞƚĂůůĞĞŶŶŝĞƵǁĞŝŶnjŝĐŚƚĞŶŐĞǀĞŶŝŶ ĚĞƉĂƚŚŽŐĞŶĞƐĞ͕ŬůŝŶŝƐĐŚĞŬĞŶŵĞƌŬĞŶĞŶďĞŚĂŶĚĞůŝŶŐǀĂŶƉĂƌĂŐĂŶŐůŝŽŵĞŶ͕ŵĂĂƌ ŽŽŬĚĞŐĞŶĞĞƐŬƵŶĚĞŝŶĚĞǀŽůůĞďƌĞĞĚƚĞďůŝũǀĞŶǀĞƌƌŝũŬĞŶ͘ 176 Addendum